Preterm birth, when babies arrive three or more weeks early, is the leading cause of infant mortality and can have serious long-term effects for the infants who do survive, says Adam Urato, a specialist in maternal-fetal medicine and assistant professor at Tufts School of Medicine. Caring for these babies is complex and expensive, costing the United States more than $26 billion annually, according to a 2007 report from the Institute of Medicine.

That’s why obstetricians and public health officials make every effort to educate women about factors that contribute to preterm birth, including smoking, drinking and using drugs or chronic illnesses such as diabetes, high blood pressure and even gum disease.

In a new research paper, Urato and his colleagues make the case for adding antidepressant use to that list of risk factors. The use of these medications during pregnancy has increased dramatically over the last two decades. Meanwhile, rates of preterm birth in the U.S. have also been climbing. (While the overall rate is about 11 percent, it varies widely across demographics.)

Urato doesn’t think that’s a coincidence. He and his colleagues combed through research conducted between 1993 and 2012, looking for answers. Their meta-analysis of the data showed a clear increase in risk for preterm birth among women who took antidepressants during their pregnancies. The paper, published in PLOS ONE on March 26, is a follow-up to a 2012 study by Urato and his colleagues that found that pregnant women on antidepressants were at increased risk for a number of complications, including miscarriage, pregnancy-related high blood pressure, birth defects and premature delivery (see “Reconsidering Antidepressants for Pregnant Women”).

Tufts Now talked with Urato, who also practices maternal-fetal medicine in the ob/gyn department at the MetroWest Medical Center, about his latest findings.

Tufts Now: Antidepressants like Prozac hit the market in the 1980s. Aren’t they well studied by now?

Adam Urato: You’d think there must be a lot of studies looking at the use of these drugs during pregnancy. But since the drugs were released more than 25 years ago, there are only 41 studies that we found that addressed this important issue of preterm birth. However, when you look at all of them, as we did in our meta-analysis, they are really quite definitive.

If you look at the raw data, 39 out of the 41 studies show an increased risk of preterm birth in the women on antidepressants, but not all were statistically significant. When you look at statistical significance and put it all together in a meta-analysis, what you find is roughly a doubling of the risk of preterm birth in women who are on these medications into the third trimester.

What’s more, several of the studies are showing very high rates of preterm birth. Ten percent is considered a high rate. But some of these studies are showing rates as high as 25 percent—and one was even as high as 30.8 percent in the women who took antidepressants.

How can you tell that it’s the medication—not the depression—causing problems with the pregnancy?

That’s the other important thing that came out of this study: it’s not the depression itself causing preterm birth. In many of the studies that looked at a depressed group of women who were not on antidepressants, we’re not finding that the depression causes preterm births. This really looks like a chemical effect, an effect of the antidepressants themselves.

This corresponds to the animal studies, which clearly show the effects of these drugs on pregnancy. It’s a little frustrating. People argue that we may try to control for depression, but the women who decide to stay on medication during pregnancy must have a different severity of depression from the women who decide to stay off of it. But truth is, in animal studies we are clearly seeing the same effects. We see pregnancy losses; we see early deliveries with antidepressant exposure.

If these effects show up in animal studies, how did these drugs get approved for use by pregnant women?

These drugs are not FDA-approved for use in pregnant women. The FDA label on these drugs contains a section on pregnancy. It warns about possible cardiac defects, persistent pulmonary hypertension and newborn behavioral syndrome, but the label doesn’t warn about preterm birth, which it should. One of my next projects will be to get the FDA to pay attention to these clear scientific findings. The evidence now is very compelling that we can make a very strong argument that the FDA needs to strengthen its warning to pregnant women.

Why is it so important for the FDA labeling to be updated?

I take care of pregnant women daily, and I counsel many women on these medications. The message that a lot of pregnant women and women of child-bearing age and their doctors are getting is that these drugs are basically safe in pregnancy. That’s absolutely not what the science is showing.

One piece of misinformation that’s out there is that people continue to compare giving these drugs to pregnant women to giving insulin to women with diabetes. It’s actually not like that at all. When you treat pregnant patients who are diabetic with insulin, they get much better outcomes. They have fewer complications. They have fewer miscarriages. By controlling their diabetes with insulin, their pregnancies do better.

But we are not seeing that with antidepressants. We consistently see worse outcomes in the treated group. The science is showing clearly that these drugs, when used during pregnancy, are associated with miscarriages, birth defects, preterm births, newborn problems and possible long-term effects. That message is really not getting out to women of child-bearing age and the doctors who take care of them.

How did you first become interested in this issue? Is it something you observed in your practice?

I went to medical school in the 1990s and did my training in the late ’90s. We’ve seen this explosion of antidepressant use during pregnancy since that time. I needed to be able to counsel the patients I take care of, and the way I approach questions like this is through research. I wanted to be able to provide the best counseling possible. When you look into the scientific studies available, the findings about the effects of these chemicals are really concerning.

So do you advise your patients not to take antidepressants during their pregnancies? Doesn’t that have risks, too?

People always ask me, What about a woman who says, “I will kill myself if I go off my Zoloft”? That’s not a difficult question. She needs to stay on her Zoloft. But the truth is, most women aren’t in that category, and we need to get out accurate information to pregnant woman and the public so that everyone can make the choice that’s best for them.

Our point is not to ignore depressed pregnant women. They need good treatment and care. The issue is how to care for them. We know now from the scientific evidence that antidepressants do not provide a significant clinical benefit for many patients with depression, and in fact, other modalities such as exercise or psychotherapy provide as good or better outcomes in the long term for many patients. Given that, and given that we know there are all these pregnancy complications, it’s just common sense to address depression in pregnant women—and arguably depression in anyone—with a non-drug approach first.

Jacqueline Mitchell can be reached at jacqueline.mitchell@tufts.edu.