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.

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.

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.

Obesity or diabetes: which is more hazardous to the health of the offspring?

OBJECTIVE: To examine impact on perinatal outcome of untreated gestational diabetes (GDM) and non-diabetics stratified by body mass index (BMI). RESEARCH DESIGN AND METHODS: This is a secondary analysis of our investigation of the consequences of not treating GDM. We evaluated 555 untreated GDMs matched to 1100 non-diabetics. BMI was determined using subjects' recalled pre-pregnancy weight. A primary composite variable consisted of stillbirth, neonatal macrosomia/large-for-gestational-age (LGA), neonatal hypoglycemia, erythrocytosis and hyperbilirubinemia. Secondary outcomes included shoulder dystocia, respiratory complications, cesarean delivery and pregnancy-related hypertension. RESULTS: Untreated subjects in the normal weight category had an ∼2-fold increase for composite outcome and LGA and a 7-fold increase in metabolic complications. The overweight untreated group showed composite outcome, LGA and metabolic complications 2-3-fold higher and induction of labor 5-fold higher. For obese untreated GDMs, significantly higher rates of composite outcome, LGA and metabolic complications, induction of labor and cesarean delivery were 10-, 3-, 5-, 4- and 9-fold, respectively. Perinatal outcome for normal weight untreated GDM was similar to obese non-diabetics. CONCLUSIONS: Maternal obesity and GDM independently affect adverse pregnancy outcome. The combination has a greater impact than each one alone. However, glycemic level contributes a greater portion to the adverse pregnancy equation.

Weight gain in gestational diabetes: the effect of treatment modality.

OBJECTIVE: To evaluate treatment effectiveness (diet alone, insulin or glyburide) on maternal weight gain in gestational diabetes (GDM). METHODS: GDM patients were treated with diet alone, insulin or glyburide. Weight gain was stratified into: prior to GDM diagnosis, from diagnosis to delivery and total pregnancy weight gain. Good glycemic control was defined as mean blood glucose ≤ 105 mg/dl and obesity as Body Mass Index (BMI) ≥ 30 kg/m(2), overweight BMI 25-29 kg/m(2) and normal < 25 kg/m(2). RESULTS: Total weight gain was similar in all the treatment groups. Two-thirds of weight gain occurred prior to diagnosis (diet 85%, insulin 67% and glyburide 78%). Post-diagnosis, patients on diet alone gained less weight than those on insulin or glyburide (p < 0.001); insulin-treated patients showed greater weight gain than glyburide-treated patients (p < 0.001). Patients on diet with good glycemic control showed less weight gain after diagnosis than patients on insulin or glyburide (2.8 ± 13, 6.6 ± 10, 5.2 ± 7.9 lbs, respectively, p < 0.02). Poorly-controlled patients, regardless of treatment, had similar patterns of weight gain throughout pregnancy. CONCLUSION: Patterns of maternal weight gain in GDM pregnancies are associated with treatment modality and level of glycemic control.

Oral hypoglycemic agents: do the ends justify the means?

BACKGROUND: Glyburide has replaced insulin as the first line of therapy in the treatment of gestational diabetes in the United States. Glyburide and metformin therapies were reported to be comparable to insulin yet also cost-effective, patient-friendly, and potentially compliance-enhancing. Recently, the efficacy of the use of these oral hypoglycemic drugs has been questioned. In this review, the questionable concerns will be addressed: Which diabetic drug(s) cross the placenta? What is the quality of evidence and the data source validity? Which treatment modalities are most effective in reducing the primary outcome in GDM? Which drug is most effective in improving secondary outcomes? FINDINGS: This review documents the methodological issues in study design that have impacted the results for the provision of health care interventions in GDM. The review summarizes the contents of the articles qualitatively and assesses the theoretical and empirical evidence. Multiple types of studies exist and every study design serves a specific purpose. Different study designs addressing the same question can yield varying results. The risk of presenting uncertain results without categorically knowing the direction and magnitude of the effect holds true for both randomized and nonrandomized controlled trials. The review further emphasizes the importance of achieving the targeted levels of glycemic control. CONCLUSION: The implications of this review are critical to addressing the current gaps in the literature on the efficacy of the use of oral hypoglycemic agents in GDM. The emphasis needs to be placed on patient treatment in order to manage hyperglycemia to reduce fetal and maternal morbidity. In this regard, we need to delineate proper outcome criteria that will reflect disease severity and treat using appropriate pharmacological therapy.

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.

The proposed GDM diagnostic criteria: a difference, to be a difference, must make a difference.

The new criteria for diagnosis of gestational diabetes mellitus proposed by the International Association of Diabetes in Pregnancy Study Group (IADPSG) transports back the controversy and the lack of agreement to the frontlines. The recommended criteria are based on results of the observational hyperglycemia and adverse pregnancy outcome study (HAPO). These criteria will increase the frequency of gestational diabetes diagnosis by 2-8 folds, depending upon ethnicity, and prevalence of obesity. Do the costs and implied resources justify using the proposed endpoints that will define pregnancy outcome and severity especially when the appropriate outcomes and odds ratio used to define the diagnosis are questionable? Furthermore, due to the large disparity around the globe in relation to the prevalence of gestational diabetes raises the question if single diagnostic criteria can be made to fit all?!? The current review analyzes the risks, costs and benefits that may influence the rate of gestational diabetes in relation to the worldwide prevalence.

Perspectives on the proposed gestational diabetes mellitus diagnostic criteria.

To date, The International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for the diagnosis of gestational diabetes mellitus (GDM) have not been analyzed systematically for medical, social, and economic ramifications if used in substitution for the current GDM diagnostic criteria. The IADPSG dependence on expert opinion and consensus rather than on rigorously obtained outcome measures is concerning given the dramatic changes in clinical intervention and medical-resource reallocation that would follow their wide adoption. This commentary attempts to highlight needed research as well as the key knowledge gaps that should prevent adoption of the revised criteria until their effect on perinatal outcomes and health care costs is determined. In light of the overall, ethnic, and regional variation in GDM prevalence and the demands of increased GDM diagnosis on clinical resources, it may not be realistic and practical to impose universal strategies and standards for diagnosis. The newly proposed criteria may affect medical care negatively, unnecessarily stigmatize patients with a "sick label," and adversely affect health care costs without ensuring the desired improvements in maternal and neonatal outcomes. This commentary serves as a caution to not promote a new endeavor until it has been compared rigorously with current practice and its implications are understood fully.

Male-to-female gender ratio in fetuses with increased nuchal translucency.

OBJECTIVE: To describe gender distribution in fetuses with increased nuchal translucency (NT) measurements. METHODS: All fetuses with mild (2.5-2.9 mm) and moderate (3.0-3.5 mm) NT enlargement at 12.0-12.6 weeks gestation were studied. The Z test for proportions was used to compare the gender distribution of this study group to that of all babies born at Roosevelt Hospital in 2008, and to compare the gender distributions of the subgroups. RESULTS: 5109 patients received screening at 12.0-12.6 weeks gestation. 44 fetuses had mild and 28 had moderate enlargement, with a male-to-female ratio of 3.8:1.0, much higher than the 1.06:1.0 ratio among total births at Roosevelt Hospital in 2008 (p < 0.0001). Male-to-female ratio was 7.8:1.0 in fetuses with mild and 1.8:1.0 with moderate NT enlargement (p = 0.03). Among fetuses with mild NT enlargement, 3 males had aneuploidy; among those with moderate enlargement, 6 fetuses had aneuploidy, 3 males and 3 females. Seven pregnancies with aneuploidy were voluntarily terminated. All pregnancies carried to term were healthy. CONCLUSIONS: More males than females had mild NT enlargement on first-trimester screening, but unless aneuploidy was detected they had normal birth outcomes. A slightly larger NT may be normal in males, while indicating possible fetal abnormalities in females.

Measuring glucose exposure and variability using continuous glucose monitoring in normal and abnormal glucose metabolism in pregnancy.

UNLABELLED: In pregnancy complicated by diabetes periods of hyperglycemia lead to accelerated fetal growth, resulting in a large for gestational age (LGA), or macrosomic, infant. Consequently, our aim was to measure the average volatility or variability in glucose control in women with and without diabetes in pregnancy. METHODS: Continuous glucose monitoring (CGM) was employed in 82 pregnant study subjects to collect and record unbiased self-monitored glucose values. We obtained results from 51 women with normal glucose tolerance in pregnancy (NGTP), 25 gestational diabetes (GDM) and 6 women with pregestational diabetes (PreGD) between 18 and 45 (32 ± 6) years of age. RESULTS: Significant differences (p < 0.001) were found in glucose exposure between NGT and all but PreGD; whereas the percent of time in hypoglycemia was significantly (p < 0.0001) higher in all pregnancy groups when compared to the nonpregnant sample. We conclude that CGM confirmed that diurnal glucose patterns differ throughout the day by 20% when pregnant and nonpregnant states are compared. Indeed, maintenance of a narrow range in pregnancy is characteristic in women without diabetes, and CGM throughout pregnancy is critical, if mimicking normal glucose patterns is to be achieved.

Gestational diabetes: maternal weight gain in relation to fetal growth, treatment modality, BMI and glycemic control.

OBJECTIVES: We sought to determine the impact of maternal weight gain on fetal growth in gestational diabetes (GDM) in relation to treatment modality, body mass index (BMI) and glycemic control. STUDY DESIGN: Two thousand four hundred fifty-four GDMs were evaluated. Obesity was defined as BMI >29; good glycemic control ≤ 100 mg/dl; maternal age < and >30 years; parity ± 1; large for gestational age (LGA) >90th percentile and small for gestational age (SGA) <10th percentile. RESULTS: SGA rates were similar in all groups. Obese/overweight diet-treated women in glycemic control showed a four-fold higher rate of LGA compared to insulin-treated women. A 36-lb weight gain in insulin-treated patients had a six-fold higher risk. In poor glycemic control, LGA rates were higher in all BMI/weight gain categories. Logistic regressions for LGA/SGA revealed that level of glycemia, weight gain, parity, obesity and treatment (for LGA only) were significant. CONCLUSION: Different thresholds used for different maternal BMI categories in addition to the achievement of glycemic control and pharmacological therapy will enhance pregnancy outcome.

First-trimester crown-rump length as a predictor of fetal LGA and SGA at term.

OBJECTIVE: To determine whether first-trimester crown-rump length (CRL) is associated with birthweight extremes at term. METHODS: Included in this study were all term, small for gestational age (SGA), and large for gestational age (LGA) neonates with no other obstetric complications and no abnormal outcomes of pregnancy. CRL at 12.0 to 12.6 weeks of estimated gestational age obtained during nuchal translucency screening was selected as an estimate of early fetal growth. Mean first-trimester CRL of the LGA noenates at term was compared via student's t-test with mean first-trimester CRL of SGA neonates at term. RESULTS: In all, 121 neonates were included in the study. Mean first-trimester CRL of the 63 LGA-term neonates was 62.7 ± 6.0 mm (95% confidence interval, ± 1.49 mm; range, 61.21-64.19), while that of the 58 SGA-term neonates was smaller at 58.8 ± 6.9 mm (95% confidence interval, ± 1.79 mm; range, 57.01-60.59 mm). This 3.9 mm difference between the means was statistically significant (P = 0.01). CONCLUSION: We found that birthweights of LGA and SGA neonates at term were associated with their first-trimester CRL measurements, thus, indicating that fetal growth patterns apparent early in pregnancy continue through term.

Hypoglycemia in glyburide-treated gestational diabetes: is it dose-dependent?

OBJECTIVE: To estimate whether there is a relationship between glyburide dose and the rate of hypoglycemic episodes in women with gestational diabetes mellitus (GDM). METHODS: We studied 674 women with GDM who were treated with glyburide and diagnosed from 2000 to 2009. Glucose data were downloaded from memory-based meters at each visit and analyzed to estimate the incidence of recorded episodes of hypoglycemia and the association with concurrent dose of glyburide therapy (2.5, 5, 10, 15, or 20 mg). Hypoglycemia was defined as a blood glucose of less than 50 mg/dL, further classified as "severe hypoglycemia" if the event required the assistance of another person for resuscitation, "symptomatic hypoglycemia" if it was associated with typical neurogenic symptoms, or "asymptomatic hypoglycemia" if the biochemical reading was less than 50 mg/dL with no symptoms or accompanied by mild symptoms that did not impair the patient's ability to function. RESULTS: Patients recorded a mean of 272 glucose values. Sixty-seven percent of the patients experienced no blood glucose values in the hypoglycemic range. 33% had 1-7% of their total blood glucose values within the hypoglycemic range. All recordings of hypoglycemic episodes were asymptomatic; no patient reported a severe or symptomatic hypoglycemic episode. A significant association was found between the incidence of asymptomatic hypoglycemia and mean blood glucose (P<.001). No association was found between glyburide dose and incidence of asymptomatic hypoglycemia. No association between glyburide dose or mean blood glucose value and the incidence of neonatal hypoglycemia was found. CONCLUSION: Incremental increases in glyburide dose are not associated with an increase in the incidence of hypoglycemic episodes. LEVEL OF EVIDENCE: II.

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.

Comparison of transverse and vertical skin incision for emergency cesarean delivery.

OBJECTIVE: To compare incision-to-delivery intervals and related maternal and neonatal outcomes by skin incision in primary and repeat emergent cesarean deliveries. METHODS: From 1999 to 2000, a prospective cohort study of all cesarean deliveries was conducted at 13 hospitals comprising the Eunice Kennedy Shriver National Institute of Child Health and Human Development's Maternal-Fetal Medicine Units Network. This secondary analysis was limited to emergent procedures, defined as those performed for cord prolapse, abruption, placenta previa with hemorrhage, nonreassuring fetal heart rate tracing, or uterine rupture. Incision-to-delivery intervals, incision-to-closure intervals, and maternal outcomes were compared by skin-incision type (transverse compared with vertical) after stratifying for primary compared with repeat singleton cesarean delivery. Neonatal outcomes were compared by skin-incision type. RESULTS: Of the 37,112 live singleton cesarean deliveries, 3,525 (9.5%) were performed for emergent indications of which 2,498 (70.9%) were performed by transverse and the remaining 1,027 (29.1%) by vertical incision. Vertical skin incision shortened median incision-to-delivery intervals by 1 minute (3 compared with 4 minutes, P<.001) in primary and 2 minutes (3 compared with 5 minutes, P<.001) in repeat cesarean deliveries. Total median operative time was longer after vertical skin incision by 3 minutes in primary (46 compared with 43 minutes, P<.001) and 4 minutes in repeat cesarean deliveries (56 compared with 52 minutes, P<.001). Neonates delivered through a vertical incision were more likely to have an umbilical artery pH of less than 7.0 (10% compared with 7%, P=.02), to be intubated in the delivery room (17% compared with 13%, P=.001), or to be diagnosed with hypoxic ischemic encephalopathy (3% compared with 1%, P<.001). CONCLUSION: In emergency cesarean deliveries, neonatal delivery occurred more quickly after a vertical skin incision, but this was not associated with improved neonatal outcomes. LEVEL OF EVIDENCE: II.

The proceedings of the diabetes in pregnancy study group of North America 2009 conference.

The DPSG of North America (DPSG-NA) was inaugurated in 1997, and its initial meeting was commenced in San Antonio, Texas, in 1998. Since then, the DPSG-NA has held annual meetings, which are hosted by the home institution of members of the organizing committee on a rotating basis. This yeas, the DPSG-NA held its 11 annual meeting in Baltimore, Maryland, and focused on the major controversies regarding the detection, diagnosis, and management of gestational diabetes mellitus (GDM). It included the latest information on the maternal and fetal consequences of GDM as well as summaries from the HAPO study, the Australian Carbohydrate Intolerance Study (ACHOIS) in pregnant women, and the National Institute of Child Health and Human Development Maternal Fetal Medicine (NICHD MFMU Network) study. In addition, extensive data were presented on the effectiveness of oral antihyperglycemic agents in managing GDM as well as data from studies examining their transfer across the placenta and effects on the fetus. Strategies for managing hypertensive disorders associated with GDM were also presented. Based on this year's presentations, the DPSG-NA coordinating committee has made recommendations on the screening and management of GDM and priorities for future research.