Prenatal medication use in a prospective pregnancy cohort by pre-pregnancy obesity status.

BACKGROUND: The association between obesity (body mass index (BMI) ≥ 30 kg/m2) and pattern of medication use during pregnancy in the United States is not well-studied. Higher pre-pregnancy BMI may be associated with increases or decreases in medication use across pregnancy as symptoms (e.g. reflux) or comorbidities (e.g. gestational diabetes) requiring treatment that may be associated with higher BMI could also change with advancing gestation. OBJECTIVES: To determine whether prenatal medication use, by the number and types of medications, varies by pre-pregnancy obesity status. METHODS: In a secondary data analysis of a racially/ethnically diverse prospective cohort of pregnant women with low risk for fetal abnormalities enrolled in the first trimester of pregnancy and followed to delivery (singleton, 12 United States clinical sites), free text medication data were obtained at enrollment and up to five follow-up visits and abstracted from medical records at delivery. RESULTS: In 436 women with obesity and 1750 women without obesity (pre-pregnancy BMI, 19-29.9 kg/m2), more than 70% of pregnant women (77% of women with and 73% of women without obesity) reported taking at least one medication during pregnancy, respectively (adjusted risk ratio (aRR)=1.10, 95% confidence interval (CI)=1.01, 1.20), with 81% reporting two and 69% reporting three or more. A total of 17 classes of medications were identified. Among medication classes consumed by at least 5% of all women, the only class that differed between women with and without obesity was hormones and synthetic substitutes (including steroids, progesterone, diabetes, and thyroid medications) in which women with obesity took more medications (11 vs. 5%, aRR = 1.9, 95% CI = 1.38, 2.61) compared to women without obesity. Within this class, a higher percentage of women with obesity took diabetes medications (2.3 vs. 0.7%) and progesterone (3.4 vs. 1.3%) than their non-obese counterparts. Similar percentages of women with and without obesity reported consuming medications in the remaining medication classes including central nervous system agents (50 and 46%), gastrointestinal drugs (43 and 40%), anti-infective agents (23 and 21%), antihistamines (20 and 17%), autonomic drugs (10 and 9%), and respiratory tract agents (7 and 6%), respectively (p > 0.05 for all adjusted comparisons). There were no differences in medication use by obesity status across gestation. Since the study exclusion criteria limited the non-obese group to women without thyroid disease, in a sensitivity analysis we excluded all women who reported thyroid medication intake and still a higher proportion of women with obesity took the hormones and synthetic substitutes class compared to women without obesity. CONCLUSION: Our findings suggest that pre-pregnancy obesity in otherwise healthy women is associated with a higher use of only selected medications (such as diabetes medications and progesterone) during pregnancy, while the intake of other more common medication types such as analgesics, antibiotics, and antacids does not vary by pre-pregnancy obesity status. As medication safety information for prenatal consumption is insufficient for many medications, these findings highlight the need for a more in-depth examination of factors associated with prenatal medication use.

Perinatal outcomes after bariatric surgery.

BACKGROUND: Bariatric surgery is a widely used treatment option for obesity that often provides long-term weight control and health benefits. Although a growing number of women are becoming pregnant after bariatric surgery, only a few population-based studies have assessed the impact thereof on perinatal outcomes. OBJECTIVE: This study aimed to examine the association between bariatric surgery and adverse perinatal outcomes in pregnant women and to examine whether the risk for adverse perinatal outcomes is modified by the postsurgery weight, gestational weight gain, type of bariatric surgery, timing of pregnancy after bariatric surgery, and maternal comorbidities. STUDY DESIGN: A retrospective cohort study was performed with the use of the Bariatric Surgery Registry and hospital inpatient and outpatient physician encounter records. The International Classification of Diseases, Ninth and Tenth Revision codes from hospitalizations during pregnancy and infant birth records were used to ascertain the outcomes of interest. Women eligible for BS who delivered at ≥20 weeks of gestation (n=20,213) at Kaiser Permanente Southern California hospitals (January 1, 2007 to December 31, 2018) were included in the study. Adjusted odds ratios were derived from logistic regression models with inverse probability of treatment weighting to adjust for confounding using propensity scores. RESULTS: Bariatric surgery was associated with a reduction in the risks for gestational diabetes (adjusted odds ratio, 0.60; 95% confidence interval, 0.53-0.69; P<.001), preeclampsia (adjusted odds ratio, 0.53; 95% confidence interval, 0.46-0.61; P<.001), chorioamnionitis (adjusted odds ratio, 0.45; 95% confidence interval, 0.32-0.63; P<.001), cesarean delivery (adjusted odds ratio, 0.65; 95% confidence interval, 0.59-0.72; P<.001), large for gestational age neonate (adjusted odds ratio, 0.23; 95% confidence interval, 0.19-0.29; P<.001), macrosomia (adjusted odds ratio, 0.24; 95% confidence interval, 0.19-0.30; P<.001), and neonatal intensive care unit admission (adjusted odds ratio, 0.70; 95% confidence interval, 0.61-0.81; P<.001). However, bariatric surgery was also associated with a significantly increased risk for small for gestational age neonates (adjusted odds ratio, 2.46; 95% confidence interval, 2.16-2.79; P<.001). The risk for the adverse outcomes is independent of the time interval between the surgery and subsequent pregnancy. CONCLUSION: These data suggest that there are many pregnancy outcome benefits for women with severe obesity who undergo bariatric surgery; however, women who have undergone bariatric surgery before pregnancy should be monitored closely to reduce the risk for small for gestational age neonates and postpartum hemorrhage.

Assessing the multidisciplinary team approaches to placenta accreta spectrum across five institutions within the University of California fetal Consortium (UCfC).

PURPOSE: To describe the multidisciplinary approaches to placenta accreta spectrum (PAS) across five tertiary care centers that comprise the University of California fetal Consortium (UCfC) and to identify potential best practices. MATERIALS AND METHODS: Retrospective review of all cases of pathologically confirmed invasive placenta delivered from 2009 to 2014 at UCfC. Differences in intraoperative management and outcomes based on prenatal suspicion were compared. Interventions assessed included ureteral stent use, intravascular balloon use, anesthetic type, gynecologic oncology (Gyn Onc) involvement, and cell saver use. Intervention variation by institution was also assessed. Analyses were adjusted for final pathologic diagnosis. Chi-square, Fisher's exact, Student's t-test, and Mann-Whitney's U-test were used as appropriate. Binary logistic regression and multivariable linear regression were used to adjust for confounders. RESULTS: One hundred and fifty-one cases of pathologically confirmed invasive placenta were identified, of which 82% (123) were suspected prenatally. There was no correlation between the degree of invasion on prenatal imaging and use of each intervention. Ureteral stents were placed in 33% (41) of cases and did not reduce GU injury. Intravascular balloons were placed in 29% (36) of cases and were associated with shorter OR time (161 versus 236 min, p < .01) and lower estimated blood loss (EBL) (1800 versus 2500 ml, p < .01). General endotracheal anesthesia (GETA) was used in 70% (86). EBL did not differ between GETA and regional anesthesia. Gyn Onc was involved in 58% (71) of cases and EBL adjusted for final pathology was reduced with their involvement (2200 versus 2250 ml, p = .02) while OR time and intraoperative complications did not differ. Cell saver was used in 20% (24) and was associated with longer OR time (296 versus 200 min, p < .01). Use of cell saver was not associated with a difference in EBL or number of units of packed red cells transfused. All analyses were adjusted for pathologic severity of invasion. CONCLUSIONS: Intravascular interventions such as uterine artery balloons and the inclusion of Gynecologic Oncologists as part of a multidisciplinary approach to treating PAS reduce EBL. Additionally, the placement of intravascular balloons may reduce OR time. No significant differences were seen in outcomes when comparing the use of ureteral stents, general anesthesia, or institutions. A team of experienced operators with a standard approach may be more significant than specific practices.

Fetal Growth Patterns in Pregnancies With First-Trimester Bleeding.

OBJECTIVE: To assess the relationship between first-trimester vaginal bleeding and fetal growth patterns. METHODS: We conducted a secondary analysis of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singletons, a prospective cohort study of low-risk, nonobese women with healthy lifestyles. Duration of bleeding was self-reported at enrollment (10 0/7 to 13 6/7 weeks of gestation) and categorized as 0, 1, or more than 1 day. Longitudinal measures of fetal biometrics were obtained in up to six study visits, and estimated fetal weight was computed. Growth trajectories were created for biometrics and estimated fetal weight. When global tests among groups was significant (P<.05), week-specific global and pairwise differences were tested. Birth weight and risk of a small-for-gestational-age (SGA) neonate were secondary outcomes. All analyses were adjusted for maternal age, weight, height, parity, and racial-ethnic group and neonatal sex in a sensitivity analysis. RESULTS: In 2,307 eligible women, 410 (17.8%) reported first-trimester bleeding, of whom 176 bled for 1 day and 234 bled for more than 1 day. Women with more than 1 day of bleeding demonstrated decreased fetal abdominal circumference from 34 to 39 weeks of gestation compared with women without bleeding. For women with more than 1 day of bleeding, compared with women without bleeding, estimated fetal weight was 68-107 g smaller from 35 to 39 weeks of gestation. Mean birth weight at term was 88 g smaller, confirming differences in calculated fetal weight, and SGA neonates were delivered to 148 (8.5%), 9 (5.7%), and 33 (15.7%) women in the no bleeding, 1 day, and more than 1 day of bleeding groups, respectively. CONCLUSION: More than 1 day of first-trimester vaginal bleeding was associated with smaller estimated fetal weight late in pregnancy driven by smaller abdominal circumference. The magnitude of decrease in birth weight was small, albeit comparable with observed decreases associated with maternal smoking. It remains unknown whether early pregnancy bleeding is associated with short-term or long-term morbidity and whether additional intervention would be of benefit. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00912132.

Prescription and Other Medication Use in Pregnancy.

OBJECTIVE: To characterize prescription and other medication use in a geographically and ethnically diverse cohort of women in their first pregnancy. METHODS: In a prospective, longitudinal cohort study of nulliparous women followed through pregnancy from the first trimester, medication use was chronicled longitudinally throughout pregnancy. Structured questions and aids were used to capture all medications taken as well as reasons they were taken. Total counts of all medications taken including number in each category and class were captured. Additionally, reasons the medications were taken were recorded. Trends in medications taken across pregnancy and in the first trimester were determined. RESULTS: Of the 9,546 study participants, 9,272 (97.1%) women took at least one medication during pregnancy with 9,139 (95.7%) taking a medication in the first trimester. Polypharmacy, defined as taking at least five medications, occurred in 2,915 (30.5%) women. Excluding vitamins, supplements, and vaccines, 73.4% of women took a medication during pregnancy with 55.1% taking one in the first trimester. The categories of drugs taken in pregnancy and in the first trimester include the following: gastrointestinal or antiemetic agents (34.3%, 19.5%), antibiotics (25.5%, 12.6%), and analgesics (23.7%, 15.6%, which includes 3.6%; 1.4% taking an opioid pain medication). CONCLUSION: In this geographically and ethnically diverse cohort of nulliparous pregnant women, medication use was nearly universal and polypharmacy was common. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01322529.

Comparison of staples vs subcuticular suture in class III obese women undergoing cesarean: a randomized controlled trial.

BACKGROUND: Obesity is a risk factor for infectious morbidity and wound complications after cesarean delivery. There are currently insufficient data to determine optimal skin closure technique for cesarean delivery, specifically for those women with class III obesity, defined as a body mass index ≥40 kg/m2. OBJECTIVE: We sought to compare stainless steel staples vs subcuticular suture for skin closure for cesarean delivery in class III obese women with body mass index ≥40 kg/m2. STUDY DESIGN: We conducted a randomized controlled trial at 2 teaching hospitals from 2015 through 2016 in which women with body mass index ≥40 kg/m2 undergoing cesarean delivery were randomly assigned to stainless steel staples or subcuticular suture skin closure. The primary outcome was composite wound complication defined as superficial or deep separation and infection occurring up to 6 weeks following delivery. Secondary outcomes included operative time, and patient pain and satisfaction scores. RESULTS: A total of 242 women were enrolled. In all, 119 in the staples group and 119 in the subcuticular suture group were analyzed. Maternal demographics and characteristics were similar in both groups. The composite wound complication frequency was 19.3% in the staples group and 17.6% in the subcuticular suture group (P = .74) with an overall wound complication incidence of 18.5% in the entire study cohort. There were also no differences in the frequencies of infection, or in superficial or deep wound separation between the 2 study groups. In a univariate analysis of predictors of wound complications, only current tobacco use was a significant predictor of wound complications (relative risk, 4.97; 95% confidence interval, 1.37-18.03; P = .02). Fewer women with staple closure would choose the same method with a future delivery (P = .01), however, self-reported pain and concern about wound healing were equal between the 2 groups. CONCLUSION: In class III obese women undergoing cesarean delivery, there was no difference in composite wound outcome up to 6 weeks postpartum between those who had staples and those who had subcuticular suture skin closure.

Role of early second-trimester uterine artery Doppler screening to predict small-for-gestational-age babies in nulliparous women.

BACKGROUND: Trophoblastic invasion of the uterine spiral arteries substantially increases compliance to accommodate increased blood flow to the placenta. Failure of this process impedes uterine artery blood flow, and this may be detected by uterine artery Doppler flow studies. However, the clinical utility of uterine artery Doppler flow studies in the prediction of adverse pregnancy outcomes in a general population remains largely unknown. OBJECTIVE: We sought to determine the utility of early second-trimester uterine artery Doppler studies as a predictor of small-for-gestational-age neonates. STUDY DESIGN: Nulliparous women with a viable singleton pregnancy were recruited during their first trimester into an observational prospective cohort study at 8 institutions across the United States. Participants were seen at 3 study visits during pregnancy and again at delivery. Three indices of uterine artery Doppler flow (resistance index, pulsatility index, and diastolic notching) were measured in the right and left uterine arteries between 16 weeks 0 days' and 22 weeks 6 days' gestation. Test characteristics for varying thresholds in the prediction of small for gestational age (defined as birthweight <5th percentile for gestational age [Alexander growth curve]) were evaluated. RESULTS: Uterine artery Doppler indices, birthweight, and gestational age at birth were available for 8024 women. Birthweight <5th percentile for gestational age occurred in 358 (4.5%) births. Typical thresholds for the uterine artery Doppler indices were all associated with birthweight <5th percentile for gestational age (P < .0001 for each), but the positive predictive values for these cutoffs were all <15% and areas under receiver operating characteristic curves ranged from 0.50-0.60. Across the continuous scales for these measures, the areas under receiver operating characteristic curves ranged from 0.56-0.62. Incorporating maternal age, early pregnancy body mass index, race/ethnicity, smoking status prior to pregnancy, chronic hypertension, and pregestational diabetes in the prediction model resulted in only modest improvements in the areas under receiver operating characteristic curves ranging from 0.63-0.66. CONCLUSION: In this large prospective cohort, early second-trimester uterine artery Doppler studies were not a clinically useful test for predicting small-for-gestational-age babies.

Sleep During Pregnancy: The nuMoM2b Pregnancy and Sleep Duration and Continuity Study.

Study Objectives: To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables. Methods: Multisite prospective cohort study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16-21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women <18 years of age or with pregestational diabetes or chronic hypertension were excluded from participation. Women wore a wrist activity monitor and completed a sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant. Results: Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of <7 hours; 2.6% had a sleep duration of >9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset. Conclusions: Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy.

Augmented H2S production via cystathionine-beta-synthase upregulation plays a role in pregnancy-associated uterine vasodilation.

Endogenous hydrogen sulfide (H2S) synthesized via metabolizing L-cysteine by cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE) is a potent vasodilator and angiogenic factor. The objectives of this study were to determine if human uterine artery (UA) H2S production increases with augmented expression and/or activity of CBS and/or CSE during the menstrual cycle and pregnancy and whether exogenous H2S dilates UA. Uterine arteries from nonpregnant (NP) premenopausal proliferative (pPRM) and secretory (sPRM) phases of the menstrual cycle and pregnant (P) women were studied. H2S production was measured by the methylene blue assay. CBS and CSE mRNAs were assessed by quantitative real-time PCR, and proteins were assessed by immunoblotting and semiquantitative immunofluorescence microscopy. Effects of H2S on rat UA relaxation were determined by wire myography ex vivo. H2S production was greater in NP pPRM and P than NP sPRM UAs and inhibited by the specific CBS but not CSE inhibitor. CBS but not CSE mRNA and protein were greater in NP pPRM and P than NP sPRM UAs. CBS protein was localized to endothelium and smooth muscle and its levels were in a quantitative order of P >NP UAs of pPRM>sPRM. CSE protein was localized in UA endothelium and smooth muscle with no difference among groups. A H2S donor relaxed P > NP UAs but not mesentery artery. Thus, human UA H2S production is augmented with endothelium and smooth muscle CBS upregulation, contributing to UA vasodilation in the estrogen-dominant physiological states in the proliferative phase of the menstrual cycle and pregnancy.

Pilot Study to Evaluate Compliance and Tolerability of Cranberry Capsules in Pregnancy for the Prevention of Asymptomatic Bacteriuria.

OBJECTIVES: To evaluate the compliance with and tolerability of daily cranberry capsule ingestion for asymptomatic bacteriuria (ASB) prevention in pregnancy. DESIGN: A total of 49 pregnant women from two sites were randomly assigned to cranberry or matching placebo, two doses daily, at gestational ages less than 16 weeks. Patients were followed monthly for urinary tract infection until delivery. Up to seven monthly visits were scheduled for each patient. Delivery data were evaluated. RESULTS: Of 38 evaluable patients, the mean compliance rate over the study period was 82% (range, 20%-100%). This compliance rate and the 74% of patients achieving good (≥75%) compliance were similar between those who received cranberry capsules and placebo. Compliance evaluation revealed that most patients stopped capsule consumption after 34-38 weeks of participation. Multivariate logistic regression and longitudinal analysis showed a significant interaction time effect with cranberry treatment. However, cranberry consumption was not a significant predictor of gastrointestinal intolerance or study withdrawal. Although 30% of patients withdrew for various reasons, only 1 withdrew because of intolerance to the cranberry capsules. Loss to follow-up was mostly due to provider change (9 of 49 [18%]) and therapy disinterest (4 of 49 [8%]). Seven cases of ASB occurred in 5 patients: 2 of 24 (8%) in the cranberry group and 3 of 25 (12%) in the placebo group. No cases of cystitis or pyelonephritis were observed. CONCLUSION: One third of pregnant women could not complete the study protocol for various reasons. Compliance with and tolerability of cranberry capsule ingestion appear good; these capsules provide a potentially effective means to prevent ASB in pregnancy. Further studies with large samples are necessary to confirm the findings.

S-nitrosylation of cofilin-1 mediates estradiol-17ß-stimulated endothelial cytoskeleton remodeling.

Rapid nitric oxide (NO) production via endothelial NO synthase (eNOS) activation represents a major signaling pathway for the cardiovascular protective effects of estrogens; however, the pathways after NO biosynthesis that estrogens use to function remain largely unknown. Covalent adduction of a NO moiety to cysteines, termed S-nitrosylation (SNO), has emerged as a key route for NO to directly regulate protein function. Cofilin-1 (CFL1) is a small actin-binding protein essential for actin dynamics and cytoskeleton remodeling. Despite being identified as a major SNO protein in endothelial cells, whether SNO regulates CFL-1 function is unknown. We hypothesized that estradiol-17ß (E2ß) stimulates SNO of CFL1 via eNOS-derived NO and that E2ß-induced SNO-CFL1 mediates cytoskeleton remodeling in endothelial cells. Point mutation studies determined Cys80 as the primary SNO site among the 4 cysteines (Cys39/80/139/147) in CFL1. Substitutions of Cys80 with Ala or Ser were used to prepare the SNO-mimetic/deficient (C80A/S) CFL1 mutants. Recombinant wild-type (wt) and mutant CFL1 proteins were prepared; their actin-severing activity was determined by real-time fluorescence imaging analysis. The activity of C80A CFL1 was enhanced to that of the constitutively active S3/A CFL1, whereas the other mutants had no effects. C80A/S mutations lowered Ser3 phosphorylation. Treatment with E2ß increased filamentous (F)-actin and filopodium formation in endothelial cells, which were significantly reduced in cells overexpressing wt-CFL. Overexpression of C80A, but not C80S, CFL1 decreased basal F-actin and further suppressed E2ß-induced F-actin and filopodium formation compared with wt-CFL1 overexpression. Thus, SNO(Cys80) of cofilin-1 via eNOS-derived NO provides a novel pathway for mediating estrogen-induced endothelial cell cytoskeleton remodeling.

Selected vaginal bacteria and risk of preterm birth: an ecological perspective.

We examined the community ecology of vaginal microbial samples taken from pregnant women with previous preterm birth experience to investigate whether targeted pathogenic and commensal bacteria are related to risk of preterm birth in the current pregnancy. We found a significant correlation between the community structure of selected bacteria and birth outcome, but the correlation differed among self-reported racial/ethnic groups. Using a community ordination analysis, we observed infrequent co-occurrence of Mycoplasma and bacteria vaginosis associated bacteria 3 (BVAB3) among black and Hispanic participants. In addition, we found that the vaginal bacteria responded differently in different racial/ethnic groups to modifications of maternal behavioral (ie, douching and smoking) and biological traits (ie, body mass index [BMI]). Even after accounting for these maternal behaviors and traits, the selected vaginal bacteria was significantly associated with preterm birth among black and Hispanic participants. By contrast, white participants did not exhibit significant correlation between microbial community and birth outcome. Findings from this study affirm the necessity of considering women's race/ethnicity when evaluating the correlation between vaginal bacteria and preterm birth. The study also illustrates the importance of studying the vaginal microbiota from an ecological perspective, and demonstrates the power of ecological community analysis to improve understanding of infectious disease.

Persistent pulmonary hypertension of the newborn following elective cesarean delivery at term.

OBJECTIVE: To evaluate the frequency of persistent pulmonary hypertension of the newborn (PPHN) following elective cesarean at greater than 34 weeks' gestation in an academically affiliated community hospital. METHODS: Retrospective cohort study involving chart review of 300 newborns with PPHN between 1999 and 2006. Infants less than 34 weeks' or with congenital anomalies were excluded. Subjects were divided into two groups: (1) intended vaginal delivery and (2) elective cesarean. RESULTS: A total of 125 neonates were included. In all, 46 were delivered vaginally, 53 by cesarean after a trial of labor, and 26 by elective cesarean. No statistically significant differences were noted between groups in birth weight, gestational age, or length of stay. The crude relative risk (RR) of PPHN in cesareans prior to labor (elective cesareans) when compared to intended vaginal deliveries was 2.0 (95% CI 1.3-3.1). The RR of PPHN in elective cesareans when compared to spontaneous labor resulting in vaginal deliveries was 3.4 (95% CI 2.1-5.5). The adjusted RRs for these outcomes comparing the same delivery groups when considering gestational age at birth (less vs. equal to or more than 37 weeks') were 2.2 (95% CI 1.4-3.4) and 3.7 (95% CI 2.3-6.1), and birth weight (less vs. equal to or more than 2500 g) were 1.9 (95% 1.3-3.0) and 3.4 (95% CI 2.1-5.5), respectively. The incidence of PPHN in the elective cesarean group was 6.9 per 1000 deliveries. The number of cesareans to be avoided to prevent one case of PPHN in this cohort was 387 (number needed to harm, 95% CI 206.8-3003.1). CONCLUSIONS: Our findings include a high rate of PPHN following elective cesarean delivery, and suggest that physicians should consider this added morbidity when performing elective cesareans.

Perspectives of SLIT/ROBO signaling in placental angiogenesis.

A novel family of evolutionally conserved neuronal guidance cues, including ligands (i.e., Slit, netrin, epherin, and semaphorin) and their corresponding receptors (i.e., Robo, DCC/Unc5, Eph and plexin/ neuropilin), has been identified to play a crucial role in axon pathfinding and branching as well as neuronal cell migration. The presence of commonalities in both neural and vascular developments has led to some exciting discoveries recently, which have extended the functions of these systems to vascular formation (vasculogenesis) and development (angiogenesis). Some of these ligands and receptors have been found to be expressed in the vasculature and surrounding tissues in physiological and pathological conditions. It is postulated that they regulate the formation and integrity of blood vessels. In particular, it has been shown that the Slit/Robo pair plays a novel role in angiogenesis during tumorigenesis and vascular formation during embryogenesis. Herein we summarize briefly the characteristics of this family of neuronal guidance molecules and discuss the extra-neural expression and function of the Slit/Robo pair in angiogenesis in physiological and pathological settings. We report expression of Robo1 protein in capillary endothelium and co-expression of Slit2 and Robo1 proteins in syncytiotrophoblast in healthy term human placental villi. These cellular expression patterns implicate that the Slit/Robo signaling plays an autocrine and/or paracrine role in angiogenesis and trophoblast functions. We also speculate a possible role of this system in pathophysiological placental angiogenesis.

U.S. Food and Drug Administration drug approval: slow advances in obstetric care in the United States.

The process for drug approval in the United States is complex and time-consuming. There are comparatively few drugs with U.S. Food and Drug Administration (FDA)-approved indications for obstetric use in this country at this time; however, several are under development. We review the process for drug approval and recount the approval histories of obstetric drugs reviewed in the recent past. We also outline the current status of two progestational agents that are under development. For a variety of reasons, including a small market compared with others such as cardiology or oncology, and the potential of being drawn into medical-legal litigation, sponsors are disinclined to pursue drug development for obstetric purposes in this country. We compare the procedures for review and approval of drugs in the United States with those in Europe, and note that recent changes within the FDA may result in not only more drugs being approved but also changes in labeling of already approved drugs. Special programs to facilitate drug development and reforms to modernize the process and improve safety are discussed. These may result in changes in labeling of already approved drugs. Obstacles such as funding and liability are also discussed.

Pregnancy management after cervical surgery.

PURPOSE OF REVIEW: An amplified risk of adverse pregnancy outcomes after excisional cervical surgery has been identified. Procedures such as cold-knife conization, laser conization, loop electrosurgical excision procedure, and trachelectomy increase the risk of preterm delivery and preterm premature rupture of membranes. Few studies have evaluated prenatal care considerations after these procedures. This review discusses pregnancy management after cervical surgery. RECENT FINDINGS: Data showing an association between excisional and ablative procedures of the cervix and subsequent preterm delivery or preterm premature rupture of membranes are increasing and include more recent information from larger case series and meta-analyses. The need for appropriate and evidence-based management strategies during subsequent pregnancy has arisen. Screening for genital tract infection, sonographic cervical length surveillance, and progesterone administration for cervical shortening may lead to improved pregnancy outcomes in women at high risk for preterm delivery, including women who have undergone cervical surgery. Modifiable risk factors such as depth of conization and procedure-to-pregnancy time interval should be recognized and clinicians should avoid overtreatment for preinvasive cervical lesions. SUMMARY: A number of procedures performed for a variety of indications can be considered excisional cervical surgery. As a result, no standard recommendations for pregnancy management following cervical surgery exist. Given the increased risk of pregnancy complications, certain screening tests or interventions may be appropriate for these women.

Successful pregnancy in a patient with severe combined immunodeficiency syndrome treated with bone marrow transplantation.

BACKGROUND: We present the case of a patient with a history of severe combined immunodeficiency (SCID) syndrome successfully treated with bone marrow transplantation. Her resultant Rh alloimmunization complicated her first pregnancy. CASE: The patient was diagnosed with SCID syndrome after a series of opportunistic infections. The patient underwent bone marrow transplantation, receiving the graft from her haploidentical father. Once pregnant, her antepartum course was complicated by Rh alloimmunization resulting from her bone marrow transplantation, changing her blood antigen status from D-positive to D-negative. Antenatally, she was closely managed with serial middle cerebral artery Doppler measurements and delivered a healthy baby girl at term. CONCLUSION: Bone marrow transplantation in a patient with SCID syndrome resulted in Rh isoimmunization, complicating pregnancy management.

Alterations in saliva steroid hormone levels after oral mifepristone administration in women with pregnancies of greater than 41 weeks' gestation.

The objective of this study is to describe the effects of oral mifepristone administration on saliva levels of estradiol, estriol, progesterone, and cortisol in women with postdates pregnancy. As an adjunct to a randomized controlled trial comparing 200 mg oral mifepristone to placebo for cervical ripening and labor induction in women with pregnancies greater than 41 weeks' gestation, saliva samples were obtained before drug administration and every 6 hours thereafter for 24 hours. Estradiol, estriol, progesterone, and cortisol levels were measured by radioimmunoassay. Ninety-seven participants received mifepristone, and 83 received placebo. Saliva steroid hormone data were available for 71 mifepristone-and 60 placebo-treated women. Mean baseline saliva estradiol, estriol, progesterone, and cortisol levels were similar between study groups. At 24 hours after study medication administration, saliva estradiol, estriol, progesterone, and cortisol levels in the mifepristone group were significantly elevated compared with baseline. There was no significant change in hormone levels in the placebo group. Oral mifepristone significantly increased saliva estradiol, estriol, progesterone, and cortisol compared with placebo. This may reflect mifepristone's antiglucocorticoid properties. These hormone elevations may contribute to the mechanism by which mifepristone causes cervical ripening and increases myometrial activity.

Management of pregnancy after radical trachelectomy: case reports and systematic review of the literature.

This article reviews the existing literature on pregnancy outcomes following radical trachelectomy for low-stage cervical carcinoma and describes the guidelines in our institution for obstetrical management after managing two pregnancies following radical trachelectomy. We performed a literature search in PUBMED, MEDLINE, and EMBASE for the keywords "radical trachelectomy," "pregnancy," or "fertility" from 1994 to the present. All observational studies were included, and duplicate cases were excluded from our review. In addition to our cases, 14 studies were reviewed and included. Selection criteria included case reports or series detailing pregnancy outcomes including gestational age at delivery. Data regarding pregnancy outcomes were tabulated from the reports with focus on additional procedures such as vaginal occlusion and delivery outcomes. Where data were unclear, the authors personally contacted the authors of previously published manuscripts for further data. Our results revealed that 40% of women conceived following radical trachelectomy. Of them they had a preterm delivery rate of 25%, and 42% culminated in delivery of a live born infant at term. The use of the vaginal occlusion procedure did not appear to prolong gestation when compared with those women who did not have the procedure, but the majority of successful pregnancy outcomes have occurred with a cerclage in place. In conclusion, successful pregnancy outcome is possible after radical trachelectomy for cervical cancer, with two thirds of pregnancies resulting in a live birth, including those of both cases reported. There is a higher frequency of adverse perinatal outcomes in these patients, however, and careful interdisciplinary planning and counseling prior to undertaking the trachelectomy is recommended.