tag:theconversation.com,2011:/uk/topics/birth-defects-2955/articlesBirth defects – The Conversation2023-03-16T16:34:44Ztag:theconversation.com,2011:article/2018552023-03-16T16:34:44Z2023-03-16T16:34:44ZNew PFAS guidelines – a water quality scientist explains technology and investment needed to get forever chemicals out of US drinking water<figure><img src="https://images.theconversation.com/files/515625/original/file-20230315-3073-baa7d7.jpg?ixlib=rb-1.1.0&rect=24%2C111%2C8218%2C5363&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">PFAS can be found in hundreds of water systems in the U.S.</span> <span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/close-up-of-young-asian-woman-pouring-water-from-royalty-free-image/1299286918?phrase=pouring%20water%20into%20glass&adppopup=true">d3sign/Moment via Getty Images</a></span></figcaption></figure><p><em>Harmful chemicals known as PFAS can be found in everything from <a href="https://www.msn.com/en-us/health/medical/dangerous-chemicals-found-in-baby-supplies-pet-food-packaging/ar-AA18o3wY">children’s clothes</a> to <a href="https://doi.org/10.1016/j.scitotenv.2020.140017">soil</a> to <a href="https://theconversation.com/what-are-pfas-and-why-is-the-epa-warning-about-them-in-drinking-water-an-environmental-health-scientist-explains-185015">drinking water</a>, and regulating these chemicals has been a <a href="https://theconversation.com/pfas-forever-chemicals-are-widespread-and-threaten-human-health-heres-a-strategy-for-protecting-the-public-142953">goal of public and environmental health researchers</a> for years. On March 14, 2023, the U.S. Environmental Protection Agency proposed what would be the first set of <a href="https://www.epa.gov/newsreleases/biden-harris-administration-proposes-first-ever-national-standard-protect-communities">federal guidelines regulating levels of PFAS in drinking water</a>. The guidelines will be open to public comment for 60 days before being finalized.</em></p>
<p><em><a href="https://scholar.google.com/citations?user=edLoshMAAAAJ&hl=en&oi=ao">Joe Charbonnet</a> is an environmental engineer at Iowa State University who develops techniques to remove contaminants like PFAS from water. He explains what the proposed guidelines would require, how water utilities could meet these requirements and how much it might cost to get these so-called forever chemicals out of U.S. drinking water.</em></p>
<h2>1. What do the new guidelines say?</h2>
<p>PFAS are <a href="https://theconversation.com/regulating-forever-chemicals-3-essential-reads-on-pfas-201263">associated with a variety of health issues</a> and have been a focus of environmental and public health researchers. There are thousands of members of this class of chemicals, and this proposed regulation would set the allowable limits in drinking water for six of them.</p>
<p>Two of the six chemicals – PFOA and PFOS – are <a href="https://www.epa.gov/assessing-and-managing-chemicals-under-tsca/fact-sheet-20102015-pfoa-stewardship-program">no longer produced in large quantities</a>, but they <a href="https://theconversation.com/what-are-pfas-and-why-is-the-epa-warning-about-them-in-drinking-water-an-environmental-health-scientist-explains-185015">remain common in the environment</a> because they were so widely used and break down extremely slowly. The new guidelines would allow for no more than four parts per trillion of PFOA or PFOS in drinking water.</p>
<p>Four other PFAS – GenX, PFBS, PFNA and PFHxS – would be regulated as well, although with higher limits. These chemicals are common replacements for PFOA and PFOS and are their close chemical cousins. Because of their similarity, they cause harm to human and environmental health <a href="https://pfastoxdatabase.org/">in much the same way</a> as legacy PFAS.</p>
<p>A few states have already established their own limits on levels of PFAS in drinking water, but these new guidelines, if enacted, would be the first legally enforceable federal limits and would affect the entire U.S. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A water droplet sitting on a piece of fabric." src="https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=506&fit=crop&dpr=1 600w, https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=506&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=506&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=635&fit=crop&dpr=1 754w, https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=635&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/515627/original/file-20230315-2738-19docw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=635&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Chemicals used to create water-repellent fabrics and nonstick pans often contain PFAS and leak those chemicals into the environment.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File:A_water_droplet_DWR-coated_surface2_edit1.jpg#/media/File:A_water_droplet_DWR-coated_surface2_edit1.jpg">Brocken Inaglory/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>2. How many utilities will need to make changes?</h2>
<p>PFAS are harmful <a href="https://pubs.acs.org/doi/full/10.1021/acs.est.2c02765">even at extremely low levels</a>, and the proposed limits reflect that fact. The allowable concentrations would be comparable to a few grains of salt in an Olympic-size swimming pool. Hundreds of utilities all across the U.S. <a href="https://www.ewg.org/interactive-maps/pfas_contamination/map/">have levels of PFAS above the proposed limits</a> in their water supplies and would need to make changes to meet these standards. </p>
<p>While many areas have been tested for PFAS in the past, many systems have not, so health officials don’t know precisely how many water systems would be affected. A recent study used existing data to estimate that about <a href="https://doi.org/10.1021/acs.estlett.0c00713">40% of municipal drinking water supplies</a> may exceed the proposed concentration limits.</p>
<h2>3. What can utilities do to meet the guidelines?</h2>
<p>There are two major technologies that most utilities consider for removing PFAS from drinking water: <a href="https://www.epa.gov/sdwa/overview-drinking-water-treatment-technologies">activated carbon or ion exchange systems</a>. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="A membrane treatment system." src="https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/515628/original/file-20230315-20-qih6p1.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Water treatment systems can use activated carbon or ion exchange to remove PFAS from drinking water.</span>
<span class="attribution"><a class="source" href="https://www.gettyimages.com/detail/photo/industry-sustainability-water-purification-filter-royalty-free-image/1382353791?phrase=water%20purification%20plant&adppopup=true">Paola Giannoni/E+ via Getty Images</a></span>
</figcaption>
</figure>
<p>Activated carbon is a charcoal-like substance that PFAS stick to quite well and can be used to remove PFAS from water. In 2006, the town of Oakdale, Minnesota, <a href="https://doi.org/10.1186%2Fs12940-020-00591-0">added an activated carbon treatment step</a> to its water system. Not only did this additional water treatment bring PFAS levels down substantially, there were significant improvements in <a href="https://doi.org/10.1186/s12940-020-00591-0">birth weight and the number of full-term pregnancies</a> in that community after the change. </p>
<p>Ion exchange systems work by flowing water over charged particles that can remove PFAS. Ion exchange systems are typically even better at lowering PFAS concentrations than activated carbon systems, but they are <a href="https://doi.org/10.1039/D2EW00080F">also more expensive</a>.</p>
<p>Another option available to some cities is simply finding alternative water sources that are less contaminated. While this is a wonderful, low-cost means of lowering contamination, it points to a major disparity in environmental justice; more rural and less well-resourced utilities are <a href="https://perma.cc/3HTS-8E3H">unlikely to have this option</a>.</p>
<h2>4. Is such a major transition feasible?</h2>
<p>By law, the EPA must consider not just human health but also the feasibility of treatment and the potential financial cost when <a href="https://www.epa.gov/ground-water-and-drinking-water/national-primary-drinking-water-regulations">setting maximum contaminant levels in drinking water</a>. While the proposed limits are certainly attainable for many water utilities, the costs will be high.</p>
<p>The federal government has made available <a href="https://www.epa.gov/newsreleases/biden-harris-administration-announces-2-billion-bipartisan-infrastructure-law-funding">billions of dollars</a> in funding for treating water. But some estimates put the total cost of meeting the proposed regulations for the entire country at around <a href="https://www.politico.com/news/2022/09/13/the-battle-over-who-pays-to-clean-up-chemicals-00056136">US$400 billion</a> – much more than the available funding. Some municipalities may seek financial help for treatment from nearby polluters, while others may raise water rates to cover the costs.</p>
<h2>5. What happens next?</h2>
<p>The EPA has set a 60-day period for public comment on the proposed regulations, after which it can finalize the guidelines. But many experts expect the EPA to <a href="https://www.eenews.net/articles/pfas-rule-sets-up-sprawling-legal-war/">face a number of legal challenges</a>. Time will tell what the final version of the regulations may look like. </p>
<p>This regulation is intended to keep the U.S. in the enviable position of having some of the <a href="https://epi.yale.edu/epi-results/2020/component/h2o">highest-quality drinking water</a> in the world. As researchers and health officials learn more about new chemical threats, it is important to ensure that every resident has access to clean and affordable tap water.</p>
<p>While these six PFAS certainly pose threats to health that merit regulation, there are thousands of PFAS that likely have very <a href="https://www.youtube.com/watch?v=EBjQYUjEUb4">similar impacts on human health</a>. Rather than playing chemical whack-a-mole by regulating one PFAS at a time, there is a growing consensus among researchers and public health officials that <a href="https://doi.org/10.1021/acs.estlett.0c00255">PFAS should be regulated as a class of chemicals</a>.</p><img src="https://counter.theconversation.com/content/201855/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Joe Charbonnet receives funding from the US EPA for research that is not directly related to PFAS. This article contains links to resources from the Green Science Policy Institute, which previously employed Dr. Charbonnet. </span></em></p>The drinking water systems serving over 70 million people may not meet newly proposed water quality standards. It could cost hundreds of billions of dollars to fix that.Joe Charbonnet, Assistant Professor of Environmental Engineering, Iowa State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1301812020-01-23T18:46:54Z2020-01-23T18:46:54ZJoaquin Phoenix’s lips are not like Napoleon’s − here’s what everyone should know about cleft lip<figure><img src="https://images.theconversation.com/files/311185/original/file-20200121-117933-16v4fic.jpg?ixlib=rb-1.1.0&rect=122%2C47%2C3176%2C2227&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Joaquin Phoenix won the award for outstanding performance by a male actor in a leading role for 'Joker' at the 26th annual Screen Actors Guild Awards. </span> <span class="attribution"><a class="source" href="https://newsroom.ap.org/detail/26thAnnualSAGAwards-PressRoom/6f4e297798694088b9f9603784f48604">Jordan Strauss/Invision via AP</a></span></figcaption></figure><p>Starring in the <a href="https://collider.com/napoleon-global-box-office-78-million/">November 2023 film “Napoleon,”</a> Joaquin Phoenix is back in the limelight, along with the prominent scar on his upper lip. You may recall in 2020, after discussing Phoenix’s appearance on her talk show, Wendy Williams received near universal <a href="https://www.today.com/health/wendy-williams-blasted-mocking-joaquin-phoenix-s-cleft-palate-scar-t171887">condemnation</a> for mocking those affected with cleft lip – a common birth defect in which the upper lip does not form completely while still an embryo. Note that it is also unclear whether Phoenix has a cleft lip or simply a scar. To her credit, Williams was quick to apologize. Regardless, this renewed attention to Phoenix’s scar offers another opportunity to highlight how people with facial differences (and their families) often feel stigmatized and can face discrimination and <a href="https://doi.org/10.4103/2231-0746.200336">social isolation</a>. </p>
<p>We have each devoted major portions of our professional lives to understanding what causes clefts and to the treatment and advocacy of those affected. <a href="https://scholar.google.com/citations?user=2Nq1fLsAAAAJ&hl=en">We are</a> <a href="https://scholar.google.com/citations?user=GYMrNdIAAAAJ&hl=en">geneticists</a> and a <a href="https://www.dental.pitt.edu/people/bernard-j-costello-dmd-md">pediatric craniomaxillofacial surgeon</a>. The three of us felt this was an opportunity to explain how clefts form and how clefts affect the people who live with them. And what, if anything, can be done to prevent them?</p>
<h2>The ABCs of clefting</h2>
<p>There are several different types of facial clefts. The most common are cleft lip, when the upper lip does not form properly, leaving a gap, and cleft palate, when the roof of the mouth does not close while a baby is developing in utero.</p>
<p>These birth defects arise very early during development when the embryo is about the size of a grain of rice. At this stage, the face is merely a collection of swellings rapidly growing toward one another in order to <a href="https://doi.org/10.1038/nrg2933">fuse together</a> and form the lips, nose and palate. Thus, in a way, everyone starts out with clefts of the lip and palate.</p>
<p>In most cases, these swellings fuse before the end of the first trimester of pregnancy, forming an intact lip and palate. When this fails to happen, a child is born with a cleft of the lip, the palate or both. Worldwide, facial clefts are estimated to occur in <a href="https://doi.org/10.4103/2231-0746.200336">1 in 700 births</a>, making it one of the most common birth defects. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration showing before and after depictions of cleft lip and cleft lip palate repair" src="https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=245&fit=crop&dpr=1 600w, https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=245&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=245&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=308&fit=crop&dpr=1 754w, https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=308&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/311628/original/file-20200123-162240-i0s4a3.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=308&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Cleft lip and palate are two of the most common birth defects worldwide.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/0/09/Cleft_Lip_%26_Cleft_Palate_Repair.png">BruceBlaus/Wikimedia</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<h2>How clefts harm quality of life</h2>
<p>People with cleft lip and palate, as well as their families, face many issues associated with these birth defects. Although clefts may seem like cosmetic problems, they adversely affect basic functions like eating and speaking. Children with clefts must endure multiple corrective surgeries, often beginning when they are only a few months old. However, the surgeries are often just the beginning. </p>
<p>Many years of intensive orthodontic treatment and speech therapy are routinely needed. The <a href="https://doi.org/10.1111/j.1601-0825.2009.01588.x">total lifetime treatment cost</a> is estimated to be at least US$200,000 per individual. Beyond immediate medical care, individuals born with a cleft also tend to <a href="https://doi.org/10.1136/archdischild-2017-313777">experience more learning difficulties</a>, <a href="https://doi.org/10.1136/archdischild-2017-313777">higher mortality rates</a> at all stages of life and <a href="https://doi.org/10.1093/aje/kwi132">higher risk for other disorders</a>, such as breast, brain and colon cancers. </p>
<p>Children born in the U.S. with these conditions are lucky to have these supports, given the myriad challenges cleft lips and palates present. There are superb teams dedicated to <a href="https://acpa-cpf.org/">advocacy</a>, to their <a href="https://acpacares.org">care</a> and <a href="https://www.smiletrain.org/">support</a>, and <a href="https://www.asha.org/advocacy/">who work</a> to address the needs of the children and their families.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Person holding baby with cleft lip next to another person holding a clipboard" src="https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/311207/original/file-20200121-117907-1ydz595.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">In China, orphanages mostly house children abandoned by their families because of serious medical issues, including cleft lip.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Emptying-The-Orphanages/badb3d4b1c0f4a89a3d7b8f16f3c3bb4/2/0">AP Photo/Ng Han Guan</a></span>
</figcaption>
</figure>
<h2>Multiple factors cause clefts</h2>
<p>Facial clefts have likely been around for as long as people have. An early example is the pharaoh Tutankhamun, better known as King Tut, who suffered from a <a href="https://doi.org/10.1001/jama.2010.121">partial cleft palate</a>.</p>
<p>Because clefts are often externally visible features, many have tried to explain their occurrence. An early hypothesis suggested that the mother was pregnant during an <a href="https://doi.org/10.1597/06-113.1">eclipse</a>, while <a href="http://www.opensourceshakespeare.org/views/plays/play_view.php?WorkID=midsummer&Act=5&Scene=1&Scope=scene&LineHighlight=2252#2252">Shakespeare</a> attributed the feature to an intervention by mischievous sprites. Many cultures also believed that clefts were “<a href="https://doi.org/10.1146/annurev-genom-090711-163729">in the blood</a>,” or familial, which aligns with current understanding.</p>
<p>Our group at the University of Pittsburgh has spent many years trying to understand the causes of clefts, with some notable successes.</p>
<p>Clefts are considered “complex” by those who study birth defects, meaning that they result from a combination of environmental factors during pregnancy and family genetics. Some of the environmental causes include taking certain <a href="https://doi.org/10.1186/s12916-017-0845-1">prescription medications</a> and <a href="https://doi.org/10.1080/15459624.2018.1484127">exposure to some toxins</a> during pregnancy. </p>
<p>The completion of the <a href="https://doi.org/10.1080/15459624.2018.1484127">Human Genome Project</a> in the late 1990s and early 2000s provided important scientific tools for us to tease out the genetic factors leading to complex traits such as facial clefts. To date, scientists have identified at least <a href="https://doi.org/10.12688/f1000research.9503.1">30 possible genetic regions</a> increasing the risk of facial clefts, and we suspect that there are still many more regions to discover. </p>
<p>However, population-level studies such as the ones that identified those 30 genetic regions can tell us only so much. Researchers still face a major challenge identifying the specific genes that confer risk to specific individuals and families. There are other mysteries as well, such as why cleft palate alone is more common in girls, but when cleft palate is combined with cleft lip, it is <a href="https://doi.org/10.1016/S0140-6736(09)60695-4">more common in boys</a>.</p>
<h2>Are clefts preventable?</h2>
<p>Parents who have a child with a cleft sometimes blame themselves. This is unfortunate, because there are still no known measures parents can take that will definitively prevent a facial cleft.</p>
<p>Doctors do know that <a href="https://doi.org/10.1016/j.annepidem.2016.11.009">smoking</a> and <a href="https://doi.org/10.1001/archpediatrics.2011.185">poor nutrition</a> during pregnancy can increase the chances of having a baby with a cleft. There is also some evidence that <a href="https://doi.org/10.1097/SCS.0000000000004488">supplementation with folic acid</a> before and during pregnancy may provide some protection. </p>
<p>As scientists learn more about the genetic and environmental risk factors for clefting, new actionable evidence will hopefully emerge that will bolster prevention efforts. Our most important task, however, is to work toward improving the quality of life for those affected. That starts with understanding.</p>
<p><em>This article was updated on Nov. 27, 2023 to note Joaquin Phoenix’s role in the film “Napoleon.”</em></p><img src="https://counter.theconversation.com/content/130181/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mary L. Marazita receives funding from the National Institutes of Health, primarily the National Institute of Dental and Craniofaical Research. </span></em></p><p class="fine-print"><em><span>Bernard J Costello is affiliated with the AACMFS and ACPA. Past-president of the American Academy of Craniomaxillofacial Surgeons and Past-President of the American Cleft Palate-Craniofacial Association. </span></em></p><p class="fine-print"><em><span>Seth M. Weinberg receives funding from the National Institutes of Health. </span></em></p>Joaquin Phoenix has previously been mocked for a facial scar that some have assumed is a cleft lip. Two geneticists and a surgeon explain what causes this common birth defect.Mary L. Marazita, Director, Center for Craniofacial and Dental Genetics; Professor of Oral Biology and of Human Genetics, University of PittsburghBernard J. Costello, Associate Vice Chancellor and Professor, University of PittsburghSeth M. Weinberg, Professor of Oral and Craniofacial Sciences and Human Genetics, University of PittsburghLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1116252019-02-14T19:07:53Z2019-02-14T19:07:53ZYou need more than just testes to make a penis<figure><img src="https://images.theconversation.com/files/258965/original/file-20190214-1721-14ua0u2.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Testosterone is primarily made in the testes, and creates many of the characteristics we see in adult men. </span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/jeans-man-on-dark-background-766127614">from www.shutterstock.com</a></span></figcaption></figure><p>In prenatal ultrasounds or at delivery, many new parents look between their baby’s legs: the presence of a penis is taken as a strong sign that it’s a boy.</p>
<p>For humans and other animals, development of a penis was thought to be driven by “male hormones” (androgens) produced entirely by the testes of the male fetus as it grows in the uterus. </p>
<p>However, a <a href="http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3000002">new paper</a> released today indicates this might not be the case. Instead, some of the masculinising hormones that drive penis development may come from other sources in the developing fetus. These include the liver, the adrenals (small glands found on the kidneys) and placenta. </p>
<p>For the first time, this work comprehensively looks at the possible sites of hormone production outside the testes and their role in regulating masculinisation – the process of gaining typical male characteristics. This helps us see how we develop as embryos, and might feed into a bigger picture of why disorders of penis development are increasing.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/our-relationship-with-dick-pics-its-complicated-103444">Our relationship with dick pics: it's complicated</a>
</strong>
</em>
</p>
<hr>
<h2>Testosterone is not enough</h2>
<p>The penis develops from an embryonic structure called the genital tubercle or GT. </p>
<p>The GT is present in both males and females, and develops into either a clitoris or penis, depending on its exposure to hormones secreted by the developing gonads (ovaries or testes). </p>
<p>In females, the developing ovaries do not produce early hormones and the GT becomes feminised, forming a clitoris. </p>
<p>In males, the developing testes produce testosterone. This circulates in the developing fetus and causes masculinisation of target tissues and induces penis development from the GT. </p>
<p>Testosterone itself is a relatively weak hormone. It is converted in the penis to another hormone called dihydrotestosterone (DHT), which has a much more potent masculinising effect. </p>
<p>It is the local conversion of testosterone to DHT within the tissue that is important for penis development and other changes. </p>
<p>There are several ways in which the fetus can make DHT. The most simple is via conversion from testicular testosterone (the so-called “canonical” pathway). However, DHT can also be produced via other steroid hormone pathways active in many tissues, which is explored further in this new paper. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/what-makes-you-a-man-or-a-woman-geneticist-jenny-graves-explains-102983">What makes you a man or a woman? Geneticist Jenny Graves explains</a>
</strong>
</em>
</p>
<hr>
<h2>Common birth defects</h2>
<p>Understanding the pathways that control penis development is important. Disorders affecting penis development are among the most common birth defects seen in humans, with hypospadias (a disorder affecting development of the urethra) currently affecting around <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2083775/">1 in every 115 live males born in Australia</a>, and rates are on the rise. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=424&fit=crop&dpr=1 600w, https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=424&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=424&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=533&fit=crop&dpr=1 754w, https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=533&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/258647/original/file-20190213-90504-lw517s.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=533&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The urethra, the hole through which urine passes out of the body, is found in a range of different locations in the disorder known as hypospadias</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-vector/newborn-malformation-hypospadia-main-types-315283037?src=q7V1zs7wS25RVKHm_q7jsg-1-2">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>In fact, the incidence of hypospadias has <a href="https://www.ncbi.nlm.nih.gov/pubmed/11392374">doubled over the past 40 years</a>. Such a rapid increase in incidence has been attributed to environmental factors, with endocrine disrupting chemicals (EDCs) being proposed as a major cause. EDCs are man-made chemicals used in many industries – for example, in the production of plastics, cosmetics, flame retardants and pesticides. They can interfere with hormone and metabolic systems in our bodies.</p>
<p>Of the <a href="https://endocrinedisruption.org/interactive-tools/tedx-list-of-potential-endocrine-disruptors/search-the-tedx-list">1,484 EDCs currently identified</a>, a large number are known to negatively affect male reproductive development. </p>
<p>Many <a href="https://www.publish.csiro.au/RD/RD18505">studies</a> have identified how EDCs negatively affect organs, such as the liver and adrenals, leading to diseases and disorders which damage the health of these organs and disturb male development. </p>
<h2>Backdoor pathway</h2>
<p>By measuring hormones from blood samples and tissues during the second trimester of human fetal development, this new research helps us understand the pathways driving the production of DHT, and masculinisation of the penis. </p>
<p>It suggests that in addition to the canonical pathway (testosterone from the testis converted to DHT in the GT and driving penis development), male steroids are synthesised by other organs, such as the placenta, liver and adrenal gland via a process called the “backdoor” pathway to contribute to masculinisation. Notably, the backdoor pathway was <a href="https://www.ncbi.nlm.nih.gov/pubmed/12538619">first discovered</a> through research conducted here in Australia on marsupials. </p>
<p>The findings of this research suggest that EDCs might have effects in non-reproductive tissues, including the adrenals and liver, and then cause male reproductive diseases such as hypospadias. </p>
<p>Also, it indicates that placental defects, such as intrauterine growth restriction that results in babies being born small, might contribute to male reproductive diseases in humans. </p>
<p>Further research is now required to follow-up on these interesting findings to explore possible new causal pathways of disorders that begin during pregnancy.</p><img src="https://counter.theconversation.com/content/111625/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Dr Mark Green receives funding from the National Health and Medical Research Council, as well as the University of Melbourne for his research on fertility and endocrine disruptors. He is the Secretary for the Society for Reproductive Biology (SRB) and advisor on the effects of endocrine disruptors to the Victorian Assisted Reproductive Treatment Authority (VARTA). </span></em></p><p class="fine-print"><em><span>Andrew Pask receives funding from the Australian Research Council and National Health and Medical Research Council. </span></em></p>Disorders affecting penis development are among the most common birth defects seen in humans, and rates are on the rise.Mark Green, Merck Serono Senior Lecturer in Reproductive Biology, The University of MelbourneAndrew Pask, Professor, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1061332018-11-02T14:02:50Z2018-11-02T14:02:50ZPrenatal blood screening may predict Zika virus-associated fetal defects<figure><img src="https://images.theconversation.com/files/243532/original/file-20181101-83632-e9ou8n.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">These photos show mothers or family members holding infants born with microcephaly, one of many serious medical problems caused by congenital Zika syndrome.</span> <span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/The-Week-That-Was-in-Latin-America-Photo-Gallery/85c344048add4b1093762419d8a22c69/80/0">AP Photo/Felipe Dana</a></span></figcaption></figure><p><em><a href="https://theconversation.com/zika-y-embarazo-analisis-de-sangre-prenatal-podria-predecir-malformaciones-fetales-106289">Leer en español</a></em>.</p>
<p>The sudden and rampant <a href="http://www.who.int/emergencies/zika-virus/en/">outbreak of Zika virus in 2016</a> terrified pregnant women, particularly those residing in Zika-endemic regions, such as Brazil, as well as those in the U.S. Their fear was justified given the link between Zika virus infection during pregnancy with having a small head, a condition known as microcephaly, and other congenital defects.</p>
<p>The absence of early prenatal diagnosis, or treatment, for birth defects has left thousands of <a href="https://www.cdc.gov/pregnancy/zika/data/pregwomen-uscases.html">mothers-to-be</a> worrying about their baby’s well-being. Others, meanwhile, have terminated their pregnancy rather than risk having a child with <a href="https://doi.org/10.1056/NEJMc1605389">birth defects</a>. </p>
<p><a href="http://uscmmi.com/jaejunglab/">Our research</a> revolves around mosquito-borne viruses such as Chikungunya virus and Zika virus. Each causes a distinct set of symptoms. Chikungunya virus produces debilitating persistent joint pain in adults and neurological symptoms in children; Zika virus causes defects in babies. In <a href="http://uscmmi.com/jaejunglab/">Jae Jung’s lab</a> at the University of Southern California, we are investigating the mechanisms that underlie the devastating consequences of these viral infections and developing new prenatal diagnostic tests to determine whether Zika babies are in good health.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/243523/original/file-20181101-83651-peb2ik.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A fellow student gently strokes Jose Wesley Campos, who was born with the Zika-caused microcephaly birth defect, at an early education daycare center in Bonito, Brazil.</span>
<span class="attribution"><a class="source" href="http://www.apimages.com/metadata/Index/Brazil-Zika-Kids-Boy-in-Bucket/fe3a773313b04610b33f237ac677bf9a/5/0">AP Photo/Eraldo Peres</a></span>
</figcaption>
</figure>
<h2>Zika and pregnancy</h2>
<p>Zika is the first mosquito-borne virus known to cause congenital defects. <em>Aedes aegypti</em>, one of the most invasive and widespread species of mosquito, is the primary vector for transmitting Zika. When healthy individuals, who are not pregnant, are infected with the Zika virus the infection often escapes notice because the <a href="https://www.cdc.gov/zika/symptoms/symptoms.html">symptoms are mild</a> or negligible. However, infection during the first and second trimester of pregnancy boosts the risk of miscarriages and diverse fetal defects such as <a href="https://doi.org/10.1056/NEJMoa1602412">eye abnormalities, neurological impairment</a> and in more severe cases, <a href="http://doi.org/10.1056/NEJMp1605367">microcephaly</a>.</p>
<p>Health workers try to assess the health of Zika babies using ultrasound during the second trimester or later. But it is difficult to see from these images whether the baby has developmental abnormalities. </p>
<p>On the other hand, fetal MRI captures high-resolution snapshots of the fetus. But this imaging technique can only be used in the second or third trimesters – when it is more difficult to terminate a pregnancy. A diagnostic assay that could detect abnormalities early in the pregnancy could alleviate the mother’s stress and make it easier to make swift reproductive decisions.</p>
<h2>Developing a new diagnostic test</h2>
<p>During the Zika outbreak in Brazil, there were other co-circulating mosquito-borne viruses such as Dengue virus and Chikungunya virus. So we also chose to take blood samples from women from the U.S. where these viruses are not endemic. <a href="https://doi.org/10.1172/jci.insight.124152">In our recent research</a>, we surveyed blood samples from 74 pregnant women: 30 were Zika-positive, 30 were negative and 14 were from women in Los Angeles. This study was led by <a href="http://uscmmi.com/jaejunglab/principal-investigator">Jae Jung</a>, in collaboration with <a href="https://portal.fiocruz.br/servico/laboratorio-de-doencas-febris-agudas">Patrícia Brasil</a> of the Instituto Nacional de Infectologia Evandro Chagas in Brazil, and <a href="https://www.uclahealth.org/karin-nielsen">Karin Nielsen-Saines</a> and <a href="https://www.mbi.ucla.edu/faculty/genhong-cheng/">Genhong Cheng</a> of UCLA.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=469&fit=crop&dpr=1 600w, https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=469&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=469&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=590&fit=crop&dpr=1 754w, https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=590&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/243520/original/file-20181101-83654-4aioi.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=590&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">A researcher in Jae Jung’s lab investigates brain defects in specimens of fetal tissue obtained from a Zika-infected patient.</span>
<span class="attribution"><span class="source">Weiqiang Chen</span></span>
</figcaption>
</figure>
<p>Our findings revealed an elevated production of 16 specific protein biomarkers, which are present in the blood of pregnant women who gave birth to babies with developmental delays and eye abnormalities. These biomarkers are potentially useful for predicting the outcomes of Zika pregnancies simply using blood specimens from the mother-to-be at any stage of pregnancy.</p>
<p>The number of Zika cases has dramatically declined following the major outbreaks in 2016. Yet, many Zika babies are still suffering from the dire consequences of prenatal infection. With the widespread abundance of <em>Aedes</em> mosquitoes, and the fact that Zika virus has not been eradicated, new outbreaks of Zika can occur anytime. </p>
<p>We are continuing our research to understand how Zika disrupts the development of the fetus, treatment strategies for babies affected by the virus, and ways to prevent Zika infection in the first place. Only when we have a thorough understanding of Zika infections can we assure the health of future generations.</p><img src="https://counter.theconversation.com/content/106133/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>The authors do not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and have disclosed no relevant affiliations beyond their academic appointment.</span></em></p>There is no vaccine or medicine for Zika. But researchers have identified factors in the blood that signal a fetus has Zika-related birth defects, helping mothers decide whether to terminate a pregnancy.Suan-Sin Foo, Postdoctoral scholar, University of Southern CaliforniaWeiqiang Chen, Postdoctoral scholar, University of Southern CaliforniaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1051222018-10-24T22:49:13Z2018-10-24T22:49:13ZWe need answers to the thalidomide tragedy – to ensure drug safety today<figure><img src="https://images.theconversation.com/files/242108/original/file-20181024-71032-whb66m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">An animal experiment in a laboratory of the pharmaceutical company "Chemie Gruenenthal," which manufactured the drug Thalidomide, in West Germany in 1969. Thalidomide was prescribed by doctors as a mild sleeping pill and for relief of morning sickness but caused the miscarriage and birth of thousands of children with severe malformations globally.</span> <span class="attribution"><span class="source">(AP Photo/File)</span></span></figcaption></figure><p>In 2015, after decades of fruitless lobbying, Canadian survivors of thalidomide <a href="https://www.theglobeandmail.com/news/national/for-canadian-thalidomide-victims-compensation-is-fair-but-long-overdue/article24585168/">finally received compensation from the federal government</a>. </p>
<p>The drug was a supposedly mild sleeping pill, a “<a href="https://www.macleans.ca/society/health/thalidomide-was-a-disaster-and-its-available-in-canada-again/">wonder drug</a>” that helped pregnant women with the symptoms of morning sickness. It caused an estimated <a href="https://www.cbc.ca/news/health/thalidomide-explainer-1.4434746">24,000 babies to be born with severely deformed limbs</a> and other major medical problems globally.</p>
<p>Now, a new book, <em><a href="https://www.onwardsandupwards.org/the-thalidomide-catastrophe/?v=3e8d115eb4b3">The Thalidomide Catastrophe</a></em>, by three European campaigners for people affected by thalidomide raises new questions about the conduct of governments and the companies involved. </p>
<p>It only mentions Canada in passing, but the questions it poses are equally relevant here. </p>
<p>What was the basis for approving thalidomide (sold in Canada under the name Kevadon by the William S. Merrell Co.)? When did the government first learn about the side effects from thalidomide? How quickly did it act after learning about these side effects?</p>
<h2>Canada slow to act</h2>
<p>According to a <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1849754/pdf/canmedaj00968-0046.pdf">history of events</a> put together by the company, Merrell submitted data on animal and clinical studies to the Department of National Health and Welfare (the predecessor of Health Canada) on Sept. 8, 1960, and received approval to market thalidomide on Nov. 22, 1960.</p>
<p>This means government officials worked their way through a 500-page document in under 11 weeks. This raises questions about how comprehensive that document was. What information did it contain?</p>
<p>April 1, 1961, saw the actual appearance of thalidomide on drugstore shelves. Merrell claims it didn’t know about birth defects until Nov. 29, 1961. According to a <em>Globe and Mail</em> story from Aug. 2, 1962, health officials were informed about this problem two days later.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=500&fit=crop&dpr=1 600w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=500&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=500&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=628&fit=crop&dpr=1 754w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=628&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/242104/original/file-20181024-71023-1b4d9qz.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=628&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Members of the Thalidomide Survivors Task Group hold a news conference on Parliament Hill, in Ottawa, December, 2017. Clockwise from left are Fiona Sampson, Mary Ryder, Alexandra Niblock and Lee Ann Dalling.</span>
<span class="attribution"><span class="source">THE CANADIAN PRESS/Fred Chartrand</span></span>
</figcaption>
</figure>
<p>However, Chemie Grünenthal, the company that discovered thalidomide and marketed it in Germany, should have had grounds for strongly suspecting problems with the drug long before that. </p>
<p><em>The Thalidomide Catastrophe</em> documents how the American company Smith, Kline and French tested the drug in 1958 with a view to licensing it from Grünenthal but declined, partly because in its testing there were deformed babies born to two women. </p>
<p>In 1959, a doctor working at Grünenthal was told about additional babies with birth defects. Was this information not given to Merrell when it licensed thalidomide for sales in Canada?</p>
<p>As the news about babies with severe birth defects due to thalidomide became increasingly difficult to ignore, it was pulled off the German market in late November 1961 and at about the same time in the United Kingdom. However, it remained available in Canada for another three months until the federal government asked Merrell to withdraw it.</p>
<p>Health Minister J. Waldo Monteith, in a <em>Globe and Mail</em> story of July 27, 1962, denied that the government had delayed taking action and claimed that the additional three months was because reports of safety problems were “sketchy.” Is it likely that two European governments would have acted on sketchy information? </p>
<p>Moreover, in December 1961, an Australian doctor named W.G. McBride <a href="https://doi.org/10.1016/S0140-6736(61)90927-8">published a letter</a> in the major British medical journal, <em>The Lancet</em>, about birth defects among women who had used thalidomide in pregnancy. How long would it have taken Canadian health officials to contact Dr. McBride?</p>
<h2>Drug safety blamed on patients</h2>
<p>One reason for the slowness of Canadian officials might be due to the person in charge of the Food and Drugs Directorate, Dr. C.A. Morrell. </p>
<p>Henning Sjöström and Robert Nilsson reported in their book, <em><a href="https://www.goodreads.com/book/show/4753228-thalidomide-and-the-power-of-the-drug-companies">Thalidomide and the Power of the Drug Companies</a></em>, that after thalidomide was removed from the Canadian market a number of doctors wrote to the government protesting the move. </p>
<p>In reply to one such letter, Morrell responded: </p>
<blockquote>
<p>“I think if the medical profession would take a stand… that there is every possibility that thalidomide could indeed be reinstated on the Canadian market and to this end I would encourage you to urge strongly your colleagues to express themselves to us on this question.”</p>
</blockquote>
<p>Subsequently, in 1964, in testimony before a House of Commons Committee, Morrell seemed to place the safety problems on the users of the drug: </p>
<blockquote>
<p>“I think the hazard is the inability to control the user of thalidomide after it is on the market. I am referring now to the medicine cabinet at home; you do not know who will take a pill today. Everyone wants to take pills.” </p>
</blockquote>
<p>After Morrell left the government in 1965, he joined the board of Ciba-Geigy (now part of Novartis), a major multinational Swiss drug company.</p>
<h2>More than 400 babies affected</h2>
<p>Did the officials at the Department of National Health and Welfare make mistakes in approving thalidomide? Did Merrell tell them everything it knew? Why did Canada wait three months longer than Germany and the U.K. to decide that thalidomide was too unsafe to be sold? </p>
<p>Some may wonder why we need answers to questions almost 60 years later. But if there were mistakes and withholding of information, we can learn from this — to prevent similar tragedies happening in the future.</p>
<p>In Canada, there were over 100 babies born with problems attributed to thalidomide, but the authors of <em>The Thalidomide Catastrophe</em> estimate that there could have been over 400 babies, many dying early in life. </p>
<p>These people and their families deserve answers. It’s the duty of the Canadian government to find out the answers.</p><img src="https://counter.theconversation.com/content/105122/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>In 2015-2018, Joel Lexchin was a paid consultant on three projects: one looking at indication-based prescribing (United States Agency for Healthcare Research and Quality), a second to develop principles for conservative diagnosis (Gordon and Betty Moore Foundation) and a third deciding what drugs should be provided free of charge by general practitioners (Government of Canada, Ontario Supporting Patient Oriented Research Support Unit and the St Michael’s Hospital Foundation). He also received payment for being on a panel that discussed a pharmacare plan for Canada (Canadian Institute, a for-profit organization), a panel at the American Diabetes Association, for a talk at the Toronto Reference Library and for writing a brief for a law firm. He is currently a member of research groups that are receiving money from the Canadian Institutes of Health Research and the Australian National Health and Medical Research Council. He is member of the Foundation Board of Health Action International and the Board of Canadian Doctors for Medicare.</span></em></p>A new book, ‘The Thalidomide Catastrophe,’ raises new questions about the conduct of corporations involved. It is the duty of governments to find out the answers.Joel Lexchin, Professor Emeritus of Health Policy and Management, York University, Emergency Physician at University Health Network, Associate Professor of Family and Community Medicine, University of TorontoLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1017022018-08-23T13:51:39Z2018-08-23T13:51:39ZHow an app is helping to collect genetic data in Ethiopia and Ghana<figure><img src="https://images.theconversation.com/files/232652/original/file-20180820-30596-199dq81.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Genetic data holds a wealth of health information.</span> <span class="attribution"><span class="source">CI Photos/Shutterstock</span></span></figcaption></figure><p>Genetic technologies are poised to change the world. Want to eradicate a human disease such as cystic fibrosis or improve a person’s ability to run impossible distances or lift unimaginable weights? This may be possible in the future by using something called <a href="https://www.livescience.com/58790-crispr-explained.html">CRISPR to edit</a> an organism’s genetic makeup. How about rapidly sequencing a newborn’s genome, similar to an early scene in the 1997 movie <a href="https://nerdist.com/20-year-anniversary-gattaca-genetics/">Gattaca</a>? Next-generation sequencing may make this fiction a reality. </p>
<p>As these technologies continue to increase in ability and decrease in cost, we may soon be living in an age of genomics-informed health care.</p>
<p>Unfortunately, the “we” in the previous sentence only applies to at best 7% of the world’s population. For everyone else technologies such as next-generation sequencing and CRISPR gene editing are more science fiction than nonfiction. </p>
<p>Low or middle-income countries are where this technology is needed the most as they harbor the largest <a href="https://www.marchofdimes.org/global-report-on-birth-defects-the-hidden-toll-of-dying-and-disabled-children-full-report.pdf">burden of birth defects</a> and genetic diseases. Yet almost all low-income countries and many middle-income countries <a href="http://whqlibdoc.who.int/publications/2011/9789241501149_eng.pdf">lack</a> the necessary personnel, technology, infrastructure, and public and medical education capabilities needed to introduce medical genetics services.</p>
<p>To address this gap, my colleagues and I created the <a href="https://www.nature.com/articles/s41436-018-0069-6">MiGene Family History App</a>. It’s an Android-based mobile application that aims to introduce medical genetics services into low and middle-income countries. </p>
<p>The app is used by health care providers and collects and stores patient and family histories. It generates personalised genetic counselling information that can be delivered to patients and their families. And the data can also be used for epidemiologic analysis. </p>
<p>The app has already been piloted in an Ethiopian hospital and has since been rolled out to a teaching hospital in Ghana.</p>
<p>It’s important to point out that the technology the app uses is far from what’s required to perform genome sequencing or gene editing in Ethiopia. But our work is one of the many preliminary steps needed to bring attention to the need for genetic services in low and middle-income countries. </p>
<h2>Pilot project in Ethiopia</h2>
<p>The MiGene Family History App was designed jointly by teams at the University of Michigan and St. Paul’s Hospital Millennium Medical College in Addis Ababa. It was then programmed by xHub, a technology group in Ethiopia’s capital.</p>
<p>The first version of the app focuses on paediatric birth defects and genetic diseases. These include heart malformations, Down Syndrome, and neural tube defects. So we launched the app in the Paediatric and Obstetrics and Gynaecology departments at St. Paul’s. We also conducted <a href="https://www.nature.com/articles/s41436-018-0069-6">a study</a> about the app’s value and ease of use.</p>
<p>MiGene was loaded onto physicians’ and nurses’ tablets. It was then used to collect data in both departments, but with a focus on the general paediatrics ward. The staff told us they found the app easy to use. The app allowed us to provide the hospital with data on the incidence of birth defects and genetic diseases in the institution. For instance, we found that <a href="https://www.nature.com/articles/s41436-018-0069-6">approximately 12%</a> of all admitted patients were affected with a birth defect or genetic disease. Heart malformations and Down Syndrome were the most common conditions present. </p>
<p>Having this data will help to inform future decisions taken by Ethiopia’s ministry of health. For instance, it can assess the success of interventions such as the country’s <a href="https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-017-1506-2">folic acid</a> supplementation efforts, which were introduced as a strategy to decrease the incidence of birth defects of the brain, spine, or spinal cord. </p>
<p>While our study was intentionally small in scope, if use of the MiGene Family History App is expanded to other regions within Ethiopia it will provide more representative population data. </p>
<p>One of our most interesting <a href="https://www.nature.com/articles/s41436-018-0069-6">findings</a> was that the incidence of birth defects and genetic diseases at St. Paul’s was nearly identical to the incidence of birth defects and genetic diseases in <a href="https://www.nature.com/articles/s41436-018-0069-6">previously studied</a> children’s hospitals in high-income countries. </p>
<p>This confirms something that geneticists have long known: genetic disease affects everyone and doesn’t discriminate. That’s why it’s so crucial that the benefits of genetic technology are not limited to only those individuals fortunate enough to have been born into a rich country.</p>
<h2>Taking the tech further</h2>
<p>After the success of the pilot study in Ethiopia, MiGene Family History App has been expanded to include adult-onset non-communicable diseases such as cancer, hypertension, diabetes, and cardiovascular disease. It’s still in use at St. Paul’s and is now also being used at Korle Bu Teaching Hospital in Accra, Ghana.</p>
<p>Our future plans include improving the genetic testing capabilities available at St. Paul’s and launching a genetic counselling training curriculum at the hospital. This focus on patient and health care provider education is vital when introducing a new medical technology, such as genetic testing, into a country or region.</p><img src="https://counter.theconversation.com/content/101702/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>This work was funded by grants from the University of Michigan Department of Pediatrics including the Intramural Research
Funding Program (Benz Birth Defects Research Award) and the Percy and Mary Murphy Children’s Research Fund.</span></em></p>There is a need for genetic services in low and middle-income countries.Shane C Quinonez, Biochemical Geneticist, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/949362018-05-04T09:53:25Z2018-05-04T09:53:25ZWhy it’s important to test drugs on pregnant women<figure><img src="https://images.theconversation.com/files/216835/original/file-20180430-135840-1rqqqpx.jpg?ixlib=rb-1.1.0&rect=0%2C61%2C998%2C517&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/405634465?src=ltxQLk8AXmTbnpWKLbzgKA-1-28&size=medium_jpg">Joe Besure/Shutterstock.com</a></span></figcaption></figure><p>Vulnerable groups, such as children, prisoners and people with limited mental capacity, are usually excluded from drug trials. And, until quite recently, it was considered unethical to test drugs on pregnant women, too (the <a href="http://broughttolife.sciencemuseum.org.uk/broughttolife/themes/controversies/thalidomide">thalidomide</a> scandal is probably not too far from people’s minds). But the tide is turning. The US Food and Drug Administration (FDA) recently published a draft <a href="https://www.fda.gov/ucm/groups/fdagov-public/@fdagov-drugs-gen/documents/document/ucm603873.pdf">guidance</a> for how and when to include pregnant women in drug trials. </p>
<p>According to <a href="http://dtb.bmj.com/content/51/6/61.short?g=w_dtb_currentissue_tab">Drug and Therapeutic Bulletin</a>, about one in ten pregnant women have a chronic medical condition that requires medication. And at least four in ten women take some form of medication during their pregnancy. Yet there is no drug-safety information for these women to rely on. Many women probably forgo their meds for precisely this reason. But, as the FDA guidance points out, this could result in more harm to the woman and the unborn child than if she had taken the drugs. </p>
<p>Pregnant women are entitled to high-quality, evidence-based healthcare as much as the rest of the population. The benefits and burdens of research must be distributed fairly. Pregnant women should no longer be considered a vulnerable group – at least, not in the context of drug testing.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=435&fit=crop&dpr=1 600w, https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=435&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=435&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=547&fit=crop&dpr=1 754w, https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=547&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/217242/original/file-20180502-153866-mxxev4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=547&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">The potential risks to the unborn child should be minimal.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/546641992?src=fdBODHDzAii2kHKaXZ-h9A-1-28&size=medium_jpg">GagliardiImages/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>There is nothing specific about pregnancy that makes a woman unable to provide informed consent or renders her susceptible to influence or coercion. Of course, there are potential risks to mother and baby in taking part in this kind of research, and these risks must taken seriously, but they are not reason enough for excluding pregnant women from participating. </p>
<p><a href="https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf">Ethical guidelines</a>, prepared by the Council for International
Organisations of Medical Sciences and the World Health Organisation, state that if research has no prospect of direct benefit to the pregnant woman, the risks to the foetus must be minimal (minimal risk being generally understood as the risks involved in everyday life). When research is likely to have a direct clinical benefit for pregnant woman, an increase over minimal risk may be permitted. </p>
<p>These guidelines can be difficult to interpret. For example, the concept of “minimal risk” is vague and may depend on context. It is also unclear how much risk to a foetus is acceptable if there is a prospect of direct benefit to the pregnant woman. </p>
<p>Suppose a treatment only available through research could save a pregnant woman’s life, but placed her foetus at a significant risk of being born with severe disabilities. Here, the potential benefits to the pregnant woman must be weighed against the potential risks to the future child. It is very often unclear how this balance should be struck.</p>
<h2>We can’t just avoid the issue</h2>
<p>Fortunately, a great deal of potential clinical research involving pregnant women does not require such a careful balancing of risks and benefits. Millions of pregnant women are already using various <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2747530/#R18">drugs</a>. They could easily form a research population, investigating dosing and pregnancy outcome. Such studies would involve little or no additional risk to the foetus or the pregnant woman.</p>
<p>Simply avoiding the issue is not a viable solution. Guidelines, like those issued by the FDA, are useful and are needed to increase consistency in the regulation. Further funding for research, investigating drugs in pregnant women and for pregnant women, is needed. </p>
<p>Ethicists must continue to work to develop frameworks for managing the risk-benefit trade offs between woman and foetus. Failure to do so will continue to deprive pregnant women of a fair distribution of the benefits of research.</p><img src="https://counter.theconversation.com/content/94936/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mackenzie Graham receives funding from the Wellcome Trust. </span></em></p>The FDA recently issued a draft guidance for testing drugs in pregnant women. Here’s why it’s a good thing.Mackenzie Graham, Research Fellow, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/922322018-02-23T17:07:46Z2018-02-23T17:07:46ZFinding the Achilles heel of the ‘cat parasite’ could mean more effective treatment for toxoplasmosis and malaria<figure><img src="https://images.theconversation.com/files/207654/original/file-20180223-108110-rxc6dm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">shutterstock</span> </figcaption></figure><p>Most people know <a href="http://www.parasitesinhumans.org/toxoplasma-gondii.html">toxoplasma gondii</a> as the “<a href="http://www.petsandparasites.org/cat-owners/toxoplasmosis/">cat parasite</a>”, usually passed to humans through contact with infected cat poo – like when you clean out the cat tray and forget to wash your hands. But it can also be transmitted via contaminated or undercooked meat, or from handling soil that has come into contact with infected cat poo or infected dead animals.</p>
<p>It is thought that around <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=1290077">one-third of the UK population</a> carries a dormant form of the parasite, but symptoms of infection in healthy adults tend to go unnoticed because they are so mild or are mistaken for the common cold.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=591&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=591&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=591&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=743&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=743&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207660/original/file-20180223-108150-9zj2gj.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=743&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Toxoplasmosis is particularly dangerous for pregnant women and can cause miscarriage or birth defects in babies.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/close-pregnant-belly-537404308">Shutterstock</a></span>
</figcaption>
</figure>
<p>But for those with compromised immune systems, such as people with AIDs or cancer, the parasite can cause a disease called <a href="https://www.nhs.uk/conditions/toxoplasmosis/">toxoplasmosis</a>. When the toxoplasma “wakes up” from its dormant stage, which happens in those with weakened immune systems, it can cause stroke and death – and in infants it can cause severe brain damage. This is because the active parasite replicates inside cells in the brain until these cells “break”. Toxoplasmosis is particularly <a href="https://www.nhs.uk/conditions/toxoplasmosis/">dangerous</a> to unborn babies if the mother gets infected for the first time during pregnancy and can cause miscarriage and birth defects.</p>
<h2>Treating the disease</h2>
<p>In 2015, one of the main toxoplasmosis drugs, Daraprim, <a href="https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html">hit the headlines</a> in America after drug manufacturer Turing Pharmaceuticals raised the price from $13.50 to $750 a tablet. Treatments for toxoplasmosis often have serious <a href="https://www.ncbi.nlm.nih.gov/pubmed/1359410/">side effects</a> such as toxicity in the liver and suppression of bone marrow that helps produce blood cells. There are also no drugs currently available that clear out the dormant form of the parasite.</p>
<p>But now a team of <a href="http://lilachsheiner.wixsite.com/sheinerlab-wtcmp">researchers</a> at Glasgow University has conducted a <a href="http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006836">study</a> highlighting the importance of <a href="http://pfam.xfam.org/family/pf00085">thioredoxins</a> – enzymes that have unique characteristics in the toxoplasma parasite that are different from human and animal enzymes.</p>
<p>The team discovered that these thioredoxins are essential for the parasite’s survival and we are now working with industry partners to create new drugs which will effectively target this enzyme and kill the parasite without affecting the human host. Discovering this enzyme means we have found this potentially deadly parasite’s Achilles heel.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=839&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=839&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=839&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1055&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1055&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207665/original/file-20180223-108128-xbe6xv.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1055&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Glasgow University has created a series of comics to explain the parasite in graphic form.</span>
<span class="attribution"><a class="source" href="https://www.gla.ac.uk/media/media_525175_en.pdf">Jamie Hall, Edward Ross,/Wellcome Centre for Molecular Parasitology, Glasgow University</a>, <span class="license">Author provided</span></span>
</figcaption>
</figure>
<p>More and more <a href="https://www.ncbi.nlm.nih.gov/pubmed/26976749">studies</a> highlight the fact that toxoplasma parasites are sensitive to <a href="http://www.scienceinschool.org/content/cellular-redox-%E2%80%93-living-chemistry">redox imbalance</a> – a condition inside cells that the thioredoxin enzymes respond to. Redox is a chemical state that exists in the parasite cell (as it does in human cells too). Redox imbalance is a sort of chemical stress that interferes with the normal activities of the cell; in humans for example, it is believed to contribute to the ageing process. In toxoplasma, the discovered enzyme helps the cell adjust to this stress and continue to survive. </p>
<p>In the same way, other <a href="http://www.toxoplasmosis.org/infotox.html">members</a> of the group of parasites to which toxoplasma belongs are also sensitive to <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Siciliano%2C+Mol+Microbiol+104%2C+306+(2017">redox changes</a>, which makes the environment inside them too chemically stressful, so they die because they can no longer perform their normal activities.</p>
<h2>Raising hopes about malaria</h2>
<p>The toxoplasma parasite is an important experimental model for this group, and it is often used to learn about the biology of other parasites, such as those that cause <a href="https://www.nhs.uk/conditions/malaria/">malaria</a>. This is because the cells of toxoplasma and malaria-causing parasites contain the <a href="https://www.nature.com/scitable/topicpage/the-apicoplast-an-organelle-with-a-green-14231555">same unique structures</a>.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=730&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=730&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=730&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=917&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=917&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207663/original/file-20180223-108125-11chkt8.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=917&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Mosquitos can transmit the malarial parasite when they bite humans, which leads to blood infection.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-photo/close-mosquito-sucking-blood-on-human-372765109">Shutterstock</a></span>
</figcaption>
</figure>
<p>Having found that the parallel thioredoxin in the malaria-causing parasite has similar characteristics to the toxoplasma one, but are also different from the human enzyme, we are hopeful this work can also be translated to the malaria parasite. The team is now conducting new research to confirm that this malaria enzyme is essential for the malaria parasite’s survival, potentially paving the way for the development of more effective anti-malarial drugs.</p>
<p>In malaria – as with toxoplasmosis – we lack treatments that kill the parasite at the stage where it does not produce symptoms. Targeting the parasite’s thioredoxin enzyme may make the parasites vulnerable at stages of their life that are crucial for infection and dissemination, which means it could be stopped in its tracks. </p>
<p>As an academic research group, our original interest in this work was not about drug discovery, but to learn about how parasites function and how evolution has provided them with special tools to survive. But stumbling across this particular enzyme which is a promising target for new drugs has provided us with an opportunity to explore their potential – and a very welcome bonus that highlights how crucial basic research is to the ongoing progress of healthcare and technology.</p><img src="https://counter.theconversation.com/content/92232/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Lilach Sheiner receives funding from Biotechnology and Biological Sciences Research Council (BBSRC), Royal Society of Edinburgh (RSE) and the Wellcome Trust</span></em></p>An unexpected breakthrough looks promising for finding new drugs to treat two deadly diseases.Lilach Sheiner, Senior Lecturer and Research Fellow, Parasitology, University of GlasgowLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/906932018-02-23T04:58:01Z2018-02-23T04:58:01ZChildren with facial difference have a lot to teach us about body image<figure><img src="https://images.theconversation.com/files/207203/original/file-20180221-161923-1axu1ki.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The film Wonder tells the story of a boy with severe facial defects.</span> <span class="attribution"><a class="source" href="http://www.imdb.com/title/tt2543472/mediaviewer/rm178017792">IMDb/Lionsgate, Mandeville Films, Participant Media, Walden Media</a></span></figcaption></figure><p>The recently released film <a href="http://www.imdb.com/title/tt2543472/"><em>Wonder</em></a> is based on the true story of Auggie, a boy born with a severe facial deformity. The film picks up at the point where Auggie, having been home-schooled by his mother, attends a regular school for the first time and must negotiate the varied reactions – not just of his new peers, but of their parents and the other adults.</p>
<p>Auggie was born with <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/treacher-collins-syndrome">Treacher Collins syndrome</a>, a genetic disorder that affects the development of the skull, jaw and cheekbones and causes facial defects and hearing loss. People can be born with facial differences, or they can be acquired through trauma, burns or treatment of facial tumours.</p>
<p>Either way, these differences can have as big an impact on life as loss of a limb or a chronic illness. People often associate plastic surgery with enhancement of beauty, but a more common aim, especially for surgeons who work with children, is to restore facial appearance to the point where a normal life becomes possible.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/ngiK1gQKgK8?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Auggie has had 27 surgeries to help him see and breathe.</span></figcaption>
</figure>
<p>Much more than just a loss of attractiveness, a facial defect affects every aspect of daily life, because faces are so important to us as social beings. And yet, despite significant challenges, children with facial difference tend to score better on perceptions of body image than their “normal” counterparts. </p>
<p>By studying how people with facial difference overcome their challenges, we may not only find ways to help other such children, but also learn how to help all young people be comfortable with how they look and who they are. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/why-we-dont-know-what-causes-most-birth-defects-78592">Why we don't know what causes most birth defects</a>
</strong>
</em>
</p>
<hr>
<h2>The wonder of faces</h2>
<p>Try to draw someone’s face. Unless you’re a skilled artist, it’ll be difficult to produce an image that actually looks like that person.</p>
<p>This is because within the very narrow parameters of facial features (eyes, a nose, a mouth) faces are so different we expect to be able to recognise a particular face in a crowd, possibly having seen it only once and from a different angle. With more than 7 billion people in this world, it’s truly extraordinary that everyone’s face is unique.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=924&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=924&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=924&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1161&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1161&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207207/original/file-20180221-161935-11c0act.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1161&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">It’s very difficult to capture another person’s face in a drawing, because of the nuances of human perception.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Of course it’s not the face itself that’s extraordinary, but our ability to perceive it. We are programmed to effortlessly identify the most subtle differences between faces in a way we are not for other shapes or body parts. </p>
<p>This is one reason why, despite all the advances in plastic surgery in the last century, from microsurgery to face transplantation, our surgical efforts to reconstruct faces still sometimes appear inadequate.</p>
<p>Our sensitivity to subtle differences in facial appearance contributes to the challenges people like Auggie face each day. Faces are the primary means through which we navigate the many minor social exchanges of daily life. </p>
<p>Studies show that, in casual interactions, people <a href="http://onlinelibrary.wiley.com/doi/10.1111/j.1559-1816.1982.tb00855.x/full">tend to have certain responses</a> to those with a facial difference, such as standing further away, or to the side. These changes are subtle, but full of social meaning.</p>
<p>A more pervasive problem is unwanted attention in public spaces, from rude and intrusive comments to invasive curiosity. In <em>Wonder</em>, when Auggie first walks across a busy schoolyard, conversation stops as faces turn to him. Psychologist <a href="https://slideheaven.com/facial-disfigurement-problems-and-management-of-social-interaction-and-implicati.html">Frances MacGregor</a> has elegantly described this unique problem faced by people with a visible difference: </p>
<blockquote>
<p>The ‘civil inattention’ that is normally conferred by strangers on one another and that makes it possible to move anonymously and unhindered in public spaces is a right and a privilege most longed for by facially disfigured people who […] are victims of intrusions and invasions of privacy, against which they have little or no protection.</p>
</blockquote>
<h2>Facial difference and body image</h2>
<p>Given the challenges of looking different, and the important role of the face in identity, it might be expected adolescents with facial difference would score poorly on measures of body image and well-being.</p>
<p>However, <a href="http://journals.sagepub.com/doi/full/10.1597/15-167">research done in the UK</a> has shown when a standard body image questionnaire was administered to adolescents with cleft lip and palate or a craniofacial condition like Auggie, those with facial difference actually scored, on average, better on some measures of body image than their “normal” counterparts. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/207202/original/file-20180221-161932-1wfcx5b.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Children with a cleft palate generally score higher on body image tests than those who have ‘normal’ faces.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>There may be several reasons for this. Studies <a href="https://www.sciencedirect.com/science/article/abs/pii/S1740144503000056">consistently find</a> that the severity of a visible difference is a poor predictor of its psychological impact. Much more important is the quality of a person’s social skills. People with facial difference often develop strategies for smoothing over social awkwardness, such as ways of introducing the issue into conversation early and quickly moving on, or using humour to deflect attention. </p>
<p>Better body image scores may reflect greater social maturity and a comfort in their own skin, which adolescents who have not had to face such problems have not yet achieved.</p>
<p>On the flip side, children without a visible difference don’t score as well on body image measures as children who actually do. This and a wealth of other research indicates that, in the age of social media, selfies and consumer culture, we’re facing <a href="http://www.bbc.com/news/health-41972951">a rise in body image dissatisfaction</a>. </p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/social-media-can-damage-body-image-heres-how-to-counteract-it-65717">Social media can damage body image – here's how to counteract it</a>
</strong>
</em>
</p>
<hr>
<p>Australian teenagers <a href="https://www.missionaustralia.com.au/what-we-do/research-evaluation/youth-survey">consistently rate</a> body image as one of their greatest concerns in life – above bullying, drugs and a range of problems that might be thought more important. </p>
<p>Body dissatisfaction is a key risk factor for eating disorders, and a key symptom of a condition known as <a href="https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/body-dysmorphic-disorder-bdd">body dysmorphic disorder</a> (BDD). People with BDD develop obsessive concerns with particular aspects of their appearance, including features others perceive as normal.</p>
<p>They <a href="https://link.springer.com/article/10.1007/s00266-017-0869-0">often seek surgery</a> to correct their perceived problems and, not surprisingly, are rarely satisfied with the outcome. They can undergo multiple cosmetic operations, often from a series of different surgeons, before their condition is recognised. Plastic surgeons have anecdotally reported seeing increasing numbers of <a href="https://www.surgery.org/media/statistics">young people seeking cosmetic procedures</a>.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/body-dysmorphic-disorder-and-cosmetic-surgery-are-surgeons-too-quick-to-nip-and-tuck-74234">Body dysmorphic disorder and cosmetic surgery: are surgeons too quick to nip and tuck?</a>
</strong>
</em>
</p>
<hr>
<p>An important and unanswered question concerning BDD is whether it’s an isolated condition or one extreme of a <a href="https://journals.lww.com/psnjournalonline/Abstract/2010/07000/Psychosocial_Predictors_of_an_Interest_in_Cosmetic.11.aspx">spectrum of behaviour</a>. Body dissatisfaction in young people could have serious consequences for their mental and physical health.</p>
<p>Researchers will now focus on how children and adolescents <a href="http://www1.uwe.ac.uk/hls/research/appearanceresearch.aspx">cope with facial and other differences</a>, and how the knowledge gained can be applied to help others with a facial difference. This will inform ways to better <a href="https://www.youtube.com/watch?v=RxNhE0iGkzo">educate young people</a> to feel better about how they look.</p><img src="https://counter.theconversation.com/content/90693/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Anthony Penington receives funding from the Jigsaw Foundation. He is chair of the scientific committee of the Australasian Foundation for Plastic Surgery.</span></em></p>People with facial difference often develop strategies for smoothing over social awkwardness, such as ways of introducing the issue into conversation early or using humour to deflect attention.Anthony Penington, Professor of Paediatric Plastic and Maxillofacial Surgery, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/880332017-12-06T10:39:24Z2017-12-06T10:39:24ZWhy I can’t agree with the conclusions of the report on Primodos<figure><img src="https://images.theconversation.com/files/197766/original/file-20171205-23037-1ybedna.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">
</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/411340213?src=h8BcvFwDt7sdSZD9bTH_Dg-1-14&size=medium_jpg">u3d/Shutterstock</a></span></figcaption></figure><p>Campaigners have long argued that the hormone pregnancy test, <a href="https://theconversation.com/is-primodos-the-forgotten-thalidomide-50673">Primodos</a>, caused birth defects, but a UK government expert panel recently <a href="https://www.gov.uk/government/publications/report-of-the-commission-on-human-medicines-expert-working-group-on-hormone-pregnancy-tests">dismissed these claims</a>.</p>
<p>So what evidence is there for the Commission on Human Medicines’ (CHM) conclusion? As it happens, not a lot. There were only a handful of studies looking at whether Primodos could harm the developing baby, and most are <a href="https://www.ncbi.nlm.nih.gov/pubmed/11502156">decades old</a>. Some of these studies suggest that Primodos caused birth defects; some do not. But the limited number of studies, their age and the different tests used to assess the effect of Primodos on the embryo, makes it difficult to be 100% conclusive. </p>
<p>Campaigners, perhaps unsurprisingly, suggest a <a href="https://news.sky.com/story/primodos-mps-attack-whitewash-report-into-deformity-drug-11128902">cover up</a>. </p>
<p>MPs have also raised concerns in parliament and have demanded an independent, judge-led public <a href="https://news.sky.com/story/calls-for-public-inquiry-over-primodos-pregnancy-drug-after-sky-news-documentary-10810463">inquiry</a> as they suggest the process wasn’t transparent. The MPs also want to know why regulatory issues on drug safety and testing, while Primodos was on the market, were not investigated as part of the CHM report.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/7ZRkCNUQvBA?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">MPs demand independent judge-led inquiry.</span></figcaption>
</figure>
<h2>Continuing concerns</h2>
<p><a href="https://theconversation.com/is-primodos-the-forgotten-thalidomide-50673">Primodos</a> consisted of two active ingredients, norethisterone acetate (a type of artificial progesterone) and ethinyl estradiol (a type of artificial oestrogen). Today, norethisterone acetate is used in some oral contraceptive pills but at much lower doses than in Primodos. It is also used at much higher doses than in Primodos to treat conditions such as <a href="https://bnf.nice.org.uk/drug/norethisterone.html#pregnancy">breast cancer</a>. But the authors of the CHM report say that their findings should reassure women “who may inadvertently become pregnant whilst taking these hormones for contraception or gynaecological <a href="https://www.gov.uk/government/publications/report-of-the-commission-on-human-medicines-expert-working-group-on-hormone-pregnancy-tests">indications</a>”.</p>
<p>As a contraceptive, norethisterone, works by changing the lining of the uterus to make it less able for a fertilised egg to <a href="http://www.netdoctor.co.uk/medicines/sexual-health/a7099/micronor-norethisterone/">implant</a>. For the Primodos pregnancy test, women were advised to take one pill on two consecutive days. If the woman menstruated – usually within three to six days of taking the pills – it was a sign that she wasn’t pregnant. If she didn’t menstruate, she was pregnant. But we don’t know if Primodos damaged or changed the uterine lining, which may have affected the embryo. </p>
<p>Some of the old scientific studies suggest that higher doses of these components of Primodos could be harmful to the embryo. We also now know that prolonged and continued use of artificial hormones, such as norethisterone, can affect the <a href="https://bnf.nice.org.uk/drug/norethisterone.html#pregnancy">sex of male babies</a>.</p>
<h2>Let’s have better studies</h2>
<p>The conclusion of the CHM report relies on studies that are <a href="https://www.ncbi.nlm.nih.gov/pubmed/11502156">30 to 40 years old</a>. These studies were carried out using very different techniques and tests than are used today. The studies are also contradictory. With no new tests carried out, is it really possible to conclude that Primodos and its components are safe? </p>
<p>Taking a medicine during pregnancy and having a child born with damage does not always mean it was the medicine that caused the damage. There are other factors that could also be involved, such as genetic problems. But research is needed to determine the answer. So, while it might turn out that Primodos did not cause damage to the embryo, this new CHM report does not provide definitive evidence that it was safe. </p>
<p>To address this issue and provide definitive and transparent answers, it is important that further scientific research, using advanced, modern tools and methods, is carried out – and the entire process should be transparent. Until this is done, the issue of Primodos and its alleged link to birth defects is not going to go away anytime soon.</p>
<p>A spokesperson for Bayer AG, the firm that acquired Schering, the maker of Primodos, said: </p>
<blockquote>
<p>Bayer notes that a review by an independent expert working group on hormone pregnancy tests of the Commission on Human Medicines has found, consistent with Bayer’s view, based on all available data, that the scientific evidence does not support a causal association between the use of hormonal pregnancy tests, such as Primodos, and birth defects or miscarriage.</p>
</blockquote><img src="https://counter.theconversation.com/content/88033/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Neil Vargesson has received funding from Wellcome Trust, National Insititutes of Health, The Royal Society, Newlife, Sarcoma UK to carry out research in the lab. Neil Vargesson has received no funding to carry out Primodos research. Neil Vargesson has shared his research findings on Primodos with the UK Medicine and Healthcare products Regulatory Agency and discussed Primodos with alleged Primodos survivors.</span></em></p>A panel of experts has ruled that Primodos did not cause birth defects. But what’s the science behind their decision?Neil Vargesson, Senior Lecturer in Developmental Biology, University of AberdeenLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/823152017-08-11T05:04:05Z2017-08-11T05:04:05ZPregnant women shouldn’t start taking vitamin B3 just yet: reports it prevents miscarriage and birth defects are overblown<figure><img src="https://images.theconversation.com/files/181722/original/file-20170810-27649-1wsyju7.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">The much-hyped study didn't actually test vitamin B3 supplementation in humans. </span> <span class="attribution"><span class="source">from www.shutterstock.com</span></span></figcaption></figure><p><a href="http://www.abc.net.au/news/2017-08-10/vitamin-b3-supplements-can-prevent-miscarriage-and-birth-defects/8785566">Reports</a> on a <a href="http://www.smh.com.au/national/health/breakthrough-discovery-finds-cause-and-affordable-cure-for-miscarriage-multiple-births-defects-victor-chang-institute-scientists-announce-20170809-gxsq6k.html">new study</a> claim supplementation with vitamin B3 during pregnancy could prevent miscarriages and birth defects. </p>
<p>So should all pregnant women start taking B3 supplements? Not so fast. While this is an interesting and well-done study, the researchers didn’t actually give vitamin B3 to any humans, so we need a lot more information before we can recommend it.</p>
<h2>What the study found</h2>
<p><a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1616361">The study</a> identified genetic causes of a rare type of birth defect called “VACTERL association”. VACTERL stands for vertebral defects, anal atresia (problems with the tissue closing the anus), cardiac defects, tracheo-esophageal fistula (an abnormal connection between the windpipe and the foodpipe), renal anomalies (kidney defects), and limb abnormalities. Affected babies have anomalies in at least three of these. </p>
<p><a href="https://ghr.nlm.nih.gov/condition/vacterl-association#statistics">US statistics show</a> about one in 10,000-40,000 babies are affected by VACTERL association and some of these babies die. There are about <a href="http://www.aihw.gov.au/publication-detail/?id=60129557656">310,000 babies born in Australia</a> each year.</p>
<p>The study authors looked at the genes of 13 families affected by this type of birth defect. For the defect to be passed on to offspring it has to be present in both parents’ genes - if it’s only present in one gene the other healthy one will compensate. </p>
<p>They pinpointed the variations in two genes responsible for these defects in four of the families. These two genes play a role in making “nicotinamide adenine dinucleotide” or NAD, which <a href="https://www.ncbi.nlm.nih.gov/pubmed/18429699">helps cells make</a> energy out of glucose. NAD also <a href="https://www.ncbi.nlm.nih.gov/pubmed/22138132">assists in repairing DNA</a>. NAD is synthesised in the body from tryptophan, an amino acid, or from niacin, also known as vitamin B3.</p>
<hr>
<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/why-we-dont-know-what-causes-most-birth-defects-78592">Why we don't know what causes most birth defects</a>
</strong>
</em>
</p>
<hr>
<p>Then the authors genetically engineered mice and deleted these genes. They found that without them the mice had NAD deficiency, and similar malformations in their offspring. </p>
<p>However, when they provided extra niacin to pregnant mice, the pups were relatively normal despite the absent gene. </p>
<h2>What does this mean?</h2>
<p>This does NOT mean that taking niacin/vitamin B3 in pregnancy prevents miscarriages and all birth defects. </p>
<p>It means that high levels of niacin in pregnancy compensates for defects in the two selected genes, and prevents <em>mice</em> from experiencing miscarriage and birth defects in offspring. The paper does not report on human miscarriage or on malformations in human organs. The study did not supplement pregnant women with vitamin B3, or with anything else.</p>
<p>There have been previous studies showing mutations in other genes are also associated with VACTERL and it’s likely that different genes contribute to these malformations. Not all babies with VACTERL will have the same mutations. </p>
<p>But it’s important we understand the role of different genes in birth anomalies and this paper has not only identified genetic mutations in two genes, but also the mechanism by which they cause them and an easily obtained potential remedy for these cases.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=502&fit=crop&dpr=1 754w, https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=502&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/181748/original/file-20170811-1153-7vc8hb.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=502&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Several B vitamins are related to birth defects.</span>
<span class="attribution"><span class="source">from www.shutterstock.com</span></span>
</figcaption>
</figure>
<h2>Other causes of miscarriage</h2>
<p>A large number of genes when deleted in mice have been shown to cause miscarriage and malformations. Many of these are not involved in the NAD pathway. Most have not been associated with human miscarriage but a few may be. </p>
<p>For example, deficiency in an immune system molecule (cytokine) called “GM-CSF” <a href="https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod60.2.251">has been shown to cause</a> miscarriage and defects in the placenta in mice. Addition of this molecule to IVF embryos <a href="https://academic.oup.com/jcem/article/89/12/6139/2844463/Thyrotropin-TSH-Induced-Production-of-Vascular">prevents miscarriage in mice</a> and in humans <a href="https://digital.library.adelaide.edu.au/dspace/handle/2440/80451">prevents miscarriage</a> in high-risk women (those who have previously had a miscarriage following IVF). This is but one example unrelated to NAD.</p>
<h2>Can supplements prevent birth defects?</h2>
<p>From 1986-2007, 5.9% of South Australian births (so 590 out of 10,000) were <a href="http://www.wch.sa.gov.au/services/az/other/phru/birthdefect.html">complicated by congenital malformations</a>, most of which were not severe or life threatening. The most common malformations are in the urinary and genital systems (164/10,000 births) and the cardiovascular system (119/10,000) and range from mild to severe life-threatening malformations requiring extensive surgery. </p>
<p>For many of these there is no known cause nor remedy. For neural tube (brain and spine/spinal cord) defects such as spina bifida (which occur in 16 in 10,000 births), maternal supplementation with folic acid from one month before conception and in the first trimester of pregnancy <a href="https://www.ranzcog.edu.au/RANZCOG_SITE/media/RANZCOG-MEDIA/Women's%20Health/Statement%20and%20guidelines/Clinical-Obstetrics/Vitamin-and-mineral-supplementation-in-pregnancy-(C-Obs-25)-Review-Nov-2014,-Amended-May-2015.pdf?ext=.pdf">has been shown to reduce their incidence</a>.</p>
<p>The Australian population is <a href="http://www.nrv.gov.au/nutrients/niacin">not considered to be deficient in niacin</a>. Most breakfast cereals have niacin added to them as do some flours for baking; it is also present in meat, green vegetables and whole grain cereals.</p>
<p>A <a href="http://onlinelibrary.wiley.com/doi/10.1002/bdra.20648/abstract">2010 study in California</a> showed that in women who did not use micronutrient supplements in pregnancy, low dietary intakes of folate, niacin, riboflavin, and vitamins B12, A and E were associated with one specific major heart defect but not another. So not one, but a number of micronutrients are involved in birth defects, notably several B vitamins.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=526&fit=crop&dpr=1 600w, https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=526&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=526&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=661&fit=crop&dpr=1 754w, https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=661&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/181752/original/file-20170811-1188-1ke9v2r.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=661&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Not all of the reports are backed by the science.</span>
<span class="attribution"><a class="source" href="https://www.victorchang.edu.au/pregnancy-breakthrough">Screenshot, victorchang.edu.au</a></span>
</figcaption>
</figure>
<p>Clearly, folic acid supplementation to prevent neural tube defects has been successful, but <a href="https://www.ncbi.nlm.nih.gov/pubmed/19880541">emerging evidence suggests a potential downside</a>. Specifically, the babies of women who supplemented with folic acid in late pregnancy were more likely to have persistent asthma in early childhood. </p>
<p>Since 2009 we’ve had mandatory fortification of flour for bread-making with folic acid in Australia and New Zealand. Together with folic acid supplementation in pregnancy, pregnant women are getting high amounts of folic acid. Given folate plays a part in gene expression (the process by which information from a gene is used), it’s possible too much may not be a good thing. But we’re yet to see hard evidence of this.</p>
<p>This new study is scientifically excellent and the authors have great credentials. But media reports, and the <a href="https://www.victorchang.edu.au/pregnancy-breakthrough">research institution itself</a>, have made claims not supported by the science. Whether niacin is useful in human miscarriage has not been studied. The birth defects studied in the paper are rare and whether the findings apply to others is yet to be determined.</p>
<p>So potential parents need to be aware that, no, we have not found a way to prevent miscarriages and birth defects. And potential mothers should not start supplementing their diets with high levels of vitamin B3 because it hasn’t been tested in humans, and we don’t know what effects it will have.</p><img src="https://counter.theconversation.com/content/82315/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Claire Roberts works for University of Adelaide. She receives funding from NHMRC, NIH NICHD and University of Adelaide. </span></em></p>The new study on birth defects and vitamin B3 has important implications, but researchers didn’t actually give any of this vitamin to humans.Claire Roberts, Lloyd Cox Professorial Research Fellow, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/785922017-06-08T19:25:51Z2017-06-08T19:25:51ZWhy we don’t know what causes most birth defects<figure><img src="https://images.theconversation.com/files/172181/original/file-20170605-20586-sgg1qn.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">About 3% of babies are born with birth defects, when there is a problem with how they develop in the womb.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/411340129?src=8_HRpVr2qj1DFZqztQ4QrA-2-85&size=medium_jpg">from www.shutterstock.com</a></span></figcaption></figure><p>The development of a baby, from the time of fertilisation through to the moment of birth, is an incredibly complex journey. Most of the time the result is a perfect new baby. However, in <a href="https://www.cdc.gov/ncbddd/birthdefects/facts.html">about 3% of babies</a> mistakes happen and a birth defect occurs. This is when an anatomical difference has come about as the baby develops in the womb.</p>
<p>Birth defects (also known as congenital anomalies) are a major cause of <a href="https://www.cdc.gov/nchs/products/databriefs/db279.htm">infant hospitalisation and deaths</a> in the first year of life. These are not only costly to manage in the health-care system, but can also have an enormous impact on the lives of the child and their family.</p>
<p>Some birth defects are relatively mild, can be repaired with simple surgery and the child will go on to lead a perfectly normal life. These include an additional little finger or webbing between two toes.</p>
<p>Other types, including serious <a href="https://www.mja.com.au/journal/2012/197/3/congenital-heart-disease-current-knowledge-about-causes-and-inheritance">heart defects</a> and facial deformities such as <a href="http://www.rch.org.au/kidsinfo/fact_sheets/Cleft_Lip_and_Palate_an_overview/">cleft lip and palate</a>, are more complex to manage. These may involve treatment spanning childhood and into adolescence.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/172183/original/file-20170605-20578-l8e1nv.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Children born with a cleft lip (above) are offered surgery to correct this common birth defect.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/success?src=AE4bGoW-NCVhXMEt6f6vdQ-1-9">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Some birth defects are so severe the baby cannot live outside the womb. These kinds usually involve major malformation of essential structures, such as <a href="https://www.cdc.gov/ncbddd/birthdefects/anencephaly.html">anencephaly</a> where the brain fails to form.</p>
<p>When a single cause affects multiple systems in the body the birth defect is described as a syndrome. An example is <a href="http://www.downsyndrome.org.au/">Down syndrome</a>. This is one of the most common birth defects in Australia and causes intellectual disability and other physical and learning challenges.</p>
<p>The outlook for children with syndromes, like the syndromes themselves, is highly variable. A syndromic birth defect is not necessarily more severe than an isolated birth defect. However, the involvement of multiple systems or structures may require ongoing management to ensure the best outcomes for the child and their family.</p>
<h2>What causes birth defects?</h2>
<p>Birth defects have two major causes, environmental and genetic. </p>
<p>Environmental causes (known as teratogens) include medicines that can harm the unborn baby. The most high-profile of these was <a href="https://theconversation.com/thalidomide-taught-us-to-use-medications-with-care-during-pregnancy-not-to-stop-using-them-51862">thalidomide</a>, which women took for morning sickness in the late 1950s and early 1960s. It led to thousands of babies born with irreversible congenital defects ranging from limb deformities (phocomelia) to facial malformations.</p>
<p>A more recently identified environmental cause of birth defects is the <a href="http://www.who.int/csr/disease/zika/en/">Zika virus</a>, which leads to <a href="https://theconversation.com/explainer-what-is-microcephaly-and-what-is-its-relationship-to-zika-virus-54049">microcephaly</a> (babies born with smaller-than-normal heads).</p>
<p>More everyday factors include alcohol and smoking, which have been associated with an <a href="http://www.aihw.gov.au/child-health/risk-factors/">increased risk</a> of abnormalities. Estimates from the USA suggest <a href="https://www.cdc.gov/ncbddd/fasd/data.html">0.1-1% of children</a> may be affected by alcohol in the womb. And smoking during pregnancy is associated with a <a href="http://www.tobaccoinaustralia.org.au/3-8-infant-health-and-smoking">range of conditions</a>, including heart defects and facial clefts.</p>
<p>Environmental factors can also involve physical restriction that may occur in the womb from <a href="http://jech.bmj.com/content/70/11/1114">twin pregnancies</a>.</p>
<p>The genetic causes of birth defects are equally diverse. These include chromosomal abnormalities in conditions like <a href="http://www.downsyndrome.org.au/">Down syndrome</a> (an extra copy of chromosome 21) and errors in specific genes such as the <a href="http://www.yourgenome.org/facts/what-is-achondroplasia">FGFR3 gene</a>, which causes a form of dwarfism.</p>
<h2>But most causes remain a mystery</h2>
<p>Recent US <a href="http://www.bmj.com/content/357/bmj.j2249">research</a> examined the frequency and causes of birth defects by looking at medical records for over 270,000 births between 2005 and 2009. The researchers found 5,504 cases of birth defects, or about 2% of total births.</p>
<p>But they found the cause behind only one in five of these birth defects. The rest (79.8%) remained a mystery.</p>
<p>Of the known causes, 94.4% were genetic, 4.1% resulted from environmental exposure (teratogens) and 1.4% were linked with twin pregnancies.</p>
<p>The study also confirmed <a href="https://npesu.unsw.edu.au/surveillance/congenital-anomalies-australia-2002-2003">Australian findings</a> that individual birth defects seem to affect a higher proportion of males than females; we still don’t know why.</p>
<h2>Where to from here?</h2>
<p>This study highlights reasons for hope. The 4.1% of birth defects resulting from teratogen exposure were mainly caused by uncontrolled <a href="http://www.mydr.com.au/diabetes/diabetes-and-getting-pregnant">diabetes</a> in women before becoming pregnant. While the mechanism for this is unclear, this figure could be reduced through increased education of women intending to become pregnant to ensure their diabetes is controlled before and during pregnancy.</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/172186/original/file-20170605-20569-fof7ai.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Controlling a woman’s diabetes before she becomes pregnant reduces her chance of having a child with a birth defect.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/download/confirm/552199903?src=xkZZVKGo6IjBrt_ktxrowQ-1-21&size=medium_jpg">from www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Yet, the finding that the cause of nearly 80% of birth defects remains unknown is confronting and highlights the scale of the task ahead.</p>
<p>In Australia, for instance, we do not have a clear picture of the types and frequencies of birth defects across the nation. This is because we have state-based systems that collect different information.</p>
<p>Birth defects are also diverse, affecting many different structures in the body. Each specific birth defect results from a different cause, most of which are genetic. Identifying the factors responsible requires each birth defect to be examined independently so that individuals with a particular condition can be grouped and studied together. This takes time, research and funding.</p>
<p>Greater support for genetics research and information collection on birth defects would allow us to understand the origins of these conditions. Only then can we be begin the task of intervention and prevention to reduce the burden of these conditions on health-care systems and families.</p>
<hr>
<p><em>If you have concerns about birth defects, please speak to your doctor. For more information and support, contact the <a href="http://www.gsnv.org.au/">Genetic Support Network of Victoria</a> or the <a href="http://www.geneticandrarediseasenetwork.org.au/">Genetic and Rare Disease Network</a>.</em></p><img src="https://counter.theconversation.com/content/78592/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Peter Farlie receives funding from the National Health and Medical Research Council Australia. </span></em></p>We still don’t know what’s behind four out of every five birth defects. But that can change.Peter Farlie, Developmental Biologist, Murdoch Children's Research InstituteLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/779452017-05-19T05:14:10Z2017-05-19T05:14:10ZShould I stop taking Prozac if I’m pregnant?<figure><img src="https://images.theconversation.com/files/169884/original/file-20170518-24325-65g27r.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Deciding whether or not to continue on medication in pregnancy is always a balancing act.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>Women, and perhaps their doctors, may be concerned when they <a href="http://www.dailymail.co.uk/femail/article-4516894/Antidepressants-cause-birth-defects-new-study-found.html">see reports of a study</a> showing an association between taking fluoxetine, an antidepressant also known as Prozac, during pregnancy and birth defects in children. </p>
<p>These findings aren’t new. We’ve known for some time of an <a href="https://theconversation.com/pregnant-women-taking-antidepressants-shouldnt-panic-about-birth-defect-claims-44358"><em>association</em> between taking antidepressants</a> (selective serotonin reuptake inhibitors or SSRIs, specifically fluoxetine and paroxetine) during pregnancy and a higher risk of birth malformation in babies.</p>
<p>But is a knee-jerk reaction to stop taking antidepressants when you discover you’re pregnant warranted? It’s important to take a step back – there are many factors to consider, one of which is that whether antidepressants themselves <em>cause</em> birth defects has never been proven. And stopping medication could lead the woman to relapse into depression, which can be a risk to the baby in itself. </p>
<h2>What was the recent study?</h2>
<p>Studies that have shown an association between antidepressants and birth defects have largely been <a href="https://www.ncbi.nlm.nih.gov/pubmed/21646927">observational</a>. Observational studies, in this instance, mean those following women from early pregnancy to the postpartum period (immediately after birth), recording information related to their health and that of the fetus, and later, child.</p>
<p>The recent paper published in the <a href="http://onlinelibrary.wiley.com/doi/10.1111/bcp.13321/abstract?utm_source=AusSMC+mailing+list&utm_campaign=4f179e2d4a-EMAIL_CAMPAIGN_2017_05_17&utm_medium=email&utm_term=0_90d9431cd5-4f179e2d4a-132722317">British Journal of Clinical Pharmacology</a> was a meta-analysis of such studies. This research method takes a number of similar studies (in this case 16 observational studies exploring fluoxetine use during pregnancy) and pools the results.</p>
<p>It concluded that taking fluoxetine in the first trimester of pregnancy increased the risk of birth defects in the child by 18%. These defects might include the child being born with spina bifida, or having an extra ureter (the duct though which urine passes from the kidney to the bladder). </p>
<p>More specifically, it found that heart-related defects increased by 36%. This included both septal defects (holes in the heart wall), many of which are minor and do not require intervention, and non-septal defects (such as malformations in a heart valve or vessels).</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/170047/original/file-20170519-12263-cu4n3a.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Observational studies follow people over time recording information under observation.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>In terms of population-level risk, these percentage increases mean for every 100 women not on antidepressants who have babies with a defect, 118 women on antidepressants will have babies with a defect. And for every 100 women not on an antidepressant who have babies with a heart defect, 136 women on antidepressants will have babies with a heart defect. </p>
<p>This is a real increased risk, but it is a small increase considering the baseline risk is small. Across the general population, <a href="http://www.heart.org/HEARTORG/Conditions/CongenitalHeartDefects/UnderstandYourRiskforCongenitalHeartDefects/Understand-Your-Risk-for-Congenital-Heart-Defects_UCM_001219_Article.jsp">only eight per 1000 of all deliveries</a>, which includes the babies of women on antidepressants, will be born with a heart defect.</p>
<hr>
<p><em><strong>For more detail</strong>: <strong><a href="https://theconversation.com/what-you-need-to-know-to-understand-risk-estimates-67643">What you need to know to understand risk estimates</a></strong></em></p>
<hr>
<h2>Association isn’t causation</h2>
<p>It’s important to note, however, that none of the studies in the meta-analysis were randomised controlled trials: where one group is randomly chosen to receive the drug being tested, while another group receives a placebo or different drug.</p>
<p>Such trials would be unethical in pregnant women. So we can only “test” for outcomes in children of women who take drugs during pregnancy by observing them. Then we can only conclude whether taking the drug was <em>associated</em> with an increased risk to the baby, rather than the drug having <em>caused</em> the risk. </p>
<p>The observational studies on women and their babies cannot be considered equivalent in quality to randomised controlled trials. This is because we are not comparing two equivalent groups: women who take antidepressants and those who don’t. We are observing women who have many differences, which can sometimes also be risk factors.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=515&fit=crop&dpr=1 600w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=515&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=515&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=647&fit=crop&dpr=1 754w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=647&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/170049/original/file-20170519-12237-jvce8t.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=647&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Randomised controlled trials, where two similar groups are used to test a drug, are superior to observational studies.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
</figcaption>
</figure>
<p>Women taking fluoxetine will be doing so due to poor mental health, which is often associated with other health issues, such as gestational diabetes. Some studies suggest <a href="https://www.ncbi.nlm.nih.gov/pubmed/17519397">gestational diabetes could lead to heart defects</a> in the fetus. Poor mental health is also associated with higher levels of smoking, alcohol and illicit drug use, which are <a href="https://www.ncbi.nlm.nih.gov/pubmed/355285">well known to adversely impact</a> fetal development.</p>
<p>Just by observing women over time, we can’t know whether it was one of these other factors that caused a higher increase in risk, or the antidepressants. And not all the studies in the meta-analysis controlled for other risk factors. </p>
<p>Studies that controlled for alcohol use, for instance, showed a lower, 13% increase in heart malformations, compared to 31% in those that did not. And none of the studies controlled for the dose of the drug women were taking. It is likely the fetuses exposed to 80mg daily of fluoxetine are going to be at higher risk of birth defects than those exposed to 20mg daily.</p>
<h2>The safest course of action</h2>
<p>Deciding whether or not to continue on medication in pregnancy is always a balancing act: the risk to the mother of being off the medication, and the effects of her being unwell on the fetus, versus the risk of medication to the fetus. </p>
<p>Australian guidelines suggest women who have been well for a year or more, only ever had one episode of depression or anxiety, were never suicidal and kept functioning (going to work for instance) when unwell, could <a href="https://www.ranzcp.org/Files/Resources/Publications/CPG/Clinician/CPG_Clinician_Full_Depression-pdf.aspx">likely stop taking their antidepressants</a> with little risk.</p>
<p>But for those with more serious, recurrent illnesses, <a href="http://www.preventionweb.net/files/670_72351.pdf">there is no risk-free option</a>. The likelihood the illness will recur when off medication is high, and this itself puts the fetus at risk.</p>
<p>Women who are unwell have poorer self-care and may be at <a href="https://www.ncbi.nlm.nih.gov/pubmed/15633850">risk of suicide</a>. Infants born to women who were unwell in pregnancy are also more likely to have higher levels of the stress hormone cortisol at birth. This continues throughout their lives and is a probable marker for a <a href="https://www.ncbi.nlm.nih.gov/pubmed/26610204">higher risk of their own mental health issues</a>.</p>
<h2>Prozac hardly used in pregnancy</h2>
<p>Authors of the recent study noted fluoxetine was the most frequently prescribed medication in pregnant women. This may be true in other countries but is unlikely to be the case in Australia. </p>
<p>We have <a href="https://www.ncbi.nlm.nih.gov/pubmed/10722179">known for some time</a> fluoxetine, as well as another SSRI paroxetine, has been linked with a small increased risk in birth defects. Fluoxetine has a long half-life, which means it stays longer in the system than other SSRIs, including in the baby after delivery. This makes it less attractive to use in pregnant women. </p>
<p>Australian guidelines advise a <a href="http://www.racgp.org.au/afp/2014/april/perinatal-mental-health/">SSRI with a shorter half-life</a>, and without the specific risk identified with fluoxetine, be prescribed for pregnant women.</p>
<p>Ideally, a woman will see her doctor when planning a pregnancy and, with her partner, will decide on the best options in their specific case. By reducing weight and stopping smoking, alcohol and illicit drugs, as well as deciding what to do about their antidepressant, women will ensure the risk to them and their babies is as low as possible.</p><img src="https://counter.theconversation.com/content/77945/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Anne Buist has received research and educational grants from numerous pharmacuetical companies over the last thirty years; in the last five years this has been Astrazeneca and Ostsuko-Lundbeck; she is doing occasional current paid talks for the latter but these talks do not include discussion of medication. </span></em></p>A study has shown an association between antidepressants in pregnancy and risk to the baby. But there are many factors to consider if deciding whether to stay on an antidepressant if you’re pregnant.Anne Buist, Director of Women’s Mental Health at Austin Health – Northpark Private Hospital, Professor, The University of MelbourneLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/638102016-11-21T02:23:05Z2016-11-21T02:23:05ZHealth Check: are cosmetics containing Vitamin A safe during pregnancy?<figure><img src="https://images.theconversation.com/files/145118/original/image-20161109-16721-1o1q1ct.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Pregnant women are told to avoid vitamin A due to the risk of birth defects, but does anti-ageing cream count?</span> <span class="attribution"><span class="source">from www.shutterstock.com.au</span></span></figcaption></figure><p>Cosmetics promise us many things, but could certain types of skin-care products containing vitamin A be harmful to unborn children? </p>
<p><a href="https://en.wikipedia.org/wiki/Vitamin_A">Vitamin A</a> is one of the most recognisable vitamins. It’s essential for tissue development and plays an important role in vision. In many developing countries, <a href="http://www.who.int/nutrition/topics/vad/en/">childhood vision problems</a> are due to vitamin A deficiency. </p>
<p>Too much vitamin A can be harmful too, as <a href="https://www.theguardian.com/science/antarctica-live/2013/dec/04/douglas-mawson-antarctic-trek">Antarctic trekkers discovered</a>. When starving, they ate their dogs (including their livers, which are high in Vitamin A) and suffered illness and eventually death. </p>
<p>Vitamin A is also important for skin integrity and function. Vitamin A is actually a group of related unsaturated fatty compounds that includes <a href="https://en.wikipedia.org/wiki/Retinol">retinol</a>, retinal and retinoic acid. Vitamin A and synthetic analogues of vitamin A are used to treat a variety of skin conditions, as well as some forms of cancer. </p>
<p>As well as dermatological uses of vitamin A, it may be found in some “anti-ageing” cosmetics and sunscreens because of its effect on the skin. </p>
<p>However, because vitamin A plays a role in foetal development, using pharmaceutical levels of vitamin A during pregnancy may interfere with the development of the foetus and cause deformities, especially of the face and palate. Is there a risk of this occurring with cosmetics?</p>
<h2>What vitamin A is used for</h2>
<p>Acne is a complex long-term inflammatory disease of the skin that centres on the hair follicle. There are excessive secretions in the follicle, too much protein is made and bacteria infect the site. Acne can range from mild to moderate to severe disease with the potential for disfiguring scarring.</p>
<p>Acne is resistant to many of the treatments that would usually be used in an inflammatory disease. Therapy for acne can be complex, but vitamin A in the form of “<a href="https://en.wikipedia.org/wiki/Tretinoin">tretinoin</a>” or “isotretinoin” plays a significant role in treating acne. Synthetic vitamin A is also used.</p>
<p>While most of these products are rubbed on the skin, oral isotretinoin is the treatment of choice for severe adult acne. Typical concentrations of trentinoin cream range from 0.01% to 0.1%.</p>
<p>Both Tretinoin and retinol have been incorporated into a variety of cosmetics and sunscreens. Tretinoin stimulates supporting cells in the skin to make more of the <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699641/">supporting structure of the skin</a>, which reduces wrinkling and some of the damaging effects of sunlight on skin. </p>
<p>Tretinoin can also normalise some of the pigment changes in skin with ageing and sun exposure. While the <a href="http://www.ncbi.nlm.nih.gov/pubmed/23839179">initial research</a> was done on tretinoin, retinol has been shown to be <a href="http://www.ncbi.nlm.nih.gov/pubmed/25607905">effective in cosmetic applications</a> as well (although around ten times less potent than tretinoin). Cosmetics available in Australia appear to have retinol in them, rather than any other form of vitamin A.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=636&fit=crop&dpr=1 600w, https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=636&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=636&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=799&fit=crop&dpr=1 754w, https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=799&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/145119/original/image-20161109-16691-ut2o7j.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=799&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Many anti-ageing creams contain Vitamin A.</span>
<span class="attribution"><a class="source" href="http://www.biovea.net/au/product_detail.aspx?PID=4287&TI=GGLAU&C=N&gclid=CJnnwqzFmtACFYmSvQodDAALZA">Screenshot, Biovea</a></span>
</figcaption>
</figure>
<p>While it’s generally accepted the ranges of tretinoin or retinol in cosmetics are similar to those found in pharmaceutically active products, this information can be very difficult to find. It’s also hard to find which “anti-ageing” products these compounds are actually in. </p>
<p>While some internet-based sales sites prominently feature their retinol content and one group claims to have a high 1% retinol content product (compared to 0.1% for tretinoin), another prominent anti-ageing product lists retinol under “inactive ingredients” with no actual concentration given.</p>
<p>Finding health warnings on cosmetics is variable as well. Aside from the risks of birth defects, tretinoin and retinol are both associated with adverse effects, ranging from <a href="http://www.nps.org.au/medicines/skin/acne-medicines/tretinoin-acne-medicines/retrieve-cream">rash and dry skin to irritation and burning</a>. </p>
<p>Some cosmetics sites and products mention this, some don’t. None of the products I surveyed mention issues with birth defects in any easy-to-find place.</p>
<h2>Vitamin A compounds and birth defects</h2>
<p><a href="http://www.medscape.com/viewarticle/492119">Oral consumption of isotretinoin</a> has been clearly shown to produce birth defects. However, tretonin and retinol applied to the skin are less likely to be associated with birth defects. </p>
<p>Tretonin is poorly absorbed from the skin and rapidly broken down. In animal studies tretinoin applied to the skin at levels higher than used in humans produced no birth defects. For example in rats, concentrations of 0.5 milligrams per kilogram per day were applied to the skin without effect. </p>
<p>Fewer studies have been done with retinol, but it too is <a href="http://www.ncbi.nlm.nih.gov/pubmed/18511092">poorly absorbed</a> through the skin.</p>
<p>Overall, poor absorption and the small surface area the retinoids were applied to would suggest the levels achieved in the blood would be too low to harm the developing child. </p>
<p>There were early <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114665/">case reports</a> (isolated reports after use of the product) of birth defects following skin application of tretinoin in humans. Since then there have been four relatively large studies in humans where pregnant women who were or were not exposed to tretinoin were followed for birth defects. No differences in birth defects were found between the groups (for recent reviews see <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3114665/">here</a> and <a href="http://www.ncbi.nlm.nih.gov/pubmed/24528911">here</a>).</p>
<p>In the most <a href="http://onlinelibrary.wiley.com/doi/10.1177/0091270011429566/abstract">recent and largest study</a> reported in 2012, 235 pregnant women exposed to a variety of retinoids applied to the skin from the beginning of pregnancy were compared with 444 controls. No differences were seen between groups in rates of spontaneous abortion, minor birth defects or major birth defects. No child showed features of retinoid embryopathy (birth defects caused by Vitamin A).</p>
<h2>The bottom line</h2>
<p>Despite the low risk suggested by these studies, experts still suggest pregnant women avoid applying vitamin A-based formulations to their skin during early pregnancy.</p>
<p>On the other hand, if you have used a cosmetic containing a retinol or a similar vitamin A-like compound during pregnancy, there’s no need to panic. Stop using the product and consult with your health care professional. </p>
<p>If you are planning to becoming pregnant, it would be wise to check any “anti-ageing” cosmetics or sunscreens to determine which ones have retinol or other forms of vitamin A in them (you may have to do some sleuthing) and, as always, have a conversation with your health care professional.</p><img src="https://counter.theconversation.com/content/63810/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ian Musgrave receives funding from the National Health and Medical Research Council to study adulterants and contaminants in herbal medicines. He has previously received funding from both the Australian Research Council and the NHMRC for Alzhiemer's related research. </span></em></p>Anti-ageing cosmetics are common and many contain forms of vitamin A, but are there any risks using vitamin A on your skin during pregnancy?Ian Musgrave, Senior lecturer in Pharmacology, University of AdelaideLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/639452016-08-24T20:26:32Z2016-08-24T20:26:32ZExplainer: arthrogryposis – the congenital disorder linked to Zika<figure><img src="https://images.theconversation.com/files/135096/original/image-20160823-30209-151i6d4.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">With more birth abnormalities linked to Zika, effects of the virus may be more sinister than we thought. </span> <span class="attribution"><a class="source" href="http://www.bmj.com/content/354/bmj.i3899">BMJ 2016</a></span></figcaption></figure><p>While we’re used to seeing the distressing images of small heads caused by infection with the Zika virus during pregnancy, <a href="http://www.bmj.com/content/354/bmj.i3899">a recent study</a> has suggested the virus may be linked to another congenital birth disorder, namely <a href="http://www.ncbi.nlm.nih.gov/pubmed/23622356">arthrogryposis</a>. </p>
<p>Arthrogryposis is where a baby’s joints are deformed due to a shortening (known as contractures) of the muscles from before birth. Arthrogryposis is derived from Greek and the literal translation means “curving of joints”. It is thought to arise from reduced or absent movement of the baby while it’s in the uterus, so the joints develop abnormally.</p>
<p>Arthrogryposis multiplex congenita is a condition in which the contractures of the joints are severe and affect many joints. It is also frequently accompanied by muscle weakness. Distal arthrogryposis is milder and generally affects the hands and feet. </p>
<p>The <a href="http://www.ncbi.nlm.nih.gov/pubmed/23622356">incidence of arthrogryposis</a> is about one in 3,000 people, but cases where contractures affect only one joint or body area (such as clubfoot) are much more common.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/135097/original/image-20160823-30257-10z9b82.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Arthrogryposis of the feet (clubfoot).</span>
<span class="attribution"><span class="source">Wikimedia Commons</span></span>
</figcaption>
</figure>
<h2>What causes it?</h2>
<p>Inherited mutations in a number of genes <a href="http://www.ncbi.nlm.nih.gov/pubmed/21984750">have been shown</a> to cause both the severe and milder forms of arthrogryposis. These genes affect <a href="http://www.ncbi.nlm.nih.gov/pubmed/24704792">proteins</a> that are <a href="http://www.ncbi.nlm.nih.gov/pubmed/26004201">important for the function of the brain</a>, peripheral nerves (nerves that connect the brain and spinal cord to the entire body), skeletal muscle and <a href="https://ojrd.biomedcentral.com/articles/10.1186/s13023-015-0364-0">connective tissue</a>. </p>
<p><a href="http://www.ncbi.nlm.nih.gov/pubmed/9260643">Arthrogryposis can also arise in the setting of</a> maternal illness such as myotonic dystrophy (a form of muscular dystrophy), myasthenia gravis (a rare chronic autoimmune disease causing muscular weakness), untreated lupus (a skin condition) or metabolic imbalances. It has been linked to lack of space or compromised blood flow in the uterus, and to drugs such as muscle relaxants, cocaine and alcohol. </p>
<p>More than <a href="http://www.ncbi.nlm.nih.gov/pubmed/23622356">300 different disorders</a> that include features of arthrogryposis have been <a href="http://www.ncbi.nlm.nih.gov/pubmed/8923935">described</a>, but this doesn’t necessarily mean these disorders <em>cause</em> arthrogryposis.</p>
<p>A virus found in cows called the Akabane virus has been associated with arthrogryposis and hydranencephaly (where parts of the brain are missing and there is fluid in the cavity) in calves. <a href="http://www.ncbi.nlm.nih.gov/pubmed/23622356">Infection of pregnant sheep</a> with this virus resulted in changes in the central nervous system and arthrogryposis in lambs. Until recently, arthrogryposis was not thought to be caused by infections that were present at birth.</p>
<h2>Arthrogryposis and Zika</h2>
<p>Most people infected with the Zika virus do not show any signs of being infected. Some experience mild symptoms such as fever, rash, joint pain and conjunctivitis, which go away on their own.</p>
<p>However, an increase in the number of children born with <a href="https://theconversation.com/explainer-what-is-microcephaly-and-what-is-its-relationship-to-zika-virus-54049">microcephaly</a> (small heads) has been reported in regions with high levels of Zika virus. <a href="http://www.ncbi.nlm.nih.gov/pubmed/27412681">Mounting evidence suggests</a> Zika is responsible.</p>
<p>Recently, three separate studies have reported a link between Zika infection during pregnancy and arthrogryposis in the newborn infant. </p>
<p>In an isolated case in Spain, Zika virus was detected in a pregnant woman at 17 weeks gestation. Ultrasound scans at 19 weeks revealed foetal malformations. The pregnancy was terminated and autopsy revealed hydrocephalus (enlargement of brain cavities due to excess fluid) and the severe form of arthrogryposis. Zika virus <a href="http://www.ncbi.nlm.nih.gov/pubmed/27336620">was detected in the umbilical cord</a> and foetal brain.</p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=893&fit=crop&dpr=1 600w, https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=893&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=893&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1123&fit=crop&dpr=1 754w, https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1123&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/135098/original/image-20160823-30249-dibi7r.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1123&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Arthrogryposis multiplex congenita is the most severe form of the condition.</span>
<span class="attribution"><span class="source">Wikimedia Commons</span></span>
</figcaption>
</figure>
<p>In a series of five cases published in <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30883-2/abstract">The Lancet</a>, Zika virus was detected in brain tissue from three babies that were born with microcephaly and later died, including two that also had severe arthrogryposis. Zika virus <a href="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30883-2/abstract">was also detected</a> in tissues from two further cases of spontaneous abortion. </p>
<p>There is growing evidence Zika virus can cause congenital brain malformations and arthrogryposis as well as miscarriage. Most recently, <a href="http://www.bmj.com/content/354/bmj.i3899">a study reported</a> seven Brazilian cases of arthrogryposis in which three children had positive tests for Zika virus infection. Brain imaging showed all cases had malformations of the brain, a reduced brain volume, increased space in the four ventricles of the brain that produce spinal fluid, and alterations of the brainstem and cerebellum at the back of the skull. </p>
<p>High-resolution imaging of the joints did not reveal abnormalities. This <a href="http://www.bmj.com/content/354/bmj.i3899">study concluded</a> the joint deformities were likely a consequence of poor brain and peripheral nerve function, which resulted in a fixed posture in the uterus. So the Zika virus <em>itself</em> may not have caused the deformities, but the virus’ effect on the brain may have contributed to limited movement in the womb.</p>
<p>So while the link between the Zika virus and arthrogryposis is not yet proven, it is further evidence the consequences of Zika virus infection during pregnancy may contribute to a spectrum of abnormalities.</p><img src="https://counter.theconversation.com/content/63945/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Gina Ravenscroft receives funding from the NHMRC, WA Department of Health and the French Muscular Dystrophy Association (AFM). </span></em></p><p class="fine-print"><em><span>Michelle Giles does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Arthrogryposis is where a baby’s joints are deformed due to a shortening (known as contractures) of the muscles from before birth.Michelle Giles, Associate Professor, Department of infectious diseases and Dept of Obstetrics and gynaecology, Monash UniversityGina Ravenscroft, Research Fellow in neuromuscular disease and genetics, The University of Western AustraliaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/624632016-08-05T15:28:17Z2016-08-05T15:28:17ZI’m an OB-GYN treating women with Zika: This is what it’s like<figure><img src="https://images.theconversation.com/files/133175/original/image-20160804-513-11plkej.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Talking with patients who've had Zika is tough.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-159741362/stock-photo-the-pregnant-woman-who-has-an-examination.html?src=YPd0wl-YeKuWW_3sd1XLZQ-5-37">Pregnant woman and doctor image via www.shutterstock.com.</a></span></figcaption></figure><p>As a medical student, I remember reading books about the early days of the HIV epidemic and wondering what it was like for doctors to take care of patients who had a new, unknown disease. It seemed to me like it would be frightening for both patients and doctors alike. I didn’t expect that early in my career as an OB-GYN, I would be caught in the middle of another new disease outbreak – Zika.</p>
<p>Most people who catch this virus feel fine. Some will end up with a fever, rash, aches and pains and red eyes (conjuntivitis), or rarely, a serious nerve disorder called <a href="http://www.cdc.gov/zika/about/gbs-qa.html">Guillain-Barre</a>. But in pregnancy there can be very serious consequences to the baby. As of July 28, the World Health Organization reports that nearly <a href="http://apps.who.int/iris/bitstream/10665/246261/1/zikasitrep28Jul2016-eng.pdf?ua=1">2,000 babies are affected</a> with <a href="http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html">microcephaly</a> or central nervous system malformations associated with Zika worldwide.</p>
<p>I teach and practice obstetrics and gynecology at the University of Miami Hospital and Jackson Memorial Hospital, and I treat pregnant women who have been infected with Zika: so far over a dozen women. We began preparing to care for infected women in January. Now, it is part of the daily care we provide. And with first known cases of local mosquito-borne transmission <a href="http://www.nytimes.com/2016/07/30/health/zika-virus-florida-case.html">in the continental U.S.</a> reported in Wynwood, a neighborhood in Miami, the risk has become even more real.</p>
<p>How am I, and other doctors who care for pregnant women, dealing with this new disease? </p>
<h2>Confirming the diagnosis</h2>
<p>When I talk to patients these days, I ask them where they or family members have traveled recently. These are questions OB-GYNs across the country <a href="http://www.cdc.gov/mmwr/volumes/65/wr/mm6529e1.htm?s_cid=mm6529e1_e">may ask pregnant patients</a>. And since I practice in Miami, I might also ask patients if they have been in Wynwood, the neighborhood where local mosquito transmission has occurred. Since Zika is primarily spread by mosquitoes, I also talk with patients about avoiding mosquito bites and using bug repellent. Sexual transmission is also possible, and we talk about that, too.</p>
<p>The patients I worry about the most now are those who live or work in Wynwood and those who’ve traveled to countries where Zika is more widespread, or those who show the symptoms of Zika infection. We are being vigilant for evidence of spread to other parts of the Miami area.</p>
<p>If I am worried that a pregnant patient has been infected with Zika, I order tests to confirm the diagnosis. The state of Florida has announced that starting next week there will be free Zika testing for all pregnant women through the Department of Health. </p>
<p>If a Zika infection is confirmed, we then have to talk about the risks that she is willing to accept in her pregnancy. If a patient infected with Zika is in her first or second trimester, then we can talk about staying pregnant or having an abortion.</p>
<p>While we think that the first trimester is the time of greatest risk, we still don’t know if there is ever a safe point in pregnancy. So how much risk is she willing to accept? What would it mean to have a sick baby in her family? How would she get support no matter what options she chooses? Those answers will be different for everyone.</p>
<p>And these conversations are difficult, because there is still so much we don’t know about Zika.</p>
<p>For instance, we don’t know how many pregnant women who are infected with Zika will have babies with brain problems - there is no perfect percentage I can give her so she can weigh her options. </p>
<p>One study from Brazil found that of the women who were pregnant, had symptoms of Zika and had blood tests confirming infection, a startling <a href="http://dx.doi.org/10.1056/NEJMoa1602412">29 percent of the pregnancies</a> had some sort of issue, such as microcephaly or abnormal brain structure, for instance. But other computer modeling studies have put the risk for the general population of pregnant women who are infected in the first trimester at about <a href="http://dx.doi.org/10.1016/S0140-6736(16)00651-6">1 percent</a>. It’s these wide ranges in outcomes that makes counseling patients so difficult.</p>
<p>And that’s not the only unknown about Zika. </p>
<p>How does the virus get into the fetus? Researchers <a href="http://dx.doi.org/10.1016/j.chom.2016.07.002">are still figuring that out</a>. In which trimester does infection pose the highest risk? As with other infections in pregnancy, it seems that the <a href="http://dx.doi.org/10.1016/j.epidem.2016.03.001">first trimester is the most at risk</a>, but there are still plenty of unknowns. And do complications for the fetus vary by time of infection? It is going to take time to understand all of the risks.</p>
<p>To answer these questions, countries are creating registries of pregnant women with Zika to gather data about what happens to their pregnancies and the babies after birth. Departments of health in each state keep anonymized data on all pregnant women with Zika. This data gets fed into the CDC’s surveillance system, <a href="http://www.cdc.gov/zika/hc-providers/registry.html">the U.S. Zika Pregnancy Registry</a>.</p>
<p>As of July 28, the CDC was monitoring over <a href="http://www.cdc.gov/zika/geo/pregwomen-uscases.html">900 pregnant women</a> in the United States and U.S. territories with laboratory evidence of Zika infection based on blood testing. Researchers want to know if these babies have the same mental development and meet the same milestones as other infants, or if they have eye or ear problems that cannot be seen on ultrasound or immediately after birth. The CDC also reports <a href="http://www.cdc.gov/zika/geo/pregnancy-outcomes.html">15 babies with birth defects</a> from pregnancies with laboratory evidence of Zika infection and six pregnancy losses in the United States and District of Columbia, as of July 28.</p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=385&fit=crop&dpr=1 600w, https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=385&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=385&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=483&fit=crop&dpr=1 754w, https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=483&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/133168/original/image-20160804-481-vi82qo.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=483&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Ultrasounds are helpful, but can’t detect everything.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-395886538/stock-photo-medical-images-collage-of-ultrasound-during-woman-pregnancy-showing-fetus-in-third-month.html?src=OSK7IPwaaTzXRkJ2QprP6w-1-6">Ultrasound image via www.shutterstock.com.</a></span>
</figcaption>
</figure>
<h2>Planning for birth</h2>
<p>If a woman is in her third trimester and has been infected with Zika, at each visit we focus on planning for birth, monitoring the baby by ultrasound and reviewing the latest research together. </p>
<p>Since this is such a fast-moving and public epidemic, we are sharing the research with our patients to keep them involved and help them understand why it is so important to collect as much information as possible. </p>
<p>We might also plan for monthly ultrasounds. It is possible that a baby that looks normal on one ultrasound may show problems on a later ultrasound. Some problems can develop over time and become obvious later. However, ultrasounds can’t detect every problem, and microcephaly isn’t the only problem Zika can cause. So, we plan her delivery at a hospital with pediatricians who know about Zika and can be prepared to care for the newborn, and look at the baby’s eyes and ears and in some cases do brain imaging tests after birth. </p>
<p>Even with planning, there are still many questions we can’t answer for our patients. For instance, if a baby is born with microcephaly, we don’t know the exact issues that the baby might have. This means the mother won’t know right away if her child will lead a normal life or will always need medical care. </p>
<h2>A dose of humility</h2>
<p>Physicians like me are learning about Zika along with our patients. This takes a dose of humility on our part and an understanding from our patients that we learn something new every single day. </p>
<p>With daily news and internet updates, patients are able to stay just as up-to-date as the doctors. I will have patients print out a news article or a research finding and bring it to their appointment, highlighted and with questions in the margins.</p>
<p>But this barrage of media can also lead to confusion and concern when the information is constantly changing. For this reason, it is so important to have open lines of communication with our patients, and be honest about the uncertainties.</p><img src="https://counter.theconversation.com/content/62463/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Christine Curry does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Physicians like me are learning about Zika along with our patients. This takes a dose of humility on our part and an understanding from our patients that we learn something new every single day.Christine Curry, Assistant Professor of Obstetrics and Gynecology, University of MiamiLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/617762016-08-01T03:07:18Z2016-08-01T03:07:18ZIn Zika, echoes of US rubella outbreak of 1964-65<figure><img src="https://images.theconversation.com/files/132268/original/image-20160727-21564-16ebip6.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A display used to educate the public on rubella vaccination and the mother-to-fetus transmission of this virus.</span> <span class="attribution"><a class="source" href="https://phil.cdc.gov/phil/details.asp">Centers for Disease Control and Prevention via Public Health Image Library</a></span></figcaption></figure><p>Just over 50 years ago, a highly contagious but seemingly harmless virus swept through the United States, infecting as many as <a href="http://www.cdc.gov/vaccines/pubs/pinkbook/rubella.html#congenital">12.5 million people</a>. In both adults and children, the virus presented as a mild illness, but caused birth defects in some babies born to women who were infected while pregnant.</p>
<p>Does this sound familiar? Though separated by time and place, there are surprising similarities in the social issues raised by the rubella outbreak of 1964-65 and the recent Zika outbreak in South America. </p>
<p>Both viruses can cause birth defects, a fact that ties them to social issues surrounding pregnancy, women’s health and the politics of abortion. </p>
<p>The rubella epidemic, with an estimated <a href="http://aje.oxfordjournals.org/content/92/3/162.full.pdf+html">20,000 affected newborns</a>, changed medical and public consciousness about the virus. Some have recently argued that it even <a href="http://news.nationalgeographic.com/2016/02/160205-zika-virus-rubella-abortion-brazil-birth-control-womens-health-history/">changed ideas about abortion</a>. </p>
<p>As a sociologist who studies medicine and science, I am interested in understanding the narratives we develop about disease. I examined the rubella outbreak in my 2008 book, <a href="https://books.google.ca/books/about/The_Vaccine_Narrative.html?id=9fqdGAAACAAJ&redir_esc=y&hl=en">“The Vaccine Narrative,”</a> and how perceptions of the disease interacted with stories about vaccination. </p>
<p>Unlike other vaccines, the rubella vaccine conferred no direct benefits to recipients. Instead, it promised to prevent possible future birth defects and to reduce rubella-related abortions; for rubella vaccine, the health of the woman mattered almost entirely in terms of her status as a potential mother.</p>
<h2>The rubella outbreak of 1964-65 – and access to abortion</h2>
<p>In the spring of 1964, doctors in North America confirmed that the <a href="http://www.cdc.gov/vaccines/pubs/surv-manual/chpt15-crs.html">deafness and blinding cataracts</a> they found in massive numbers of children had been caused by rubella. </p>
<p>Before the this outbreak, rubella was obscure, but not unknown. Unlike Zika, which is primarily transmitted by mosquitoes, rubella can spread through casual contact. In fact it was was endemic in Western populations, with <a href="http://archpedi.jamanetwork.com/article.aspx?articleid=503198">more than 80 percent of the population exposed to the disease</a> before rubella vaccination was introduced in 1969. </p>
<p>Health professionals had known <a href="https://books.google.ca/books?id=yiUrAAAAYAAJ&pg=RA1-PA168&lpg=RA1-PA168&dq=Congenital+Defects+in+Infants+Following+Infectious+Diseases+during+Pregnancy&source=bl&ots=3AddxjRWU4&sig=Lba4ti_sazcTTTibpZdBfWnIL18&hl=en&sa=X&ved=0ahUKEwiUq6qrp_jNAhXMHx4KHfUSCuIQ6AEINzAE#v=onepage&q&f=false">since 1943</a> that rubella sometimes caused birth defects, called Congenital Rubella Syndrome (CRS). In another parallel with Zika, people infected with rubella are often asymptomatic. Even when people do have symptoms, they are fairly mild.</p>
<p>Researchers isolated the rubella virus <a href="http://archpedi.jamanetwork.com/article.aspx?articleid=503144">only in 1962</a>, and there was <a href="http://query.nytimes.com/gst/abstract.html?res=9E06E1DF1F30E033A25752C2A9629C946491D6CF&legacy=true">no blood test until 1965</a>. </p>
<p>Before the blood test was available, a doctor’s clinical diagnosis of rubella could access a <a href="http://scholarlycommons.law.case.edu/cgi/viewcontent.cgi?article=4360&context=caselrev">medical exception</a> to the ban on abortions that existed in most states, called a “therapeutic abortion.” This exception considered the physical and mental health of the woman as medically relevant for whether an abortion could happen. Decisions about rubella-related abortion happened in the context of the doctor-patient relationship.</p>
<p>Because rubella was so common, and because an infected person could be asymptomatic, some physicians had argued as early as the 1950s that <a href="http://scholarworks.umb.edu/cgi/viewcontent.cgi?article=1205&context=nejpp">rubella served as a convenient way to circumvent the laws restricting abortion</a>. </p>
<p>In fact, prior to Roe v. Wade in 1973, a rubella diagnosis was <a href="http://scholarlycommons.law.case.edu/cgi/viewcontent.cgi?article=4360&context=caselrev">one of the main ways</a> for women to obtain safe abortions, performed by qualified doctors, without either physician or patient subject to prosecution. </p>
<p>Even when abortion was illegal throughout the U.S., the law recognized the primacy of the doctor-patient relationship, deferring to <a href="https://books.google.ca/books?id=FK4pBXGvQzoC&printsec=frontcover&source=gbs_ge_summary_r&cad=0#v=onepage&q&f=false">the authority of American medicine</a> and the privacy of women’s medical decisions. Roe v. Wade, which legalized abortion in the U.S., is built on the right to privacy.</p>
<h2>The development of the vaccine</h2>
<p>In the aftermath of the 1964-65 epidemic, epidemiologists predicted that another rubella epidemic – along with thousands of babies born deaf or blind – would begin in 1970. This spurred the effort to develop a rubella vaccine to prevent birth defects. However, another goal was to reduce what vaccine researchers at the time often referred to as “fetal wastage,” a euphemism for abortion. In fact, many in the medical profession at that time appeared to view women’s health as secondary to the importance of pregnancies brought to term with healthy babies and avoiding “<a href="http://scholarworks.umb.edu/cgi/viewcontent.cgi?article=1205&context=nejpp">unnecessary abortions</a>.”</p>
<p>A preventive vaccine became available in 1969, and versions are currently in wide use; it is the “R” in the trivalent childhood MMR vaccine. Today, the Centers for Disease Control and Prevention reports that rubella, once endemic, has been <a href="http://www.cdc.gov/vaccines/pubs/surv-manual/chpt15-crs.html">all but eliminated in the U.S.</a>, and rubella-related birth defects with it.</p>
<p>In 1970 when the predicted epidemic failed to materialize, credit went to mass vaccination <a href="http://www.nejm.org/doi/full/10.1056/NEJM197602052940604">(despite some uncertainties, as the population had already been largely immune)</a>. This meant that the underlying social issues that rubella had raised – the role of medicine in regulating access to abortion; whether the physical and mental effects of birth defects <em>on women</em> justified an abortion – would be deferred. </p>
<p>Still, the realization that birth defects were an important consideration in the politics of abortion <a href="http://digitalcommons.law.yale.edu/cgi/viewcontent.cgi?article=2089&context=fss_papers">made therapeutic abortion more available</a> between 1965 and the 1973 Roe v. Wade decision, as blood tests replaced clinical diagnoses, though the rate of rubella-related birth defects remained unknown. </p>
<h2>Parallels with Zika</h2>
<p>The rubella outbreak happened in a context where abortion was illegal – save for medical exceptions. In much of South America, where Zika’s effect has been greatest, access to <a href="https://theconversation.com/zika-and-abortion-will-the-virus-prompt-latin-america-to-rethink-abortion-and-birth-control-55200">safe abortion is severely restricted</a>. </p>
<p>As Zika has spread in Latin America, researchers have found that <a href="http://news.utexas.edu/2016/06/22/abortion-demand-increases-with-zika-virus-advisories">abortion requests have increased</a>, setting the stage for a replay of the history of rubella. As with rubella, in areas where Zika has become prevalent and abortion is almost always illegal, <a href="https://www.theguardian.com/global-development/2016/jul/19/zika-emergency-pushes-women-to-challenge-brazil-abortion-law">women have begun to demand access to therapeutic abortions</a>. </p>
<p>Perhaps, therefore, medical and public health measures will stop Zika, as they did rubella for North Americans. </p>
<p>But developing a vaccine for Zika or halting its spread will not address the social issues that the virus has raised: women’s right to control their own bodies, concerns about “fetal wastage” and the relative importance of healthy, live births versus women’s mental and physical health.</p><img src="https://counter.theconversation.com/content/61776/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Jacob Heller does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Though separated by time and place, there are surprising similarities in the the social issues raised by the rubella outbreak of 1964-65 and the recent Zika outbreak in South America.Jacob Heller, Associate Professor, SUNY Old WestburyLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/506732016-02-08T10:21:48Z2016-02-08T10:21:48ZIs Primodos ‘the forgotten thalidomide’?<figure><img src="https://images.theconversation.com/files/106311/original/image-20151216-30063-gmanv3.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Human embryo at 5 weeks</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/cat.mhtml?autocomplete_id=&language=en&lang=en&search_source=&safesearch=1&version=llv1&searchterm=embryo&media_type=images&media_type2=images&searchtermx=&photographer_name=&people_gender=&people_age=&people_ethnicity=&people_number=&color=&page=1&inline=234278743">www.shutterstock.com</a></span></figcaption></figure><p>Primodos, an oral hormonal pregnancy test, was introduced to the UK in the late 1950s. A decade later, claims were made by some researchers that Primodos was linked to birth defects. </p>
<p>Isabel Gal, a paediatrician at Queen Mary’s Hospital for Children in Surrey, England, was the first to publish a paper (1967) suggesting a link between Primodos and <a href="http://www.nature.com/nature/journal/v216/n5110/abs/216083a0.html">birth defects</a>. Several other studies subsequently suggested links between hormonal pregnancy tests (HPTs) and birth defects including to the <a href="http://www.sciencedirect.com/science/article/pii/0002937886903522">limbs</a>, <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1631672/">face</a>, neural <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1675979/">tube</a> and <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1606075/">heart</a>. Other studies found no association.</p>
<p>Primodos continued to be used in the UK until 1978. The drug was voluntarily withdrawn from the market, <a href="https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/424821/Primodos_public_call_for_evidence_-_April_2015.pdf">for commercial reasons,</a> following the arrival of urine-based pregnancy tests. </p>
<p>Schering, the German company which made Primodos, and Bayer, which now owns Schering, continues to deny any link between deformities in children and the drug.</p>
<h2>How Primodos works</h2>
<p>Primodos consists of two <a href="https://desdaughter.files.wordpress.com/2015/02/primodos.jpg?w=600&h=316">active ingredients</a>: norethisterone, an artificial progesterone, and ethinyl estradiol, an artificial oestrogen.</p>
<p>If a woman wanted to find out if she was pregnant, she would take the Primodos pills. If she menstruated, it indicated that she wasn’t pregnant. And if she didn’t menstruate, it confirmed that she was pregnant.</p>
<p>Although Primodos is no longer available, the drug’s main ingredient, norethisterone, is still used – but at much lower doses – to treat a range of health problems, including abnormal bleeding from the uterus, endometriosis, and amenorrhoea (absence of menstruation). It can also be used as an emergency contraceptive (the “morning-after pill”) in combination with other hormones. </p>
<h2>Inconclusive results</h2>
<p>Not all studies have found <a href="http://www.sciencedirect.com/science/article/pii/S0140673673931541">statistically significant associations</a> between <a href="http://onlinelibrary.wiley.com/doi/10.1002/tera.1420270109/abstract">Primodos and birth defects</a>. A recent <a href="http://www.sciencedirect.com/science/article/pii/S0890623813003882">study</a> of patient data found an association between the use of HPTs and neural tube problems, and a very strong association with a rare bladder abnormality. But the authors point out that this type of rare defect is not seen in children born to mothers who used other types of hormone drugs, including oral contraceptive pills that contain progesterone, <a href="http://www.ncbi.nlm.nih.gov/pubmed/2143279">during pregnancy</a>. </p>
<figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/106663/original/image-20151218-27875-13sz52v.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Studies have to rely on old patient records.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/downloading_tips.mhtml?code=&id=336471029&size=medium&image_format=jpg&method=download&super_url=http%3A%2F%2Fdownload.shutterstock.com%2Fgatekeeper%2FW3siZSI6MTQ1MDQ4MDU0MywiYyI6Il9waG90b19zZXNzaW9uX2lkIiwiZGMiOiJpZGxfMzM2NDcxMDI5IiwiayI6InBob3RvLzMzNjQ3MTAyOS9tZWRpdW0uanBnIiwibSI6IjEiLCJkIjoic2h1dHRlcnN0b2NrLW1lZGlhIn0sImxocVllS3ZzV1VabDVpaWRPVlVDVDZ4blRiTSJd%2Fshutterstock_336471029.jpg&racksite_id=ny&chosen_subscription=1&license=standard&src=2xyeQNS8Ur7uqYTDKEepig-1-1">www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>These types of studies use data collected a few decades ago, when the methods for collecting data weren’t perhaps as stringent as they are today. They also rely on the memory of mothers as to when in their pregnancy they took the drug. </p>
<p>Another problem is that the HPT test simply determined whether a woman was pregnant or not. It couldn’t determine how long she had been pregnant for, so knowing the precise time of exposure is difficult. </p>
<p>Also, the somewhat limited experimental evidence from animal studies exposed to Primodos or exposed to its active components are also inconclusive. Some data shows <a href="http://www.ncbi.nlm.nih.gov/pubmed/6676180">negative effects</a> (including <a href="http://www.ncbi.nlm.nih.gov/pubmed/11502156">death</a>) and other studies indicate little or <a href="http://www.ncbi.nlm.nih.gov/pubmed/11502156">no direct effect</a> on embryo development. </p>
<h2>Making the case</h2>
<p>The point in pregnancy when HPTs were used varied depending on when the woman became aware that she might be pregnant. If we assume four to seven weeks after conception, then this is a period of incredibly rapid growth and organ formation in the embryo. Anything altering this process could result in birth defects. </p>
<p>The severity and type of defect could be related to the timing of exposure through disrupting organ formation, as demonstrated for <a href="https://theconversation.com/thalidomide-the-drug-with-a-dark-side-but-an-enigmatic-future-50330">thalidomide</a>. However, there’s an approximate 3% rate of naturally occurring birth defects in the world. So it’s possible that the damage in the people exposed to Primodos could be due to other factors. </p>
<p>However, the effect of <a href="http://www.ncbi.nlm.nih.gov/pubmed/11502156">synthetic hormones on embryonic development</a> is not well studied and their effects can depend on the timing of exposure as well as the dose. </p>
<p>Since Primodos was taken off the market not much published research has been carried out on animals to understand what the drug may or may not do to the embryo. And many of the studies that were carried out were conducted decades ago when analytical methods and tools were not as advanced as they are today.</p>
<p>Today, norethisterone is used to control a variety of hormonal conditions, but it is not recommended for use in pregnancy. There is also speculation that it may have been used to <a href="http://www.sciencedirect.com/science/article/pii/S0890623813003882">induce abortions</a>. All of these things taken together mean questions about the safety of Primodos persist. </p>
<h2>At last, a formal inquiry</h2>
<p>Today, the debate about whether or not Primodos was responsible for birth defects still rages. And the demands for an <a href="http://www.telegraph.co.uk/news/health/10819186/Is-this-the-forgotten-thalidomide.html">apology and compensation</a> are getting louder. </p>
<p>Hopefully, answers will soon be forthcoming. Early in 2015, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) <a href="http://www.telegraph.co.uk/technology/2016/02/01/lord-lawson-google-tax-row-shows-that-corporation-tax-has-had-it/">issued a call for evidence</a> for any information considered relevant to a possible association between the use of oral HPTs and adverse effects on the pregnancy or subsequent birth defects in the child. The evidence will be reviewed by a group of independent experts. An MHRA appointed inquiry panel will report its findings this year. It will hopefully determine, once and for all, whether Primodos deserves to be called “the forgotten thalidomide”.</p><img src="https://counter.theconversation.com/content/50673/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Neil Vargesson receives or has received funding for his research from the Royal Society, Wellcome Trust, Imperial College London, University of Aberdeen. I have been contacted by and spoken with alleged Primodos affected people and discussed the scientific evidence for and against its actions.</span></em></p>The MHRA has opened an inquiry on the once popular pregnancy test pills. Did they really cause birth defects in children born in the 1970s?Neil Vargesson, Senior Lecturer in Developmental Biology, University of AberdeenLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/534252016-01-27T10:48:16Z2016-01-27T10:48:16ZExplainer: where did Zika virus come from and why is it a problem in Brazil?<p>From October 2015 to January 2016, there were <a href="http://www.cdc.gov/mmwr/volumes/65/wr/mm6503e2er.htm">almost 4,000 cases</a> of babies born with <a href="http://www.cdc.gov/ncbddd/birthdefects/microcephaly.html">microcephaly</a> in Brazil. Before then, there were <a href="http://www.bbc.com/news/world-latin-america-35368401">just 150 cases</a> per year.</p>
<p>The suspected culprit is a mosquito-borne virus called Zika. Officials in <a href="http://www.bbc.com/news/world-latin-america-35388842">Colombia, Ecuador, El Salvador and Jamaica</a> have suggested that women delay becoming pregnant. And the Centers for Disease Control and Prevention has advised <a href="http://www.cdc.gov/mmwr/volumes/65/wr/mm6502e1.htm">pregnant women to postpone travel</a> to countries where Zika is active. </p>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=359&fit=crop&dpr=1 600w, https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=359&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=359&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=451&fit=crop&dpr=1 754w, https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=451&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/109095/original/image-20160124-441-1j32g9m.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=451&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Countries and territories with active Zika virus transmission.</span>
<span class="attribution"><a class="source" href="http://www.cdc.gov/zika/geo/index.html">Centers for Disease Control and Prevention</a></span>
</figcaption>
</figure>
<p>The World Health Organization <a href="http://www.paho.org/hq/index.php?option=com_content&view=article&id=11605&Itemid=0&lang=en">says</a> it is likely that the virus will <a href="http://www.cnn.com/2016/01/25/health/who-zika-virus-americas/">spread</a>, as the mosquitoes that carry the virus are found in almost every country in the Americas.</p>
<p>Zika virus was discovered almost 70 years ago, but wasn’t associated with outbreaks until 2007. So how did this formerly obscure virus wind up causing so much trouble in Brazil and other nations in South America? </p>
<h2>Where did Zika come from?</h2>
<p>Zika virus <a href="http://www.sciencedirect.com/science/article/pii/0035920352900424">was first detected</a> in Zika Forest in Uganda in 1947 in a rhesus monkey, and again in 1948 in the mosquito <em>Aedes africanus</em>, which is the forest relative of <em>Aedes aegypti</em>. <em>Aedes aegypti</em> and <em>Aedes albopictus</em> can both spread Zika. <a href="http://wwwnc.cdc.gov/eid/article/17/5/10-1939_article">Sexual transmission</a> between people has also been reported. </p>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=436&fit=crop&dpr=1 600w, https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=436&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=436&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=548&fit=crop&dpr=1 754w, https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=548&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/109251/original/image-20160126-19651-1eko782.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=548&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Aedes aegypti. Emil August Goeldi (1859-1917).</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/5/50/Aedes_aegypti_E-A-Goeldi_1905.jpg">via Wikimedia Commons.</a></span>
</figcaption>
</figure>
<p>Zika has a lot in common with dengue and chikungunya, another emergent virus. All three originated from West and central Africa and Southeast Asia, but have recently expanded their range to include much of the tropics and subtropics globally. And they are all spread by the same species of mosquitoes.</p>
<p>Until 2007 very few cases of Zika in humans were reported. Then an outbreak occurred on Yap Island of Micronesia, infecting approximately <a href="http://www.ncbi.nlm.nih.gov/pubmed/19516034">75 percent of the population</a>. Six years later, the <a href="http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20929">virus appeared in French Polynesia</a>, along with outbreaks of dengue and chikungunya viruses. </p>
<h2>How did Zika get to the Americas?</h2>
<p>Genetic analysis of the virus revealed that the strain in Brazil was most similar to one that had been circulating <a href="http://www.sciencedirect.com/science/article/pii/S1477893915002057">in the Pacific</a>.</p>
<p>Brazil had been on alert for an introduction of a new virus following the 2014 FIFA World Cup, because the event concentrated people from all over the world. However, no Pacific island nation with Zika transmission had competed at this event, making it less likely to be the source. </p>
<p>There is another theory that Zika virus may have been introduced following an international canoe event held in Rio de Janeiro in August of 2014, which hosted competitors from various Pacific islands. </p>
<p>Another possible route of introduction was overland from Chile, since that country had detected a case of Zika disease in a returning traveler from Easter Island. </p>
<h2>Most people with Zika don’t know they have it</h2>
<p>According to research after the Yap Island outbreak, the vast majority of people (<a href="http://www.nejm.org/doi/full/10.1056/NEJMoa0805715#t=articleTop">80 percent</a>) infected with Zika virus will never know it – they do not develop any symptoms at all. A minority who do become ill tend to have fever, rash, joint pains, red eyes, headache and muscle pain lasting up to a week. And no deaths had been reported. </p>
<p>However, in the aftermath of the Polynesian outbreak it became evident that Zika was associated with <a href="http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm">Guillain-Barré syndrome</a>, a life-threatening <a href="http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20720">neurological paralyzing condition</a>. </p>
<p>In early 2015, Brazilian public health officials sounded the alert that Zika virus had been detected in <a href="http://www.promedmail.org/">patients with fevers</a> in northeast Brazil. Then there was a similar uptick in the number of cases of Guillain-Barré in <a href="http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=32879&lang=en">Brazil and El Salvador</a>. And in late 2015 in Brazil, cases of microcephaly started to emerge.</p>
<p>At present, the link between Zika virus infection and microcephaly isn’t confirmed, but the virus has been found in <a href="http://onlinelibrary.wiley.com/doi/10.1002/uog.15831/full">amniotic fluid</a> and <a href="http://www.paho.org/hq/index.php?option=com_docman&task=doc_view&Itemid=270&gid=32879&lang=en">brain tissue</a> of a handful of cases. </p>
<p>How Zika might affect the brain is unclear, but a study from the 1970s revealed that the virus could replicate in neurons of young mice, <a href="http://link.springer.com/article/10.1007%2FBF01249709">causing neuronal destruction</a>. Recent genetic analyses suggest that strains of Zika virus may <a href="http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002636">be undergoing mutations</a>, possibly accounting for <a href="http://biorxiv.org/content/biorxiv/early/2015/11/25/032839.full.pdf">changes in virulence</a> and its ability to infect mosquitoes or hosts.</p>
<h2>The Swiss cheese model for system failure</h2>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=404&fit=crop&dpr=1 600w, https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=404&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=404&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=507&fit=crop&dpr=1 754w, https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=507&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/109062/original/image-20160122-403-8l6eh.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=507&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The Swiss cheese model of accident causation.</span>
<span class="attribution"><a class="source" href="https://commons.wikimedia.org/wiki/File%3ASwiss_cheese_model_of_accident_causation.png">Davidmack via Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>One way to understand how Zika spread is to use something called the <a href="https://en.wikipedia.org/wiki/Swiss_cheese_model">Swiss cheese model</a>. Imagine a stack of Swiss cheese slices. The holes in each slice are a weakness, and throughout the stack, these holes aren’t the same size or the same shape. Problems arise when the holes align. </p>
<p>With any disease outbreak, multiple factors are at play, and each may be necessary but not sufficient on its own to cause it. Applying this model to our mosquito-borne mystery makes it easier to see how many different factors, or layers, coincided to create the current Zika outbreak.</p>
<h2>A hole through the layers</h2>
<p>The first layer is a fertile environment for mosquitoes. That’s something my colleagues and I have studied in the Amazon rain forest. We found that deforestation followed by agriculture and regrowth of low-lying vegetation provided a much <a href="http://www.ncbi.nlm.nih.gov/pubmed/19556558">more suitable environment for the malaria mosquito carrier</a> than pristine forest. </p>
<p>Increasing urbanization and poverty create a fertile environment for the mosquitoes that spread dengue by creating <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317603/">ample breeding sites</a>. In addition, climate change may raise the <a href="http://www.ncbi.nlm.nih.gov/pubmed/24893017">temperature and/or humidity</a> in areas that previously have been below the threshold required for the mosquitoes to thrive. </p>
<p>The second layer is the introduction of the mosquito vector. <em>Aedes aegypti</em> and <em>Aedes albopictus</em> have expanded their geographic range in the past few decades. Urbanization, changing climate, air travel and transportation, and waxing and waning control efforts that are at the mercy of economic and <a href="http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0060874">political factors</a> have led to these mosquitoes spreading to new areas and coming back in areas where they had previously been eradicated.</p>
<p>For instance, in Latin America, continental mosquito eradication campaigns in the 1950s and 1960s led by the Pan American Health Organization conducted to battle yellow fever dramatically <a href="http://online.liebertpub.com/doi/full/10.1089/vbz.2011.0696">shrunk the range of <em>Aedes aegypti</em></a>. Following this success, however, interest in maintaining these mosquito control programs waned, and between 1980 and the 2000s the <a href="http://online.liebertpub.com/doi/full/10.1089/vbz.2011.0696">mosquito had made a full comeback</a>.</p>
<p>The third layer, susceptible hosts, is critical as well. For instance, chikungunya virus has a tendency to infect very large portions of a population when it first invades an area. But once it blows through a small island, <a href="http://www.paho.org/hq/index.php?option=com_topics&view=readall&cid=5927&Itemid=40931&lang=en">the virus may vanish</a> because there are very few susceptible hosts remaining. </p>
<p>Since Zika is new to the Americas, there is <a href="http://www.paho.org/hq/index.php?option=com_content&view=article&id=11605&Itemid=0&lang=en">a large population of susceptible hosts</a> who haven’t previously been exposed. In a large country, Brazil for instance, the virus can continue circulating without running out of susceptible hosts for a long time.</p>
<p>The fourth layer is the introduction of the virus. It can be very difficult to pinpoint exactly when a virus is introduced in a particular setting. However, studies have associated increasing air travel with the spread of certain viruses such <a href="http://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0002769">as dengue</a>. </p>
<p>When these multiple factors are in alignment, it creates the conditions needed for an outbreak to start.</p>
<h2>Putting the layers together</h2>
<p>My colleagues and I are studying the role of these “layers” as they relate to the outbreak of yet another mosquito-borne virus, <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa1212628">Madariaga virus</a> (formerly known as Central/South American eastern equine encephalitis virus), which has caused numerous cases of encephalitis in the Darien jungle region of Panama. </p>
<p>There, we are examining the association between deforestation, mosquito vector factors, and the susceptibility of migrants compared to indigenous people in the affected area.</p>
<p>In our highly interconnected world which is being subjected to massive ecological change, we can expect ongoing outbreaks of viruses originating in far-flung regions with names we can barely pronounce – yet.</p><img src="https://counter.theconversation.com/content/53425/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Amy Y. Vittor has received funding from the Institute for Social and Environmental Transition International, NIH Fogarty International Center, NIH NIAID Global Health training grant, New York Community Trust Fund, and the University of Florida. </span></em></p>Zika was discovered almost 70 years ago, but wasn’t associated with outbreaks until 2007. So how did this formerly obscure virus wind up causing so much trouble in Brazil?Amy Y. Vittor, Assistant Professor of Medicine, University of FloridaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/470922015-12-07T19:18:06Z2015-12-07T19:18:06ZWhy did thalidomide’s makers ignore warnings about their drug?<p>In the 1950s, German company Chemie Grünenthal developed a “wonder drug” sleeping pill that it marketed around the world as safe for everyone, including expectant mothers. This mild sedative was also found to mitigate the effects of morning sickness, resulting in increased use by the population that turned out to be most vulnerable to its risks.</p>
<p>Shortly after the drug came on the market, reports of infant deaths and startling birth malformations were made worldwide. Grünenthal rigorously denied thalidomide’s association with these adverse effects for a long time.</p>
<p>It took until 1962 for the pill to be banned in most countries and decades of extensive legal battles ensued. More than half a century later, the <a href="http://www.nytimes.com/2013/09/23/booming/the-death-and-afterlife-of-thalidomide.html?_r=3">thalidomide crisis</a> is continuing to shed insights on pharmaceutical ethics, scientific integrity and professional wrongdoing.</p>
<h2>Scientists are people too</h2>
<p>Fifty-six years after the first known victim of thalidomide was born to a Grünenthal employee, the company’s chief executive officer Harold Stock issued an <a href="http://www.nytimes.com/2012/09/02/world/europe/grunenthal-group-apologizes-to-thalidomide-victims.html">apology</a>, which did little to appease victims.</p>
<p>Stock said Grünenthal researchers had conducted all possible tests on thalidomide based on latest science. This is directly contradicted by the work of Dr Frances Kelsey, who in 1960, despite <a href="https://helix.northwestern.edu/article/thalidomide-tragedy-lessons-drug-safety-and-regulation">pressure</a> from supervisors at the Food and Drug Administration (FDA), refused thalidomide’s application for sale in the United States.</p>
<p>She <a href="http://www.theglobeandmail.com/life/health-and-fitness/health/frances-oldham-kelsey-averted-a-thalidomide-tragedy-because-she-wouldnt-be-rushed/article25976972/">noted important gaps</a> in the data used to support the claim that thalidomide was safe for pregnant women. Kelsey’s training in pharmacology helped her notice the lack of evidence. So if Kelsey saw the obvious shortfalls in thalidomide’s safety profile, then what did Grünenthal scientists know, or ought to have known?</p>
<p>Conventional wisdom suggests that scientists do science; that they are specially trained professionals who conduct research in a way that systematically explores the unknown, minimises bias, and reaches beyond assumptions using latest information and technology.</p>
<p>Whether they work in universities or pharmaceutical companies, scientists are supposed to be governed by scientific principles before anything else. Kelsey demonstrated this principle when she resisted pressure from above. But given her heroine status, this may be the exception and not the norm.</p>
<p>For pragmatic scientists who depend on their employment or research funding, these principles could be compromising. Relaxing them can be rationalised as normal or acceptable, with <a href="https://www.youtube.com/watch?v=JSV4VZ8gdUQ">hidden biases</a> taking root and impacting how they conduct research and subsequent results.</p>
<p>Subtle decisions (often perfectly legal) can distort medical research and corrupt scientific knowledge. With most of us believing we are “good people”, it follows that scientists may resist acknowledging their subtle shifts in approach and there are always reasons to explain it away. </p>
<p>Grünenthal’s alleged “omit then deny” strategy fits this perfectly. </p>
<p>By not conducting the tests Kelsey inquired about, Grünenthal could free itself from evidence that would limit its market for the drug. By claiming it was not normal practice to test for the effects of medications on developing fetuses, Grünenthal could argue against any obligation to conduct these tests.</p>
<p>Indeed, the claim that these tests were uncommon <a href="http://www.theguardian.com/society/2014/nov/14/-sp-thalidomide-pill-how-evaded-justice">formed one of the pillars</a> upholding Grünenthal’s denial of responsibility. </p>
<h2>Corporate culture and Nazi war crimes</h2>
<p>Some <a href="http://www.heraldsun.com.au/news/the-last-german-war-secret/story-e6frf7jo-1226082393923">have speculated</a> that Grünenthal’s culture was tainted because several World War II <a href="http://www.smh.com.au/entertainment/books/silent-shock-review-an-extraordinary-story-with-villains-and-brave-heroes-20150601-ghbvx5.html">Nazi war criminals</a> – including Otto Ambros, a scientist found guilty of mass murder at the Nuremberg trials – had been employed there. </p>
<p>But how much should we rely on this “bad apple” narrative when trying to make sense of the thalidomide crisis?</p>
<figure class="align-left ">
<img alt="" src="https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=806&fit=crop&dpr=1 600w, https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=806&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=806&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1013&fit=crop&dpr=1 754w, https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1013&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/102449/original/image-20151119-19367-1usi6k4.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1013&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Grünenthal employee Otto Ambros was found guilty of mass murder at the Nuremberg trials.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/6/60/Otto_Ambros.jpg">By US Army photographers/Wikimedia Commons</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>The reality is that many pharmaceutical companies have and continue to be <a href="http://www.nytimes.com/2012/07/03/business/glaxosmithkline-agrees-to-pay-3-billion-in-fraud-settlement.html?_r=0">fined, charged, and accused of unethical behaviour</a> related to production and marketing of their drugs.</p>
<p>The scientists who conduct research on these drugs and become tied up in unethical practices are less often like Nazi war criminals, and more often like us. They take pride in their work and have no intention to harm others. But they face pressures that lead to compromises with implications they may choose not to consider.</p>
<p>Complicating matters is the <a href="https://searchworks.stanford.edu/view/3944226">unique set of risks</a> faced by scientists who speak up for public safety against the wishes of their funders or superiors. In doing so, they risk their reputations, employment and future funding opportunities.</p>
<p>German paediatrician Dr Widukund Lenz was allegedly <a href="https://news.google.com/newspapers?nid=1350&dat=19680629&id=fyZPAAAAIBAJ&sjid=nAEEAAAAIBAJ&pg=7035,904347&hl=en">threatened with legal action</a> by Grünenthal after he suggested a possible link between thalidomide, while it was still being sold, and birth deformities.</p>
<p>Allegations have also been made that Grünenthal attempted to corrupt science by blocking medical publications. In one case, they were allegedly successful at convincing a medical journal to purposely delay publication of an article by neurologist Dr Horst Frenkel that <a href="https://books.google.ca/books?id=AVgAFk6u_CMC&pg=PA48&lpg=PA48&dq=Dr.+Horst+Frenkel&source=bl&ots=_zcbw3-Vz8&sig=UiHk16PdlfpFi11cRaWUQy_w3CU&hl=en&sa=X&ved=0CBwQ6AEwAGoVChMItb3g4M2HyQIVCUuICh1-Xw21#v=onepage&q=Dr.%20Horst%20Frenkel&f=false">demonstrated thalidomide’s negative side effects</a>. Again, the drug was still being sold at this time.</p>
<p>Attempting to corrupt the scientific process is not something unique to this particular pharmaceutical company. In fact, attacks on scientists and <a href="http://www.hup.harvard.edu/catalog.php?isbn=9780674047143">attempts to distort science</a> are a growing concern. </p>
<p>The <a href="http://link.springer.com/article/10.1007%2Fs11948-003-0017-x">story of Canadian scientist Nancy Olivieri</a> especially highlights the tremendous personal costs scientists face speaking up for public safety. The drug company partially funding Olivieri’s research (that planned to market the drug after trials) threatened her with legal action if she followed through on her ethical obligation to inform patients and the scientific community the drug she was testing on them was potentially toxic and could be ineffective.</p>
<p>But, like Kelsey, Olivieri went ahead despite “severe consequences”. She received the <a href="http://www.aaas.org/page/2009-award-scientific-freedom-and-responsibility-recipient">2009 AAAS Award for Scientific Freedom and Responsibility</a> for her “… determination that patient safety and research integrity come before institutional and commercial interests”.</p>
<h2>What now?</h2>
<p>More than half a century after the thalidomide crisis, we are still haunted by the opportunity for compromised science. </p>
<p>Just this year, doctors <a href="http://www.macleans.ca/society/health/what-you-dont-know-about-a-leading-morning-sickness-drug/">raised red flags on another popular drug for morning sickness</a> (called Diclectin in Canada and Diclegis in the United States) that is being prescribed in as many as 50% of live births in some countries. </p>
<p>Concerned experts claim the published results on Diclectin overstate its benefits, understate its risks, and ignore safer (and cheaper) vitamin alternatives. </p>
<p>Research integrity and the institutional structures that support scientific research are key to understanding and eliminating scientific compromises. Without this understanding, we can’t truly progress beyond the “Grünenthal science” that underscored the thalidomide tragedy.</p>
<p><em>Stay tuned for other instalments in the <a href="https://theconversation.com/au/topics/thalidomide">thalidomide series</a> this week.</em></p><img src="https://counter.theconversation.com/content/47092/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Garry Gray received funding from the Edmond J Safra Center for Ethics at Harvard University. </span></em></p>Thalidomide’s manufacturer, Chemie Grünenthal, marketed the drug as safe for pregnant women despite reports it was causing malformations in newborns. Why such blatant denial?Garry Gray, Assistant Professor, Sociology, University of VictoriaLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/509682015-12-06T19:21:06Z2015-12-06T19:21:06ZInfographic: a snapshot of the thalidomide tragedy<figure><img src="https://images.theconversation.com/files/106390/original/image-20151216-30110-o93026.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">.. </span> </figcaption></figure><figure class="align-center ">
<img alt="" src="https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=5116&fit=crop&dpr=1 600w, https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=5116&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=5116&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=6429&fit=crop&dpr=1 754w, https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=6429&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/104346/original/image-20151203-22473-cs1x6r.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=6429&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption"></span>
</figcaption>
</figure><img src="https://counter.theconversation.com/content/50968/count.gif" alt="The Conversation" width="1" height="1" />
Thalidomide was marketed as a safe, sleep-inducing drug, but when taken during pregnancy it could cause severe birth defects.Emil Jeyaratnam, Data + Interactives Editor, The ConversationSasha Petrova, Section Editor: EducationLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/509702015-12-06T19:18:32Z2015-12-06T19:18:32ZTimeline: key events in the history of thalidomide<p><em>The timeline below is best viewed on a full screen browser window. To navigate the timeline, click on the arrow on the right to move forward (and on the left to move back).</em></p>
<iframe src="https://cdn.knightlab.com/libs/timeline3/latest/embed/index.html?source=1IK0CeI2BNcxDV8dU04ea-4rtuPN1MS3rMZpWdzs5SvU&font=Default&lang=en&initial_zoom=2&height=1000" width="100%" height="1050" frameborder="0"></iframe><img src="https://counter.theconversation.com/content/50970/count.gif" alt="The Conversation" width="1" height="1" />
Documents reveal thalidomide’s manufacturer was warned about possible harms as early as 1956.Emil Jeyaratnam, Data + Interactives Editor, The ConversationSasha Petrova, Section Editor: EducationLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/491272015-10-21T03:37:14Z2015-10-21T03:37:14ZMedications pregnant women should take, avoid, and think about<figure><img src="https://images.theconversation.com/files/98953/original/image-20151020-23235-1fnh9xm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Some medications are harmful to take while pregnant, but for others it can be more harmful if you don't take them.</span> <span class="attribution"><span class="source">from www.shutterstock.com</span></span></figcaption></figure><p>In a <a href="http://www.nps.org.au/media-centre/media-releases/repository/Be-Medicinewise-Week-2015-Stop-and-think-about-medicines-during-pregnancy-and-breastfeeding">recent survey</a>, one-third of Australian women who were pregnant or had a child 11 years or younger said they had taken either a prescription or over-the-counter medicine during pregnancy.</p>
<p>Women take prescribed, over-the-counter, complementary and lifestyle medications for various reasons when planning or during their pregnancy. </p>
<p>Many women take micronutrient supplements before, during and after pregnancy to ensure they and their baby are receiving adequate vitamins and minerals. A common one is folic acid, <a href="http://www.health.gov.au/antenatal">which helps prevent</a> birth defects in the baby’s brain and spinal cord.</p>
<p>Many women also take medications for pregnancy-related conditions such as morning sickness. </p>
<p>Medication during pregnancy may also be necessary due to incidental illnesses such as coughs and colds, or to manage a pre-existing condition. </p>
<p>For women to be able to assess the risks and benefits of a medicine in pregnancy, they need to understand three key concepts.</p>
<p>First, all couples have a <a href="http://www.australianprescriber.com/magazine/37/2/38/40">3-5% risk</a> of having a baby with a major birth defect. This is known as a “background risk” because it exists for everyone. Untreated maternal disease, such as epilepsy or depression, <a href="http://www.cfp.ca/content/60/3/242.full">can increase this background risk</a>. </p>
<p>If a medicine is potentially implicated as contributing to an adverse event, the risk from the medicine needs to be increased above the background risk. Unlike our grandmothers, women today expect a happy and healthy pregnancy outcome. This can lead to couples looking for something else to blame, including medication, when things go wrong. </p>
<p>Second, there are <a href="http://www.cambridge.org/us/academic/subjects/medicine/obstetrics-and-gynecology-reproductive-medicine/obstetrics-gynaecology-and-womens-health">critical time points</a> during a pregnancy when medicines are likely or unlikely to impact on pregnancy outcome. </p>
<p>A common time to seek help is when medication exposure occurs prior to the woman realising she is pregnant. The following table highlights that in the first four weeks from the last menstrual period, medication does not change the woman’s baseline pregnancy risk of a birth defect. This reassurance can reduce unnecessary anxiety for the rest of the pregnancy.</p>
<iframe src="https://datawrapper.dwcdn.net/jLo3T/1/" frameborder="0" allowtransparency="true" allowfullscreen="allowfullscreen" webkitallowfullscreen="webkitallowfullscreen" mozallowfullscreen="mozallowfullscreen" oallowfullscreen="oallowfullscreen" msallowfullscreen="msallowfullscreen" width="100%" height="500"></iframe>
<p>Finally, for a medication to be proven to cause birth defects, it must meet certain “<a href="http://onlinelibrary.wiley.com/doi/10.1002/tera.1420200322/abstract">rules</a>”. It must:</p>
<p>• produce deformities in more than 3-5% of mothers exposed </p>
<p>• produce a consistent pattern of deformities </p>
<p>• be given in sufficient dosage</p>
<p>• be given at the precise moment the vulnerable fetal body organ is forming. Once the organ has formed, the fetus is at no greater risk from the drug than a child or an adult.</p>
<h2>What this means for pregnant couples</h2>
<p>While it is common sense to minimise unnecessary exposure to medication, the risk of adverse effects on unborn babies is likely to be higher from an untreated maternal disease than from the medication used to treat the condition. </p>
<p>Medication-induced birth defects tend to be overestimated by the public. There are <a href="http://www.amazon.com/Chemically-Induced-Birth-Defects-Edition/dp/0824702654">very few medications</a> that must be absolutely avoided during pregnancy. </p>
<p>The <a href="http://www.tga.gov.au/hp/medicines-pregnancy.htm">Australian Categorisation System for Prescribing Medicines in Pregnancy</a> gives some initial guidance on things that should be avoided or drugs for which medical advice should be sought before being used in pregnancy. </p>
<h2>Medications to avoid</h2>
<p>The following medicines should be avoided, particularly during the first trimester:</p>
<ul>
<li><p>Thalidomide. Used in the late 1950s to treat morning sickness, thalidomide was found to cause severe limb defects.</p></li>
<li><p>Vitamin A derivatives from supplements or medicines (such as etretinate and isotretinoin) <a href="http://www.nejm.org/doi/full/10.1056/NEJM199511233332101">have been found</a> to cause malformations of the head, heart, brain and spinal cord in significant dosages.</p></li>
<li><p>Certain anticancer drugs and immune-system-modifying medicines (for example, those used for rheumatoid arthritis or inflammatory bowel disease) should be avoided because they could affect fetal immunity or cell growth.</p></li>
<li><p>Alcohol in chronic or high dose can cause fetal alcohol syndrome, where offspring show differences in their face and head, are smaller or shorter than average, and have learning and behavioural difficulties.</p></li>
<li><p>Other medications such as the epilepsy drug phenytoin, the anticoagulant warfarin, the mood stabilisers valproate and lithium (to treat bipolar disorder) have all been linked to severe birth defects.</p></li>
</ul>
<h2>Medications that are safer to take than not</h2>
<p>Untreated maternal disease, such as epilepsy or depression, can <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344179/">increase the likelihood</a> of a child being born with defects. </p>
<p>It may be more harmful for the fetus if the mother stops medication prescribed for her chronic condition during the pregnancy. This could include antidepressants, asthma inhalers or anti-convulsants. </p>
<h2>Other medications</h2>
<p>Most medicines fall into this category, so the first step is to decide if the medicine is needed or not. The need to manage symptoms such as headache, cough or cold during the pregnancy is subjective, but non-drug options such as rest, sleep or steam should not be forgotten. </p>
<p>If the woman decides to use a medication, then she should look for a Category A medicine as her preferred option on the <a href="http://www.tga.gov.au/hp/medicines-pregnancy.htm">Australian Categorisation System for Prescribing Medicines in Pregnancy</a>. Category A means large numbers of women have taken the drug without adverse affects to her or the unborn baby.</p>
<p>By reading the packaging, labels and information that come with a medicine and asking questions of their primary health carers (doctor and pharmacist), women can get the right advice to use medication safely in pregnancy.</p><img src="https://counter.theconversation.com/content/49127/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Treasure McGuire does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>A third of Australian women take medication while pregnant. So what’s safe and what’s not?Treasure McGuire, Senior Lecturer in Pharmacy, The University of QueenslandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/443582015-07-09T00:09:55Z2015-07-09T00:09:55ZPregnant women taking antidepressants shouldn’t panic about birth defect claims<figure><img src="https://images.theconversation.com/files/87722/original/image-20150708-31567-bgtl8s.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Women planning a family who abruptly stop using antidepressants may be putting themselves in harm's way.</span> <span class="attribution"><a class="source" href="https://www.flickr.com/photos/lastyearsgirl_/3775445831/in/photolist-6KC9vD">Lis Ferla/Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>No one in the world has greater proscriptions on her behaviour than a pregnant woman in the developed world. And <a href="http://www.bmj.com/lookup/doi/10.1136/bmj.h3190">research published today in the BMJ</a> – and the mass of media coverage it will inevitably inspire – will add a new and potentially dangerous rule to the list.</p>
<p>The commotion I’m expecting is based on a study that suggests a link between a common class of antidepressants, known as selective serotonin re-uptake inhibitors (SSRIs), and birth defects. These findings are not new. </p>
<p>For almost a decade now, we’ve known about <a href="http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152062.htm">the potential association between paroxetine</a>, a member of this drug class, and a slightly increased risk of minor heart defects in children when mothers in first trimester use this drug. But women suffering depression and hoping to start a family may face a <a href="http://www.ncbi.nlm.nih.gov/pubmed/15811496">greater harm if they abruptly stop taking their antidepressants</a>. </p>
<h2>A difficult test</h2>
<p>The potential for congenital effects from drug exposure in pregnancy has concerned the general public <a href="http://www.sciencedirect.com/science/article/pii/S0140673661909278">since the early 1960s</a>, when <a href="http://www.abc.net.au/radionational/programs/drawingroom/the-shocking-thalidomide-cover-up/6569442">thalidomide was found to cause limb defects</a>. We now tend to look for <a href="http://www.ncbi.nlm.nih.gov/pubmed/2228814">a causal drug</a> every time a woman bears a child with some form of congenital anomaly, and forget that there’s actually a background rate of children who will be born with a defect of some kind. In fact, between <a href="https://npesu.unsw.edu.au/sites/default/files/npesu/surveillances/Congenital%20anomalies%20in%20Australia%202002-2003.pdf">two and four Australian women for every 100</a> will bear a child with a minor or major birth defect. </p>
<p>This BMJ paper, no doubt unintentionally, plays to the fears raised by the thalidomide case. If you just read the abstract or try to work through its elegant statistical analysis, it’s tempting to accept the results from a paper published in a highly regarded journal at face value. And its central claim is clearly sensational enough for the media to cover the research in good faith, even though the story may promote fear in a relatively vulnerable group of women. </p>
<p>But there are not only key flaws in this study. Similar birth registry studies that suggest a causal association between this class of antidepressants and birth defects are also problematic. Let me explain why.</p>
<p>The best way to scientifically determine a causal association between a drug and an adverse outcome is to run a controlled randomised trial with one group receiving the drug and a similar group not receiving it. But it’s ethically not appropriate to do this with pregnant women. </p>
<p>Instead, we have to rely on research where we observe outcomes of people with a common characteristic – pregnant women taking antidepressants, for instance – over time (cohort studies). Or studies that identify two existing groups of people with a differing outcome, and compare them on the basis of some supposed causal attribute (case control studies). Such studies examine data to find possible “red flags”. </p>
<p>But research like this is open to misinterpretation because it’s impossible to account for all the causes of an effect. If I said there was an association between “number of churches” in a city and its “crime rate”, for instance, you would rightly be sceptical. But if I swapped “number of churches” to “city size”, and could still draw the same graph, only one of these associations is likely to be true. The problem with epidemiological research like this is that there could be any number of causes contributing to an observed effect. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=465&fit=crop&dpr=1 600w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=465&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=465&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=584&fit=crop&dpr=1 754w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=584&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/87849/original/image-20150708-31590-14bc5ji.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=584&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption"></span>
</figcaption>
</figure>
<p>A number of maternal diseases, such as diabetes and epilepsy, may increase birth defect rates, as can untreated depression. Indeed, babies born to women with untreated depression are at <a href="http://aje.oxfordjournals.org/content/157/1/14.full.pdf+html">risk of prematurity</a>, low birth weights and <a href="http://www.ncbi.nlm.nih.gov/pubmed/11573032">cognitive or behavioural difficulties</a>. Untreated depression also has other <a href="http://www.ncbi.nlm.nih.gov/pubmed/15633850">adverse maternal outcomes</a>, such as <a href="http://www.ncbi.nlm.nih.gov/pubmed/15339755">developing postpartum depression and suicidality</a>, increased <a href="http://www.ncbi.nlm.nih.gov/pubmed/15339755">risk of hospital admission and pregnancy complications</a>, including <a href="http://www.ncbi.nlm.nih.gov/pubmed/10725477">pre-eclampsia</a>.</p>
<p>Importantly, in the BMJ study, pregnant women with depression taking SSRIs in early pregnancy were not compared with untreated pregnant women with depression in early pregnancy. In fact, women with depression, anxiety, bipolar disorder or obsessive compulsive disorder but not reporting any antidepressant use were excluded from the study. This means that we don’t have a true baseline risk from which we can compare a possible increased risk from SSRI use in pregnancy. </p>
<h2>True testing</h2>
<p>For a drug to be a “proven” cause of birth defects, <a href="http://trove.nla.gov.au/work/21362667?selectedversion=NBD193939">several criteria must be met</a>. It must:</p>
<ol>
<li> Produce deformities in more than 2% to 4% of mothers exposed (that is, the incidence rate must be higher than baseline); </li>
<li> Produce a consistent pattern of deformities; </li>
<li> Be given in sufficient dosage (as this adverse effect is dose-related effect); </li>
<li> Be given at the precise moment the vulnerable fetal body organ is forming. Once the organ has formed, the fetus is at no greater risk from the drug than a child or an adult.</li>
</ol>
<p>Much of this information is not accessible in data collected from pregnancy registries, which is what most studies rely on.</p>
<p>Where does this leave our now anxious woman who is taking an antidepressant and planning a pregnancy or already pregnant? She needs to have a frank and open discussion with her prescriber about the true benefits and risks of her antidepressant medication in pregnancy. Together, they can make a shared decision on how best to proceed.</p>
<p>The BMJ study, together with many other registry studies, suggest that of the various drugs known as SSRIs, sertraline appears to have a reasonable safety track record for pregnancy outcomes. In fact, it’s fairly similar to that of mothers not taking an antidepressant. This would be a good first option for women of reproductive age and first-time users of antidepressants.</p>
<p>But it may not work for every woman. An alternative SSRI or an antidepressant from another class may be needed to control moderate to severe depression in non-responders. </p>
<p>Reputable publications have a duty of care to provide a lay explanation of how research that may invoke unnecessary anxiety or controversy should be interpreted by the general public. They need to clearly explain the limitations of such research in terms that can be easily understood by everyone. </p>
<p>If this had been done when the <a href="https://www.nhlbi.nih.gov/whi/">Women’s Health Initiative study</a>, which suggested hormone replacement therapy caused breast cancer, was first published in JAMA, we would not have had <a href="http://www.ncbi.nlm.nih.gov/pubmed/22612615">millions of women suffering</a> recurrence of their menopausal symptoms by unnecessarily abrupt withdrawal of their medication before seeking medical advice.</p>
<p>We don’t want this to happen too with SSRI antidepressants. Women should remember that the risk of having uncontrolled depression is greater for baby and her than the small absolute increased risk of birth defect that may be associated with specific antidepressants.</p><img src="https://counter.theconversation.com/content/44358/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Treasure McGuire does not work for, consult, own shares in or receive funding from any company or organisation that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Research published today has found an association between commonly used antidepressants and birth defects. But pregnant women face greater harms from stopping their medication abruptly.Treasure McGuire, Senior Lecturer in Pharmacy, The University of QueenslandLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/324762014-11-03T05:30:30Z2014-11-03T05:30:30ZPregnant women must be studied too<figure><img src="https://images.theconversation.com/files/61295/original/twtgxmzy-1412868444.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Pills ok during pregnancy? We can't know if we don't study them.</span> <span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-18257989/photo-pregnant-woman-holding-medicine-nine-month-third-trimester.html?src=8pEa9Ry2emMCWlis6N3KJg-1-93">Medications image via www.shutterstock.com</a></span></figcaption></figure><p>Imagine being pregnant while having a chronic health condition such as diabetes, hypertension, depression or asthma, or being diagnosed with an illness while pregnant. Amazingly, your doctor may not know exactly what treatments or drugs, or what dose, will work best for you. This is a reality faced by <a href="http://www.ncbi.nlm.nih.gov/pubmed/21514558">millions of American women</a> every day.</p>
<p>The simple fact is, pregnant women get sick and <a href="http://www.un.org/apps/news/story.asp?NewsID=47735">sick women</a> get pregnant. Meanwhile, rates of <a href="http://www.fightchronicdisease.org/sites/fightchronicdisease.org/files/docs/PFCDAlmanac_ExecSum_updated81009.pdf">chronic disease are rising</a> and women are having children at an <a href="http://www.cdc.gov/nchs/data/nvsr/nvsr62/nvsr62_09.pdf">older age</a>. Stopping medication or avoiding new treatments is not always the optimal approach. Significant knowledge gaps exist because pregnant women have historically been <a href="http://dij.sagepub.com/content/48/2/145.abstract">excluded from medical research</a>, mainly due to concerns about the effect on the fetus. But even a normal pregnancy has risks.</p>
<h2>Medication conundrum</h2>
<p>There is a common belief that medication during pregnancy is unhealthy and unwise. Past tragedies – such as the limb-reduction birth defects related to first trimester thalidomide exposure – serve to support careful consideration of the risks and benefits of drug treatment. But avoiding all medication use is not a realistic possibility.</p>
<p>Failing to take medication, taking inappropriate doses or not being prescribed a needed treatment can be harmful or fatal for a mother or her unborn child. Today, an American woman will take at least one and on average four <a href="http://www.sciencedirect.com/science/article/pii/S0002937811002195">medications</a> during her pregnancy. Health care professionals, though, often have inadequate information about how a drug works during pregnancy because most medications <a href="http://onlinelibrary.wiley.com/doi/10.1002/pds.3495/full">have not been evaluated</a> in pregnant women. </p>
<p>Confronted with this lack of data, a woman who is pregnant or nursing may stop taking drugs or breastfeeding, even though that may not be the best course of action. With more information about both the benefits and risks of drug exposure, she might choose to continue medications that improve her short-term and long-term health and quality of life while minimizing harm to herself or her baby.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=899&fit=crop&dpr=1 600w, https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=899&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=899&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1130&fit=crop&dpr=1 754w, https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1130&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/61296/original/rw5qz79s-1412868885.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1130&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Without the data, pregnant women are left guessing.</span>
<span class="attribution"><a class="source" href="http://www.shutterstock.com/pic-131704958/photo-pregnant-woman-taking-supplements-at-home.html?src=8pEa9Ry2emMCWlis6N3KJg-1-61">Woman image via www.shutterstock.com</a></span>
</figcaption>
</figure>
<p>Moreover, newer medications shown to be effective in non-pregnant patients have the potential to improve disease outcomes in pregnancy, but have not yet been tested in pregnant women. For example, newer treatments for hepatitis C may help prevent the <a href="http://www.healthline.com/health-slideshow/hepatitis-c-and-pregnancy#1">mother-to-child transmission of hepatitis C</a>, but they need to be studied in pregnancy.</p>
<p>Unfortunately, this lack of new scientific information leads to <a href="http://www.ncbi.nlm.nih.gov/pubmed/23359404">uncertainty</a> for health care professionals about how to prescribe needed medications and sometimes results in no treatment at all for pregnant or breastfeeding patients with an illness. Worse, in the search for answers, many pregnant women turn to the internet and social media, which often results in conflicting, confusing and just plain wrong advice.</p>
<h2>Rx: collect more data</h2>
<p>Our nation must do better. Currently women – pregnant or not – are vastly underrepresented in clinical trials. Pregnant women should determine what level of risk they are willing to take. A robust, transparent informed consent process can help them make this decision. Though pregnant women have participated in some studies, most research protocols continue to exclude pregnant or breastfeeding women, and this just has to change. </p>
<p>Additionally, we need to improve data collection related to drugs and pregnancy, which is currently inadequate to make informed decisions. For example, the US Food and Drug Administration keeps a list of what are called <a href="http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm134848.htm">Pregnancy Exposure Registries</a> that collect health information, mostly on birth defects and infant health, from researchers and drug companies about women who take medicines or vaccines while pregnant.</p>
<p>Existing data from these registries should be standardized and easily accessible to support sound decision-making by providers and patients. Pregnancy registries should be required for new drugs, and registries must capture not just adverse events but healthy outcomes to create a baseline of both positive and negative medical data. </p>
<p>Also the US Office of Management and Budget should finalize the long-pending FDA <a href="http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm093307.htm">Pregnancy and Lactation Labeling Rule</a>, which would provide patients and prescribers detailed, updated information about fetal risk, clinical considerations and the quality of studies available for each drug.</p>
<p>Federal policymakers and the medical community must re-evaluate the <a href="http://www.fda.gov/ScienceResearch/SpecialTopics/WomensHealthResearch/ucm133348.htm">near-exclusion</a> of pregnant women from medical research and strengthen requirements to collect as much data as possible, including follow-up with women who become pregnant and drop out of a study.</p>
<p>Incentives, such as longer exclusivity clauses or fast track designation for an unmet need, must be created for pharmaceutical companies to perform lab research and clinical trials focusing on pregnancy when seeking approval for new drugs that may be used by pregnant women.</p>
<p>By taking these actions, pregnant women will be better served by medical research. With <a href="https://www.cia.gov/library/publications/the-world-factbook/geos/us.html">62 million women</a> in the United States of childbearing age and <a href="http://www.cdc.gov/nchs/data/nvsr/nvsr62/nvsr62_01.pdf">4 million births</a> each year, getting the best possible health care is vitally important now and for generations to come. </p>
<hr>
<p><em>This piece was co-authored by Martha Nolan, JD, Vice President of Public Policy at the <a href="http://www.womenshealthresearch.org/site/PageServer?pagename=homepage">Society for Women’s Health Research</a>.</em></p><img src="https://counter.theconversation.com/content/32476/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Katherine Wisner has received funding from NIMH, NICHD, and the Department of Psychiatry at Northwestern receives Consultation Fees from Dr. Wisner's work with Quinn-Emanuel Law firm, which represents pharmaceutical companies. </span></em></p><p class="fine-print"><em><span>Vincenzo Berghella does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.</span></em></p>Imagine being pregnant while having a chronic health condition such as diabetes, hypertension, depression or asthma, or being diagnosed with an illness while pregnant. Amazingly, your doctor may not know…Katherine Wisner, Professor in Psychiatry and Behavioral Sciences and Obstetrics and Gynecology, Northwestern UniversityVincenzo Berghella, Professor of Obstetrics and Gynecology, Thomas Jefferson UniversityLicensed as Creative Commons – attribution, no derivatives.