Gary D.V. Hankins

Zika Virus and Pregnancy: A Review of the Literature and Clinical Considerations.

The latest Zika virus (ZIKV) outbreak has reached epidemic proportions as it spreads throughout South and Central America. In November 2015, the Brazilian Ministry of Health reported a 20-fold increase in the number of cases of neonatal microcephaly, which corresponds geographically and temporally to the ZIKV outbreak. Case reports have provided some evidence of a causal link between maternal ZIKV infection, fetal microcephaly, and intracranial calcifications. The sparse data regarding ZIKV in pregnancy come solely from case reports and personal communications, and recommendations for management of ZIKV exposure during pregnancy are rapidly evolving. Our objective is to review and synthesize the current literature regarding ZIKV as it pertains to pregnancy and provide some assistance to clinicians who may have to manage a pregnant patient with potential exposure to ZIKV. We will also explore certain aspects of related viruses in pregnancy in hopes to shed light on this little-known topic.

Proceedings from the American College of Rheumatology Reproductive Health Summit: the management of fertility, pregnancy, and lactation in women with autoimmune and systemic inflammatory diseases.

Most autoimmune and systemic inflammatory diseases are more common in women than in men, including women of child-bearing age. Therefore, for many of our patients, family planning is an important clinical issue. The management of pregnancy in autoimmune diseases is complex, benefitting optimally from a multidisciplinary approach that takes into consideration: prepregnancy counseling; treatments received prior to, during, and after pregnancy; early recognition of both obstetric complications and medical complications relating to the underlying disease; prenatal fetal development; and postnatal management of the

Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats

Elevated maternal testosterone levels are shown to cause fetal growth restriction, eventually culminating in sex-specific adult-onset hypertension that is more pronounced in males than in females. In this study, we tested whether uteroplacental and fetoplacental disturbances underlie fetal growth restriction and if these changes vary in male and female placentas. Pregnant Sprague-Dawley rats were injected with vehicle (n=16) or testosterone propionate (0.5 mg/kg per day from gestation day 15–19; n=16). On gestation day 20, we quantified uterine artery blood flow using microultrasound, visualized placental arterial network using x-ray microcomputed tomography, determined fetoplacental hypoxia using pimonidazole and hypoxia-inducible factor-1&agr;, and used Affymetrix array to determine changes in placental expression of genes involved in vascular development. Plasma testosterone levels increased 2-fold in testosterone-injected rats. Placental and fetal weights were lower in rats with elevated testosterone. Uterine artery blood flow was lower, and resistance index was higher in the testosterone group. Radial and spiral artery diameter and length, the number of fetoplacental arterial branches, and umbilical artery diameter were reduced in the testosterone group. In addition, markers of hypoxia in the placentas and fetuses were elevated in the testosterone group. The magnitude of changes in placental vasculature and hypoxia was greater in males than in females and was associated with sex-specific alteration of unique sets of genes involved in angiogenesis and blood vessel morphogenesis. The results demonstrate that elevated testosterone during gestation induces a decrease in uterine arterial blood flow and fetal sex–related uteroplacental vascular changes, which may set the stage for subsequent sex differences in adult-onset diseases.

Proposed diagnostic criteria for the case definition of amniotic fluid embolism in research studies

Amniotic fluid embolism is a leading cause of maternal mortality in developed countries. Our understanding of risk factors, diagnosis, treatment, and prognosis is hampered by a lack of uniform clinical case definition; neither histologic nor laboratory findings have been identified unique to this condition. Amniotic fluid embolism is often overdiagnosed in critically ill peripartum women, particularly when an element of coagulopathy is involved. Previously proposed case definitions for amniotic fluid embolism are nonspecific, and when viewed through the eyes of individuals with experience in critical care obstetrics, would include women with a number of medical conditions much more common than amniotic fluid embolism. We convened a working group under the auspices of a committee of the Society for Maternal-Fetal Medicine and the Amniotic Fluid Embolism Foundation whose task was to develop uniform diagnostic criteria for the research reporting of amniotic fluid embolism. These criteria rely on the presence of the classic triad of hemodynamic and respiratory compromise accompanied by strictly defined disseminated intravascular coagulopathy. It is anticipated that limiting research reports involving amniotic fluid embolism to women who meet these criteria will enhance the validity of published data and assist in the identification of risk factors, effective treatments, and possibly useful biomarkers for this condition. A registry has been established in conjunction with the Perinatal Research Branch of the Eunice Kennedy Shriver National Institute of Child Health and Human Development to collect both clinical information and laboratory specimens of women with suspected amniotic fluid embolism in the hopes of identifying unique biomarkers of this condition.

Prenatal Testosterone Exposure Induces Hypertension in Adult Females via Androgen Receptor–Dependent Protein Kinase Cδ–Mediated Mechanism

Prenatal exposure to excess testosterone induces hyperandrogenism in adult females and predisposes them to hypertension. We tested whether androgens induce hypertension through transcriptional regulation and signaling of protein kinase C (PKC) in the mesenteric arteries. Pregnant Sprague–Dawley rats were injected with vehicle or testosterone propionate (0.5 mg/kg per day from gestation days 15 to 19, SC) and their 6-month-old adult female offspring were examined. Plasma testosterone levels (0.84±0.04 versus 0.42±0.09 ng/mL) and blood pressures (111.6±1.3 versus 104.5±2.4 mm Hg) were significantly higher in prenatal testosterone–exposed rats compared with controls. This was accompanied with enhanced expression of PKC&dgr; mRNA (1.5-fold) and protein (1.7-fold) in the mesenteric arteries of prenatal testosterone–exposed rats. In addition, mesenteric artery contractile responses to PKC activator, phorbol-12,13-dibutyrate, was significantly greater in prenatal testosterone–exposed rats. Treatment with androgen receptor antagonist flutamide (10 mg/kg, SC, BID for 10 days) significantly attenuated hypertension, PKC&dgr; expression, and the exaggerated vasoconstriction in prenatal testosterone–exposed rats. In vitro exposure of testosterone to cultured mesenteric artery smooth muscle cells dose dependently upregulated PKC&dgr; expression. Analysis of PKC&dgr; gene revealed a putative androgen responsive element in the promoter upstream to the transcription start site and an enhancer element in intron-1. Chromatin immunoprecipitation assays showed that androgen receptors bind to these elements in response to testosterone stimulation. Furthermore, luciferase reporter assays showed that the enhancer element is highly responsive to androgens and treatment with flutamide reverses reporter activity. Our studies identified a novel androgen-mediated mechanism for the control of PKC&dgr; expression via transcriptional regulation that controls vasoconstriction and blood pressure.

Pharmacokinetics of metoprolol during pregnancy and lactation

The objective of this study was to evaluate the steady‐state pharmacokinetics of metoprolol during pregnancy and lactation. Serial plasma, urine, and breast milk concentrations of metoprolol and its metabolite, α‐hydroxymetoprolol, were measured over 1 dosing interval in women treated with metoprolol (25–750u2009mg/day) during early pregnancy (nu2009=u20094), mid‐pregnancy (nu2009=u200914), and late pregnancy (nu2009=u200915), as well as postpartum (nu2009=u20099) with (nu2009=u20094) and without (nu2009=u20095) lactation. Subjects were genotyped for CYP2D6 loss‐of‐function allelic variants. Using paired analysis, mean metoprolol apparent oral clearance was significantly higher in mid‐pregnancy (361u2009±u2009223 L/h, nu2009=u20095, Pu2009<u2009.05) and late pregnancy (568u2009±u2009273 L/h, nu2009=u20098, Pu2009<u2009.05) compared with ≥3 months postpartum (200u2009±u2009131 and 192u2009±u200998 L/h, respectively). When the comparison was limited to extensive metabolizers (EMs), metoprolol apparent oral clearance was significantly higher during both mid‐ and late pregnancy (Pu2009<u2009.05). Relative infant exposure to metoprolol through breast milk was <1.0% of maternal weight‐adjusted dose (nu2009=u20093). Because of the large, pregnancy‐induced changes in metoprolol pharmacokinetics, if inadequate clinical responses are encountered, clinicians who prescribe metoprolol during pregnancy should be prepared to make aggressive changes in dosage (dose and frequency) or consider using an alternate beta‐blocker.

Amniotic fluid embolism: diagnosis and management

OBJECTIVEnWe sought to provide evidence-based guidelines regarding the diagnosis and management of amniotic fluid embolism.nnnSTUDY DESIGNnA systematic literature review was performed using MEDLINE, PubMed, EMBASE, and the Cochrane Library. The search was restricted to English-language articles published from 1966 through March 2015. Priority was given to articles reporting original research, in particular randomized controlled trials, although review articles and commentaries were consulted. Abstracts of research presented at symposia and scientific conferences were not considered adequate for inclusion. Evidence reports and published guidelines were also reviewed, and additional studies were located by reviewing bibliographies of identified articles. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used for defining the strength of recommendations and rating quality of the evidence. Consistent with US Preventive Task Force guidelines, references were evaluated for quality based on the highest level of evidence.nnnRESULTS AND RECOMMENDATIONSnWe recommend the following: (1) we recommend consideration of amniotic fluid embolism in the differential diagnosis of sudden cardiorespiratory collapse in the laboring or recently delivered woman (GRADE 1C); (2) we do not recommend the use of any specific diagnostic laboratory test to either confirm or refute the diagnosis of amniotic fluid embolism; at the present time, amniotic fluid embolism remains a clinical diagnosis (GRADE 1C); (3) we recommend the provision of immediate high-quality cardiopulmonary resuscitation with standard basic cardiac life support and advanced cardiac life support protocols in patients who develop cardiac arrest associated with amniotic fluid embolism (GRADE 1C); (4) we recommend that a multidisciplinary team including anesthesia, respiratory therapy, critical care, and maternal-fetal medicine should be involved in the ongoing care of women with AFE (Best Practice); (5) following cardiac arrest with amniotic fluid embolism, we recommend immediate delivery in the presence of a fetus ≥23 weeks of gestation (GRADE 2C); (6) we recommend the provision of adequate oxygenation and ventilation and, when indicated by hemodynamic status, the use of vasopressors and inotropic agents in the initial management of amniotic fluid embolism. Excessive fluid administration should be avoided (GRADE 1C); and (7) because coagulopathy may follow cardiovascular collapse with amniotic fluid embolism, we recommend the early assessment of clotting status and early aggressive management of clinical bleeding with standard massive transfusion protocols (GRADE 1C).

A review of oral labetalol and nifedipine in mild to moderate hypertension in pregnancy

Hypertension is the most commonly encountered medical condition in pregnancy, contributing significantly to maternal and perinatal morbidity and mortality. Mild to moderate hypertension in pregnancy is defined as systolic blood pressure of 140-159 mmHg or diastolic blood pressure of 90-109 mmHg (7-9% of pregnancies). When treating hypertension in pregnancy, not only do physiologic changes of pregnancy have an effect on the pharmacokinetics and pharmacodynamics of the drugs used, but the pathophysiology of hypertensive disorders of pregnancy also have an effect. To date, evidence is lacking on the pharmacokinetics and pharmacodynamics of commonly used antihypertensive drugs, which often times leads to suboptimal treatment of hypertensive pregnant women. When considering which agents to use for treatment of mild to moderate hypertension, specifically in gestational and chronic hypertension, oral labetalol and nifedipine are valid options. An overview of the profile for use, safety, and current pharmacokinetic data for each agent is presented here.

Quantitative determination of metformin, glyburide and its metabolites in plasma and urine of pregnant patients by LC-MS/MS

This report describes the development and validation of an LC-MS/MS method for the quantitative determination of glyburide (GLB), its five metabolites (M1, M2a, M2b, M3 and M4) and metformin (MET) in plasma and urine of pregnant patients under treatment with a combination of the two medications. The extraction recovery of the analytes from plasma samples was 87-99%, and that from urine samples was 85-95%. The differences in retention times among the analytes and the wide range of the concentrations of the medications and their metabolites in plasma and urine patient samples required the development of three LC methods. The lower limit of quantitation (LLOQ) of the analytes in plasma samples was as follows: GLB, 1.02 ng/mL; its five metabolites, 0.100-0.113 ng/mL; and MET, 4.95 ng/mL. The LLOQ in urine samples was 0.0594 ng/mL for GLB, 0.984-1.02 ng/mL for its five metabolites and 30.0 µg/mL for MET. The relative deviation of this method was <14% for intra-day and inter-day assays in plasma and urine samples, and the accuracy was 86-114% in plasma, and 94-105% in urine. The method described in this report was successfully utilized for determining the concentrations of the two medications in patient plasma and urine.

Maternal safety of the delayed-release doxylamine and pyridoxine combination for nausea and vomiting of pregnancy; a randomized placebo controlled trial

BackgroundNausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expecting mothers. In April 2013 the FDA approved the delayed release combination of doxylamine succinate and -pyridoxine hydrochloride (Diclegis®) for NVP, following a phase 3 randomized trial in pregnant women. The fetal safety of this medication has been proven by numerous studies. However, because it is the only FDA-approved medication for NVP that is likely to be used by a large number of pregnant women, its maternal safety is an important public health question. The Objective is to evaluate the maternal safety of doxylamine succinate -pyridoxine hydrochloride delayed-release preparation (Diclegis® as compared to placebo.MethodsWe randomized women suffering from NVP to receive Diclegis® (nu2009=u2009131) or placebo (nu2009=u2009125) for 14xa0days at doses ranging from 2–4 tablets a day, based on a pre-specified titration protocol response to symptoms. Adverse events were collected through patient diaries, clinical examination and laboratory testing.ResultsDoxylamine succinate 10xa0mg and pyridoxine hydrochloride 10xa0mg use was not associated with an increased rate of any adverse event over placebo, including CNS depression, gastrointestinal or cardiovascular involvement.ConclusionsDoxylamine succinate–pyridoxine hydrochloride delayed release combination is safe and well tolerated by pregnant women when used in the recommended dose of up to 4 tablets daily in treating nausea and vomiting of pregnancy.Trial RegistrationClinical Trial Registration No: NCT00614445.