You might think that telling women about the potential risks of taking antidepressants during pregnancy would be uncontroversial. You might think that a drug regulator considering the evidence on these risks would be uncontroversial. You would be wrong!
The medical establishment backlash to the recent FDA panel hearing has been extraordinary. The panel, convened by the new FDA chair, respected surgeon, Marty Makary, was set up to hear evidence on the potential risks of antidepressants during pregnancy and childbirth (the discussion can be viewed here). It is true that this was an unusual and, in my view, momentous event. In the past, drug regulators have generally kow-towed to drug company interests and medical establishment views, reassuring the public about the safety of drugs. But that has changed in the US, for now, and the panel included a range of experts, including the authors, who have been critical of the establishment line that antidepressants are safe and effective.
In the view of the medical establishment, however, the panel was ‘alarmingly unbalanced’. The American College of Obstetricians and Gynecologists claimed panel members ‘made outlandish and unfounded claims’. Massachusetts General Hospital Center for Women’s Mental Health suggested they ‘ignored or diminished the risks associated with untreated depression in the mother’. The discussion ‘undermines the agency’s mission to protect and promote public health’ and would put patients’ lives at risk by deterring them from seeking effective treatment: ‘For pregnant people who need SSRIs, they are life-changing and lifesaving’. Media coverage followed suit, with NPR, NBC News, and The Guardian accusing the panel of spreading ‘misinformation’.
The medical institutions insisted that ‘SSRIs are safe in pregnancy and that most do not increase the risk of birth defects’ and that ‘SSRIs during pregnancy appear to confer minimal risk’, and that these are outweighed by the risks of ‘untreated depression’.
These statements are misleading and the FDA and the public deserve to judge for themselves whether the evidence suggests that using antidepressants in pregnancy is safe and worthwhile. This was the evidence that was put to the FDA in the recent panel.
The main argument of those who are keen to reassure women (including the representative of the establishment view on the panel itself, Dr Roussos-Ross), is that taking antidepressants is necessary because untreated depression presents risks to the mother and baby, and these are greater than the minimal risks associated with the drugs themselves.
There are two problems here. The first is that depression is associated with social deprivation, smoking, obesity, and other factors known to be harmful in pregnancy, and these are not always adequately controlled for in studies reporting links between depression and pregnancy complications. The use of antidepressants is also sometimes ignored. For example, a typical study (cited in the Massachusetts General Hospital Center statement) claims depression during pregnancy is associated with low birthweight and pre-term birth (prematurity) but completely fails to examine the possibility that the use of antidepressants may have explained the results. Surely, in a contest between an emotional state and a foreign chemical for the cause of foetal abnormalities, the chemical should be the prime suspect?
One of us, maternal-fetal medicine specialist Adam Urato, has suggested the best explanatory framework for understanding the effects of antidepressants in pregnancy is the Harmful Chemical Model. In contrast to claims by antidepressant proponents, this suggests that taking antidepressants is ‘not like using insulin in pregnant diabetics’.
The second problem is the often-unspoken assumption that antidepressants have significant benefits in treating depression.
The way the benefits of antidepressants are presented is completely at odds with the data. At best, antidepressants show a very modest benefit over placebo in terms of reducing symptoms of depression after a few weeks of treatment. As I told the FDA panel, this is not in dispute. Meta-analyses of hundreds of trials consistently show that the average difference between antidepressants and a placebo is around 2 points on the 52-point Hamilton rating scale (the most commonly used depression rating scale). And despite decades of trying, no subgroup has ever been identified that shows a larger response. Trials involving people with anxiety show the same sort of very small difference. This is what the evidence shows, before it is massaged by categorising it into responders and non-responders or other manipulations that make the difference seem more impressive than it really is.
This modest effect has not been shown to be the result of a targeted effect on an underlying depression mechanism (such as the rectifying of a chemical imbalance or abnormality of the serotonin system). Indeed, it is likely to be an amplified placebo effect, due to the fact that in many trials people can identify whether they have got the real drug or not better than chance. People who guess they got the real drug do better than those who think they got the placebo, even when there is no actual difference. If it is due to a pharmacological effect, this is likely to be the emotional numbing or apathy the drugs can produce. In theory, a mild degree of numbing may reduce acute feelings of distress or anxiety, but the fact that the differences from placebo are so small and insignificant suggests it doesn’t translate into tangible benefits. Also, being numbed doesn’t sound like a good state to be in when looking after a baby.
So the whole argument that antidepressants are necessary to prevent the complications of untreated depression is fallacious. Yes, it’s not great to be a depressed mother, and depressed pregnant women deserve compassionate care, but there are other ways to help people with depression, and antidepressants don’t appear to produce significant benefits for most patients in any case.
Moreover, antidepressants do not improve pregnancy outcomes by reducing the risks that are associated with depression (although likely caused by something else – social deprivation or antidepressant use, for example), such as pre-term birth and low birth weight. In study after study mothers taking antidepressants have worse pregnancy outcomes (i.e. more miscarriage, more preterm birth, more postpartum hemorrhage.) In some of these studies the researchers “adjust” or “correct” the data and the associations lose statistical significance, but virtually none of the available studies in almost four decades of research show improved pregnancy outcomes in women taking antidepressants.
So what about the claims that antidepressants are safe in pregnancy or that the risks are minimal?
In the early noughties one of us (Prof Moncrieff) reviewed a paper on the links between congenital abnormalities and paroxetine. There was evidence of a small increased risk of cardiac malformations in the babies of mothers who had taken paroxetine during pregnancy. She recommended that the paper advised against using this antidepressant in pregnancy because although the effect was small, and uncontrolled confounding factors may have contributed, this had to be balanced against the lack of significant benefits from taking antidepressants. The editor told the authors of the paper to ignore her.
A couple of years later, the FDA issued an advisory warning about the risk of birth defects, particularly congenital cardiac malformations, associated with paroxetine. The manufacturer changed the labelling of paroxetine to a category D (positive evidence of foetal risk).
Debate has raged since then about whether other antidepressants, or antidepressants as a whole, are associated with congenital abnormalities. First of all, it is important to note that there are many studies that find that women who take an SSRI or an SNRI are more likely to have a baby with a birth defect, especially a heart defect, including carefully conducted studies by researchers from the CDC (the US Centers for Disease Control and Prevention). Second, animal models and preclinical research suggests that serotonin plays a key role in embryonic development, including the development of organ systems, and in the structure and function of the placenta. Therefore, drugs that disrupt normal serotonin activity are biologically plausible candidates for producing foetal malformations and other adverse effects on foetal development.
However, as advocates of the drugs rightly point out, women who take antidepressants may be at an increased risk of having a foetal abnormality in the first place, because they are more likely, for example, to have a physical health condition, to be a smoker or to be taking other medication. Adjusting for these factors reduces the strength of the associations between antidepressants and birth defects in some studies.
Yet, in other studies associations persist after adjustment, and are sometimes even strengthened, which just illustrates that the process depends on what you adjust for, exactly, and how.
Some of these studies attempt to control for the presence or severity of depression for example, but it’s not clear that this is a legitimate thing to do, or that it has been done in a way that enables the effects of antidepressants and the effects of having depression or another mental disorder to be distinguished.
‘Confounding’ factors do likely account for some of the association between antidepressants and birth defects, but it is dangerous to assume they account for all of it, given that the link is found so consistently, and the effects of adjustment are so varied. Nevertheless, the increased risk of birth defects is generally low. This is why the efficacy of the drugs is a critical consideration. If they worked amazingly, then a given patient might find a small elevation of risk to be acceptable. But they don’t.
Incidentally, some risks are strongly elevated. A recent CDC analysis using the US birth defect register found that the odds of anencephaly and craniorachischisis was raised 9.14 times in women taking venlafaxine.
Antidepressants have been linked with numerous other adverse effects on pregnancy and subsequent child development. These include miscarriage, premature birth and post-natal haemorrhage. The UK regulator, the MHRA, issued a warning about the risks of post-partum haemorrhage in 2021, pointing out that ‘SSRIs and SNRIs are known to increase bleeding risks due to their effect on platelet function’.
There is also evidence that antidepressants may be implicated in serious pregnancy complications such as pre-eclampsia and placental abruption.
Again, it has been suggested that some of these effects may be due to the effects of depression or other factors that are more frequent in depressed women. One study found that the association between antidepressants and miscarriage, for example, was weaker when the analysis was restricted to depressed women alone than when looking at a population level. However, miscarriage rates were still increased in antidepressant users compared to non-users to a small, but statistically significant extent. In contrast, a study looking at pre-term birth found the rate of prematurity was still substantially elevated in women who took SSRIs (at 24.4%) compared with the rate in women with a mood disorder who did not take antidepressants (7.9%).
Although some effects remain uncertain, and are likely to be small, animal research in sheep, as well as rats and mice, confirms that antidepressants, including SSRIs, are associated with negative outcomes including foetal malformations, prematurity, decreased birth weight, and higher rates of infant death.
Some complications are common. Up to a third of babies born to women taking SSRIs during the last weeks of pregnancy show what’s euphemistically called ‘poor neonatal adaptation’. This syndrome is characterised by breathing and feeding problems, increased or decreased muscle tone, constant crying, hypoglycemia, vomiting and temperature instability. When severe it can involve respiratory distress, dehydration and convulsions. It may be a withdrawal syndrome, like those of babies born to mothers addicted to opioids, or it may be a manifestation of the toxicity of the drugs as they are slowly excreted from the baby’s system. Ultrasound studies suggest babies are affected while they are still in the womb, showing heightened motor activity and disrupted sleep. Official literature plays this syndrome down and reassures people that symptoms are ‘transient and resolve spontaneously.’ It can be serious, however, and a small follow-up study detected that babies who had suffered this syndrome had problems with social behaviour two and six years later.
A rare but dangerous complication called persistent pulmonary hypertension of the newborn is also associated with antidepressant use in pregnancy. This involves a failure of the vessels in the lungs to relax, thus hindering oxygen reaching the lungs. It has a 5-10% death rate and is quite, but not very, rare (occurring in about 2 out of every 1000 live births). The use of antidepressants increases the number of babies who get it by about 3 to 3.5 per 1000 births. A significant proportion (around 13% in one study) of babies exposed to antidepressants during pregnancy will show respiratory distress and need acute delivery room resuscitation.
There is also a body of evidence on the health and development of the children of women who have taken antidepressants during pregnancy. Many studies suggest that these children are more likely than the average child to be diagnosed with autism or to show problems with language and behaviour. Again, this research may be influenced by other factors, such as autistic traits in mothers themselves, but some large, well-adjusted studies suggest a link. For example, a study published in the BMJ found that children exposed to antidepressants during pregnancy had increased rates of autism compared to the children of women who had a diagnosis of a mental disorder but did not take antidepressants. Moreover, animal research provides compelling evidence of a drug-related effect. Studies show that maternal use of SSRIs reduces the social interactions and play of the offspring, along with general activity levels and exploratory behaviour.
SSRI exposure during development has also been show to impair the sexual activity of the offspring when they reach adolescence. This makes sense. We know that one of the main effects of SSRIs is to impact sexual function in adults who take them, and that this impairment can persist after the drugs are stopped.
If we accept the Harmful Chemical Model, these findings are not surprising. As Dr Urato said during the panel ‘never before in human history have we chemically altered developing babies like this. Especially the developing fetal brain.’
Official advice and media coverage has focused on reassuring the public that benefits of antidepressants outweigh the risks of the drugs in pregnancy. But this has it wrong. First off, benefits in mood appear minimal and benefits in pregnancy outcomes haven’t been shown. But even more importantly, it’s the mother herself who must weigh the risks and decide for herself whether to take the drugs. Dismissing the risks and reassuring women that these drugs are ‘safe’ is a paternalistic approach that obscures the central role of the pregnant woman herself.
Since the thalidomide tragedy, society has generally taken the view that subjecting the developing foetus to foreign chemicals is risky and best avoided if possible. Yet medical leaders are cavalier about the potential risks of antidepressants. Their attitude illustrates a deep-seated attachment to antidepressants that seems to blind many doctors to their harmful effects. This is also evident in attempts to play down the significance of antidepressant withdrawal and antidepressant-induced persistent sexual dysfunction. On pregnancy, as in these other situations, the public have a right to know what the evidence consists of and to make up their own minds. As Dr Urato concluded elsewhere: ‘The FDA should add stronger warnings to the label. And the media must start accurately covering the topic and properly informing the public’.
