Congenital malformations and preeclampsia associated with integrase inhibitor use in pregnancy: A single-center analysis.

BACKGROUND: Antiretroviral therapy (ART) decreases perinatal HIV transmission, but concerns exist regarding maternal and infant safety. We compared the incidence of congenital malformations and other adverse outcomes in pregnancies exposed to integrase inhibitor (INSTI) versus non-INSTI ART. SETTING: Single-site review of all pregnancies among women living with HIV between 2008 and 2018. METHODS: We used binomial family generalized estimating equations to model the relationship of congenital anomalies and pregnancy outcomes with exposure to INSTI or dolutegravir (DTG) versus non-INSTI ART. RESULTS: Among 257 pregnancies, 77 women received ≥1 INSTI (54 DTG, 14 elvitegravir, 15 raltegravir), 167 received non-INSTI, and 3 had missing data. Fifty congenital anomalies were identified in 36 infants. Infants with first-trimester DTG or any first-trimester INSTI exposure had higher odds of congenital anomalies than infants with first-trimester non-INSTI exposure (OR = 2.55; 95%CI = 1.07-6.10; OR = 2.61; 95%CI = 1.15-5.94, respectively). Infants with INSTI exposure after the second trimester had no increased odds of anomalies. Women with INSTI exposure had higher odds of preeclampsia (OR = 4.73; 95%CI = 1.70-13.19). Among women who received INSTI, grade ≥3 laboratory abnormalities were noted in 2.6% while receiving the INSTI and 3.9% while not receiving the INSTI, versus 16.2% in women who received non-INSTI. There was no association between INSTI exposure and other pregnancy outcomes. CONCLUSION: In our cohort, first-trimester INSTI exposure was associated with increased rates of congenital anomalies and use of INSTI during pregnancy was associated with preeclampsia. These findings underscore the need for continued monitoring of the safety of INSTI in pregnancy.

Correlation of continuous glucose monitoring profiles with pregnancy outcomes in nondiabetic women.

OBJECTIVE: To determine whether hyperglycemic excursions detected by continuous glucose monitoring (CGM) correlate with birth weight percentile and other pregnancy outcomes, and whether CGM correlates better with these outcomes than a single glucose value from a 1-hour glucose challenge test (GCT). STUDY DESIGN: This was a prospective observational study of 55 pregnant patients without preexisting diabetes, who wore a CGM device for up to 7 days, between 24 and 28 weeks' gestation. The area under the curve (AUC) of hyperglycemic excursions above various thresholds (110, 120, 130, 140, and 180 mg/dL) was calculated. These AUC values, and results from a standard 50-g GCT, were correlated with our primary outcome of birth weight percentile, and secondary outcomes of unplanned operative delivery, pregnancy complications, delivery complications, fetal complications, and neonatal complications. RESULTS: A consistent correlation was seen between all AUC thresholds and birth weight percentile (r = 0.29, p < 0.05 for AUC-110, -120, -130, and -140; r = 0.25, p = 0.07 for AUC-180). This correlation was stronger than that of 1-hour oral GCT (r = -0.02, p = 0.88). There was no association between AUC values and other outcomes. CONCLUSIONS: Among nondiabetic pregnant patients, hyperglycemic excursions detected by CGM show a stronger correlation to birth weight percentile than blood glucose values obtained 1-hour after a 50-g oral GCT.

Maternal glucose response to betamethasone administration.

OBJECTIVE: This study aims to describe the pattern of maternal glucose response to betamethasone administration using a continuous glucose monitoring system. STUDY DESIGN: A prospective observational trial was conducted among women receiving clinically indicated betamethasone between 24 and 34 weeks gestation. At the time of initial betamethasone administration, a continuous glucose monitoring device was inserted which measured interstitial fluid glucose levels every 5 minutes. Glucose levels were monitored for 7 days, until delivery, or until hospital discharge, whichever came first. We recorded the percentage of time women spent above three glucose thresholds: 110, 144, and 180 mg/dL, respectively. RESULTS: A total of 17 women were enrolled at the time of betamethasone administration and data were available for 15 patients. There were 11 nondiabetic and 4 diabetic women. Both diabetic and nondiabetic women had the highest recorded blood glucose readings between 24 and 48 hours after the first injection of betamethasone. In that period, nondiabetic women spent 73, 40, and 17% of the time with blood glucose levels above the 110, 144, and 180 mg/dL thresholds, respectively. CONCLUSION: Nondiabetic women receiving betamethasone manifest significant hyperglycemia after betamethasone administration. If delivery is imminent, maternal glucose response to betamethasone may need to be monitored to prevent possible neonatal hypoglycemia.

Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications.

There is strong evidence that overproduction of soluble fms-like tyrosine kinase-1 (sFLT1) in the placenta is a major cause of vascular dysfunction in preeclampsia through sFLT1-dependent antagonism of VEGF. However, the cause of placental sFLT1 upregulation is not known. Here we demonstrated that in women with preeclampsia, sFLT1 is upregulated in placental trophoblasts, while VEGF is upregulated in adjacent maternal decidual cells. In response to VEGF, expression of sFlt1 mRNA, but not full-length Flt1 mRNA, increased in cultured murine trophoblast stem cells. We developed a method for transgene expression specifically in mouse endometrium and found that endometrial-specific VEGF overexpression induced placental sFLT1 production and elevated sFLT1 levels in maternal serum. This led to pregnancy losses, placental vascular defects, and preeclampsia-like symptoms, including hypertension, proteinuria, and glomerular endotheliosis in the mother. Knockdown of placental sFlt1 with a trophoblast-specific transgene caused placental vascular changes that were consistent with excess VEGF activity. Moreover, sFlt1 knockdown in VEGF-overexpressing animals enhanced symptoms produced by VEGF overexpression alone. These findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta by sequestering excess maternal VEGF and suggest that a local increase in VEGF can trigger placental overexpression of sFLT1, potentially contributing to the development of preeclampsia and other pregnancy complications.

Continuous glucose monitoring in pregnancy: new frontiers in clinical applications and research.

Current treatment of diabetes in pregnancy relies on intermittent self-monitoring of blood glucoses using finger sticks to monitor capillary blood glucoses. Continuous glucose monitoring (CGM) systems are an emerging technology that allow frequent glucose measurements (every 5 min) and the ability to monitor glucose trends in real time. Although these devices are currently expensive and mildly invasive to use, there is huge potential for their use in both the research and clinical realms. From a research perspective, there is the potential to better understand glucose metabolism in pregnancy, both in patients with and without diabetes. For the treating clinician, CGM has the potential to improve detection of hyperglycemic excursions as well as asymptomatic hypoglycemia and the data to improve management of glucose levels in diabetes patients. In this article, we review current literature examining use of CGM in both research and clinical applications.

Decreased circulating soluble Tie2 levels in preeclampsia may result from inhibition of vascular endothelial growth factor (VEGF) signaling.

OBJECTIVES: Recent studies have found dysregulation in circulating levels of a number of angiogenic factors and their soluble receptors in preeclampsia. In this study, we examined the mechanism of production of soluble Tie2 (sTie2) and its potential connection to the failure of vascular remodeling in preeclamptic pregnancies. DESIGN/SETTING/PATIENTS: Serum samples were collected prospectively from 41 pregnant subjects at five different time points throughout pregnancy. Five of these subjects developed preeclampsia. For a second study, serum and placental samples were collected at delivery from preeclamptic and gestational age-matched controls. We examined serum sTie2 levels, and angiopoietin 1, angiopoietin 2, and Tie2 mRNA expression and localization in placental samples from the central basal plate area. We also examined the effects of vascular endothelial growth factor (VEGF) and a matrix metalloproteinase (MMP) inhibitor on proteolytic shedding of Tie2 in uterine microvascular endothelial cells. RESULTS: Serum sTie2 levels were significantly lower in preeclamptic subjects starting at 24-28 wk of gestation and continued to be lower through the time of delivery. In culture experiments, VEGF treatment significantly increased sTie2 levels in conditioned media, whereas the MMP inhibitor completely blocked this increase, suggesting that VEGF-induced Tie2 release is MMP dependent. CONCLUSIONS: Our data suggest, for the first time, an interaction between VEGF and Tie2 in uterine endothelial cells and a potential mechanism for the decrease in circulating sTie2 levels in preeclampsia, likely through inhibition of VEGF signaling. Further studies on VEGF-Tie2 interactions during pregnancy should provide new insights into the mechanisms underlying the failure of vascular remodeling in preeclampsia and other pregnancy complications.

Stercoral perforation of the colon with favorable pregnancy outcome.

BACKGROUND: Stercoral perforation of the colon is a rarely reported disease with high mortality rate. Our literature review identified one prior case reported during pregnancy, with mortality in both mother and infant. CASE: A nulliparous female presented at 36 weeks of gestation with fever, tachycardia, and severe abdominal pain. She delivered by cesarean when purulent ascites and stercoral perforation of the sigmoid colon were discovered. After a sigmoid resection with end colostomy, she and her infant recovered uneventfully. CONCLUSION: Stercoral perforation of the colon is rare in pregnancy. Prompt surgical treatment is necessary. Surgical exploration may be warranted in the pregnant patient with unexplained abdominal pain.

Cesarean delivery outcomes after a prolonged second stage of labor.

OBJECTIVE: We hypothesized that prolonged second stage of labor increases the incidence of unintentional hysterotomy extensions at cesarean delivery. STUDY DESIGN: A retrospective cohort of term pregnant women who underwent primary cesarean delivery after failed second stage of labor at Stanford University was assessed for hysterotomy extensions and other maternal and neonatal morbidities. Groups included second stage length of 1-3 hours and >4 hours. Data were analyzed with the use of chi-square and Fisher's exact tests. RESULTS: Of the 239 women who were studied, the second stage of labor lasted 1-3 hours in 82 patients and >4 hours in 157 patients. Prolonged second stage of labor was associated with unintentional hysterotomy extensions (40% vs 26%; P = .03), particularly to the cervix (29% vs 5%; P = .005), and with surgery that lasted >90 minutes (9% vs 1%; P = .01). The incidence of hysterotomy extensions was associated positively with the length of the second stage. Other maternal and neonatal morbidities were similar between groups. CONCLUSION: Prolonged second stage of labor is associated with an increase in unintentional hysterotomy extensions at cesarean delivery and prolonged operative time. The future risk of hysterotomy extensions merits further investigation.