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Maternal use of certain drugs during pregnancy can result in transient neonatal signs consistent with withdrawal or acute toxicity or cause sustained signs consistent with a lasting drug effect. In addition, hospitalized infants who are treated with opioids or benzodiazepines to provide analgesia or sedation may be at risk for manifesting signs of withdrawal. This statement updates information about the clinical presentation of infants exposed to intrauterine drugs and the therapeutic options for treatment of withdrawal and is expanded to include evidence-based approaches to the management of the hospitalized infant who requires weaning from analgesics or sedatives.

This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies. This workshop is part of continuing efforts to raise the awareness of the public for women who choose to breastfeed their infants.

Objective To delineate the pharmacokinetics of oseltamivir and its active metabolite oseltamivir carboxylate during pregnancy. Physiologic changes of pregnancy, including increased renal filtration and secretion, may increase the clearance of oseltamivir carboxylate. Study Design Sixteen pregnant women taking oseltamivir for prophylaxis or treatment of suspected/proven influenza infection were enrolled. Twenty-three non-pregnant reproductive-age females served as the control group. The primary pharmacokinetic endpoint was area under the plasma concentration-time curve (AUC) for oseltamivir carboxylate. Results Pregnancy did not alter the pharmacokinetic parameters of the parent compound, oseltamivir. However, for oseltamivir carboxylate the area under the plasma concentration-time curve (AUC) was significantly lower (p=0.007) and the apparent clearance significantly higher (p=0.006) in pregnant women compared with non-pregnant women. Conclusions Pregnancy produces lower systemic levels of oseltamivir carboxylate. Increasing the dose and/or dosing frequency of oseltamivir during pregnancy may be necessary in order to achieve comparable exposure in pregnant and non-pregnant women.

Abstract. Despite the fact that a significant percentage of the population is unable to swallow tablets and capsules, these dosage forms continue to be the default standard. These oral formulations fail many patients, especially children, because of large tablet or capsule size, poor palatability, and lack of correct dosage strength. The clinical result is often lack of adherence and therapeutic failure. The American Association of Pharmaceutical Scientists formed a Pediatric Formulations Task Force, consisting of members with various areas of expertise including pediatrics, formulation development, clinical pharmacology, and regulatory science, in order to identify pediatric, manufacturing, and regulatory issues and areas of needed research and regulatory guidance. Dosage form and palatability standards for all pediatric ages, relative bioavailability requirements, and small batch manufacturing capabilities and creation of a viable economic model were identified as particular needs. This assessment is considered an important first step for a task force seeking creative approaches to providing more appropriate oral formulations for children.

Pregnant and breastfeeding women have been rendered therapeutic orphans as they have been historically excluded from clinical trials. Labelling for most approved drugs does not provide information about safety and efficacy during pregnancy. This lack of data is mainly due to ethico-legal challenges that have remained entrenched in the post-diethylstilbestrol and thalidomide era, and that have led to pregnancy being viewed in the clinical trial setting primarily through a pharmacovigilance lens. Policy considerations that encourage and/or require the inclusion of pregnant or lactating women in clinical trials may address the current lack of available information. However, there are additional pragmatic strategies, such the employment of pharmacometric tools and the introduction of innovative clinical trial designs, which could improve knowledge about the safety and efficacy of medication use during pregnancy and lactation. This paper provides a broad overview of the pharmacoepidemiology of drugs used during pregnancy and lactation, and offers recommendations for regulators and researchers in academia and industry to increase the available pharmacokinetic and -dynamic understanding of medication use in pregnancy.

OBJECTIVE The purpose of this study was to estimate pharmacokinetic parameters and to evaluate placental transport of 17-hydroxyprogesterone caproate (17-OHPC) in singleton gestation. STUDY DESIGN Sixty-one women who received weekly injections of 17-OHPC underwent 2 pharmacokinetic studies at 20 + 0 to 24 + 6 weeks’ gestation (study 1) and 31 + 0 to 34 + 6 weeks’ gestation (study 2); daily blood samples were obtained between injections. In 18 women, blood samples were obtained over a 28-day period beyond the last injection (extended study). Maternal and/or cord blood were obtained at delivery. RESULTS The half-life (median ± SD) of 17-OHPC was 16.2 ± 6 days. Concentrations of 17-OHPC were higher during study 2 than during study 1. Body mass index affected maternal 17-OHPC concentrations. Cord:maternal 17-OHPC concentration ratios averaged 0.2; 17-OHPC was detectible in cord plasma 44 days after the last maternal injection. CONCLUSION The apparent half-life of 17-OHPC is long, and pharmacokinetic parameters vary widely between subjects and are affected by maternal body mass index. The drug crosses the placental barrier.

This Commentary addresses issues related to exposures to teratogens and makes the case for increased research into the safety of medications during pregnancy for mothers and fetuses. Not only are medications commonly used during pregnancy, but evidence points to an increasing prevalence and number of drug exposures experienced by the embryo or fetus, particularly during the critical first trimester of pregnancy. Although the first trimester represents a particularly vulnerable period of organogenesis, exposures during other gestational time periods may also be associated with deleterious outcomes. In addition to the changing (and in many cases unknown) risks to a developing fetus, other challenges to studying medication exposures and their effects during pregnancy include the dramatic changes in physiology that occur in pregnant women and the ethical dilemmas posed by including this vulnerable population in randomized controlled trials of safety and efficacy. However, without adequate knowledge of the pharmacokinetics, pharmacodynamics, efficacy, and safety of medication use in pregnancy, women may be under-dosed to minimize exposure or not treated at all, resulting in inadequate treatment and potential harm to the mother and her baby. The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is undertaking studies on medications and teratogenic exposures during pregnancy, including alcohol, maternal diabetes, oral hypoglycemic agents, and antiviral medications, through several of its research networks. Although this is a start, there is a critical need for further research on medications used during pregnancy, especially their effects on both the mother and her developing child.