Pharmacological treatment of gestational diabetes mellitus: point/counterpoint.

Controversies persist over the most efficacious pharmacologic treatment for gestational diabetes mellitus. For purposes of accuracy in this article, the individual American College of Obstetricians and Gynecologists Practice Bulletin and American Diabetes Association Standards of Medical Care positions on each issue are quoted and then deliberated with evidence of counter claims presented in point/counterpoint. This is a review of all the relevant evidence for the most holistic picture possible. The main issues are (1) which diabetic drugs cross the placenta, (2) the quality of evidence and data source validity, (3) the rationale for the designation of glucose control as the primary outcome in gestational diabetes mellitus, and (4) which drugs (metformin, glyburide, or insulin) are most effective in improving secondary outcomes. The concept that 1 drug fits all, whether it be insulin, glyburide, or metformin, is a fallacy. Different drugs provide certain benefits but not all the benefits and not to all patients. In addition, the steps in the gestational diabetes mellitus management decision path and the current cost of the use of insulin, glyburide, or metformin are addressed. In the future, we must consider studying the potential of diabetic drugs that currently are used in nonpregnancy and incorporating the concept of precision medicine in the decision tree to maximize pregnancy outcomes.

Prevention of obesity and diabetes in pregnancy: is it an impossible dream?

The obesity and diabetes epidemic is an unintended consequence of economic, social, and technological changes. In nonpregnancy, people identified as high risk to develop type 2 diabetes may delay progression by 30-70% with lifestyle interventions and pharmacological agents. In pregnancy, lifestyle interventions have been the primary focus to prevent fetal short- and long-term complications that may evolve into substantial weight gain and gestational diabetes mellitus. The dilemma for obstetricians is whether diabetes and obesity can be prevented and not simply treated after the fact. Interventions after women become pregnant may be too late to see the kinds of meaningful improvements in child and maternal health because there is a short interval from gestational diabetes mellitus diagnosis to delivery. Therefore, future efforts need to incorporate quality research, lifestyle interventions that designate time of initiation and duration during pregnancy, the preventative intervention of a prepregnant "fourth trimester," coupled with the concept of precision medicine so that there is the potential to make the impossible dream a reality.

The History and Contributions of the Diabetes in Pregnancy Study Group of North America (1997-2015).

The Diabetes in Pregnancy Study Group of North America (DPSG-NA) was founded in 1997 in San Antonio, Texas, out of the recognition that the field of maternal-fetal medicine should support and conduct research to address the specialized needs of pregnant women with type 1, type 2, or gestational diabetes mellitus. Since its inception, the DPSG-NA meetings have become a vehicle for the dissemination of data, gathered through collaboration among basic, translational, and clinical researchers and care centers, both in the United States and abroad. Although the meetings cover a range of topics related to diabetes in pregnancy, they have often highlighted a major, timely issue. Utilizing presentations, roundtable discussions, and debates, members of the DPSG-NA discussed the latest research, treatments, and approaches to significantly improve the health and wellbeing of pregnant women with diabetes and their offspring. The following commentary highlights the major contributions of each meeting.

Glycemic targets for the optimal treatment of GDM.

Lowering glucose is of pivotal importance in the treatment of diabetes in pregnancy. A spectrum of different glucose thresholds can be established and used appropriately to prevent each complication. This article outlines the concept of normality and what definition of normality should be used to evaluate the relationship between the level of glycemia and perinatal outcome.

The impact of tobacco use on preterm premature rupture of the membranes.

OBJECTIVE: To determine if tobacco use increases the incidence of preterm premature rupture of the membranes (pPROM) or alters perinatal outcomes after pPROM. STUDY DESIGN: This is a secondary analysis of the databases of three completed Eunice Kennedy Shriver National Institute of Child Health and Human Development-supported Maternal Fetal Medicine Units Network studies. Self-reported tobacco exposure data was obtained. Its relationship with the incidence of pPROM and associated neonatal outcome measures were assessed. RESULTS: There was no difference in the incidence of pPROM when comparing nonsmokers to those using tobacco. Although a trend was seen between the incidence of pPROM and the amount smoked, this did not reach statistical significance. Among the patients with pPROM, the use of tobacco was not associated with an increase in perinatal morbidity. CONCLUSION: Our data do not support a significant relationship between tobacco use and pPROM.

Timing of elective repeat cesarean delivery at term and neonatal outcomes.

BACKGROUND: Because of increased rates of respiratory complications, elective cesarean delivery is discouraged before 39 weeks of gestation unless there is evidence of fetal lung maturity. We assessed associations between elective cesarean delivery at term (37 weeks of gestation or longer) but before 39 weeks of gestation and neonatal outcomes. METHODS: We studied a cohort of consecutive patients undergoing repeat cesarean sections performed at 19 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network from 1999 through 2002. Women with viable singleton pregnancies delivered electively (i.e., before the onset of labor and without any recognized indications for delivery before 39 weeks of gestation) were included. The primary outcome was the composite of neonatal death and any of several adverse events, including respiratory complications, treated hypoglycemia, newborn sepsis, and admission to the neonatal intensive care unit (ICU). RESULTS: Of 24,077 repeat cesarean deliveries at term, 13,258 were performed electively; of these, 35.8% were performed before 39 completed weeks of gestation (6.3% at 37 weeks and 29.5% at 38 weeks) and 49.1% at 39 weeks of gestation. One neonatal death occurred. As compared with births at 39 weeks, births at 37 weeks and at 38 weeks were associated with an increased risk of the primary outcome (adjusted odds ratio for births at 37 weeks, 2.1; 95% confidence interval [CI], 1.7 to 2.5; adjusted odds ratio for births at 38 weeks, 1.5; 95% CI, 1.3 to 1.7; P for trend <0.001). The rates of adverse respiratory outcomes, mechanical ventilation, newborn sepsis, hypoglycemia, admission to the neonatal ICU, and hospitalization for 5 days or more were increased by a factor of 1.8 to 4.2 for births at 37 weeks and 1.3 to 2.1 for births at 38 weeks. CONCLUSIONS: Elective repeat cesarean delivery before 39 weeks of gestation is common and is associated with respiratory and other adverse neonatal outcomes.

A randomized, controlled trial of magnesium sulfate for the prevention of cerebral palsy.

BACKGROUND: Research suggests that fetal exposure to magnesium sulfate before preterm birth might reduce the risk of cerebral palsy. METHODS: In this multicenter, placebo-controlled, double-blind trial, we randomly assigned women at imminent risk for delivery between 24 and 31 weeks of gestation to receive magnesium sulfate, administered intravenously as a 6-g bolus followed by a constant infusion of 2 g per hour, or matching placebo. The primary outcome was the composite of stillbirth or infant death by 1 year of corrected age or moderate or severe cerebral palsy at or beyond 2 years of corrected age. RESULTS: A total of 2241 women underwent randomization. The baseline characteristics were similar in the two groups. Follow-up was achieved for 95.6% of the children. The rate of the primary outcome was not significantly different in the magnesium sulfate group and the placebo group (11.3% and 11.7%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.77 to 1.23). However, in a prespecified secondary analysis, moderate or severe cerebral palsy occurred significantly less frequently in the magnesium sulfate group (1.9% vs. 3.5%; relative risk, 0.55; 95% CI, 0.32 to 0.95). The risk of death did not differ significantly between the groups (9.5% vs. 8.5%; relative risk, 1.12; 95% CI, 0.85 to 1.47). No woman had a life-threatening event. CONCLUSIONS: Fetal exposure to magnesium sulfate before anticipated early preterm delivery did not reduce the combined risk of moderate or severe cerebral palsy or death, although the rate of cerebral palsy was reduced among survivors. (ClinicalTrials.gov number, NCT00014989.)

Maternal and neonatal outcomes of repeat cesarean delivery in women with a prior classical versus low transverse uterine incision.

We compared maternal and neonatal outcomes following repeat cesarean delivery (CD) of women with a prior classical CD with those with a prior low transverse CD. The Maternal Fetal Medicine Units Network Cesarean Delivery Registry was used to identify women with one previous CD who underwent an elective repeat CD prior to the onset of labor at ≥36 weeks. Outcomes were compared between women with a previous classical CD and those with a prior low transverse CD. Of the 7936 women who met study criteria, 122 had a prior classical CD. Women with a prior classical CD had a higher rate of classical uterine incision at repeat CD (12.73% versus 0.59%; P < 0.001), had longer total operative time and hospital stay, and had higher intensive care unit admission. Uterine dehiscence was more frequent in women with a prior classical CD (2.46% versus 0.27%, odds ratio 9.35, 95% confidence interval 1.76 to 31.93). After adjusting for confounding factors, there were no statistical differences in major maternal or neonatal morbidities between groups. Uterine dehiscence was present at repeat CD in 2.46% of women with a prior classical CD. However, major maternal morbidities were similar to those with a prior low transverse CD.

Mode of delivery in women with antepartum fetal death and prior cesarean delivery.

We describe obstetric outcomes in a group of patients with prior cesarean delivery (CD) presenting with an intrauterine fetal demise (IUFD). A secondary analysis of an observational study of women with prior CD was performed. All antepartum singleton pregnancies with a prior CD and IUFD ≥20 weeks' gestation or 500 g were evaluated. Two hundred nine patients met inclusion criteria for analysis. The mean gestational age ± standard deviation at delivery was 31.3 ± 6.5 weeks. The trial of labor rate was 75.6% (158/209), and the vaginal birth after cesarean (VBAC) success rate was 86.7%. Labor induction or augmentation occurred in 83.3% of attempted VBAC. Uterine rupture occurred in five women (2.4%), and in 3.4% of those being induced but none of these required hysterectomy. Women with a history of previous CD and an IUFD often undergo trial of labor with a high VBAC success rate. Uterine rupture complicates 2.4% of such cases.

Perioperative antibiotic prophylaxis for nonlaboring cesarean delivery.

OBJECTIVE: To estimate the efficacy of antibiotic prophylaxis at the time of nonlaboring cesarean delivery in reducing postpartum infection-related complications. METHODS: We performed a secondary analysis of an observational study of cesarean deliveries performed at 13 centers from 1999-2000. Patients were included if they had cesarean delivery before labor, did not have intrapartum infection, and were not given antibiotics at delivery for reasons other than prophylaxis. The occurrence of postpartum endometritis, wound infection, and other, less common infection-related complications was compared between those who did and did not receive antibiotic prophylaxis. Results were adjusted for smoking, payer status, gestational age and body mass index at delivery, race, diabetes, antepartum infections, presence of anemia, operative time, type of cesarean delivery (primary or repeat), and center. RESULTS: Of the 9,432 women who met study criteria, the 6,006 (64%) who received antibiotic prophylaxis were younger, heavier at delivery, and were more likely to be African American, receive public insurance, and have diabetes. Patients who received antibiotic prophylaxis were less likely to develop postpartum endometritis (121 [2.0%] compared with 88 [2.6%], adjusted odds ratio [OR] 0.40, 95% confidence interval [CI] 0.28-0.59) or wound infection (31 [0.52%] compared with 33 [0.96%], adjusted OR 0.49, 95% CI 0.28-0.86). CONCLUSION: Antibiotic prophylaxis at the time of nonlaboring cesarean delivery significantly reduces the risks of postpartum endometritis and wound infection. LEVEL OF EVIDENCE: III.

The frequency and complication rates of hysterectomy accompanying cesarean delivery.

OBJECTIVE: To estimate the frequency, indications, and complications of cesarean hysterectomy. METHODS: This was a prospective, 2-year observational study at 13 academic medical centers conducted between January 1, 1999, and December 31, 2000, on all women who underwent a hysterectomy at the time of cesarean delivery. Data were abstracted from the medical record by study nurses. The outcomes included procedure frequency, indications, and complications. RESULTS: A total of 186 cesarean hysterectomies (0.5%) were performed from a cohort of 39,244 women who underwent cesarean delivery. The leading indications for hysterectomy were placenta accreta (38%) and uterine atony (34%). Of the hysterectomy cases with a diagnosis recorded as accreta, 18% accompanied a primary cesarean delivery, and 82% had a prior procedure (P<.001). Of the hysterectomy cases with atony recorded as a diagnosis, 59% complicated primary cesarean delivery, whereas 41% had a prior cesarean (P<.001). Major maternal complications of cesarean hysterectomy included transfusion of red blood cells (84%) and other blood products (34%), fever (11%), subsequent laparotomy (4%), ureteral injury (3%), and death (1.6%). Accreta hysterectomy cases were more likely than atony hysterectomy cases to require ureteral stents (14% compared with 3%, P=.03) and to instill sterile milk into the bladder (23% compared with 8%, P=.02). CONCLUSION: The rate of cesarean hysterectomy has declined modestly in the past decade. Despite the use of effective therapies and procedures to control hemorrhage at cesarean delivery, a small proportion of women continue to require hysterectomy to control hemorrhage from both uterine atony and placenta accreta. LEVEL OF EVIDENCE: II.

Can a prediction model for vaginal birth after cesarean also predict the probability of morbidity related to a trial of labor?

OBJECTIVE: The objective of the study was to determine whether a model for predicting vaginal birth after cesarean (VBAC) can also predict the probabilty of morbidity associated with a trial of labor (TOL). STUDY DESIGN: Using a previously published prediction model, we categorized women with 1 prior cesarean by chance of VBAC. Prevalence of maternal and neonatal morbidity was stratfied by probability of VBAC success and delivery approach. RESULTS: Morbidity became less frequent as the predicted chance of VBAC increased among women who underwent TOL (P < .001) but not elective repeat cesarean section (ERCS) (P > .05). When the predicted chance of VBAC was less than 70%, women undergoing a TOL were more likely to have maternal morbidity (relative risk [RR], 2.2; 95% confidence interval [CI], 1.5-3.1) than those who underwent an ERCS; when the predicted chance of VBAC was at least 70%, total maternal morbidity was not different between the 2 groups (RR, 0.8; 95% CI, 0.5-1.2). The results were similar for neonatal morbidity. CONCLUSION: A prediction model for VBAC provides information regarding the chance of TOL-related morbidity and suggests that maternal morbidity is not greater for those women who undergo TOL than those who undergo ERCS if the chance of VBAC is at least 70%.

Does information available at admission for delivery improve prediction of vaginal birth after cesarean?

We sought to construct a predictive model for vaginal birth after cesarean (VBAC) that combines factors that can be ascertained only as the pregnancy progresses with those known at initiation of prenatal care. Using multivariable modeling, we constructed a predictive model for VBAC that included patient factors known at the initial prenatal visit as well as those that only become evident as the pregnancy progresses to the admission for delivery. We analyzed 9616 women. The regression equation for VBAC success included multiple factors that could not be known at the first prenatal visit. The area under the curve for this model was significantly greater ( P < 0.001) than that of a model that included only factors available at the first prenatal visit. A prediction model for VBAC success, which incorporates factors that can be ascertained only as the pregnancy progresses, adds to the predictive accuracy of a model that uses only factors available at a first prenatal visit.

Labor outcomes with increasing number of prior vaginal births after cesarean delivery.

OBJECTIVE: To estimate the success rates and risks of an attempted vaginal birth after cesarean delivery (VBAC) according to the number of prior successful VBACs. METHODS: From a prospective multicenter registry collected at 19 clinical centers from 1999 to 2002, we selected women with one or more prior low transverse cesarean deliveries who attempted a VBAC in the current pregnancy. Outcomes were compared according to the number of prior VBAC attempts subsequent to the last cesarean delivery. RESULTS: Among 13,532 women meeting eligibility criteria, VBAC success increased with increasing number of prior VBACs: 63.3%, 87.6%, 90.9%, 90.6%, and 91.6% for those with 0, 1, 2, 3, and 4 or more prior VBACs, respectively (P<.001). The rate of uterine rupture decreased after the first successful VBAC and did not increase thereafter: 0.87%, 0.45%, 0.38%, 0.54%, 0.52% (P=.03). The risk of uterine dehiscence and other peripartum complications also declined statistically after the first successful VBAC. No increase in neonatal morbidities was seen with increasing VBAC number thereafter. CONCLUSION: Women with prior successful VBAC attempts are at low risk for maternal and neonatal complications during subsequent VBAC attempts. An increasing number of prior VBACs is associated with a greater probability of VBAC success, as well as a lower risk of uterine rupture and perinatal complications in the current pregnancy. LEVEL OF EVIDENCE: II.

Cesarean delivery for the second twin.

OBJECTIVE: To examine maternal and infant outcomes after a vaginal delivery of twin A and a cesarean delivery of twin B, and to identify whether the second twin experienced increased short-term morbidity as part of a combined route of delivery. METHODS: Between January 1, 1999, and December 31, 2000, a prospective cohort study of all cesarean deliveries was conducted at 13 university centers. This secondary analysis was limited to women with twin gestations who experienced labor and underwent cesarean delivery. We compared outcomes of the second twin in women who had vaginal delivery of the first twin and a cesarean delivery of the second twin to those who had cesarean delivery of both twins. RESULTS: One thousand twenty-eight twin pregnancies experienced labor and underwent cesarean delivery; 179 (17%) had a combined vaginal/cesarean delivery. Gestational age at delivery was 34.6 weeks in both groups (P=.97). The rupture of membranes to delivery interval was longer in the combined group (3.2 compared with 2.3 hours, P<.001). Endometritis and culture-proven sepsis in the second twin were more common in the combined group, respectively (n=24, odds ratio 1.6, 95% confidence interval, 1.0-2.7; n=15, odds ratio 1.8, 95% confidence interval, 1.0-3.4). These differences were not significant after logistic regression analysis. There were no statistically significant differences in an arterial cord pH of less than 7.0, Apgar score less than or equal to 3 at 5 minutes, seizures, grade III or IV intraventricular hemorrhage, hypoxic ischemic encephalopathy, or neonatal death. CONCLUSION: Combined twin delivery may be associated with endometritis and neonatal sepsis when compared with a twin delivery where both are delivered by cesarean in twin pregnancies experiencing labor. More serious neonatal sequelae, including hypoxic ischemic encephalopathy and death, were not affected by the route of delivery of the second twin.

Previous preterm cesarean delivery and risk of subsequent uterine rupture.

OBJECTIVE: To determine if women with a history of a previous preterm cesarean delivery experienced an increased risk of subsequent uterine rupture compared with women who had a previous nonclassic term cesarean delivery. METHODS: A prospective observational study was performed in singleton gestations that had a previous nonclassic cesarean delivery from 1999 to 2002. Women with a history of a previous preterm cesarean delivery were compared with women who had a previous term cesarean delivery. Women who had both a preterm and term cesarean delivery were included in the preterm group. RESULTS: A prior preterm cesarean delivery was significantly associated with an increased risk of subsequent uterine rupture (0.58% compared with 0.28%, P<.001). When women who had a subsequent elective cesarean delivery were removed (remaining n=26,454) women with a previous preterm cesarean delivery were still significantly more likely to sustain a uterine rupture (0.79% compared with 0.46%, P=.001). However, when only women who had a subsequent trial of labor were included, there was still an absolute increased risk of uterine rupture, but it was not statistically significant (1.00% compared with 0.68%, P=.081). In a multivariable analysis controlling for confounding variables (oxytocin use, two or more previous cesarean deliveries, a cesarean delivery within the past 2 years, and preterm delivery in the current pregnancy), patients with a previous preterm cesarean delivery remained at an increased risk of subsequent uterine rupture (P=.043, odds ratio 1.6, 95% confidence interval 1.01-2.50) compared with women with previous term cesarean delivery. CONCLUSION: Women who have had a previous preterm cesarean delivery are at a minimally increased risk for uterine rupture in a subsequent pregnancy when compared with women who have had previous term cesarean deliveries.

Can myometrial electrical activity identify patients in preterm labor?

OBJECTIVE: The objective of the study was to determine whether myometrial electrical activity can differentiate false from true preterm labor. STUDY DESIGN: Electrical uterine myography (EUM) was measured prospectively on 87 women, gestational age less than 35 weeks. The period between contractions, power of contraction peaks and movement of center of electrical activity (RMS), was used to develop an index score (1-5) for prediction of preterm delivery (PTD) within 14 days of the test. The score was compared with fetal fibronectin (fFN) and cervical length (CL). RESULTS: Patients delivering within 14 days from testing showed a higher index and mean RMS (P = .000). No patients with EUM index scores of 1-2 delivered in this time frame. Combining EUM with CL or fFN increased predictability. Logistic regression revealed that history of PTD and EUM index had 4- to 5-fold increased risk for PTD. Gestational age at testing, body mass index, fFN, and CL were nonsignificant contributors to PTD risk. CONCLUSION: Measuring myometrial electrical activity may enhance identification of patients in true premature labor.

Maternal-Fetal Medicine Units Network cesarean registry: impact of shift change on cesarean complications.

OBJECTIVE: This study was undertaken to evaluate the effect of change of shift for physicians and nurses on complications associated with cesarean delivery. STUDY DESIGN: 17,996 term women undergoing an unscheduled cesarean delivery in 13 centers from 1999-2000 were included. Maternal and neonatal morbidities were evaluated by time of infant delivery vis-à-vis nursing change of shift (6 AM-8 AM, 2 PM-4 PM, 10 PM-12 AM vs all other hours). The sample was then limited to weekdays only and physician shift changes were evaluated (physician shift change 6 AM-8 AM, 5 PM-7 PM vs all others). A composite of 30 maternal morbidities was also evaluated by logistic regression, controlling for potentially confounding factors. RESULTS: Physician change of shift had no measurable effect on maternal and neonatal outcomes. Neonatal facial nerve palsies were increased at nursing change of shift (5 vs 0) as were hysterectomies (33 [0.24%] vs 23 [0.53%]; P < .007). Nursing change of shift had no impact on composite maternal morbidity after controlling for age, race, insurance, medical problems, prior incision type, weekend day, and prenatal care (odds ratio = 0.98; 95% confidence interval = 0.89-1.08). CONCLUSION: Physician change of shift does not appear to be associated with an increase in morbidities. However, cesarean delivery during nursing change of shift is associated with increased risk of neonatal facial nerve palsy and hysterectomy. Further investigation is needed to understand the cause of this association.

Prediction of uterine rupture associated with attempted vaginal birth after cesarean delivery.

OBJECTIVE: The purpose of this study was to develop a model that predicts individual-specific risk of uterine rupture during an attempted vaginal birth after cesarean delivery. STUDY DESIGN: Women with 1 previous low-transverse cesarean delivery who underwent a trial of labor with a term singleton were identified in a concurrently collected database of deliveries that occurred at 19 academic centers during a 4-year period. We analyzed different classification techniques in an effort to develop an accurate prediction model for uterine rupture. RESULTS: Of the 11,855 women who were available for analysis, 83 women (0.7%) had had a uterine rupture. The optimal final prediction model, which was based on a logistic regression, included 2 variables: any previous vaginal delivery (odds ratio, 0.44; 95% CI, 0.27-0.71) and induction of labor (odds ratio, 1.73; 95% CI, 1.11-2.69). This model, with a c-statistic of 0.627, had poor discriminating ability and did not allow the determination of a clinically useful estimate of the probability of uterine rupture for an individual patient. CONCLUSION: Factors that were available before or at admission for delivery cannot be used to predict accurately the relatively small proportion of women at term who will experience a uterine rupture during an attempted vaginal birth after cesarean delivery.