Should pregnant women be included in phase IV clinical drug trials?

Relatively few drugs, especially those recently approved by the US Food and Drug Administration, have published human pregnancy experience. Although all drugs contain animal reproduction data, these are usually not predictive of human risk. Clinical trials in pregnant women are rarely conducted because of ethical and legal concerns, and it may be many years before sufficient observational data are collected to guide clinical treatment decisions. Because many of these drugs will be used in pregnancy, human data are needed shortly after the drugs come to the market. Lack of human data leads to uncertainty over whether a drug can be safely prescribed for a pregnant patient. Unless there are compelling scientific and ethical reasons to exclude them, pregnant women should be included in phase IV clinical trials (postmarketing studies to obtain additional information, including the risks, benefits, and optimal use of a drug). This paper examines how physicians currently counsel pregnant women when there are no human data and proposes an alternative method in which knowledge regarding risks associated with the use of drugs during pregnancy can be enhanced in a clinical trial setting.

The pharmacologic management of nausea and vomiting of pregnancy.

Nausea and vomiting are common in early pregnancy. Forty percent or more of pregnant women may continue to suffer beyond the first trimester and 10% beyond the second trimester. A focus of the assessment is to confirm that the nausea and vomiting is due to the pregnancy and not some other cause. Nonpharmacologic options, particularly dietary modification, are a mainstay of treatment. For those who continue to experience symptoms, pharmacologic management can be employed. The combination of doxylamine succinate/pyridoxine hydrochloride was reintroduced in the United States following FDA approval in early 2013. The product was given a pregnancy safety rating of A and is recommended as first-line pharmacologic treatment for NVP. Other options include antihistamines, metoclopramide, ondansetron, phenothiazines, and after the first trimester, corticosteroids.

Obstetrical opportunities: will pharmacy ever realize them?

Based on a survey of the American College of Clinical Pharmacy Women's Health Practice and Research Network and our own experience, the pharmacy profession has limited involvement in obstetric pharmacotherapy. We believe that such involvement in pregnancies with complicated conditions can result in significant improvement of pregnancy outcomes. Moreover, we believe this involvement would be welcomed by the physicians caring for these patients. This commentary documents current obstetrical pharmacy practices and proposes changes for the profession of pharmacy to consider.

Use of duloxetine in pregnancy and lactation.

OBJECTIVE: To report a case of a woman who used duloxetine during pregnancy and breast-feeding. CASE SUMMARY: A 29-year-old woman was treated with duloxetine for depression during the second half of an uncomplicated gestation. She gave birth at term to a healthy female infant. A cord blood sample was obtained at birth. The mother continued the antidepressant while exclusively breast-feeding her infant. One month later, we collected blood and milk samples from the mother and a single blood sample from the infant. All samples were analyzed for the presence and concentrations of duloxetine. DISCUSSION: Duloxetine crosses the placenta at term and is excreted into breast milk. No evidence of developmental or other type of toxicity was observed in the infant at birth or during the first 32 days after birth. The published literature detailing human pregnancy experience with this antidepressant is limited to 11 cases in which women became pregnant while taking duloxetine. In 10 cases, the drug was discontinued when pregnancy was diagnosed and no outcome data were reported. In the eleventh case, an infant exposed to duloxetine 90 mg/day developed neonatal behavioral syndrome. One study examined the excretion of duloxetine into breast milk, but the mothers discontinued nursing for the study. In the present case, no adverse effects from exposure to the drug in milk were noted in the exclusively breast-fed infant. The possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded because long-term follow-up has not been conducted in infants exposed to duloxetine in utero or during nursing. CONCLUSIONS: No developmental toxicity or other signs of toxicity were observed in an infant exposed to duloxetine during the second half of gestation and during breast-feeding in the first 32 days after birth. However, the possibility of functional/neurobehavioral deficits appearing later in life cannot be excluded.

Better data needed from pregnancy registries.

This article is a consensus position statement from the Research Committee of the Organization of Teratology Information Specialists (OTIS). The Committee believes that more specific information on the timing and dose of drug exposures from pregnancy birth defect registries sponsored by pharmaceutical companies (herein called pregnancy registries) would improve the estimation of risk for developmental toxicity (i.e., growth alteration, structural anomalies, functional/neurobehavioral deficits, or death). Specifically, the Committee believes that the exposure timing should be stated in gestational weeks and days rather than simply weeks. In addition, the Committee believes that the exposure dose should be stated in patient-specific terms, such as body weight (mg/kg) or body surface area (mg/m(2)) rather than simply dose strength. Although the focus of this position is pregnancy registries, it also is applicable to any source of medication-induced embryo-fetal toxicity.

High-dose carisoprodol during pregnancy and lactation.

OBJECTIVE: To report a case of use of high-dose carisoprodol during pregnancy and breast-feeding. CASE SUMMARY: A 28-year-old woman with severe back muscle spasm took carisoprodol 2800 mg/day before and throughout an uncomplicated pregnancy and while exclusively breast-feeding her infant during the first month after birth. Serum drug concentrations of carisoprodol and the active metabolite meprobamate were measured in the mother and infant. Concentrations of these agents also were measured in breast milk. Developmental toxicity was not observed in the near-term infant, whose birth weight was at the 10th percentile for gestational age. Only slight sedation was noted in the infant during breast-feeding, and no signs or symptoms of withdrawal were noted when nursing was stopped. DISCUSSION: Carisoprodol and meprobamate are excreted into breast milk. Although the published human pregnancy data are limited to 15 cases, carisoprodol does not appear to cause developmental toxicity (growth restriction, structural anomalies, functional/neurobehavioral deficits, or death), even when the mother is taking high doses. No signs or symptoms of withdrawal were noted in our infant or in a previously published case when breast-feeding was stopped. Long-term follow-up has not been conducted in exposed infants, and the possibility of functional/neurobehavioral l deficits appearing later in life cannot be excluded. CONCLUSIONS: Except for mild sedation, no other toxicity was observed in a near-term infant exposed to carisoprodol throughout gestation and during breast-feeding in the first month after birth.

Oral antidiabetic agents in pregnancy and lactation: a paradigm shift?

OBJECTIVE: To provide information on the use of oral antidiabetic agents in pregnancy and breast-feeding. DATA SOURCES: Primary articles were identified by a MEDLINE search (1966-March 2007) using the MeSH headings: pregnancy in diabetics, pregnancy, polycystic ovary syndrome, hypoglycemic agents, glipizide, glyburide, metformin, rosiglitazone, pioglitazone, clinical trial, controlled clinical trial, multicenter study, randomized controlled trial, case-control studies, and cohort studies. STUDY SELECTION AND DATA EXTRACTION: All studies using oral antidiabetic agents in pregnancy were evaluated and relevant data were included in the discussion. DATA SYNTHESIS: Studies of glyburide and glipizide have found little or no transfer of these drugs across the placenta, whereas metformin and rosiglitazone cross readily. Animal studies have found no evidence to suggest that glyburide, glipizide, metformin, or rosiglitazone are teratogenic. In gestational diabetes, glyburide was safe and efficacious; however, 16-19% of women failed to achieve optimal glucose control. No developmental toxicity in infants was observed when metformin was used before and throughout pregnancy in women with polycystic ovarian syndrome (PCOS). Some of the studies involving patients with type 2 diabetes had methodological problems. A randomized controlled trial using metformin for gestational diabetes in the third trimester is underway. The human information is inadequate to evaluate the risk of glipizide or the thiazolidinediones in pregnancy. In breast milk, 3 studies measured nonsignificant amounts of metformin and one study was unable to detect either glyburide or glipizide. CONCLUSIONS: Neither glyburide nor metformin has caused developmental toxicity in humans. Glyburide has been used for the treatment of gestational diabetes, and metformin has been used in women with PCOS who eventually became pregnant. Additional trials are needed to better define the benefits and risks of oral antidiabetic agents in pregnancy. Metformin, glyburide, and glipizide appear to be compatible with breast-feeding.

Drug therapy during labor and delivery, part 2.

PURPOSE: The drug therapy of common conditions and complications during labor and delivery and the fetal and neonatal effects of this therapy are examined. SUMMARY: The pharmacologic therapy of common conditions that occur in labor and delivery primarily involves oxytocin and prostaglandins for cervical ripening and labor induction and systemic and regional narcotic analgesics for pain. Because most medications used in women during labor and delivery do not have Food and Drug Administration-approved labeling, pharmacists should understand the benefits and limitations of medications used in the mother. Although induction and augmentation of labor and the control of pain often require drug therapy, other, less frequent, complications may occur in labor. Drug therapies for these complications include anti-infective agents to treat maternal infection and prevent neonatal diseases; antiretrovirals to reduce perinatal HIV-1 transmission from the mother to the fetus; corticosteroids to prevent fetal lung immaturity; antihypertensives to treat preeclampsia; anticonvulsants to treat eclampsia; antibiotics to prolong pregnancy and improve neonatal outcomes after premature rupture of the membranes; tocolytics for premature labor; and oxytocin, ergot alkaloids, and prostaglandin analogues for postpartum hemorrhage. The fetal and neonatal effects of therapy for the conditions that occur during labor and delivery are usually benign, but significant morbidity and mortality involving the mother, the fetus, and the newborn are ever-present risks. CONCLUSION: Awareness of the conditions and complications requiring drug therapy during labor and delivery will allow hospital pharmacists to make knowledgeable decisions about the rapid accessibility of critical medications in the labor and delivery unit.

Drug therapy during labor and delivery, part 1.

PURPOSE: The drug therapy of common conditions and complications during labor and delivery and the fetal and neonatal effects of this therapy are examined. SUMMARY: The pharmacologic therapy of common conditions that occur in labor and delivery primarily involves oxytocin and prostaglandins for cervical ripening and labor induction and systemic and regional narcotic analgesics for pain. Because most medications used in women during labor and delivery do not have Food and Drug Administration-approved labeling, pharmacists should understand the benefits and limitations of medications used in the mother. Although induction and augmentation of labor and the control of pain often require drug therapy, other, less frequent, complications may occur in labor. Drug therapies for these complications include anti-infective agents to treat maternal infection and prevent neonatal diseases; antiretrovirals to reduce perinatal HIV-1 transmission from the mother to the fetus; corticosteroids to prevent fetal lung immaturity; antihypertensives to treat preeclampsia; anticonvulsants to treat eclampsia; antibiotics to prolong pregnancy and improve neonatal outcomes after premature rupture of the membranes; tocolytics for premature labor; and oxytocin, ergot alkaloids, and prostaglandin analogues for postpartum hemorrhage. The fetal and neonatal effects of therapy for the conditions that occur during labor and delivery are usually benign, but significant morbidity and mortality involving the mother, the fetus, and the newborn are ever-present risks. CONCLUSION: Awareness of the conditions and complications requiring drug therapy during labor and delivery will allow hospital pharmacists to make knowledgeable decisions about the rapid accessibility of critical medications in the labor and delivery unit.

Transfer of glyburide and glipizide into breast milk.

OBJECTIVE: To determine if glyburide and glipizide are excreted into breast milk and if breast-feeding from women taking these drugs causes infant hypoglycemia. RESEARCH DESIGN AND METHODS: We studied eight women who had received a single oral dose of 5 or 10 mg glyburide. Drug concentrations were measured in maternal blood and milk for 8 h after the dose. In a separate study, five women were given a daily dosage (5 mg/day) of glyburide or glipizide, starting on the first postpartum day. Maternal blood and milk drug concentrations and infant blood glucose were measured 5-16 days after delivery. RESULTS: In the single-dose glyburide study, the mean maximum theoretical infant dose (MTID) as a percent of the weight-adjusted maternal dose (WAMD) was <1.5 and <0.7% for the 5- and 10-mg doses, respectively. For the five women taking daily dosages, the mean MTID as a percent of the WAMD was <28% for glyburide and <27% for glipizide. The high estimates were due to the insensitivity of the assay. Neither glyburide nor glipizide were detected in breast milk in either study and blood glucose was normal in the three infants (one glyburide and two glipizide) who were wholly breast-fed when the drug concentrations were at steady state. CONCLUSIONS: Neither glyburide nor glipizide were detected in breast milk, and hypoglycemia was not observed in the three nursing infants. Both agents, at the doses tested, appear to be compatible with breast-feeding.

Excretion of metformin into breast milk and the effect on nursing infants.

OBJECTIVE: To determine whether metformin is excreted into breast milk and whether this exposure adversely affects the blood glucose of nursing infants. METHODS: Seven women were started on metformin 500 mg twice daily on the first day after cesarean delivery. Breastfeeding was started at the same time. Two women were excluded. Two other women stopped breastfeeding for personal reasons unrelated to the drug therapy, but did provide serum and milk samples, because they regularly pumped their breasts to maintain lactation. Peak and trough serum and milk samples were drawn between postoperative days 4 and 17. In 3 infants, blood was drawn for glucose determination at the same time as the maternal samples. RESULTS: The trough milk concentration in 1 subject was below the assay detection limit. Excluding this subject, the mean peak and trough serum metformin concentrations were 1.06 mug/mL (range 0.68-1.90 mug/mL) and 0.42 mug/mL (range 0.26-0.51 mug/mL), respectively, whereas the mean peak and trough metformin concentrations in breast milk were 0.42 mug/mL (range 0.38-0.46 mug/mL) and 0.39 mug/mL (range 0.31-0.52 mug/mL), respectively. The mean milk:serum ratio was 0.63 (range 0.36-1.00) and the mean estimated infant dose as a percentage of the mother's weight-adjusted dose was 0.65% (range 0.43-1.08%). In 3 infants, the blood glucose concentrations 4 hours after a feeding were within the normal limit, ranging from 47-77 mg/dL. CONCLUSION: Metformin is excreted into breast milk, but the amounts seem to be clinically insignificant. No adverse effects on the blood glucose of the 3 nursing infants were measured.

Drugs and chemicals in human milk.

There is continuing emphasis by many professionals and organizations on the importance of breastfeeding as optimal infant nutrition. Pediatricians are frequently asked about the safety of medications taken by the nursing mother and the risk to the infant. Most drugs and many chemicals will be transferred into milk. For a vast majority of these compounds, there is no risk to the infant. It is almost always possible for the mother to continue nursing while taking the necessary medication. This article presents an introduction to the pharmacology of the transfer of drugs into milk, discusses the importance of the infant's age in assessing safety and presents a number of maternal conditions for which drugs need to be used.

Urinary tract infections during pregnancy.

OBJECTIVE: To provide a comprehensive review of urinary tract infections (UTIs) during pregnancy. All aspects of UTIs, including epidemiology, pathogenesis, resistance, clinical features, diagnosis, treatment, and prevention, were reviewed. DATA SOURCES: MEDLINE (1966-August 2003) and Cochrane Library searches were performed using the key search terms urinary tract infection, pyelonephritis, cystitis, asymptomatic bacteriuria, and resistance. STUDY SELECTION AND DATA EXTRACTION: All article abstracts were evaluated for relevance. Only articles pertaining to pregnancy were included. The majority of published literature were review articles; the number of original clinical studies was limited. DATA SYNTHESIS: UTIs are the most common bacterial infections during pregnancy. They are characterized by the presence of significant bacteria anywhere along the urinary tract. Pyelonephritis is the most common severe bacterial infection that can lead to perinatal and maternal complications including premature delivery, infants with low birth weight, fetal mortality, preeclampsia, pregnancy-induced hypertension, anemia, thrombocytopenia, and transient renal insufficiency. Enterobacteriaceae account for 90% of UTIs. The common antibiotics used are nitrofurantoin, cefazolin, cephalexin, ceftriaxone, and gentamicin. CONCLUSIONS: Therapeutic management of UTIs in pregnancy requires proper diagnostic workup and thorough understanding of antimicrobial agents to optimize maternal outcome, ensure safety to the fetus, and prevent complications that lead to significant morbidity and mortality in both the fetus and the mother.

The use of prostaglandin E2 in pregnant patients with asthma.

OBJECTIVE: Prostaglandin E(2) is a pharmacologic agent that is used commonly in obstetrics; however, its usage in patients with asthma is unclear. The study objective was to examine pregnant patients with asthma who received prostaglandin E(2). STUDY DESIGN: All pregnancies that were given prostaglandin E(2) suppositories and/or gel were recorded prospectively from January 1989 through December 2000. Those cases with a history of asthma or active asthma were analyzed for any clinical evidence of disease exacerbation after the administration of the agent. Clinical exacerbation was defined as any respiratory complaint that followed drug usage, the initiation of bronchodilator medications by patients currently not on therapy, or an increase in bronchodilator usage by patients with active disease. RESULTS: During the study period, 2513 patients received treatment with the cervical ripening gel, of whom 158 patients had a history of asthma or active asthma. Additionally, 536 patients were administered the 20-mg suppositories, of whom 31 patients had a history of asthma or active asthma. Thus, a total of 189 patients with a history of asthma or active asthma were exposed to prostaglandin E(2), and none of the patients had any evidence of a clinical exacerbation of the disease (0/189 cases; 95% CI, 0- 2%). CONCLUSION: Based on the 95% CI of these data, the maximum risk for the development of a clinical exacerbation of asthma, if exposed to the obstetric forms of prostaglandin E(2), is < or =2%. Although all drug usage in patients with asthma should be monitored carefully, this information would support the usage of prostaglandin E(2), if obstetrically indicated, in pregnant patients with asthma.

Antepartum use of antibiotics and early-onset neonatal sepsis: the next 4 years.

OBJECTIVE: The purpose of this study was to analyze the incidence of early-onset neonatal sepsis and the presence of antibiotic resistance of the isolated bacteria and its relationship to antibiotic chemoprophylaxis that occurred during the 4 years that followed the publication of the most recent group B streptococcal guidelines. STUDY DESIGN: A prospective cohort study was performed between January 1, 1997, and December 31, 2000. All cases of early-onset neonatal sepsis were gathered prospectively. Data concerning the use of antepartum antibiotics, the isolated bacteria, and the presence of drug resistance were collected. These data were analyzed separately and were combined with published data from the preceding 6 years. RESULTS: A total of 26 cases of blood culture-proved early-onset neonatal sepsis occurred during the current 4-year study period. Group B Streptococcus was responsible for 10 cases, and the remaining 16 cases were non-group B streptococcal organisms. Of these 16 cases, 11 parturients received antibiotic chemoprophylaxis, and 10 of the isolates (91%) were resistant to the drug that was administered, compared with only one resistant bacteria (20%) in the 5 parturients who did not receive treatment (P =.01). In combining these 16 cases with the cases from the preceding 6 years, a total of 43 cases of non-group B streptococcal sepsis occurred in 49,788 deliveries. Of these, 26 mothers were given antepartum antibiotics, and 23 of the bacterial isolates (88%) exhibited resistance, compared with only 3 of the 17 cases (18%) in which antibiotics were not dispensed (P <.00001). However, because the overall use of antepartum antibiotics increased over time, the attack rate for early-onset group B Streptococcus significantly decreased by 75% (P <.000001). CONCLUSION: When early-onset neonatal sepsis develops in a case in which antepartum chemoprophylaxis was used, the bacterial isolate will most likely demonstrate resistance to the antibiotic that was administered. However, the development of early-onset group B streptococcal neonatal sepsis significantly decreased as the use of antepartum antibiotics increased. Thus, the number of prevented infections from antepartum antibiotic use may still outweigh the problems that are seen when resistant bacterial infections arise. Nevertheless, based on the current protocols, a large number of parturients are candidates for antibiotic chemoprophylaxis and this, in conjunction with the global concern of bacterial drug resistance, should be motivation to examine alternative methods, such as vaginal washing or immunotherapy, for decreasing infection.