GAP (gestational diabetes and pharmacotherapy) - study protocol for a randomized controlled, two-arm, single-site trial.

BACKGROUND: Gestational diabetes (GDM) complicates 10% of pregnancies in the US. First-line treatment is medical nutrition therapy (MNT) and exercise. Second line is pharmacotherapy. The definition of what constitutes an unsuccessful trial of MNT and exercise has not been established. Tight glycemic control has been demonstrated to reduce GDM-related neonatal and maternal clinical complications. However, it could also increase rates of small-for-gestational age and carry negative effects on patient-reported outcomes such as anxiety and stress. We will study the effect of earlier and stricter pharmacotherapy in GDM on clinical and patient-reported outcomes. METHODS: GDM and pharmacotherapy (GAP) study is a two-arm parallel, pragmatic randomized controlled trial, where 416 participants with GDM are randomized 1:1 to: 1) Intervention group - insulin initiation at 20% elevated glucose values on a weekly glucose log following MNT and exercise trial and insulin titration to keep elevated glucose values <20%; or 2) Active control group - insulin initiation at 40% elevated glucose values on a weekly log following MNT and exercise and insulin titration to keep elevated glucose values <40%. The primary outcome is a composite neonatal outcome of large-for-gestational-age, macrosomia, birth trauma, preterm birth, hypoglycemia, and hyperbilirubinemia. Secondary outcomes include preeclampsia, cesarean birth, small-for-gestational-age, maternal hypoglycemia, and patient-reported outcomes of anxiety, depression, perceived stress, and diabetes self-efficacy. CONCLUSIONS: The GAP study will investigate the optimal glycemic threshold for pharmacotherapy addition to MNT and exercise in GDM. The GAP study will promote standardization in GDM management and will have direct relevance for clinical practice.

Cervical Ripening Balloon in Combination with Methotrexate and Potassium Chloride for the Treatment of a 13-week Cervical Ectopic Pregnancy.

Background: Cervical pregnancy, an uncommon type of ectopic pregnancy, can lead to devastating consequences if not diagnosed and treated early. Despite this, there are no specific guidelines on how to treat such pregnancies especially in advanced gestational ages (GAs). Case: This is a 35-year-old patient who presented to our hospital at 13 weeks GA after failing systemic multidose methotrexate therapy for a cervical ectopic pregnancy. Given desire to preserve fertility, a minimally invasive conservative approach was taken involving potassium chloride (KCl) and methotrexate injections into the gestational sac, followed by immediate Cook intracervical double balloon placement under direct ultrasound visualization, with removal of the balloon after 72 hours, and ultimately resolution of the pregnancy 12 weeks after the removal. Conclusion: Advanced first trimester cervical ectopic pregnancy after failure of methotrexate therapy was managed successfully with minimally invasive KCl and methotrexate injections in combination with cervical ripening balloon.

O-GlcNAc transferase contributes to sex-specific placental deregulation in gestational diabetes.

INTRODUCTION: Gestational diabetes (GDM) is traditionally thought to emerge from placental endocrine dysregulations, but recent evidence suggests that fetal sex can also impact GDM development. Understanding the molecular mechanisms through which sex modulates placenta physiology can help identify novel molecular targets for future clinical care. Thus, we investigated the nutrient-sensing O-GlcNAc pathway as a potential mediator of sex-specific placenta dysfunction in GDM. METHODS: Expression levels of O-GlcNAc enzymes were measured in male and female (n = 9+/gender) human placentas based on the maternal diagnosis of GDM. We then simulated the observed differences in both BeWo cells and human syncytiotrophoblasts primary cells (SCT) from male and female origins (n = 6/gender). RNA sequencing and targeted qPCR were performed to characterize the subsequent changes in the placenta transcriptome related to gestational diabetes. RESULTS: O-GlcNAc transferase (OGT) expression was significantly reduced only in male placenta collected from mothers with GDM compared to healthy controls. Similar downregulation of OGT in trophoblast-like BeWo male cells demonstrated significant gene expression deregulations that overlapped with known GDM-related genes. Notably, placental growth hormone (GH) production was significantly elevated, while compensatory factors against GH-related insulin resistance were diminished. Inflammatory and immunologic factors with toxic effects on pancreatic ß cell mass were also increased, altogether leaning toward a decompensatory diabetic profile. Similar changes in hormone expression were confirmed in male human primary SCTs transfected with siOGT. However, down-regulating OGT in female primary SCTs did not impact hormone production. CONCLUSION: Our study demonstrated the significant deregulation of placental OGT levels in mothers with GDM carrying a male fetus. When simulated in vitro, such deregulation impacted hormonal production in BeWo trophoblast cells and primary SCTs purified from male placentas. Interestingly, female placentas were only modestly impacted by OGT downregulation, suggesting that the sex-specific presentation observed in gestational diabetes could be related to O-GlcNAc-mediated regulation of placental hormone production.

Antenatal maternal hypoglycemia in women with gestational diabetes mellitus and neonatal outcomes.

OBJECTIVE: To examine the prevalence of antenatal maternal hypoglycemia after initiation of pharmacotherapy for gestational diabetes mellitus (GDMA2) and its association with pregnancy outcomes. STUDY DESIGN: Retrospective cohort of GDMA2 women receiving either insulin or oral hypoglycemic agents. Composite neonatal outcome included macrosomia, jaundice, respiratory distress syndrome, large for gestational age, shoulder dystocia, birth trauma, 5-minute Apgar < 7, and neonatal hypoglycemia, and was compared between women with and without hypoglycemia using bivariate and multivariate analyses. RESULTS: Of 489 women included in the study, 95 (19.4%) had at least one episode of hypoglycemia, most often in the setting of glyburide. Newborns exposed to maternal hypoglycemia had higher rates of the composite neonatal outcome (54.7% vs. 38.3%, p = 0.004). After controlling for confounding factors, maternal hypoglycemia remained independently associated with the composite neonatal outcome (aOR = 1.69, 95% CI 1.04-2.72). CONCLUSION: Maternal hypoglycemia in GDMA2 was associated with higher rates of adverse neonatal outcomes.

Provider-based initiation and management of pharmacologic therapy for gestational diabetes mellitus.

OBJECTIVE: After failure of diet and exercise prescribed for gestational diabetes mellitus (GDM), pharmacotherapy initiation is recommended. The objective of this study was to examine the association between provider type and timing of pharmacotherapy initiation. METHODS: This was a retrospective cohort study of women with a singleton pregnancy and diagnosis of A2GDM (GDM requiring pharmacotherapy) delivering in a tertiary care center between 2009 and 2019. Variables including maternal demographics, GDM characteristics, and provider type (general obstetrician/gynecologists (OBGYN), maternal-fetal medicine (MFM), or endocrinology) were assessed. The percent of abnormal glucose values at pharmacotherapy initiation was compared among provider types via univariable and multivariable analyses. RESULTS: A total of 428 women were included in the analysis. Eighteen percent were managed by MFM, 54% by general OBGYN, and 28% by endocrinology. Insulin was prescribed in 45.8% of women. In univariable analysis, the percent of abnormal glucose values was higher in women managed by MFMs, compared with general OBGYN and endocrinology (58.0%±25.1, 50.0%±23.1, and 50.3%±26.8, respectively, p = .041). Women started on insulin as first-line pharmacotherapy were more likely to be managed by endocrinology (p < .001). After adjusting for confounding variables, provider type was not significantly associated with percent of abnormal glucose values at pharmacotherapy initiation, but endocrinology was more likely to initiate insulin (aOR = 9.33, 95% CI 4.27-20.39). CONCLUSIONS: Provider type was not associated with percent of elevated glucose values at the time of pharmacotherapy initiation for A2GDM, but it was associated with insulin usage as first-line pharmacotherapy.

The timing of initiation of pharmacotherapy for women with gestational diabetes mellitus.

BACKGROUND: The decision to initiate pharmacotherapy is integral in the care for pregnant women with gestational diabetes mellitus (GDM). We sought to compare pregnancy outcomes between two threshold percentages of elevated glucose values prior to initiation of pharmacotherapy for GDM. We hypothesized that a lower threshold at pharmacotherapy initiation will be associated with lower rates of adverse perinatal outcomes. METHODS: This was a retrospective cohort study of women with GDM delivering in a single tertiary care center. Pregnancy outcomes were compared using bivariable and multivariable analyses between women who started pharmacotherapy (insulin or oral hypoglycemic agent) after a failed trial of dietary modifications at two different ranges of elevated capillary blood glucose (CBG) values: Group 1 when 20-39% CBG values were above goal; Group 2 when ≥40% CBG values were above goal. The primary outcome was a composite GDM-associated neonatal adverse outcome that included: macrosomia, large for gestational age (LGA), shoulder dystocia, hypoglycemia, hyperbilirubinemia requiring phototherapy, respiratory distress syndrome, stillbirth, and neonatal demise. Secondary outcomes included cesarean delivery, preterm birth (< 37 weeks), neonatal intensive care unit (NICU) admission, and small for gestational age (SGA). RESULTS: A total of 417 women were included in the study. In univariable analysis, the composite neonatal outcome was statistically significantly higher in Group 2 compared to Group 1 (47.9% vs. 31.4%, p = 0.001). In addition, rates of preterm birth (15.7% vs 7.4%, p = 0.011), NICU admission (11.7% vs 4.0%, p = 0.006), and LGA (21.2% vs 9.1% p = 0.001) were higher in Group 2. In contrast, higher rates of SGA were noted in Group 1 (8.0% vs. 2.9%, p = 0.019). There was no difference in cesarean section rates. These findings persisted in multivariable analysis after adjusting for confounding factors (composite neonatal outcome aOR = 0.50, 95%CI [0.31-0.78]). CONCLUSIONS: Initiation of pharmacotherapy for GDM when 20-39% of CBG values are above goal, compared to ≥40%, was associated with decreased rates of adverse neonatal outcomes attributable to GDM. This was accompanied by higher rates of SGA among women receiving pharmacotherapy at the lower threshold. Additional studies are required to identify the optimal threshold of abnormal CBG values to initiate pharmacotherapy for GDM.

Placental endothelin-converting enzyme-1 is decreased in preeclampsia.

Endothelin-converting enzyme-1(ECE-1) is a key regulatory enzyme in the processing of endothelin-1 (ET-1). We quantified and localized ECE-1 in normal and preeclamptic placentas. Normal (n=6) and preeclamptic (n=6) placentas were serially sectioned for immunofluorescence (IF). Cell type specific markers identified endothelial, trophoblast, macrophage, smooth muscle, and fibroblast cells. Quantitative analyses were performed by western blot and ELISA. IF identified ECE-1 expression within the stroma and villous space. Cellular localization of ECE-1 was limited to endothelial membranes. There was significantly less ECE-1 in preeclamptic placentas, suggesting ECE-1 is important for proper regulation of ET-1 within the placenta.

Expectant Management of a Twin Pregnancy with Complete Hydatidiform Mole and Coexistent Normal Fetus.

Twin pregnancies complicated by complete hydatidiform mole coexisting with a viable fetus are rare and may result in significant complications. We describe the expectant management and our surgical approach in a 27-year-old Rh-negative woman presenting with recurrent episodes of vaginal bleeding and a twin pregnancy consisting of a molar pregnancy coexisting with a normal fetus. Inpatient management was undertaken with close maternal and fetal monitoring until cesarean delivery of a healthy female infant and histopathologically confirmed complete hydatidiform molar pregnancy (karyotype 46XX) at 34 weeks with no evidence of malignancy.

The Impact of Fetal Anomalies on Contemporary Labor Patterns.

OBJECTIVE: To compare labor patterns in pregnancies affected by fetal anomalies to low-risk singletons. STUDY DESIGN: Labor data from the Consortium on Safe Labor, a multicenter retrospective study from 19 U.S. hospitals, including 98,674 low-risk singletons compared with 6,343 pregnancies with fetal anomalies were analyzed. Repeated-measures analysis constructed mean labor curves by parity, gestational age, and presence of fetal anomaly in women who reached full dilation. Interval-censored regression analysis adjusted for covariables was used to determine the median traverse times for labor progression. RESULTS: Labor curves for all groups indicated slower labor progress for patients with fetal anomalies. The most significant trends in median traverse times were observed in the preterm nulliparous and term multiparous groups. The median traverse times from 4 cm to complete dilation in the preterm nulliparous control versus anomaly groups were 5.0 and 5.4 hours (p < 0.0001). CONCLUSION: Labor proceeds at a slower rate in pregnancies affected by anomalies.

Fatiguing Trunk Flexor Exercise Decreases Pain Sensitivity in Postpartum Women.

BACKGROUND: Low back pain (LBP) is common in the general population and among postpartum women. Abdominal muscle exercise is often used to treat LBP, but it is unknown if fatiguing abdominal muscle exercise can produce exercise-induced hypoalgesia (EIH). OBJECTIVES: To assess pressure pain thresholds (PPTs) at rest and following fatiguing trunk flexor exercise (EIH) in (1) nulligravid and postpartum women to evaluate the impact of pregnancy and childbirth and (2) nulligravid women and men to examine sex differences. METHODS: Seventy healthy adults (31 postpartum women, 23 nulligravid women, 16 men) participated. Postpartum and nulligravid women were tested twice (16-18 weeks apart) to identify changes in EIH with postpartum recovery. PPTs were measured at the nailbed and superior rectus abdominis before and after exercise to investigate systemic and local EIH, respectively. Rectus abdominis muscle thickness was assessed with ultrasound. RESULTS: Postpartum women reported lower PPTs than nulligravid women at the abdomen (p < 0.05) whereas postpartum women had lower PPTs at the nailbed during the first session only. Men reported higher nailbed PPTs (p = 0.047) and similar PPTs at the abdomen than women (p = 0.294). All groups demonstrated EIH at the abdomen (p < 0.05). Systemic EIH was absent in postpartum and nulligravid women (p > 0.05), while men demonstrated hyperalgesia. Local EIH was positively associated with muscle thickness for men and women, which was not significant at the second timepoint. LIMITATIONS: Acute exercise response may not reflect changes that occur with exercise training. CONCLUSION: Fatiguing trunk flexor exercise produced local EIH for all groups including postpartum and nulligravid women. Clinically, trunk exercises may be useful for acute pain relief for clinical populations that are characterized by pain and/or weakness in the abdominal region muscles in populations with abdominal pain syndromes.

New Insights in Peripartum Cardiomyopathy.

Significant progress in understanding the pathophysiology of peripartum cardiomyopathy, especially hormonal and genetic mechanisms, has been made. Specific criteria should be used for diagnosis, but the disease remains a diagnosis of exclusion. Both long-term and recurrent pregnancy prognoses depend on recovery of cardiac function. Data from large registries and randomized controlled trials of evidence-based therapeutics hold promise for future improved clinical outcomes.

Impaired Trunk Flexor Strength, Fatigability, and Steadiness in Postpartum Women.

PURPOSE: To determine whether postpartum women (vaginal and cesarean delivery) have deficits in trunk flexor strength, fatigability and steadiness, compared with nulligravid women, up to 26 wk postpartum. We hypothesized that postpartum women would be weaker, more fatigable, and have greater torque fluctuations than controls, with cesarean delivery showing greater deficits than vaginal delivery. METHODS: Twenty-two control women (nulligravid) and 29 postpartum women (20-40 yr, 19 who delivered via vaginal birth, 13 via Caesarian section) participated. Postpartum women were tested 8 to 10 wk and 24 to 26 wk postpartum. Control women were tested 16 to 18 wk apart. Maximal voluntary isometric contractions (MVC) were performed at multiple trunk positions with the trunk flexor muscles. To determine trunk flexor fatigability, subjects performed intermittent isometric contractions at 50% MVC (6-s contraction, 4-s rest) in upright sitting until task failure. An MVC was performed during the fatiguing task (one per minute) and at 10 and 20 min of recovery. RESULTS: At 8 and 26 wk, postpartum women (groups pooled) were weaker at all trunk angles (38% and 44% respectively, P < 0.05) than controls despite no differences in handgrip strength. Postpartum women were more fatigable (71% and 52% respectively) and had greater torque fluctuations than controls (P < 0.05). At 8 wk postpartum, women who had a cesarean delivery, were 59% more fatigable (P = 0.004) than the vaginal delivery group, with no difference between delivery types at 26 wk postpartum. CONCLUSIONS: Musculoskeletal recovery, including trunk flexor muscle strength and fatigability, is incomplete at 26 wk postpartum. These findings provide a rationale for future studies to address outcomes of rehabilitation programs specifically targeted at improving strength and fatigability of the trunk flexor muscles after pregnancy and childbirth.

Fatigability of the Lumbopelvic Stabilizing Muscles in Women 8 and 26 Weeks Postpartum.

BACKGROUND: Pregnancy and childbirth are associated with lumbopelvic pain and instability. Fatigability of the lumbopelvic stabilizing muscles after childbirth is unknown, and no clinical tests exist to assess this important metric of muscle function. OBJECTIVES: To compare fatigability of the lumbopelvic stabilizing muscles in postpartum and nulligravid (control) women using the Active Straight Leg Raise (ASLR) Fatigue Task, and to determine if fatigability is associated with inter-recti distance (IRD), physical function, and pain/disability. STUDY DESIGN: Longitudinal case-control study. METHODS: Twenty-nine nulligravid (25.4 ± 9.1 years) and 31 postpartum women (31.4 ± 5.2 years; vaginal delivery n=18) were tested at two time points, 16 weeks apart (postpartum women tested at 8-10 and 24-26 weeks postpartum). Muscular function was assessed with manual muscle testing (MMT), the ASLR Test, and a new ASLR Fatigue Task. Other measures included IRD, rectus abdominis thickness, physical activity, and six-minute walk distance. RESULTS: Postpartum women were 23% more fatigable (p=0.028) and were weaker (MMT) (p<0.001) than controls up to 26 weeks postpartum. The ASLR fatigue task (time-to-failure) was associated with smaller IRD, greater rectus abdominis thickness, higher physical activity levels, greater MMT strength, and further distance walked in six minutes (p<0.05). CONCLUSION: Postpartum women (up to 6 months) had greater fatigability of the lumbopelvic stabilizing muscles and lower physical function than nulligravid women, suggesting core muscle function and fatigability should be assessed after pregnancy and childbirth. The ASLR Fatigue Task could be a clinically useful tool to determine fatigability of the lumbopelvic stabilizing muscles in women postpartum.

Does Induction with Misoprostol Impact the Small for Gestational Age Neonate?

OBJECTIVE: To compare outcomes in small for gestational age neonates induced with misoprostol to other cervical ripening agents. We hypothesized that misoprostol use will demonstrate no significant difference in outcomes compared with alternative agents. STUDY DESIGN: Small for gestational age neonates (<10th percentile for gestational age) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) sponsored Consortium on Safe Labor database were analyzed. Neonates induced with misoprostol ± oxytocin (n = 451) were compared with neonates induced with prostaglandin E2 ± oxytocin and/or mechanical dilation ± oxytocin (n = 663). Primary outcomes included intrapartum fetal distress, cesarean section for fetal distress, cesarean section for any reason, neonatal intensive care unit admission, low 5-minute Apgar, and composite neonatal morbidity. Multiple logistic regression was used to calculate adjusted odds ratios (aORs). Data were analyzed using SAS. RESULTS: Small for gestational age neonates induced with misoprostol ± oxytocin compared with alternative agents had decreased low 5-minute Apgar scores (aOR 0.27 [0.10-0.71]). No significant differences were demonstrated among very small for gestational age neonates (<5th percentile for gestational age). CONCLUSION: Our results suggest that misoprostol does not increase risk of adverse outcomes in small for gestational age neonates; however, prospective studies are warranted to further assess optimal cervical ripening agents in this population.

Ambulatory arrhythmia monitoring in pregnant patients with palpitations.

UNLABELLED: OBJECTIVE To assess the frequency of rhythm disturbances (RDs) obtained following placement of a Holter monitor or an event loop recorder (ERT) in patients referred to cardiologists. STUDY DESIGN: Ninety-six gravidas were referred to the cardiology clinic for palpitations, syncope, or dizziness and had Holter monitoring or ERT after a baseline electroencephalogram. Arrhythmias were classified by severity. RESULTS: Gestational age at referral was 22.6 weeks ± 8.3 days. Sixty-five patients had ERTs performed, and 19 had Holter monitors. Seventy-six percent had benign arrhythmias. In our ERT cohort, history of arrhythmias showed a fourfold increase in serious RD during gestation (odds ratio [OR] 4.7, 95% confidence interval [CI] 1.1 to 20.3, p = 0.01); obesity (body mass index > 30) had a fourfold increased risk (OR 4.0, 95% CI 1.0 to 1, p = 0.03). Serious RD did not result in greater chance of cesarean delivery or induction of labor, or a newborn with arrhythmias. CONCLUSION: Most pregnant women with palpitations have benign arrhythmias. ERT appears to be a better method of diagnosis in pregnant women.

What is the optimal time for delivery in women with gestational hypertension?

OBJECTIVE: To assess the optimal timing of delivery for women with gestational hypertension. STUDY DESIGN: A multicenter database that contained 228,668 deliveries was used to extract data on gravidas with gestational hypertension. The week-specific rates of maternal and neonatal morbidity/mortality were calculated after induction of labor. Point wise 95% confidence intervals were calculated around each of these gestational age-specific rates. RESULTS: After induction of labor, the rate of maternal morbidity/mortality reached a nadir of 89.9 per 1000 live births (95% confidence interval, 68.1-111.8) at 38-38 6/7 weeks' gestation, although the rate of neonatal morbidity/mortality fell to 10.5 per 1000 live births (95% confidence interval, 2.8-18.2) at 39-39 6/7 weeks. There were only 3 total stillbirths in our study cohort. CONCLUSION: In women with gestational hypertension, induction of labor between 38- and 39-weeks' balances the lowest maternal and neonatal morbidity/mortality.

Obstetrical and perinatal outcomes among women with gestational hypertension, mild preeclampsia, and mild chronic hypertension.

OBJECTIVE: The purpose of this study was to compare maternal and neonatal outcomes of women with gestational hypertension (GHTN), mild chronic hypertension (CHTN), and mild preeclampsia at delivery. STUDY DESIGN: A multicenter database that contained 228,668 deliveries was used to extract data on gravid women with GHTN, preeclampsia, and CHTN and on women without hypertensive disease (control group). Univariate and multivariate logistic regression analyses were performed. RESULTS: There were 4918 women with GHTN, 5274 women with preeclampsia, 2531 women with CHTN, and 15,221 control subjects. Women with GHTN had the greatest risk for blood transfusion (adjusted odds ratio [aOR], 4.6; 95% confidence interval [CI], 3.4-6.3), intensive care unit admission (aOR, 25.7; 95% CI, 9.8-67.3), and lowest risk for stillbirth (aOR, 0.1; 95% CI, 0.04-0.4); women with preeclampsia had the greatest risk for postpartum hypertension (aOR, 9.6; 95% CI, 7.2-12.9). Neonates with GHTN had the greatest risk for ventilator requirements (aOR, 7.5; 95% CI, 4.6-12.4). CONCLUSION: Women with gestational hypertension and their neonates had significant risks for morbidity, compared with women with mild chronic hypertension and those with mild preeclampsia.

Update on peripartum cardiomyopathy.

Although multiple mechanisms have been postulated, peripartum cardiomyopathy (PPCM) continues to be a cardiomyopathy of unknown cause. Multiple risk factors exist and the clinical presentation does not allow differentiation among potential causes. Although specific diagnostic criteria exist, PPCM remains a diagnosis of exclusion. Treatment modalities are dictated by the clinical state of the patient, and prognosis is dependent on recovery of function. Randomized controlled trials of novel therapies, such as bromocriptine, are needed to establish better treatment regimens to decrease morbidity and mortality. The creation of an international registry will be an important step to better define and treat PPCM. This article discusses the pathogenesis, risk factors, diagnosis, management, and prognosis of this condition.

Discussion: 'Microcephaly associated with congenital heart defect' by Barbu et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Barbu D, Mert I, Kruger M, Bahado-Singh RO. Evidence of fetal central nervous system injury in isolated congenital heart defect: microcephaly at birth. Am J Obstet Gynecol 2009;201:43.e1-7.