In pregnant rats receiving oral drug at doses up to 0.85 times maximum human daily dose (MHDD) during organogenesis, fetotoxicity and dose-related increases in bone variations (reduced ossification and rudimentary rib changes) were observed. Areas of necrosis in both the liver and kidney of pregnant rats and fetuses were observed when pregnant rats were given oral drug throughout gestation at doses 1.2 times the maximum human daily dose. Animal studies using the IV formulation have not been performed. In humans, this drug and its metabolites cross the placental barrier. Large cohort studies have not found an association between maternal use in the first trimester and either adverse pregnancy outcomes or congenital malformations. Some evidence of increased risk of neurodevelopmental disorders (e.g., attention deficit hyperactivity disorder [ADHD]), respiratory illness (e.g., asthma) and reproductive toxicity (e.g., androgen disruption) has been suggested in epidemiologic studies. However, extrapolating causation from pharmaco-epidemiological studies to humans is tricky considering various confounders and biases inherent in the study design. Associations seen in clinical cohort studies need clarification with randomized clinical trials (RCTs), which would be difficult to perform ethically in pregnant populations. The mechanism by which this drug or its metabolites affect neurological development, asthma, or endocrine/reproductive toxicity is poorly understood. It is important to factor in the risk of untreated febrile illness in mother and child when evaluating risks and benefits of using this drug. There are no controlled data in human pregnancy.

Epidemiologic data, including a population based case-control study from the National Birth Defects Prevention Study (n= 11,610) and data from 26,424 live singleton births have shown no increased risk of major birth defects in children with first trimester prenatal exposure. In 2015, the US Food and Drug Administration released results of their evaluation on published research studies looking at mothers who took this drug as either an over the counter or prescription product at any time during their pregnancy and the risk of attention deficit hyperactivity (ADHD) in their babies. They found all studies reviewed had potential limitations in their designs that prevented drawing reliable conclusions. In a prospective birth cohort study (Avon Longitudinal Study or Parents and Children [ALSPAC]) maternal drug exposure was assessed by questionnaire at 18 and 32 weeks, children were assessed at 61 months. Mothers were questioned about behavioral problems in their children at 7 years old; children's behavioral problems were assessed using the Strengths and Difficulties Questionnaire (SDQ). A number of confounders were evaluated although a limitation of the study was lack of information for drug use. The authors suggest there may be an association between drug use during pregnancy and behavioral problems in childhood that may be due to an intrauterine mechanism. Further studies are needed to test alternatives to a causal explanation.

According to published animal studies, this drug may cause reduced fertility in both males and females described as decreased testicular weights, reduced spermatogenesis, reduced fertility; and reduced implantation sites, respectively.

AU TGA pregnancy category A: Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Benefit should outweigh risk

AU TGA pregnancy category: A
US FDA pregnancy category: Not Assigned

Risk Summary: A clear association of drug use and birth defects, miscarriage, or adverse maternal or fetal outcomes has not been shown with human use; animal studies have demonstrated adverse events at clinically relevant doses.

See references

Caution is recommended.

Excreted into human milk: Yes

Comments;
-This drug has been used without apparent harmful effects.
-This drug is considered compatible with breastfeeding by the American Academy of Pediatrics.

This drug is excreted into breast milk in very small amounts. Published reports reveal peak levels occur 1 to 2 hours after dosing and are undetectable after 12 hours. Reports have also shown infants ingesting 90 mL of breast milk every 3 hours would receive an average of 0.14% (range 0.04% to 0.23%) of the mother's dose; calculated to be a maximum maternal weight-adjusted dose of around 2%. Other studies have shown similar calculated maximal maternal weight adjusted doses (1.1% to 3.6%); these doses are about 0.5% of the lowest recommended infant dose of this drug. A single case of a maculopapular rash has been reported in a 2-month old nursing infant; the rash recurred on rechallenge.

See references