Neonatal outcomes and rationale for timing of birth in perinatal diabetes: a retrospective cohort study.

BACKGROUND: The American College of Obstetricians and Gynecologists recommends delivery in the 39th week of pregnancy for patients with pregestational and medication-controlled gestational diabetes with consideration for earlier delivery among those with poor glucose control. OBJECTIVE: We sought to evaluate the impact of birth before 39 weeks' gestation exclusively for diabetes-related indications on neonatal outcomes and clinician rationale for these recommendations. STUDY DESIGN: This was a retrospective cohort study of all singleton, nonanomalous pregnancies complicated by diabetes. Patients were identified through an obstetrical database containing information of 90,185 births from 2011 to 2021. Patients who delivered in a given week of gestation exclusively for diabetes-related indications were compared with ongoing pregnancies. Recommended births for other obstetrical indications were excluded from the diabetes-related indications cohorts. The primary outcome was neonatal intensive care unit admission. Secondary outcomes included neonatal intensive care unit length of stay, stillbirth, neonatal death, hypoglycemia, respiratory distress syndrome, and shoulder dystocia. For all births before 39 weeks' gestation, the electronic medical records were reviewed to confirm the rationale for the intervention for a diabetes-indicated condition. RESULTS: From the 90,185 recorded births that occurred in 2011 to 2021, 4750 patients with diabetes were identified. Of those, 30.5% (n=1449) had a recommended birth for a diabetes-related indications with 2.2% of those (n=32) occurring at 36 weeks' gestation, 7.9% (n=114) at 37 weeks' gestation, 9.7% (n=141) at 38 weeks' gestation, and 63.0% (n=913) at 39 weeks' gestation. Births that occurred at 36 and 37 weeks' gestation exclusively for diabetes-related indications had higher rates of neonatal intensive care unit admission than the respective ongoing pregnancies (62.5% vs 8.7%; P<.001 and 25.4% vs 7.2%; P<.001). There was no difference in neonatal intensive care unit admission for births at 38 or 39 weeks' gestation when compared with ongoing pregnancy. For neonates born at 36 and 37 weeks' gestation in comparison with ongoing pregnancies, the median neonatal intensive care unit length of stay was 11.0 vs 2.8 days, (P<.001) and 4.4 vs 2.6 days (P=.026), respectively. There were significantly increased rates of neonatal hypoglycemia and respiratory distress syndrome among births that occurred at 36, 37, and 38 weeks' gestation when compared with ongoing pregnancies. There were no differences in the rate of stillbirth in this cohort. Primary factors cited for early birth were poor glycemic control (71.4%), recommendation by a maternal-fetal medicine specialist (38.7%), and suspected fetal macrosomia (27.9%). Overall, 46.7%, 32.8%, and 20.6% of patients had 1, 2, or ≥3 indications, respectively, listed as rationale for early birth. Overall, few objective measures were used to recommend birth before 39 weeks' gestation owing to diabetes. CONCLUSION: In pregnancies complicated by diabetes, early birth exclusively for diabetes-related indications was associated with increased neonatal intensive care unit admission and length of stay and with neonatal morbidity. Little objective data are documented by clinicians to support their recommendations for early birth associated with diabetes. Additional clinical guidelines are needed to define suboptimal glucose control necessitating birth before 39 weeks' gestation.

Mitochondrial citrate metabolism and efflux regulate BeWo differentiation.

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established BeWo cell culture model of trophoblast differentiation. Differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

Metformin impairs trophoblast metabolism and differentiation in a dose-dependent manner.

Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing the risk of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 µM (therapeutic range) and 2000 µM (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 µM metformin-treated cells, 2000 µM metformin impaired oxidative metabolism and increased the abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 µM, but not 200 µM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impair trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes.

Investigation of Intrapartum Parenteral Magnesium Sulfate as an Independent Risk Factor for Postpartum Hemorrhage Using Quantitative Blood Loss Assessment.

BACKGROUND: Magnesium sulfate is used for seizure prophylaxis in preeclampsia and for fetal neuroprotection when delivery is anticipated before 32 weeks of gestation. Existing risk assessment tools for postpartum hemorrhage often identify the use of magnesium sulfate as an intrapartum risk factor. Previous studies examining the association between the use of magnesium sulfate and postpartum hemorrhage have relied largely on qualitative estimates of blood loss rather than quantitative estimates of blood loss. OBJECTIVE: This study aimed to determine whether intrapartum administration of magnesium sulfate is associated with an increased risk of postpartum hemorrhage using a quantitative blood loss assessment via the use of graduated drapes and weight differences in surgical supplies. STUDY DESIGN: This case-control study was conducted to test the hypothesis that intrapartum parenteral administration of magnesium sulfate is not independently associated with postpartum hemorrhage. All deliveries at our tertiary-level academic medical center between July 2017 and June 2018 were reviewed. Of note, 2 categories of postpartum hemorrhage were defined: the traditional definition (>500 mL for vaginal delivery and >1000 mL for cesarean delivery) and the contemporary definition (>1000 mL regardless of delivery mode). Statistical analyses using the chi-square test, Fisher exact test, t test, or Wilcoxon rank-sum test were performed to compare the patients who did and did not receive magnesium sulfate concerning the rates of postpartum hemorrhage, pre- and postdelivery hemoglobin level, and rates of blood transfusion. RESULTS: A total of 1318 deliveries were included, with postpartum hemorrhage rates of 12.2% (traditional definition) and 6.2% (contemporary definition). Multivariate logistic regression did not find the use of magnesium sulfate as an independent risk factor by either definition (odds ratio, 1.44 [95% confidence interval, 0.87-2.38] and 1.34 [95% confidence interval, 0.71-2.54]). The only significant independent risk factor was cesarean delivery, by both definitions (odds ratio, 2.71 [95% confidence interval, 1.85-3.98] and 19.34 [95% confidence interval, 8.55-43.72]). CONCLUSION: In our study population, intrapartum administration of magnesium sulfate was not found to be an independent risk factor for postpartum hemorrhage. Cesarean delivery was determined as an independent risk factor, consistent with previous reports.

Metformin impairs trophoblast metabolism and differentiation in dose dependent manner.

Metformin is a widely prescribed medication whose mechanism of action is not completely defined and whose role in gestational diabetes management remains controversial. In addition to increasing risks of fetal growth abnormalities and preeclampsia, gestational diabetes is associated with abnormalities in placental development including impairments in trophoblast differentiation. Given that metformin impacts cellular differentiation events in other systems, we assessed metformin's impact on trophoblast metabolism and differentiation. Using established cell culture models of trophoblast differentiation, oxygen consumption rates and relative metabolite abundance were determined following 200 µM (therapeutic range) and 2000 µM (supra-therapeutic range) metformin treatment using Seahorse and mass-spectrometry approaches. While no differences in oxygen consumption rates or relative metabolite abundance were detected between vehicle and 200 µM metformin treated cells, 2000 µM metformin impaired oxidative metabolism and increased abundance of lactate and TCA cycle intermediates, α-ketoglutarate, succinate, and malate. Examining differentiation, treatment with 2000 µM, but not 200 µM metformin, impaired HCG production and expression of multiple trophoblast differentiation markers. Overall, this work suggests that supra-therapeutic concentrations of metformin impairs trophoblast metabolism and differentiation whereas metformin concentrations in the therapeutic range do not strongly impact these processes.

Mitochondrial citrate metabolism and efflux regulates trophoblast differentiation.

Cytotrophoblasts fuse to form and renew syncytiotrophoblasts necessary to maintain placental health throughout gestation. During cytotrophoblast to syncytiotrophoblast differentiation, cells undergo regulated metabolic and transcriptional reprogramming. Mitochondria play a critical role in differentiation events in cellular systems, thus we hypothesized that mitochondrial metabolism played a central role in trophoblast differentiation. In this work, we employed static and stable isotope tracing untargeted metabolomics methods along with gene expression and histone acetylation studies in an established cell culture model of trophoblast differentiation. Trophoblast differentiation was associated with increased abundance of the TCA cycle intermediates citrate and α-ketoglutarate. Citrate was preferentially exported from mitochondria in the undifferentiated state but was retained to a larger extent within mitochondria upon differentiation. Correspondingly, differentiation was associated with decreased expression of the mitochondrial citrate transporter (CIC). CRISPR/Cas9 disruption of the mitochondrial citrate carrier showed that CIC is required for biochemical differentiation of trophoblasts. Loss of CIC resulted in broad alterations in gene expression and histone acetylation. These gene expression changes were partially rescued through acetate supplementation. Taken together, these results highlight a central role for mitochondrial citrate metabolism in orchestrating histone acetylation and gene expression during trophoblast differentiation.

Preventing caesarean section wound complications: use of a silver-impregnated antimicrobial occlusive dressing.

OBJECTIVE: To investigate the role of an adherent soft silicone antimicrobial occlusive foam silver-impregnated dressing for reduction of surgical site infections (SSI) in primary low-transverse caesarean section (1°LTCS) delivery. METHOD: Women aged 18-45 years admitted to the labour and delivery or the antepartum unit undergoing a 1°LTCS were recruited. Exclusion criteria included repeat caesarean, vertical skin incision, intrapartum fever and closure with staples. Consented participants delivered by scheduled or unscheduled 1°LTCS received the silver-impregnated dressing. Those who declined to participate and were delivered by scheduled or unscheduled caesarean received a standard gauze with tape dressing (controls). Surgical preparation and preoperative antibiotics were administered as per hospital policy. RESULTS: A total of 362 participants were consented for use of the silver-impregnated dressing, with 190 participants undergoing 1°LTCS, of whom 185 were included in the final analysis. Of those who declined to participate, 190 ultimately underwent 1°LTCS during the same time period. Cases and controls were similar in demographics, body mass index, diabetes status, labour and procedure length, and tobacco use. The overall incidence of SSI was 3.7%. A 50% reduction in incidence of SSI was observed in the silver-impregnated dressing group compared with control group (2.7% versus 4.7%, respectively), but this was not statistically significant (p=0.08; odds ratio 0.55; 95% confidence interval: 0.18-1.67). CONCLUSION: Among women undergoing 1°LTCS with subcuticular closure of a transverse incision, use of a silver-impregnated dressing reduced the rate of SSI by >50% but was not statistically significant.

Intra-abdominal saline irrigation at cesarean section: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to examine the evidence guiding intraoperative saline irrigation at cesarean sections. METHODS: We searched "cesarean sections", "pregnancy", "saline irrigation" and "randomized clinical trials" in ClinicalTrials.gov, the Cochrane Central Register of Controlled Trials, AJOL, MEDLINE, LILACS and CINAHL from inception of each database to April 2015. The primary outcomes were predefined as intraoperative nausea and emesis. The pooled results were reported as relative risk (RR) with 95% confidence interval (95% CI). RESULTS: Three randomized trials including 862 women were analyzed. Intraoperative saline irrigation was associated with a 68% increased risk of developing intraoperative nausea (RR = 1.68, 95% CI 1.36-2.06), 70% increased risk of developing intraoperative emesis (RR = 1.70, 95% CI 1.28-2.25), 92% increased risk of developing post-operative nausea and 84% increased risk of using anti-emetics post-operatively (RR = 1.84, 95% CI 0.21-2.78) when compared with controls. There were no significant differences between intraoperative saline irrigation and no treatment for post-operative emesis (RR = 1.65, 95% CI 0.74-3.67), estimated blood loss, time to return of gastrointestinal function, postpartum endometritis (RR = 0.95, 95% CI 0.64-1.40), urinary tract infection and wound infection. CONCLUSION: Intraoperative saline irrigation at cesarean delivery increases intraoperative and post-operative nausea, requiring increasing use of anti-emetics without significant reduction in infectious, intraoperative and postpartum complications. Routine abdominal irrigation at cesarean section is not supported by current data.