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.