What are the risks of using Adderall (amphetamine and dextroamphetamine) and acetazolamide during the first four weeks of pregnancy?

Risks of Adderall and Acetazolamide in First Four Weeks of Pregnancy

Adderall and acetazolamide use during the first four weeks of pregnancy should be approached with caution, with Adderall carrying potential risks for preeclampsia and preterm birth, while acetazolamide has limited evidence of teratogenicity in humans despite animal studies showing concerns.

Adderall (Amphetamine and Dextroamphetamine) Risks

Teratogenic Risk

• Dextroamphetamine has shown embryotoxic and teratogenic effects in mice at doses approximately 41 times the maximum human dose, but these effects were not seen in rabbits or rats at lower doses 1
• The American College of Obstetricians and Gynecologists suggests that amphetamines do not appear to be associated with major congenital malformations or other significant adverse developmental outcomes 2
• FDA classifies amphetamines as Pregnancy Category C, indicating that animal studies have shown adverse effects, but adequate human studies are lacking 1

Obstetric Complications

• Possible small increased risk for preeclampsia with amphetamine use (adjusted relative risk 1.29,95% CI 1.11-1.49) 2, 3
• Potential increased risk for preterm birth, particularly with continued use in later pregnancy (adjusted relative risk 1.30,95% CI 1.10-1.55) 2, 3
• Recent evidence suggests increased rates of fetal loss through abortion and miscarriage with methylphenidate, which has a similar mechanism of action to Adderall 4
• A 2024 study found that continuing dexamphetamine throughout pregnancy was associated with higher risk of preeclampsia, hypertension, postpartum hemorrhage, and neonatal special care unit admittance compared to unexposed women 5

Pharmacokinetic Considerations

• Urinary alkalinizing agents (including acetazolamide) increase the concentration of amphetamines by decreasing urinary excretion, potentially increasing blood levels and potentiating effects 1
• This drug interaction is particularly concerning when both medications are used concurrently during pregnancy 1

Acetazolamide Risks

Teratogenic Risk

• Historically, acetazolamide has not been recommended during pregnancy due to reported teratogenic effects in animal studies (rodents and rabbits) 6
• However, a study of 50 pregnancies with acetazolamide exposure before 13 weeks of gestation found no convincing evidence of adverse effects in human pregnancy 6
• The risk of spontaneous abortion was similar to control groups, and no major complications were identified in offspring of women treated with acetazolamide 6

Drug Interactions

• Acetazolamide functions as a urinary alkalinizing agent that can increase blood levels of amphetamines by decreasing their urinary excretion 1
• This interaction could potentially increase fetal exposure to amphetamines when both medications are used together 1

Neurodevelopmental Considerations

ADHD Medication and Neurodevelopment

• Untreated ADHD has been associated with increased risks for spontaneous abortion and preterm birth 2
• Discontinuing ADHD treatment during pregnancy could put both mother and baby at risk, which must be balanced against the possible risks to the baby of continuing treatment 4

Acetaminophen Comparison (Relevant Context)

• Recent evidence suggests prenatal acetaminophen exposure may be associated with increased risk of ADHD and ASD in children 7, 8
• This association appears to have a dose-dependent relationship, with stronger associations observed with use in multiple trimesters 7, 8
• While acetazolamide has different mechanisms, this highlights the importance of considering long-term neurodevelopmental outcomes for any medication used during pregnancy 7

Clinical Approach

Risk Assessment

• The decision to use either medication during early pregnancy should involve careful consideration of maternal benefits versus potential fetal risks 2, 4
• For Adderall, the number needed to harm is about 63 for amphetamine exposure and preeclampsia, and larger (>500) for other adverse outcomes 3
• For acetazolamide, while animal studies showed concerns, human data suggests lower risk than previously thought 6

Monitoring Recommendations

• If Adderall is continued during pregnancy, regular monitoring of blood pressure and pulse is essential due to increased risk of preeclampsia 2
• Monitor for signs of preterm labor, especially if treatment continues beyond the first trimester 2, 3
• Consider the potential synergistic effect when both medications are used together, which may require dose adjustments 1

Alternative Approaches

• Non-pharmacological approaches such as Dialectical Behavior Therapy (DBT) can be considered for ADHD management during pregnancy 2
• For conditions requiring acetazolamide (such as intracranial hypertension), the medication should remain a treatment option when clinically indicated, as the risks appear lower than previously thought 6

Key Caveats

• Most studies on medication safety during pregnancy have methodological limitations including self-reported exposure, lack of dosage information, and confounding factors 7
• The first four weeks of pregnancy represent a critical period of embryonic development, making medication exposure during this time particularly concerning 1
• The combined use of Adderall and acetazolamide presents additional risks due to their pharmacological interaction 1