On Antipsychotics in Pregnancy and the Problem of Confounding

Second-generation antipsychotics, also known as atypical antipsychotics, are frequently used in psychiatry, prescribed not just for psychotic disorders, but also for treatment of bipolar disorder, and for augmentation of depression or OCD treatment. Studies have shown that there is a very high risk of relapse of psychiatric disorders in pregnancy--for example, women with a history of bipolar disorder who discontinue their medications while pregnant have an 85% chance of recurrence of a mood episode while pregnant, compared to a 37% chance of recurrence when continuing to take their medications. Thus, it's important for women who are taking antipsychotics prior to pregnancy to know about the risks and benefits of continuing these medications while pregnant. Here we will focus on a recent article which looked at how taking antipsychotics in pregnancy may affect maternal and perinatal outcomes.

A large population-based cohort study looked at the question of whether or not antipsychotics affected certain maternal and perinatal health outcomes. It looked at all women who had delivered between April 2003 and December 2012 in Ontario, Canada. Data were collected from multiple linked healthcare administrative databases, which included information about medications women were taking, inpatient and outpatient claims, and demographic information. Antipsychotic exposure was defined as at least 2 consecutive filled prescriptions for an antipsychotic between conception and delivery. There were a total of 41,523 women in the study. Of these women, 1,209 were prescribed an antipsychotic, and 40,314 were not. The women were compared in 2 ways--there was an unmatched cohort, and a matched cohort. In the unmatched cohort, maternal and perinatal outcomes between women who were prescribed an antipsychotic and those who were not were compared directly. In the matched cohort, 1,021 women who were prescribed antipsychotics were matched with 1,021 women who were not, using something called a high dimensional propensity score (HDPS) algorithm.

What is a high dimensional propensity score (HDPS), you ask? It's a method commonly used in pharmaco-epidemiological studies to create less biased estimates of treatment effects. In other words, these epidemiological studies are subject to many confounders--things like age, ethnicity, multiple gestations, multi-parity, pre-existing medical problems like hypertension, diabetes, renal disease, smoking, drug use, other medications, and number of healthcare visits. Many of these confounders are observed, or known (e.g., it's easy to determine age from the databases). Researchers sometimes create a propensity score, which is a summary confounding score. The HDPS algorithm attempts to further minimize residual confounding by also incorporating proxy variables (healthcare diagnoses, procedures, and drug claims), which, when combined, can account for important confounders that are unobserved. This is extremely important, because without controlling for the unobserved confounders, we cannot know if a certain maternal or perinatal outcome is due to medication exposure, or to something else. In fact, women who take medications during pregnancy are often very different from women who do not; they tend to have more severe illness with higher risk of relapse...without controlling for this, we won't know if an outcome is related to a woman's underlying illness (severity), or to the medication she took. And this is how the HDPS is very useful.

Back to the study: the researchers looked at the following maternal medical outcomes: gestational diabetes, hypertensive disorders of pregnancy (gestational hypertension, pre-eclampsia, eclampsia), and venous thromboembolism (VTE), and the following perinatal outcomes: preterm birth (<37 weeks gestation), and extremes of newborn weight (a birth weight <3rd percentile or >97th percentile for the same sex and gestational age). What the researchers found illustrates not only the possible effects of antipsychotics on pregnancy outcomes, but also the importance of controlling for confounding. In terms of maternal outcomes in the matched cohort (where HDPS was used), there were no differences in terms of gestational diabetes, hypertensive disorders of pregnancy, and VTE between women who took antipsychotics in pregnancy and those who did not. However, in the unmatched cohort, there was an increased risk of gestational diabetes and hypertensive disorders in the antipsychotic group. In terms of perinatal outcomes, there were similar differences between the matched and unmatched cohorts. In the matched cohort, the 2 groups had no differences in preterm birth, and extremes of newborn weight. However, in the unmatched cohort without HDPS, the infants exposed to antipsychotics had an increased risk of preterm birth and weight >97th percentile. The study thus shows that when these antipsychotic users were matched with non-users who had similar pre-pregnancy morbidity (e.g., weight,  other medical conditions, diagnoses, and other variables), then the risk was about the same for both groups. Here is an illustration of the potential magnitude of bias that is created by not controlling for confounding variables. However, it also showed that the absolute rates of adverse maternal and perinatal outcomes in antipsychotic users were higher than those in the general population. Thus, for women who require antipsychotics during pregnancy, it's imperative to closely monitor their health before and during pregnancy, paying close attention to diabetes, hypertension, preterm birth and fetal growth.

Stimulants and ADHD in Pregnancy

Attention-deficit hyperactivity disorder (ADHD) is one of the most common conditions of childhood and approximately 30% of patients are estimated to continue pharmacologic treatment into adulthood (approximately 4% of the adult population suffers from ADHD). First line medications most often used to treat ADHD in adults are Dextroamphetamine (Dexedrine, Adderall) and Methylphenidate (Concerta, Ritalin, Metadate).

Similarly to what applies to most drugs, the use of stimulants in pregnancy should be individually and carefully assessed, weighing their pros and cons, risks and benefits for each woman and her needs.  In several cases of mild to moderate ADHD, the soon-to-be mother can function reasonably well without stimulants, with some behavioral modifications and/or non-stimulant medications. In more severe cases, however, they must continue on pharmacologic treatment in order to function.

We talked about the use of caffeine in pregnancy on a previous blog post. 

Alternative pharmacologic treatment options include tricyclic antidepressants, bupropion and clonidine, which have more evidence to support their safety in pregnancy than stimulants. However, large population studies have shown that the number of women who take stimulants during pregnancy has been getting progressively higher within the last decade, exposing a troubling lack of information regarding potential fetal risks in humans and urging for more post-marketing research.

A group from Boston University reviewed data from the Slone Epidemiology Center’s Birth Defects Study (BDS), an ongoing case-control surveillance effort focused on birth defects in relation to antenatal medication use in 29,540 women (19,811 cases and 9,729 controls) who were interviewed between 1998 and 2014. They noted that “In animal studies, methylphenidate has not produced teratogenic effects in mice or rats; in rabbits, only doses that were about 40 times the maximum recommended human dose resulted in an increased risk of spina bifida. Amphetamines given orally in doses approximately 1.5 and 8 times the normal human dose to both pregnant mice and rabbits had no apparent effects on fetal development, although parenteral doses at approximately 6 times the human dose resulted in fetal malformations in mice. However, it is important to note that animal studies are not predictive of human effects; teratogenicity in animals does not imply the same effect in humans, and lack of teratogenicity in animals does not ensure no effect in humans”, they conclude, adding that “The few human studies that have explored possible effects of these drugs on the fetus included only small numbers of subjects or were primarily focused on methylphenidate, while our experience indicates that amphetamine mixed salts is by far the most common (and most rapidly increasing) ADHD medication used by pregnant women in the United States”, says Louik and colleagues.

Most of the data we currently have derives from large Danish population studies. In one of them, Pottegård and colleagues evaluated data of 222 exposed and 2,220 unexposed pregnancies from 2005 to 2012 and found no statistically significant difference between the two groups in terms of risk for major congenital malformations. The same group also studied a total of 180 children exposed to methylphenidate in utero during first trimester (among whom four children with major malformations were observed) and concluded that methylphenidate exposure during pregnancy does not appear to be associated with a substantially (i.e. more than twofold) increased risk of congenital malformations.

A large cohort study monitoring 50,282 women with medication exposure during pregnancy with 367 women taking Dextroamphetamine and 215 unspecified Amphetamines in the first trimester demonstrated no increase in the risk of malformation in exposed infants. 

Based on these studies, the available data for methylphenidate suggest no increase in the risk of malformation when used at therapeutic doses.

However, there is some evidence that these infants may be at increased risk for low birth weight, preterm birth, growth retardation and neonatal withdrawal symptoms, but those findings are based on very small studies with several confounding limitations.

Good 2010 did a chart review including 267 women who had positive urine tests for methamphetamine compared to a control group of women with negative urine tests, and found a higher risk of  preterm delivery (52% vs. 17%), low Apgar scores (6% vs. 1–2%), and neonatal mortality (4% vs. 1%).

A study by Bro et al, published on the Journal of Clinical Epidemiology in 2015 on the adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy looked at 989,932 pregnancies, in which 186 (0.02%) women used MPH/ATX and 275 (0.03%) women had been diagnosed with ADHD but who did not take MPH/ATX. They found that exposure to MPH/ATX was associated with an increased risk of spontaneous abortion but also found that women with ADHD who did not take MPH/ATX also carried an increased risk. MPH/ATX was however associated with low Apgar scores <10, an association not found among women with ADHD who did not use MPH/ATX.

 In conclusion, the data on use of stimulant medications in pregnancy are too scarce to allow definitive conclusions about their reproductive safety. Available data for amphetamines suggest no increase in the risk of malformation when used at therapeutic doses, while infants might have slightly lower birth weights and lower Apgar scores.  Whenever possible, the clinician should attempt to manage ADHD symptoms through non-pharmacological strategies (e.g., behavioral modification), treat comorbidities that may aggravate the ADHD picture (mood and anxiety symptoms, sleep difficulties, alcohol and substance use), or use alternative medications that have more supporting evidence in pregnancy.

Is Lamictal safe in pregnancy?

Lamictal, also known as lamotrigine, is an anticonvulsant medication that is frequently used in psychiatry. It has been shown to be an effective maintenance medication in bipolar disorder--that is, studies have found evidence of its effectiveness in preventing depressive episodes in people with bipolar disorder. There is weaker evidence for its effectiveness in treating acute depressive episodes. Many of our patients have asked us about whether or not Lamictal is safe in pregnancy. 

The data that are available suggest that lamotrigine monotherapy is relatively safe in pregnancy. In 1992, a lamotrigine pregnancy registry was created to monitor for major congenital malformations (i.e., birth defects) in children of mothers who took lamotrigine during the first trimester. The registry collected data from 1,558 pregnancies over 18 years, and found that major congenital malformations occurred in 2.2% of exposures, which is very similar to the baseline rate of birth defects in the general population (frequently cited as between 2-4% of all pregnancies). On the other hand, the rate of birth defects in children exposed to both Lamictal and valproic acid (also known as Depakote), was 10.7%. A prospective study found evidence that the dosage of lamotrigine used affects rates of congenital malformations, with higher doses (>300 mg/ day) leading to a birth defect rate of 4.5%, but lower doses (<300 mg/day) leading to a rate of 2.0%. 

One of frequently cited risks of taking lamotrigine during the first trimester is the development of cleft lip or palate. The formation of the palate occurs between weeks 6 and 11 of gestation. The North American AED registry looked at 684 infants exposed to lamotrigine during the first trimester and found that the risk of developing cleft palate, lip, or both, was 0.73% in the exposed population, compared to 0.07% in the unexposed population. While 0.73% is 10.4x greater than 0.07%, it's important to note that the 0.73% absolute risk of developing a cleft palate or lip with lamotrigine exposure is still quite low, provided the results are accurate. Further, it's important to take the results with a grain of salt for several other reasons, including the relatively small number of women in the study population, and the lack of addressing possible confounding variables like maternal race, habits like smoking or alcohol use, exposure to other medications, and other medical problems. 

One important consideration for a patient who does decide to use Lamictal in pregnancy is that serum levels of the drug will decrease in pregnancy. Estrogen has been shown to increase the clearance, or elimination, of Lamictal, and in pregnancy, clearance increases by 250% on average. One way that this is monitored in patients who use lamotrigine for seizure control is that serum levels are obtained prior to pregnancy, and the dosage of the drug is increased during pregnancy so that serum levels remain above 65% of the pre-pregnancy level. Obtaining levels prior to and during pregnancy is not always necessary in patients who take Lamictal for bipolar disorder, but of course, could be helpful. 

The discerning reader may wonder that if estrogen increases the clearance of Lamictal, then perhaps oral contraceptives that contain estrogen will also lead to decreased Lamictal levels. That is correct! For more on this, please click here. 

I'm taking antidepressants while pregnant. Does that mean my child will develop autism?

Recently, an article linking antidepressant use in pregnancy with the risk of autism spectrum disorder in children was published in JAMA Pediatrics. What followed was a flurry of news reports like this and this, claiming that women who take SSRIs in pregnancy increase their child's risk of autism "by as much as 87%" (according to the Newsweek article). Scary news. In our clinic, many women who are either pregnant or preparing for pregnancy have asked us about whether taking antidepressant medications during pregnancy will increase the risk of autism in their children exposed in utero, so we think it's an important topic to cover.

ASD is a developmental disorder characterized by impaired communication and social interactions. More information can be found here. Right now, there is no known single cause, but we do know that risk factors for ASD include particular genetic variants, de novo mutations, maternal disease (like diabetes), and--importantly--maternal history of psychiatric disorders.   

Here's a brief summary of the JAMA article: it was a study that looked at all pregnancies that occurred in Quebec between 1/1/98 and 12/31/09. Data from from several databases were linked with unique personal identifiers to provide information about medical services, prescription drugs, hospitalization, and demographics. The researchers defined antidepressant (AD) exposure as having at least 1 prescription filled at any time during pregnancy or a prescription filled before pregnancy that overlapped with the first day of gestation. The outcome variable was whether or not children had a medical service claim or hospitalization with a diagnosis of ASD between birth and the end of follow-up. The researchers determined crude and adjusted hazard ratios (HRs) which are the expression of the hazard, or chance, of events occurring in the treatment arm as a ratio of the hazard, or chance, of the events occurring in the control arm. Basically, the HR could be expressed as follows:

The researchers found that the hazard ratio for the use of antidepressants during the second and/ or third trimester was 1.87, which is where various news sites got the 87% increased risk of ASD statistic. On the surface, this HR indicates that there is a higher chance of children being diagnosed with ASD in women who used ADs in the second and/ or third trimester than the chance of children being diagnosed with ASD in women who did not. The study authors suggest that this means that the use of antidepressants is associated with an 87% increased risk of ASD, even after taking into account particular confounders. (Of note, the hazard ratio for the use of ADs in the first trimester was 0.84.) However, when we look more closely at the study, we see a few problems with this conclusion: 

1.  The biggest problem is that maternal psychiatric illness, in particular, depression, is known to be associated with an increased risk of ASD in offspring. The study had no reliable measures of depression severity. Therefore, there is no way to tell whether the children were at higher risk for developing ASD because their mothers were taking antidepressants, or because their mothers had more severe depression. In Alison Stuebe's fantastic article on this topic in the Huffington Post, she writes the following: "The key problem is that women who take a medication when they are pregnant have a reason for taking it. Blaming the outcome on the medication, without considering the underlying disease, is like saying that umbrellas cause flooding. Taking away the umbrellas -- "not treating the rain" -- does not prevent flooding; it just means that people get soaked."
   
2.  Another problem with the author's conclusion about an 87% increased risk of autism is that the number is very misleading. If the average child has a 1.5% risk of autism (according to the CDC, the prevalence was 1.5% in 2010), then the children exposed to antidepressants in the second and/ or third trimester in this study had a risk of 2.8%, which is an absolute risk increase of 1.3%, a much more modest value than 87%. 
3. A sensitivity analysis that restricted the study population to children with ASD diagnosis confirmed by a psychiatrist of a neurologist found that the association between the use of antidepressants in the second and or third trimester and risk of ASD was no longer statistically significant (the confidence interval included 1). This means that it's important to realize that the study did not show an increased risk of ASD diagnosis in children of mothers who took antidepressants, but rather, an increased risk of a billing code (which could just indicate an evaluation) for ASD. 

Whether or not to continue taking antidepressants during pregnancy is a very personal decision, and best discussed with your clinician. It's important to remember that there are significant risks of untreated depression or anxiety in pregnancy, including prematurity, intrauterine growth restriction, and low birth weight, as well as higher rates of impulsivity, and cognitive, emotional, and behavioral problems in children. Mothers with untreated depression in pregnancy have significantly higher rates of relapse of their depression if they do not take their medications (68% compared to 26% in women who did continue taking medications during pregnancy), according to a large NIH study looking at mothers with severe depression. To put this in context, if 1000 women with severe depression stop taking their medications during pregnancy, then 680 of them would experience a relapse in major depression, while only 13 of the women would avoid an evaluation of their child for autism.