ADHD Drugs Associated With Modest Risks During Pregnancy

Norra MacReady

November 10, 2017

Two large studies of pregnant women with attention-deficit hyperactivity disorder (ADHD) suggest that stimulant medications taken during pregnancy are associated with a modestly increased risk for perinatal and placental abnormalities. The authors of both studies, though, caution that those risks must be weighed against those of untreated ADHD.

If the medication is essential to manage a woman's symptoms, "we do not find that our results concerning neonatal complications justify abstaining from therapy," Ulrika Nörby, MSc Pharm, PhD, lead author of one of the studies, told Medscape Medical News. "Poorly controlled ADHD symptoms might result in poorer adherence to antenatal care, an unhealthier lifestyle and increased maternal stress that, in turn, can affect the fetus negatively."

Jacqueline M. Cohen, PhD, lead author of the other study, echoed that point. "The increases in risk identified do not warrant abstaining from critical treatment," she told Medscape Medical News. "It is important to balance the benefits of treatment, which may improve functioning, including maintaining family relationships, adherence to prenatal care, and avoidance of substance abuse."

If anything, the results are reassuring because they suggest that "ADHD medications, taken in a controlled fashion, under the care of a doctor, with regular prenatal visits, have good pregnancy outcomes," said Tina A. Nguyen, MD, assistant professor of maternal-fetal medicine in the Department of Obstetrics and Gynecology, University of California, Los Angeles Health/David Geffen School of Medicine. Dr. Nguyen was not involved in either study.

Effects on the Infant

In their study, published online today in Pediatrics, Dr. Nörby, from the Centre of Reproduction Epidemiology, Tornblad Institute, Department of Clinical Sciences, Lund University in Sweden, and colleagues analyzed singleton births recorded in the Swedish Medical Birth Register (MBR) between July 1, 2006, and December 31, 2014. The MBR captures essentially all births in Sweden and is linked to three other national registers that contain data on prescription drugs dispensed at Swedish pharmacies and infants admitted to neonatal intensive care units (NICUs).  

The final cohort consisted of 964,734 infants, of whom 1591 (0.2%) were exposed to ADHD drugs during gestation, and another 9475 (1%) whose mothers used ADHD medications before or after, but not during, pregnancy. Stimulants accounted for 1464 (92%) of the in utero exposures, but 165 infants were born to women who used atomoxetine during pregnancy.

The rate of NICU admission among infants exposed to ADHD drugs during pregnancy was higher than that of infants whose mothers never used these agents (adjusted odds ratio [aOR], 1.5; 95% confidence interval [CI], 1.3 - 1.7), after adjustment for a variety of potential confounding factors, such as birth year, maternal age, body mass index, and smoking status, and maternal use of other drugs, such as opioids and antiepileptics. The risk also was increased in comparison with children whose mothers used the medication before or after pregnancy (aOR, 1.2; 95% CI, 1.1 - 1.4).

Maternal use of ADHD medication during pregnancy also was associated with a higher frequency of central nervous system disorders, such as seizures and congenital hypotonia, compared with no use (aOR, 1.9; 95% CI, 1.1 - 3.1) or use before or after pregnancy (aOR, 1.8; 95% CI, 1.0 - 3.3; P = .05). In addition, ADHD drug treatment  during pregnancy was also associated with an elevated risk for preterm delivery (aOR, 1.3; 95% CI, 1.1 - 1.6) compared with no use

Compared with the control group, women who used ADHD medications were significantly younger and were  more likely to be obese, to be nulliparous, to smoke, to use other medications, and to live without the child's father. These differences were especially pronounced among women treated with ADHD drugs while pregnant.

These demographic differences suggest that women who need ADHD treatment during pregnancy "in many ways are a vulnerable group," Dr Nörby told Medscape Medical News.

Consider the Context

In fact, these findings should be interpreted cautiously precisely because of the differences between the women in this study, said Sue Varma, MD, clinical assistant professor of psychiatry at the New York University Langone Medical Center in New York City. For that reason, "the results can't at this point be generalized to a population at large," she told Medscape Medical News.

Given the potential for risk to the fetus, "I would want to understand what is the mother's baseline level of functioning, and ideally I would recommend a taper off the medication, if possible," said Dr Varma, who was not involved in either study. However, she added, "if there has been a significant level of impairment, and medication is necessary, I would indeed consider it."

Placental and Perinatal Effects

In the second study, published in the December issue of Obstetrics & Gynecology, Dr Cohen, a postdoctoral research fellow in the Department of Epidemiology, Harvard T.H. Chan School of Public Health in Boston, Massachusetts, and coauthors evaluated the effects of stimulant medication for ADHD on the risk for preeclampsia, placental abruption, fetal growth restriction, and preterm birth among women enrolled in Medicaid who gave birth between 2000 and 2010.

They compared outcomes from women taking amphetamine-dextroamphetamine or methylphenidate monotherapy with outcomes among women who did not receive a prescription for any ADHD stimulant medication during the 3 months before pregnancy through 140 days after their last menstrual cycle.

To control for the possibility that ADHD was itself a risk factor, they also compared the women taking stimulants to those using atomoxetine, which they described as "a nonstimulant ADHD medication used in cases in which other stimulants are ineffective or need to be avoided as a result of side effects or potential for abuse."

The final cohort consisted of 1,466,792 women, including 4846 who used stimulants for ADHD at some time during pregnancy, 453 who used atomoxetine, and 1,461,493 in the control group.

After adjustment for demographic factors; multifetal gestation; use of alcohol, tobacco, and other drugs; obesity or overweight; and presence of certain health conditions, stimulant use was associated with a relative risk (RR) for preeclampsia of 1.29 (95% CI, 1.11 - 1.49) and amphetamine-dextroamphetamine use with an RR of 1.33 (95% CI, 1.12 - 1.58), compared with no exposure to these agents.

Similarly, stimulant use was associated with an adjusted RR for placental abruption of 1.13 (95% CI, 0.88 - 1.44), 0.91 for infants born small for gestational age (95% CI, 0.77 - 1.07), and 1.06 for preterm birth (95% CI, 0.97 - 1.16), compared with no exposure. Atomoxetine use was not associated with any of the outcomes studied in crude or adjusted analyses.

In a comparison of women who discontinued stimulant monotherapy after the first half of pregnancy, compared with those who continued it, continuation was associated with an adjusted RR for preterm birth of 1.30 (95% CI, 1.10 - 1.55). Continuation also was associated with an adjusted RR for preeclampsia of 1.26 (95% CI, 0.94 - 1.67), 1.08 for placental abruption (95% CI, 0.67 - 1.74), and 1.37 for being born small for gestational age (95% CI, 0.97 - 1.93).

Although stimulants were associated with an increased risk for preeclampsia and preterm birth, "the absolute increases in risks are small and thus, women with significant ADHD should not be counseled to suspend their ADHD treatment based on these findings," the authors write.

Taken together, the studies "point to a potential increased risk of preterm birth associated with stimulant treatment," Dr Cohen told Medscape Medical News. "Our study also suggests that stimulant ADHD medications modestly increase the risk of preeclampsia. But we found no evidence of increased risk of placental complications associated with atomoxetine, which suggests that nonstimulant ADHD medications may be safer to use in pregnancy, though more research is needed due to the smaller number exposed."

"These studies provide some reassurance to pregnant women who strongly benefit from treatment with ADHD medication that the potential increases in risk for perinatal complications are modest," she concluded.

Dr Cohen has received salary support from a research grant from GlaxoSmithKline for unrelated work. Other coauthors report receiving salary or research funding or institutional training grants from GlaxoSmithKline, Eli Lilly, Pfizer, UCB, Teva, Boehringer-Ingelheim, Takeda, Bayer, Asisa, Pacira, Baxalta, Optum, and Merck. None of the other researchers or commentators have disclosed relevant financial relationships.

Pediatrics. Published online November 1, 2017. Abstract

Obstet Gynecol. 2017;130:1192-1201. Abstract

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