Maisa Feghali

Clinical Therapeutics in Pregnancy

Most drugs are not tested for use during pregnancy, consequently, labeling, which may include information about fetal safety, includes nothing about dosing, efficacy, or maternal safety. Yet these are concerns of health care providers considering treatment of disease during pregnancy. Therefore, the practitioner treats the pregnant woman with the same dose recommended for use in adults (typically men) or may decide not to treat the disease at all. However, is the choice of not treating a woman during pregnancy better than dealing with the challenges which accompany treatment? This paper, which summarizes metabolic and physiologic changes induced by pregnancy, illustrates that standard adult dosing is likely to be incorrect during pregnancy.

Pharmacokinetics of drugs in pregnancy

Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications.

Effect of excess gestational weight gain on pregnancy outcomes in women with type 1 diabetes.

OBJECTIVE: To evaluate the prevalence and clinical effects of excess gestational weight gain on birth weight and other pregnancy outcomes in women with type 1 diabetes. METHODS: We performed a retrospective cohort study of women with type 1 diabetes delivered between 2009 and 2012. Patients with excess weight gain were identified using the 2009 Institute of Medicine weight gain recommendations adjusted for gestational age at delivery and prepregnancy body mass index (BMI) category. Demographic and outcome data were abstracted from the medical record, and pregnancy outcomes were compared between women with and without excess gestational weight gain. RESULTS: Excess gestational weight gain occurred in 114 of 175 women (65.1%). Large-for-gestational-age (LGA) birth weight occurred in 48 of 114 (42.1%) of women with excess gestational weight gain and 5 of 61 (8.2%) of women with recommended weight gain (P<.001). The association between excess maternal weight gain and LGA birth weight remained significant after adjustment for prepregnancy BMI, gestational age at delivery, nulliparity, vascular complications, and hemoglobin A1c measurements (adjusted odds ratio 8.9, 95% confidence interval 3.1–26.2, P<.001). Stratified analyses demonstrated that excess maternal weight gain is associated with LGA neonates in both normal-weight and overweight or obese women. CONCLUSIONS: Excess maternal weight gain is common and leads to higher rates of LGA neonates in both normal-weight and overweight or obese women with type 1 diabetes. Interventions designed to limit excess gestational weight gain may reduce the risk for fetal overgrowth in women with type 1 diabetes. LEVEL OF EVIDENCE: II

Adverse Outcomes and Potential Targets for Intervention in Gestational Diabetes and Obesity.

OBJECTIVE: To evaluate the association of obesity with pregnancy outcomes in women with gestational diabetes mellitus (GDM) and identify potentially modifiable risk factors for adverse outcomes in obese women with GDM. METHODS: This was a retrospective cohort study of 1,344 women with GDM who delivered between 2009 and 2012. Demographic data, blood sugar values, gestational weight gain, and maternal and neonatal outcome data were abstracted from the medical record and compared among normal-weight, overweight, and obese women. RESULTS: Overweight and obese women had higher mean fasting and postprandial blood sugars despite higher doses of and more frequent use of medication. Obesity was independently associated with macrosomia (adjusted odds ratio [OR] 2.03, 95% confidence interval [CI] 1.07–3.89, P=.03), indicated preterm birth (adjusted OR 2.21, 95% CI 1.02–4.78, P=.04), and hypertensive disorders of pregnancy (adjusted OR 2.19, 95% CI 1.38–3.49, P=.001). In our stratified analyses, obese women with fasting blood sugars greater than 88.7 mg/dL and postprandial blood sugars greater than 123.8 mg/dL had higher rates of macrosomia (13.1% compared with 5.7%, P=.004 for fasting, 13.0% compared with 6.5%, P=.01 for postprandial blood sugars) and indicated preterm birth (11.4% compared with 6.1%, P=.04 for fasting, 11.9% compared with 5.8%, P=.01 for postprandial blood sugars) when compared with obese women with lower values. Hypertensive disorders of pregnancy were significantly increased in obese women with postdiagnosis weight gain greater than 0.6 lb per week (29.4% compared with 15.2%, P<.001) when compared with obese women with less weight gain. CONCLUSION: Prepregnancy obesity is independently associated with adverse pregnancy outcomes in women with GDM, and interventions to optimize glycemic control and limit weight gain postdiagnosis may improve outcomes in these high-risk women. LEVEL OF EVIDENCE: II

Asymmetric large for gestational age newborns in pregnancies complicated by diabetes mellitus: is maternal obesity a culprit?

Objective: Evaluate the association between body mass index (BMI) and the delivery of an asymmetrically large for gestational age (A-LGA) newborn in women with diabetes. Methods: Retrospective analysis of 306 pregnancies complicated by Type 1 and 55 by Type 2 diabetes. Results: The prevalence of Type 1 and Type 2 diabetics delivering large for gestational age (LGA) infants was 42% and 49%, respectively. Of these 49% and 55% were A-LGA, respectively. Pre-pregnancy BMI was not associated with increased odds of delivering an A-LGA newborn in women with Type 1 or 2 diabetes. However, in Type 1 diabetics, each one-pound increase in maternal weight during pregnancy resulted in 4% increased odds of delivering an A-LGA newborn. For Type 2 diabetics, the odds of delivering an A-LGA infant was decreased by 10% for each 0.1 unit/kg increase in insulin dose. Conclusion: Although there is a known association between obesity and LGA in women with diabetes, we found that overweight and obese women with Type 1 or Type 2 diabetes do not have increased odds of delivering an A-LGA newborn. However, insulin dose in Type 2 diabetes and maternal weight gain in Type 1 diabetes were significantly associated with the odds of delivering an A-LGA neonate.

Maternal prepregnancy obesity and cause-specific stillbirth

BACKGROUND In high-income countries, maternal obesity is one of the most important modifiable causes of stillbirth, yet the pathways underpinning this association remain unclear. OBJECTIVE We estimated the association between maternal prepregnancy body mass index (BMI) and the risk of stillbirth defined by pathophysiologic contributors or causes. DESIGN Using a case-cohort design, we randomly sampled 1829 singleton deliveries from a cohort of 68,437 eligible deliveries at Magee-Womens Hospital in Pittsburgh, Pennsylvania (2003-2010), and augmented it with all remaining cases of stillbirth for a total of 658 cases. Stillbirths were classified based on probable cause(s) of death (maternal medical conditions, obstetric complications, fetal abnormalities, placental diseases, and infection). A panel of clinical experts reviewed medical records, placental tissue slides and pathology reports, and fetal postmortem reports of all stillbirths. Causes of fetal death were assigned by using the Stillbirth Collaborative Research Network Initial Causes of Fetal Death protocol from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. Proportional hazards models were used to estimate the BMI-stillbirth association after adjustment for confounders. RESULTS The rate of stillbirth among lean, overweight, obese, and severely obese women was 7.7, 10.6, 13.9, and 17.3 per 1000 live-born and stillborn infants, respectively. Adjusted stillbirth HRs (95% CIs) were 1.4 (1.1, 1.8) for overweight, 1.8 (1.3, 2.4) for obese, and 2.0 (1.5, 2.8) for severely obese women, respectively, compared with lean women; associations strengthened when limited to antepartum stillbirths. Obesity and severe obesity were associated with stillbirth resulting from placental diseases, hypertension, fetal anomalies, and umbilical cord abnormalities. BMI was not related to stillbirth caused by placental abruption, obstetric conditions, or infection. CONCLUSIONS Multiple mechanisms appear to link obesity to stillbirth. Interventions to reduce stillbirth among obese mothers should consider targeting stillbirth due to hypertension and placental diseases-the most common causes of fetal death in this at-risk group.

Large-for-Gestational-Age Ultrasound Diagnosis and Risk for Cesarean Delivery in Women With Gestational Diabetes Mellitus.

OBJECTIVE: To assess the accuracy of a large-for-gestational-age (LGA) ultrasound diagnosis and the subsequent risk for cesarean delivery associated with ultrasound diagnosis of LGA among women with gestational diabetes mellitus. METHODS: This was a retrospective cohort study of 903 women with GDM who delivered after 36 weeks of gestation with an ultrasound-estimated fetal weight within 31 days of delivery. Delivery outcomes were compared between women with an ultrasound diagnosis of LGA and a non-LGA ultrasound diagnosis. RESULTS: Based on ultrasound assessments, we identified 248 women with an LGA fetus and 655 women with a non-LGA fetus. Among women with an LGA ultrasound diagnosis, 56 of 248 (22.6%) delivered an LGA neonate, whereas, of women with a non-LGA ultrasound diagnosis, 18 of 655 (2.8%) delivered an LGA neonate. Ultrasound diagnosis of LGA was associated with increased risk for cesarean delivery (adjusted odds ratio [OR] 3.13, 95% confidence interval [CI] 2.10–4.67, P<.001) after adjusting for relevant covariates. Stratified analyses demonstrated that ultrasound diagnosis of LGA was associated with an increased risk for cesarean delivery whether the birth weight was between 2,500 and 3,499 g (OR 2.82, 95% CI 1.62–4.84, P<.001) or between 3,500 and 4,500 g (OR 3.47, 95% CI 2.06–5.88, P<.001). CONCLUSION: Ultrasonography significantly overestimates the prevalence of LGA in women with gestational diabetes mellitus, and an ultrasound diagnosis of LGA is associated with an increased risk for cesarean delivery independent of birth weight. LEVEL OF EVIDENCE: II

Prevention of preterm delivery with 17-hydroxyprogesterone caproate: Pharmacologic considerations

Despite advances in neonatal care, the burden of preterm birth remains high. Preterm birth is a multifactorial problem, and strategies to identify and treat medical risk factors in early pregnancy have not been effective in reducing preterm birth rates. In a sentinel clinical trial, prophylactic therapy with 17-hydoxyprogesterone caproate (17-OHPC) reduced the risk of recurrent, spontaneous preterm birth in 34% of women. As a result, clinical practice changed and extensive research on 17-OHPC followed. The increasing body of evidence demonstrated a variable efficacy of the drug. This review will examine the plausibility, pharmacology, clinical efficacy, and safety of 17-OHPC when used in the setting of preterm birth prevention. We will also discuss pharmacokinetic and pharmacodynamics data to highlight drug metabolism and mechanism of action, which will help clarify the variability in clinical outcomes and efficacy.

Preterm induction of labor: predictors of vaginal delivery and labor curves

OBJECTIVE The purpose of this study was to evaluate the labor curves of patients who undergo preterm induction of labor (IOL) and to assess possible predictors of vaginal delivery (VD). STUDY DESIGN Data from the National Institute of Child Health and Human Development Consortium on Safe Labor were analyzed. A total of 6555 women who underwent medically indicated IOL at <37 weeks of gestation were included in this analysis. Patients were divided into 4 groups based on gestational age (GA): group A, 24-27+6 weeks; B, 28-30+6 weeks; C, 31-33+6 weeks; and D, 34-36+6 weeks. Pregnant women with a contraindication to VD, IOL ≥37 weeks of gestation, and without data from cervical examination on admission were excluded. Analysis of variance was used to assess differences between GA groups. Multiple logistic regression was used to assess predictors of VD. A repeated measures analysis was used to determine average labor curves. RESULTS Rates of vaginal live births increased with GA, from 35% (group A) to 76% (group D). Parous women (odds ratio, 6.78; 95% confidence interval, 6.38-7.21) and those with a favorable cervix at the start of IOL (odds ratio, 2.35; 95% confidence interval, 2.23-2.48) were more likely to deliver vaginally. Analysis of labor curves in nulliparous women showed shorter duration of labor with increasing GA; the active phase of labor was, however, similar across all GAs. CONCLUSION Most women who undergo medically indicated preterm IOL between 24 and 36+6 weeks of gestation deliver vaginally. The strongest predictor of VD was parity. Preterm IOL had a limited influence on estimated labor curves across GAs.

Fetal development in women with diabetes: imprinting for a life-time?

Objective: To test the hypothesis that fetal exposure to a hyperglycemic intrauterine environment in women with type 1 diabetes is associated with asymmetrically distributed excessive fetal growth and imprinting consistent with adverse health issues later in life. Methods: We report findings from a feasibility study on 19 young adults, born to mothers with type 1 diabetes. Long-term follow-up of the offspring in young adulthood included: oral glucose tolerance test, body mass index (BMI), dual X-ray absorptiometry, and blood pressure (BP). We report z-BMI and z-BP to account for varying gender and age. Results: The young adults born to women with diabetes averaged 19.9 years at follow-up; 37% were female, and 21% African American. Maternal glycohemoglobin A1 concentration in the 2nd trimester was 9.2% for offspring born with asymmetric LGA and 7.5% for those born with symmetric LGA or AGA. There was significant correlation between maternal glucose control during pregnancy and fasting glucose, z-BMI and z-systolic BP in the young adults. Conclusion: The hyperglycemic intrauterine environment is associated with short-term morbidity, manifested as asymmetric LGA (the “fat” baby). In addition, increasing level of maternal hyperglycemia during pregnancy is associated with increased adiposity and elevated fasting glucose in the young adult offspring.