The tricky relationship between antidepressants and pregnancy
I suspect by the time they figure out how – if at all – antidepressants significantly affect a fetus, we will have figured out how to grow babies outside the human body and the whole question will be moot. But until that time, we must grapple with an incomplete risk-benefit equation because we lack sufficient information to make a truly informed choice – though it’s not for lack of trying.
In fact, few drugs have been studied for use during pregnancy as much as antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). These include some of the most commonly prescribed antidepressants: fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine (Luvox), paroxetine (Paxil), venlafaxine (Effexor) and sertraline (Zoloft).
Even for tricyclic antidepressants and buproprium (Wellbutrin), there are tons of data available. It’s just often inconclusive and contradictory, leading to an unending controversy over whether antidepressants actually negatively affect a fetus or not. Researchers themselves often argue vigorously about the findings related to antidepressants during pregnancy, and bias can creep up in studies in the form of different statistical methods used to analyze the data.
Most studies have generally shown very small but statistically significant increased risks for low birth weight, preterm birth or some birth defects, including several heart defects.
But before you freak out, here are the important caveats: the absolute risk (actual percentage) of these defects is extremely tiny (usually less than 1%), and the increase in risk is so small that it’s hard to tease out whether it is due to the medication, due to the underlying condition (depression or anxiety), or due to some other factor that women taking antidepressants share.
For example, one outcome associated with antidepressants is “persistent pulmonary hypertension of the newborn” (PPHN), in which a newborn’s blood does not cruise by the lungs to pick up the oxygen that it needs to distribute to the rest of the body.
But PPHN only occurs in approximately 1 to 2 out of every 1,000 infants, so even though some studies have found up to a sixfold increased risk of PPHN in newborns exposed to SSRIs, that still translates to only 6 to 12 out of every 1,000 infants.
Further, some studies showed higher rates of PPHN among untreated, depressed mothers’ infants than among the infants of mothers taking antidepressants, so it’s not even clear that antidepressants are the factor affecting PPHN risk.
Similarly, the rates of preterm birth seen among women taking antidepressants, though a little higher than among non-depressed women not taking antidepressants, are often similar to those in women with untreated depression.
One research review found infants of women taking antidepressants were an average 2.5 ounces lighter at birth than those born to non-depressed moms not taking antidepressants – but there was no difference when the women taking antidepressants were compared to untreated, depressed moms.
To complicate matters further, most studies take into account age, race, number of previous children, underlying health conditions, socioeconomics and other factors, but many don’t control for smoking, alcohol consumption or substance abuse — which all occur more frequently among women taking antidepressants.
These factors are called confounders because they can confound, or negate, the possible link between antidepressants and a particular outcome if it’s one of these factors, instead of the antidepressants, that might be contributing to the outcome.
The biggest confounder is the condition a medication is treating. Researchers can compare the rates of various outcomes among women taking antidepressants to the “background rates,” or how often those defects occur in a typical population, but that doesn’t account for the depression or anxiety the medication is treating.
After all, women who aren’t depressed don’t take antidepressants, so the best researchers can do is then compare untreated, depressed women to women taking medications and see if the rates of various outcomes are similar. And they often are. (Some researchers have proposed using rats to compare taking antidepressants during pregnancy with not taking them, but then… they’re rats, whose outcomes may or may not extend to humans. And some of those rats might be depressed anyway.)
In considering the four main areas of concern – miscarriage, major birth defects, neonatal withdrawal after birth, and long-term cognitive or behavioral effects in the child – keep in mind it’s not clear whether outcomes seen in studies are due to the medication, due to what the medication is treating, or due to lifestyle or other factors shared among antidepressant-taking moms.
The evidence on miscarriage is mixed, but even research finding an increased risk only showed a small uptick in miscarriages that might be related to the underlying depression or anxiety. One analysis, for example, found the baseline rate of miscarriages among women across six studies to be 8.7% and the rate among women taking antidepressants to be 12.4%, but the authors noted that depression couldn’t be ruled out as a contributing factor to the miscarriages. Presently, there is not convincing evidence that SSRIs cause miscarriages.
The various defects that “might” be linked to antidepressants sound disturbing, but even among women taking medications, they are extremely rare, and it’s not clear that stopping taking a medication makes a difference.
In one study, 5% of women taking SSRIs during the first trimester had a baby with some kind of major birth defect, but so did 4.5% of women who stopped taking antidepressants while pregnant. Similarly, 1.8% of those who took SSRIs and 1.6% of those who stopped taking them had children born with a heart defect.
One clue that an outcome is due to a medication and not another factor is something called a “dose-response relationship”: as the medication dosage increases, the effect should increase as well.
If a dose-response relationship does not exist, the outcome might be due to something other than the medication.
Since some research has found no dose-response relationship with antidepressants and birth defects, it’s possible any effects are due to the underlying mental health condition, to other factors, or to an interaction between these factors and the medication.
It goes by various names – neonatal withdrawal syndrome, neonatal abstinence syndrome, neonatal adaptation syndrome, postnatal adaptation syndrome, poor neonatal adaptation – but basically these all refer to the same set of symptoms can affect up to 30% of infants exposed to antidepressants during pregnancy.
Those symptoms include insomnia or excess sleeping, agitation, jitteriness or shivering, restlessness, irritability or frequent crying, poor feeding patterns, poor temperature control, respiratory distress, rapid breathing, hypoglycemia, vomiting, diarrhea or even seizures.
That’s a pretty frightening list, but the symptoms are usually mild, don’t require treatment and fade within a week after birth. Breastfed babies are less likely to develop this syndrome (since they continue to get some of the antidepressant through the milk), and moms can lessen the effect with swaddling, skin-to-skin contact, and frequent, small feedings.
Although some doctors might recommend a woman wean off antidepressants in the weeks leading up to birth to lessen the risk of this syndrome, there are significant risks in doing so.
The weeks leading up to the delivery and immediately after birth are among the highest risk for depression, and it could take a while for the mother to get her medication back up to therapeutic levels soon enough after birth to avoid postpartum depression, which could have a greater negative impact on the baby.
Long Term Effects
The data are weakest when it comes to long-term outcomes in children. So far, research involving fluoxetine and tricyclic antidepressants hasn’t found any differences in behavioral or cognitive development – including IQ, temperament, mood, language development, etc. – for exposed children compared to unexposed children. Most other studies are too small to offer much use, though they tend to find that a mother’s mood in the present has a greater effect on children’s mood and behavior than any exposures to antidepressants in the womb.
Looking at Specific Medications
Another tricky part of the research related to antidepressants during pregnancy is that some studies group all antidepressants together, some focus only on SSRIs, and some look at each drug individually.
The medications with the strongest safety data are fluoxetine and citalopram, which may be best to consider first if starting antidepressants while pregnant.
One common SSRI currently categorized as Category D – generally considered higher risk during pregnancy – is paroxetine because taking it during the first trimester has been linked to heart defects.
However, additional data since that link was first identified have called it into question. Some research has found that depressed women not taking any medication have children with similar, or even greater, rates of the same heart defects, so paroxetine may eventually need to be re-classified as we learn more (though re-classification of drugs is rare even when we do know more).
Two other types of antidepressants aside from SSRIs are tricyclic antidepressants (TCAs) and bupropion, both of which appear to pose little risk to the fetus.
One extra advantage of buproprion is that it’s also approved to treat smoking cessation and is sometimes found to benefit those with attention deficit hyperactivity disorder, so for women with ADHD or women attempting to quit smoking, buproprion offers a two- (or three-) in-one benefit that might tip the scale toward outweighing the unproven risks.
We have less data about serotonin-norepinephrine reuptake inhibitors (SNRIs), but so far, at least one (venlafaxine) hasn’t thrown up any red flags when studied in women who had unplanned pregnancies while taking it.
The Confusion Will Continue
Despite what’s been laid out here, expect to continue seeing conflicting headlines claiming one day that antidepressants are fine during pregnancy and then screeching the next day that they’re dangerous.
That’s exactly what researchers are seeing as well. For example, one review of the research found the following in studies looking at different outcomes: 12 out of 35 studies showed a link to birth defects, 4 out of 7 found a risk for miscarriage, 15 out of 19 found a risk for preterm birth, 8 out of 23 found a risk for abnormal birth weight.
Those numbers are all over the map, and new studies will probably continue that trend for two main reasons: confounders and bias. We’ve already discussed confounders, especially the conditions the medications are treating and any use of drugs, alcohol or tobacco.
But even if these are accounted for, differences in methodology, selection of participants, study type, outcomes studied and statistical analysis can all lead to differing conclusions. Even tweaking the same data in different ways can suggest different results, depending on how the numbers are crunched and how confounders are (or aren’t) considered.
Antidepressants While Breastfeeding
Regardless of what you did or didn’t take while pregnant, you may want to reassess your decision if you will be breastfeeding. Any medications you take will generally end up in breastmilk in some concentration, but it’s often low enough not to have an effect on your child.
No large studies have consistently shown any problems in babies to be linked to antidepressant use while breastfeeding. Most adverse effects that have been seen that might be related to taking SSRIs while breastfeeding have come from case reports, which means they are rare and it can’t be confirmed that the medication actually caused the symptoms.
The symptoms reported in those case reports have included uncontrollable crying for long periods, irritability, poor feeding, insomnia or weight, so if you are taking an antidepressant and your child experiences these symptoms, the best thing to do is to contact your pediatrician and discuss whether the symptoms might be related to the medication.
Because the research literature is constantly being updated with new information, the National Institutes of Health has created an incredibly helpful website called LactMed, a drugs and lactation database where you can look up any medication to find out the most recent research related to its safety while breastfeeding. The web address is http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
In light of all these contradictions and the low rates of what increased risks have been seen, the most important thing to consider in discussing your medication use with your doctor is the benefit you might receive from it. If the benefit is negligible, it may be best to skip the meds. If the benefit is significant and the risks are low and unproven, it could be riskier not to take the medication.