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.

Caffeine and Pregnancy. How much is too much?

Last week news shows such as Today announced results from a recent study from the National Institute of Child Health and Human Development that associates caffeine consumption with early pregnancy loss. Headlines stated “drinking three or more caffeinated beverages a day raised the risk of early pregnancy loss.”  These headlines further confuse the already confusing question about how much caffeine intake is “okay” if you are trying to conceive or already pregnant.

The study published in Fertility and Sterility followed 344 expectant couples and examined lifestyle factors and the rate of early pregnancy loss. The study measured the number of caffeinated beverages partners drank as well as multivitamin use before they conceived through the seventh week of pregnancy. Researchers concluded that drinking three or more caffeinated beverages a day (before conception or during pregnancy) raised the risk of early pregnancy loss by 74 percent. Male preconception consumption of caffeinated beverages was found to be just as strongly associated with pregnancy loss as females.  The study however found that if a woman took multivitamin while she was trying to become pregnant through the first seven weeks of pregnancy  there was nearly a 80 percent reduction in the risk of miscarriage.

The study however only looked at an association, meaning it doesn't prove a cause and effect relationship.  It does not prove that caffeine intake itself leads to miscarriage. Another limitation is that the study examined the number of caffeinated beverages rather than measure total caffeine intake.  Caffeine content of caffeinated beverages can vary wildly between beverages. Nor did the study control for other confounding factors (exercise, sleep, or recreation drug use).  Individuals who drink more then 3 cups of coffee a day may be different that those who do not drink coffee. If these factors are not controlled for results can be misleading. For instance, high caffeine drinkers may have higher levels of subjective stress with poorer sleep habits etc. which may contribute to fertility loss.  Cigarette smoking, alcohol consumption, and a less health conscious lifestyle have all been linked to increased coffee consumption .

A previous 2011 systematic review  published in Birth Defects Research Part B of Developmental and Reproductive Toxicology  examined  both human and animal studies and  he risk of spontaneous abortion from caffeine exposure. They  concluded there was fair to good evidence that consumption of caffeinated beverages during pregnancy at a level ≤5 to 6 mg/kg body weight/day does not increase the risk of spontaneous abortion. Very very high caffeine intake in some animal studies demonstrates some increased risk however woman drinking  over a dozen cups of coffee in a day would not approach this level of caffeine intake.

Previous publications report an association between caffeine use in pregnancy and low birth weight and preterm birth.  For instance a  2014 meta-analysis of 100,000+ women reported that increases in maternal caffeine intake during pregnancy is associated with increased risk of delivering low birth weight infants (in a dose dependent manner).  However a randomized double blind trial that analyzed the effect of reducing caffeine intake found no effect on birth weight or preterm  birth when caffeine intake was decreased by 50% in women drinking 3+ cups a day prior to study enrollment. A 2010 systematic review similarly did not demonstrate a significant association between maternal caffeine intake anytime in pregnancy and preterm birth.

Given the knowledge of literature the American College of Gynecology states there is insufficient evidence to support reducing caffeine use below 200mg/day.

For hopeful or expecting mothers the first step is to determine how much caffeine you are consuming.  Caffeine is most associated with coffee, tea, soft drinks, and energy drinks. Content and can vary dramatically between products and brands.  For example the same size coffee at Starbucks has double the caffeine content compared to McDonalds. 

Caffeine can be also be present in unexpected places such some prescription and over the counter medications such as those for flu/cold, allergy, and headaches as well as diet pills and diuretics.   Caffeine content of popular items can be found here.

Dr. Williams of the Albert Einstein College of Medicine and a spokesman for the American College of Obstetricians and Gynecologists  warns " what I do end up seeing not infrequently, an effort to really be as thorough as possible, a lot of women will go cold turkey on caffeine. And what ends up happening is invariably these women will then develop rebound headaches and take medications to treat the headaches. Those medications may be harmful.”

If you decide to cut caffeine “cold turkey” you may experience withdrawal symptoms such as headache, anxiety/irritability, constipation/diarrhea, low mood, low energy, sweating, or shakiness. Most symptoms dissipate in few days but can last as long as two weeks for heavy drinkers. Gradually decreasing caffeine content over 1-2 weeks can minimize the risk of withdrawal symptoms. Strategies for decreasing caffeine content include transitioning to decaf, switching out tea for coffee, or drinking tea with a lower caffeine content.