An important new research paper was published this week on the topic of antidepressant use during pregnancy and preterm birth. The issue is a crucial one as preterm birth (i.e. birth at less than 37 weeks gestational age) is one of the most challenging problems facing the obstetrical community today. Rates of preterm birth have been increasing over the past two decades. Babies born early have increased risks of morbidity and mortality. At the same time, rates of antidepressant use during pregnancy have increased dramatically. In the 1970s and 1980s rates of antidepressant use in pregnancy were less than 1%. These rates have rapidly increased over the past 25 years and now around 10% of pregnant American women are on these medications. So the following questions are crucial: what are the effects of antidepressant medications on pregnancy and the developing fetus? Are these medications linked to the important problem of preterm birth?
In this new research study Krista Huybrechts, MS, PhD, and her co-authors (of which I was one) did a comprehensive search of studies on women taking antidepressants during pregnancy. Of the many studies on the topic, we found 41 that had information comparing women on antidepressants to those not taking the medications, as well as information about when the patients delivered (i.e. whether they were preterm births or not.) We then did a detailed meta-analysis and found that an overwhelming majority of the studies (39 of the 41) showed increased rates of preterm birth in the antidepressant group. When all studies were combined there was roughly a doubling of preterm birth risk in women on these medications into the third trimester.
Couldn’t the increased risk just be due to the underlying depression?
The increased risk of preterm birth appeared to be due to the antidepressant exposure itself and not to the depression. Several of the studies that we reviewed controlled for maternal depression (and many included a depressed/non-medicated group) and these studies continued to find increased rates of preterm birth in the antidepressant group. There was also a suggestion in some of the studies of a dose-response effect, with women on higher doses having increased rates of preterm birth. Higher preterm birth rates were also seen in women who continued on the antidepressants throughout the pregnancy versus those who stopped.
Some have continued to argue that it could be possible that we see increased preterm birth rates in the women taking antidepressants because there are underlying differences in this group that we cannot control for. This is a reasonable comment. But the fact is that there are no randomized controlled clinical trials on this subject, so we have to rely on the observational studies that we have. These studies consistently show increased rates of preterm birth in the antidepressant-exposed group—even when controlling for underlying depression. In fact, our review is now the third review of the literature that has shown this effect. Ross, et al in 2013 and Huang, et al in 2014 demonstrated the similar findings. It is also essential to recognize that increased rates of preterm birth and other pregnancy complications are also seen in animal studies (here and here.) We see pregnancy complications when giving antidepressants to small mammals in the animal studies. Then we see many of the same exact pregnancy complications when we use them in humans—so to attribute those complications to the depression rather than the medication seems foolish.
And animal studies are important. One of the great medical tragedies of the 20th century was exposing millions of pregnant women to the drug diethylstilbestrol (DES). This drug provided no benefit to the pregnancies and caused considerable harm—leading to cancer and malformation of the reproductive systems of exposed offspring. DES was given to pregnant women for more than 30 years (1938-1971). But such harm may have been prevented if more attention was paid to the animal studies being performed in the 1930s which showed that small mammals exposed to these drugs would develop—reproductive tract abnormalities. So animal evidence is crucial. In the area of antidepressants and pregnancy, animal studies are showing that antidepressant exposure leads to increased rates of miscarriage, preterm birth, and long-term behavioral problems, like autism and sexual dysfunction.
Is it really a problem to be born a little early?
When it comes to pregnancy every week counts (in fact this is one of the March of Dimes’ slogans for early birth prevention.) We know that babies who are born early (for example, at less than 34 weeks) have significantly increased morbidity and mortality. But this is also true for so-called “late” preterm births–from 34 to 37 weeks. These babies also have higher rates of morbidity and mortality. The NICHD and the Society for Maternal-Fetal Medicine recently put out a Current Commentary statement on this that notes:
Although at less risk than infants born before 34 weeks gestation, infants born late preterm are more likely to have long-term neurodevelopmental problems and infant death than those born at term. In addition, neonates born between 34 and 37 weeks account for most admissions to the NICU and for a large proportion of health care expenditures.
This means that the consistent finding of increased preterm birth in the antidepressant-exposed group is not just statistically significant but also clinically significant—and of great importance, as these preterm babies are at increased risk of death and long-term health issues. And, in several of the studies, the risk of preterm birth was dramatically increased in the women on antidepressants. Rates of preterm birth in the 10% range would be considered high. In the antidepressant group Grzeskowiak, et al found a preterm birth rate of 24.9%, Ferreira et al found a 27.6% rate, and Latendresse et al showed that 30.8% of the women on antidepressants (almost one-third) had a preterm birth.
Won’t we see a rash of suicides if pregnant women aren’t on these medications?
A dead mother is no benefit to herself or her baby and depression during pregnancy certainly should not be ignored. Yet, in the area of antidepressants and suicide, it must be kept in mind that the SSRI antidepressants have been found to increase suicidality in young people who take them. That is why the FDA placed a black box warning on them in 2007 and it’s what was found in a 2009 review published in the British Medical Journal. The best available evidence shows increased rates of suicide with the use of antidepressants by young women and not a protective effect.
A misinformed public
The public, in general, has been misinformed on this topic. There is a widespread misconception that treating depression during pregnancy with antidepressants is like treating diabetes during pregnancy with insulin, but this is not at all correct. In diabetic pregnancies appropriately treated with insulin, we see improved outcomes in the pregnancies. This is shown in study after study of diabetic pregnancies. But the exact opposite is true with antidepressant use by pregnant women. In this case, study after study shows increased rates of pregnancy complications in the women taking the antidepressants. That is, we see more miscarriage, birth defects, preterm birth, preeclampsia, and newborn problems (such as seizures, persistent pulmonary hypertension of the newborn, EKG changes, and newborn behavioral syndrome) in the antidepressant-treated pregnancies. Long-term problems for the exposed children are unknown but current evidence shows impaired motor function and behavior, pulmonary disease, and increased rates of autism.
Why so much misinformation?
(Who has been advising pregnant women and the public in this area?)
One of the biggest problems in this area is that many of the leading researchers in perinatal psychiatry at America’s top academic institutions—the ones who should be informing the public on this issue and protecting pregnant women—are being paid by the drug makers. The stories are too numerous to review in a short piece like this, but I encourage you to read about America’s (and Canada’s) leading experts in perinatal psychiatry and how they have been funded by the drug industry (here, here, and here.) Simply put, the leading researchers who are supposed to be helping to determine if antidepressant drugs are safe for moms and babies are being paid by the companies who profit from the sales of those drugs. This creates bias (or even if you don’t think that money creates influence, it, at least, creates a harmful perception of bias.) And these so called Key Opinion Leaders (or KOLs) seem to be following the same basic script—they dismiss the animal data showing harm or ignore it altogether. They overplay the benefits of the antidepressants in treating depression and they downplay the risks. And, always, they cast doubt upon the science showing that the drugs are risky. But this “casting doubt” should come as no surprise to the public. Industry-paid scientists cast doubt on the science that demonstrates that their product causes harm—that’s what they do and have been doing since tobacco, bisphenol A, and any other number of examples.
Time for common sense
It’s time for common sense on the issue of antidepressant use by pregnant women and women of childbearing age. Depression should not be ignored. These women need good treatment and care, but the issue is how best to treat. The antidepressant drugs have been shown to increase pregnancy complications. Equally concerning, there is now good evidence that for most depressed patients, the antidepressants do not provide clinically significant benefit. Alternative approaches are available (for example, psychotherapy and exercise) that have been shown to be as good as or better than medication use. Given these facts, it only makes sense that in depressed pregnant women (and women of childbearing age) the first-line approach should be with non-drug treatments—treatments which have not been linked to preterm birth and other pregnancy complications.