David M. Haas

TOCOLYTIC THERAPY: A META-ANALYSIS AND DECISION ANALYSIS

OBJECTIVE: To determine the optimal first-line tocolytic agent for treatment of premature labor. METHODS: We performed a quantitative analysis of randomized controlled trials of tocolysis, extracting data on maternal and neonatal outcomes, and pooling rates for each outcome across trials by treatment. Outcomes were delay of delivery for 48 hours, 7 days, and until 37 weeks; adverse effects causing discontinuation of therapy; absence of respiratory distress syndrome; and neonatal survival. We used weighted proportions from a random-effects meta-analysis in a decision model to determine the optimal first-line tocolytic therapy. Sensitivity analysis was performed using the standard errors of the weighted proportions. RESULTS: Fifty-eight studies satisfied the inclusion criteria. A random-effects meta-analysis showed that all tocolytic agents were superior to placebo or control groups at delaying delivery both for at least 48 hours (53% for placebo compared with 75–93% for tocolytics) and 7 days (39% for placebo compared with 61–78% for tocolytics). No statistically significant differences were found for the other outcomes, including the neonatal outcomes of respiratory distress and neonatal survival. The decision model demonstrated that prostaglandin inhibitors provided the best combination of tolerance and delayed delivery. In a hypothetical cohort of 1,000 women receiving prostaglandin inhibitors, only 80 would deliver within 48 hours, compared with 182 for the next-best treatment. CONCLUSION: Although all current tocolytic agents were superior to no treatment at delaying delivery for both 48 hours and 7 days, prostaglandin inhibitors were superior to the other agents and may be considered the optimal first-line agent before 32 weeks of gestation to delay delivery.

Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock

Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation.

Early Abdominal Ectopic Pregnancies: A Systematic Review of the Literature

Objective: To define abdominal ectopic pregnancy outcomes by both location and treatment. Methods: Literature review of abdominal pregnancies from 1965 to August of 2009. Ectopic pregnancy exclusions were interstitial, tubal, cervical, ovarian, or those beyond 20 weeks at diagnosis/treatment. Results: There were 511 cases identified with 225 meeting the inclusion criteria. There were 7 maternal deaths (3.0%) with 18 (8%) of the early abdominal ectopic pregnancies occurring with an intrauterine device in place. Mean gestational age at the time of treatment was 10 weeks 0 days and mean maternal age was 29.7 years. The average blood loss associated with treatment was 1,450 ml. The top three sites of early abdominal ectopic pregnancies were pouches around the uterus (24.3%), serosal surface of the uterus and tubes (23.9%), and multiple sites (12.8%). Primary surgical management was performed in 208 cases (87.8%). Nonsurgical adjuvant or primary therapy included intramuscular methotrexate, intralesional methotrexate, intracardiac KCl, and artery embolization. Conclusion: Abdominal pregnancies should be considered in all patients until an intrauterine location can be confirmed. Understanding treatment options by pregnancy location may be helpful in the management of this potentially life-threatening condition.

Association between Sleep-Disordered Breathing and Hypertensive Disorders of Pregnancy and Gestational Diabetes Mellitus

OBJECTIVE To estimate whether sleep-disordered breathing during pregnancy is a risk factor for the development of hypertensive disorders of pregnancy and gestational diabetes mellitus (GDM). METHODS In this prospective cohort study, nulliparous women underwent in-home sleep-disordered breathing assessments in early (6-15 weeks of gestation) and midpregnancy (22-31 weeks of gestation). Participants and health care providers were blinded to the sleep test results. An apnea-hypopnea index of 5 or greater was used to define sleep-disordered breathing. Exposure-response relationships were examined, grouping participants into four apnea-hypopnea index groups: 0, greater than 0 to less than 5, 5 to less than 15, and 15 or greater. The study was powered to test the primary hypothesis that sleep-disordered breathing occurring in pregnancy is associated with an increased incidence of preeclampsia. Secondary outcomes were rates of hypertensive disorders of pregnancy, defined as preeclampsia and antepartum gestational hypertension, and GDM. Crude and adjusted odds ratios and 95% confidence intervals (CIs) were calculated from univariate and multivariate logistic regression models. RESULTS Three thousand seven hundred five women were enrolled. Apnea-hypopnea index data were available for 3,132 (84.5%) and 2,474 (66.8%) women in early and midpregnancy, respectively. The corresponding prevalence of sleep-disordered breathing was 3.6% and 8.3%. The prevalence of preeclampsia was 6.0%, hypertensive disorders of pregnancy 13.1%, and GDM 4.1%. In early and midpregnancy the adjusted odds ratios for preeclampsia when sleep-disordered breathing was present were 1.94 (95% CI 1.07-3.51) and 1.95 (95% CI 1.18-3.23), respectively; hypertensive disorders of pregnancy 1.46 (95% CI 0.91-2.32) and 1.73 (95% CI 1.19-2.52); and GDM 3.47 (95% CI 1.95-6.19) and 2.79 (95% CI 1.63-4.77). Increasing exposure-response relationships were observed between apnea-hypopnea index and both hypertensive disorders and GDM. CONCLUSION There is an independent association between sleep-disordered breathing and preeclampsia, hypertensive disorders of pregnancy, and GDM.

Rubella, rubeola, and mumps in pregnant women: susceptibilities and strategies for testing and vaccinating.

Objective: To estimate rubella, rubeola, and mumps (MMR) susceptibilities in pregnant women and determine the percentage not immune to rubeola or mumps, depending on rubella immunity status. A secondary objective was to assess costs of vaccination and testing programs aimed at eliminating these viral susceptibilities to determine an optimal strategy. Methods: This was an observational study of women presenting for prenatal care. All women had MMR antibody titers measured. Viral susceptibilities were compared by age, gravidity, parity, and recall of vaccine booster. A logistic regression was performed to assess for predictors of MMR immunity. A cost comparison of different screening and vaccination strategies was performed. Results: Overall, 91 (9.4%) women were susceptible to rubella, 161 (16.5%) to rubeola, and 159 (16.3%) to mumps. Three hundred seventeen (32.6%) were susceptible to at least 1 virus, whereas only 17 (1.7%) were susceptible to all 3. Of the women who were immune to rubella, a large percentage were not immune to either rubeola or mumps (n = 226, 25.6%). Only 74.2% of women who knew they had a booster vaccine were immune to all components of the MMR vaccine. Receiving a booster was predictive of immunity to all 3 viruses. A cost analysis demonstrated that broader screening strategies are more comprehensive and more expensive. Conclusion: The current screening and vaccine program has left many reproductive-aged women susceptible to rubella, rubeola, and mumps infections. Perhaps a more comprehensive viral screening program is needed to ensure immunity. Level of Evidence: II-3

Pharmacotherapy and pregnancy: highlights from the Third International Conference for Individualized Pharmacotherapy in Pregnancy.

To address provider struggles to provide evidence‐based, rational drug therapy to pregnant women, this third Conference was convened to highlight the current progress and research in the field. Speakers from academic centers, industry, and governmental institutions spoke about: the Food and Drug Administration’s role in pregnancy pharmacology and the new labeling initiative; drug registries in pregnancy; the pharmacist’s role in medication use in pregnancy; therapeutic areas such as preterm labor, gestational diabetes, nausea and vomiting in pregnancy, and hypertension; breast‐feeding and medications; ethical challenges for consent in pregnancy drug studies; the potential for cord blood banks; and concerns about the fetus when studying drugs in pregnancy. The Conference highlighted several areas of collaboration within the current Obstetrics Pharmacology Research Units Network and hoped to educate providers, researchers, and agencies with the common goal to improve the ability to safely and effectively use individualized pharmacotherapy in pregnancy. Clin Trans Sci 2011; Volume 4: 204–209

Nifedipine pharmacokinetics are influenced by CYP3A5 genotype when used as a preterm labor tocolytic

OBJECTIVE To characterize the pharmacokinetics and pharmacogenetics of nifedipine in pregnancy. STUDY DESIGN Pregnant women receiving oral nifedipine underwent steady-state pharmacokinetic testing over one dosing interval. DNA was obtained and genotyped for cytochrome P450 (CYP) 3A5 and CYP3A4*1B. Nifedipine and oxidized nifedipine concentrations were measured in plasma, and pharmacokinetic parameters were compared between those women who expressed a CYP3A5*1 allele and those who expressed only variant CYP3A5 alleles (*3,*6, or *7). RESULTS Fourteen women had complete data to analyze. Four women (29%) expressed variant CYP3A5; three of these women were also CYP3A4*1B allele carriers. The mean half-life of nifedipine was 1.68 ± 1.56 hours. The area under the curve from 0 to 6 hours for the women receiving nifedipine every 6 hours was 207 ± 138 µg·h /L. Oral clearance was different between high expressers and low expressers (232.0 ± 37.8 µg/mL versus 85.6 ± 45.0 µg/mL, respectively; p = 0.007). CONCLUSION CYP3A5 genotype influences the oral clearance of nifedipine in pregnant women.

The impact of drug metabolizing enzyme polymorphisms on outcomes after antenatal corticosteroid use

OBJECTIVE To determine the impact of maternal and fetal single nucleotide polymorphisms in key betamethasone pathways on neonatal outcomes. STUDY DESIGN DNA was obtained from women given betamethasone and their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway single nucleotide polymorphisms. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis using relevant clinical variables and genotypes to model for associations with neonatal respiratory distress syndrome was performed. RESULTS One hundred nine women delivering 117 infants were analyzed. Sixty-four infants (49%) developed respiratory distress syndrome. Multivariable analysis revealed that respiratory distress syndrome was associated with maternal single nucleotide polymorphisms in CYP3A5 (odds ratio [OR], 1.63; 95% confidence interval [CI], 1.16-2.30) and the glucocorticoid resistance (OR, 0.28; 95% CI, 0.08-0.95) and fetal single nucleotide polymorphisms in ADCY9 (OR, 0.17; 95% CI, 0.03-0.80) and CYP3A7*1E (rs28451617; OR, 23.68; 95% CI, 1.33-420.6). CONCLUSION Maternal and fetal genotypes are independently associated with neonatal respiratory distress syndrome after treatment with betamethasone for preterm labor.

A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics

Physiological changes in pregnancy, including changes in body composition and metabolic enzyme activity, can alter drug pharmacokinetics. A semi‐mechanistic metabolism model was developed to describe the pharmacokinetics of two cytochrome P450 3A (CYP3A) substrates, midazolam and nifedipine, in obstetrics patients. The model parameters were optimized to fit the data of oral midazolam pharmacokinetics in pregnant women, by increasing CYP3A‐induced hepatic metabolism 1.6‐fold in the model with no change in gut wall metabolism. Fetal metabolism had a negligible effect on maternal plasma drug concentrations. Validation of the model was performed by applying changes in volume of distribution and metabolism, consistent with those observed for midazolam, to the pharmacokinetics parameters of immediate‐release nifedipine in healthy volunteers. The predicted steady‐state areas under the concentration–time curve (AUCs) for nifedipine were within 15% of the data observed in pregnant women undergoing treatment for preterm labor. This model predicts the pharmacokinetics of two CYP3A substrates in pregnancy, and may be applicable to other CYP3A substrates as well.

The impact of glucocorticoid polymorphisms on markers of neonatal respiratory disease after antenatal betamethasone administration.

OBJECTIVE We previously demonstrated that maternal and fetal genotypes are associated independently with neonatal respiratory distress syndrome. The objective of the current study was to determine the impact of maternal and fetal single-nucleotide polymorphisms (SNPs) in key betamethasone pathways on respiratory outcomes that serve as markers for severity of disease. STUDY DESIGN DNA was obtained from women who were given betamethasone and from their infants. Samples were genotyped for 73 exploratory drug metabolism and glucocorticoid pathway SNPs. Clinical variables and neonatal outcomes were obtained. Logistic regression analysis that controlled for relevant clinical variables to determine SNP impact on bronchopulmonary dysplasia (BPD), the need for respiratory support, and surfactant therapy use was performed. RESULTS Data from 109 women who delivered 117 infants were analyzed: 14.5% of the infants experienced BPD; 70.8% of the infants needed some respiratory support after birth, and 27.5% of the infants needed surfactant therapy. In a multivariable regression analysis, gestational age at delivery was associated with most neonatal respiratory outcomes (P ≤ .01), and chorioamnionitis was associated with BPD (P < .03). The following genotypes were associated with respiratory severity outcomes: BPD-fetal Importin 13 gene (IPO13; rs4448553; odds ratio [OR], 0.01; 95% confidence interval [CI], 0.00-0.92); surfactant use-maternal IPO13 (rs2428953 and 2486014; OR, 13.8; 95% CI, 1.80-105.5; and OR, 35.5; 95% CI, 1.71-736.6, respectively). CONCLUSION Several discrete maternal and fetal SNPs in the IPO13 family may be associated with neonatal respiratory outcomes after maternal antenatal corticosteroid treatment for anticipated preterm birth.