ABSTRACT

Gestational diabetes (GDM) is characterized by glucose intolerance first manifesting during pregnancy and is an important driver for fetal macrosomia, birth injury, and neonatal metabolic alterations--particularly when persistent maternal hyperglycemia exists. Individuals with GDM face short term complications such as cesarean section and hypertensive disorders, and significantly increased risk for type 2 diabetes over the subsequent 10-20 years. Many of these concerns may be moderated with lifestyle and pharmacotherapeutic interventions to reduce maternal hyperglycemia and thereby improve maternal and neonatal health. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

PREVALANCE AND PATHOPHYSIOLOGY

The prevalence of GDM is rapidly rising, ranging from 9 to 26% of pregnancies throughout the world, and is highest in ethnic groups that have a higher incidence of Type 2 diabetes mellitus (T2DM): Hispanic, African American, Native American, and Asian or Pacific Islander individuals (1). The prevalence of GDM doubled in the past 15-20 years due to the obesity epidemic (2–4).

Insulin resistance is paired with increased insulin secretion during pregnancy; however, among individuals with GDM, inadequate β-cell compensation relative to the level of insulin resistance results in failure to maintain euglycemia (5). GDM is caused by carbohydrate intolerance due to abnormalities in at least 3 aspects of fuel metabolism: insulin resistance, impaired insulin secretion, and increased hepatic glucose production (6,7).

Although insulin resistance is a universal finding in pregnancy in GDM, the cellular mechanisms for this type of insulin resistance are multi-factorial and just beginning to be understood. Insulin binding to its receptor is unchanged in pregnant and GDM subjects, and in skeletal muscle, GLUT4 is unchanged as well (8). Pregnancy reduces the capacity for insulin-stimulated glucose transport independent of obesity, due in part to a tissue-specific decrease in insulin receptor phosphorylation and decreased expression of Insulin Receptor Substrate-1 (IRS-1), a major docking protein in skeletal muscle (9). In addition to these mechanisms, in muscles from GDM subjects, IRS-1 is further decreased and there are reciprocal and inverse changes in the degree of serine and tyrosine phosphorylation of the insulin receptor (IR) and IRS-1, further inhibiting insulin signaling (10). GDM subjects also tend to have higher circulating FFA and reduced PPAR expression in adipose tissue, a target for thiazolidinediones (11). There is evidence for a decrease in the number of glucose transporters (GLUT-4) in adipocytes in GDM subjects and an abnormal translocation of these transporters that results in the reduced ability of insulin to recruit them to the cell surface, which contributes to the overall insulin resistance of GDM (12). In GDM individuals, serum adiponectin levels have been shown to be decreased and leptin, IL-6, and TNFα were increased (13).

Although diabetes usually remits after pregnancy, up to 70% of individuals diagnosed with GDM go on to develop T2DM later in life, particularly if obesity is present (14,15). Both GDM and T2DM are aggravated by increasing obesity and age. Thus, pregnancy is a “stress test” for the eventual non-pregnancy development of glucose intolerance and GDM may represent an unmasking of the genetic predisposition of T2DM induced by the hormonal changes of pregnancy (16,17).

DATA TO SUPPORT THE SCREENING, DIAGNOSIS, AND TREATMENT OF GESTATIONAL DIABETES

As early as the 1940s, glucose intolerance and GDM separate from pregestational DM were recognized to have adverse maternal and perinatal outcomes (18). Over the course of the following 7 decades, candidates for screening or testing as well as the diagnostic criteria of GDM were debated (19,20). Early on, value was placed on recognition of GDM in order to identify individuals at risk for T2DM (21). More recently, robust studies have demonstrated the more immediate obstetric and perinatal benefits of screening, diagnosing, and treating GDM.

The first was a landmark trial conducted in Austria and New Zealand referred to as the ACHOIS trial (Australian Carbohydrate Intolerance Study in Pregnant Women), which demonstrated reduced serious perinatal outcomes with intervention/treatment of GDM versus no intervention (1% versus 4%) (22). This RCT enrolled 1000 women with either ≥1 risk factor for GDM or positive 1-hour 50 gm glucose challenge test (GCT) (≥140mg/dL) after completion of blinded 75 gm glucose tolerance test (GTT) at 24-34 weeks gestation demonstrated no severe glucose impairment. Individuals were randomized to receive dietary advice, SMBG, and insulin therapy as needed to achieve fasting glucose <99 mg/dL and 2-hour postprandial values <126 mg/dL versus routine care. The primary outcome included fetal or neonatal death, shoulder dystocia, bone fracture, and nerve palsy was reduced in the intervention/treatment group (1% versus 4%). Although the induction of labor rate was higher in the intervention group, the cesarean delivery rate was not different.

A second landmark RCT, the National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network study (NICHD MFMU Network), demonstrated significant differences in meaningful secondary outcomes (mean birth weight, neonatal fat mass, frequency of large for gestational age infants, birth weight >4000 g, shoulder dystocia, cesarean delivery, and hypertensive disorders of pregnancy) by treating mild GDM (23). A total of 958 women who met criteria for mild GDM between 24-31 weeks were randomly assigned to usual prenatal care (control) or dietary interventions, SMBG, and insulin therapy if necessary (treatment group). Although there was no significant difference in groups in the frequency of the composite outcome and no perinatal deaths in this population with very mild GDM, there were significant reductions with treatment in several pre-specified secondary outcomes. Furthermore, treatment of mild GDM was also associated with reduced rates for preeclampsia and gestational hypertension.

There is also compelling data that the risk of adverse maternal-fetal outcomes from maternal carbohydrate intolerance is along a graded continuum (24,25). The Hyperglycemia and Adverse Outcomes (HAPO) trial enrolled 25,505 pregnant women at 15 centers in nine countries, with participants completing a 2-hour 75 gm GTT at 24-32 weeks’ gestation (25). Data remained blinded if the fasting glucose ≤105 mg/dL and the 2-hour plasma glucose was ≤200 mg/dL. This trial demonstrated that a fasting blood glucose (FBG) ≥92 mg/dl, a 1-hour value ≥180 mg/dl, or a 2-hour value of ≥ 153 mg/dl increased the risk by 1.75-fold for large for gestational age (LGA) and an elevated cord-blood C-peptide consistent with fetal hyperinsulinemia. Furthermore, the fasting glucose was more strongly predictive of these outcomes than the 1-hour or 2-hour value stressing the importance of fasting glucose levels in predicting poor perinatal outcomes. The results also indicated a strong and continuous association with these outcomes and maternal glucose levels below those considered diagnostic of GDM.

DIAGNOSIS OF GESTATIONAL DIABETES

The implications of diabetes recognized for the first time in pregnancy on both maternal and perinatal outcomes have been known for nearly a century (18,26). Nevertheless, substantial controversy persists when considering which individuals warrant screening or outright diagnostic testing, at which gestational age this should occur, and the laboratory cutoffs which should confirm the diagnosis and prompt possible intervention.

Evaluation for what we currently define as GDM, for “early GDM” or for T2DM first diagnosed in pregnancy may take place in a risk-based or universal manner. In general, the basic tenants of screening as defined by the WHO are met: GDM and DM are significant health problems with significant consequences if left untreated, a suitable test exists, with benefits of screening outweighing the risks (27). The lack of consensus generally results from concerns about cost-effectiveness of differing strategies and psychological and public health burdens with increased prevalence of the condition.

Unfortunately, the historical definition of GDM as a glucose-intolerant state with onset or first recognition during pregnancy allows for inclusion of both unrecognized, pregestational, overt diabetes in addition to “true” gestational diabetes resulting from the physiologic and hormonal changes of pregnancy. Since individuals with undiagnosed pregestational diabetes are at increased risk for both maternal and fetal complications, including major malformations if their A1c is ≥ 6.5% in the first trimester, the IADPSG recommends that GDM be only diagnosed if the glucose intolerance was identified in pregnancy AND women did not qualify for pre-existing (overt) diabetes (28). The details and nuanced considerations of the current understanding of gestational diabetes as well as screening and testing modalities are described in the literature (29–31).

In the United States, the USPSTF and ACOG recommend universal screening for all pregnant individuals at 24-28 weeks gestation since prior use of historic factors alone failed to identify 50% of patients with GDM. ACOG further supports a two-step process involving a 50 gm,1-hour glucose challenge test (GCT) followed by a 100 gm, 3-hour oral glucose tolerance test (GTT) (1). Internationally, the one-step IADPSG approach is utilized more frequently. The ADA continues to recognizes that there is no clear evidence which supports IADPSG versus traditional ACOG two-step screening approach (32).

The controversy with the diagnosis of GDM relies heavily on the outcomes studied. The IADPSG recommendations are based on the HAPO trial, which showed that a single value on a 75 gm 2 hour-GTT resulted in a 1.75-fold increased risk of LGA and thus should be the basis for the diagnosis; however, critics disagree. Critics complained that a 2.0-fold increase in LGA risk instead of 1.75 could have been chosen which would not have appreciably increased the prevalence of GDM over the ACOG criteria (34,35). Nearly 90% of all of the women who met criteria for GDM using the 75 gm 2-hour GTT were diagnosed based on the FBG and 1-hour values, raising the question of whether the 2-hour value is worth the extra time and cost (36). Some countries are considering making the diagnostic criteria for GDM be based only on a FBG and 1-hour value, which would decrease subject burden and possibly cost.

Currently there is no consensus about the adoption of the IADPSG criteria over the ACOG criteria. The NIH held a Consensus Conference in March of 2013 (37). They acknowledged that the HAPO study was the first to demonstrate that glycemic thresholds currently lower than the ACOG diagnostic criteria thresholds correlated with LGA and adopting the 75 gm GTT globally would be beneficial in standardizing diagnostic criteria internationally. However, they concluded that there were insufficient data from RCTs demonstrating that adopting the lower glucose thresholds would significantly benefit the much larger population of women who make the diagnostic criteria for GDM based on the IADPSG criteria and such adoption could markedly increase cost of treatment. Further, there was a concern that adopting the IADPSG criteria could triple the prevalence of GDM, potentially outstripping the resources to treat it. A recent meta-analysis proved this to be true, with implementation associated with 75% increase in number of individuals diagnosed with GDM (38).

At the consensus conference, it was also argued that it is not clear how much the increased risk of LGA at lower glucose thresholds observed in the HAPO trial on which it was based was due to maternal obesity or mild hyperglycemia. A retrospective review of nearly 10,000 women who were diagnosed with GDM using the IADPSG criteria showed an overall GDM prevalence of 24%. After excluding women who required treatment for GDM, 75% of GDM women were overweight or obese. Although GDM nearly doubled the risk of LGA over obesity alone (22.3% versus 12.7% respectively), in women without GDM, 21.6% of LGA was attributable to being overweight and obese. The combination of GDM in addition to being overweight or obese did not add much to the attributable risk for LGA and accounted for 23.3% of LGA infants (39).

Hillier et al published the results of their pragmatic, randomized trial comparing one-step screening with two-step screening in which nearly 24,000 individuals were randomized (40). The diagnosis of GDM was roughly doubled using the one step approach versus the two-step approach, at rates of 16.5% and 8.5% respectively, (unadjusted relative risk, 1.94; 97.5% confidence interval [CI], 1.79 to 2.11) (40). Importantly, there were no significant differences between diagnostic approaches among the primary outcomes (LGA infants, perinatal composite, gestational hypertension or preeclampsia, and primary cesarean delivery). Although this study was quite large, criticisms include a sample size underpowered to detect differences in the groups, treatment of individuals with a single elevated GTT value, and suboptimal adherence to protocols (31).

RISKS TO THE MOTHER AND INFANT WITH GESTATIONAL DIABETES

The pregnancy-associated risks to the individual with GDM are an increased incidence of cesarean delivery (~25%), preeclampsia (~20%), and polyhydramnios (~20%) (46–50). The long- term risks are related to recurrent GDM pregnancies and the substantial risk of developing T2DM. Individuals with GDM represent a group with an extremely high risk (~50-70%) of developing T2DM in the subsequent 5-30 years (1,51). Individuals with fasting hyperglycemia, obesity, those belonging to an ethnic group with a high prevalence of T2DM (especially Latin-American women), or who demonstrate impaired glucose tolerance or fasting glucose at 6 weeks postpartum, have the highest risk of developing T2DM (1,51,52). Counseling with regard to diet, weight loss, and exercise is essential and is likely to improve insulin sensitivity.

Thiazolididiones, metformin, and lifestyle modifications have all been demonstrated to decrease the risk of developing T2DM in GDM women who have impaired fasting glucose or glucose intolerance postpartum (53–55).

The potential risks to the infant from GDM are similar to those in pregnancies complicated by T1DM or T2DM with suboptimal control in the second half of pregnancy (stillbirth, macrosomia, shoulder dystocia, premature delivery, neonatal hypoglycemia, hyperbilirubinemia, and NICU admission). Notably congenital malformations and miscarriage risks would not be observed with later-onset insulin resistance with GDM (1,56–58). Like pregestational DM, the degree of hyperglycemia correlates with perinatal risk. Among diet-controlled GDM pregnancies the risk of stillbirth is not increased compared to the general population (59). In addition to immediate postnatal risks, infants of GDM mothers are at increased risk for childhood and adult-onset obesity and diabetes.

MEDICAL NUTRITION MANAGEMENT AND EXERCISE

Individuals with GDM should be taught home glucose monitoring to ensure that their glycemic goals are being met throughout the duration of pregnancy. The same goals are utilized in GDM pregnancies as in pregestational DM: a fasting glucose <95mg/dL, 1-hour postprandial <140mg/dL and 2-hour postprandial <120mg/dL (1,32). The best therapy for GDM depends entirely on the severity of the glucose intolerance, the individual‘s response to non-pharmacologic or pharmacologic treatment, as well as effects on fetal growth. Diet and exercise alone will maintain the fasting and postprandial blood glucose values within the target range in at least 50% of individual with GDM. A 2018 meta-analysis evaluating diet modifications illustrated improvements in fasting and postprandial glucose values and lower need for medical treatment when compared to controls (60). Furthermore, diet modifications were also associated with lower infant birth weight and less macrosomia (60).

Nevertheless, data are limited regarding the optimal GDM diet to achieve euglycemia and avoid perinatal complications of GDM. The current recommended diet for GDM includes consumption of at least 175 gm of carbohydrate, with complex carbohydrates favored over simple carbohydrates, a minimum of 71 gm of protein, and 28 gm of fiber to provide adequate macronutrients and avoid ketosis (32). There is little evidence to support one dietary approach over another but common practice is three meals and 2-3 snacks daily to distribute carbohydrate intake and reduce postprandial hyperglycemia. The caloric intake and weight gain recommendations are also consistent with what is recommended in individuals with obesity or T2DM. We recommend multidisciplinary care with a dietician or nurse educator familiar with GDM to individualize a dietary plan.

In 2009, the Institute of Medicine (name changed to National Academy of Medicine in 2015), published recommended gestational weight gain (GWG) based on pre-pregnancy BMI, with less GWG recommended for overweight and obese individuals compared to those with normal BMI (61). Nevertheless, follow up studies demonstrated a large proportion of pregnant individuals worldwide had GWG above (27.8% and below (39.4%) the IOM guidelines, with highest mean GWG and pre-pregnancy BMI observed in North America (62). Furthermore, a variety of adverse outcomes have been observed in the setting of excess GWG, including LGA and macrosomic infants in the GDM population (63–66). As a result, the question has been raised whether weight gain less than the IOM guidelines in GDM pregnancies could improve outcomes. There are studies suggesting that weight gain less than IOM recommendations for overweight GDM women may decrease insulin requirements, cesarean delivery, and improve pregnancy outcomes without appreciably increasing SGA (67–69). Further, a third study suggesting that slight weight loss (mean of 1.4 kg) in overweight GDM women decreased birth weight without increasing small for gestational age (SGA) (70). Larger meta-analyses confirmed these findings, but failed to identify an ideal weight gain range for optimal outcomes (71).

Since postprandial glucose levels have been strongly associated with the risk of macrosomia it has been suggested that carbohydrate restriction to ~33-40% of total calories may be helpful to blunt the postprandial glucose excursions, in addition to preventing excessive weight gain (72). However, the actual dietary composition that optimized perinatal outcomes is unknown. There is also growing concern that women are substituting fat for carbohydrates which has been associated with adverse fetal programming including oxidative stress as well as an insulin resistant phenotype (73,74). Although a low carbohydrate, higher fat diet has been conventionally recommended to minimize postprandial hyperglycemia, a review of the few randomized controlled trials examining nutritional management in 250 GDM women suggested that a diet higher in complex carbohydrate and fiber, low in simple sugar and lower in saturated fat may be effective in blunting postprandial hyperglycemia, preventing worsened insulin resistance, and excess fetal growth (75). A more recent trial challenged the traditional low-carb/higher-fat diet and demonstrated that a diet with higher complex carbohydrates and lower-fat reduced fasting blood glucose and infant adiposity (76). Given these trials, a diet of complex carbohydrates is recommended over simple carbohydrates primarily due to slower digestion time which prevents rapid increases in blood glucose.

The role of exercise in GDM may be even more important than in individuals with preexisting diabetes given exercise in some individuals may lessen the need for medical therapy. This idea is similar to the evidence in non-pregnant patients with diabetes which supports weight training due to increases in lean muscle and increased tissue sensitivity to insulin. A 2013 review showed that in individuals with GDM, five of seven (~70%) activity-based interventions showed improvement in glycemic control or limiting insulin use (77). In most successful studies (3 times/week), insulin needs decrease by 2-3-fold, and overweight or obese women benefited the most with a longer delay from diagnosis to initiation of insulin therapy. Moderate exercise is well tolerated and has been shown in several trials in GDM women to lower maternal glucose levels (78–80). Using exercise after a meal in the form of a brisk walk may blunt the postprandial glucose excursions sufficiently in some women that medical therapy might be avoided.

Establishing a regular routine of modest exercise during pregnancy, per ACOG of 30 minutes of moderate-intensity aerobic activity at least 5 days/week, may also have long lasting benefits for the GDM patient who clearly has an appreciable risk of developing T2DM in the future (1).

MEDICAL TREATMENT OPTIONS

Once the diagnosis of gestational diabetes is confirmed and glycemic control exceeds target ranges despite dietary education and lifestyle changes, pharmacotherapy must be considered. Prior to the 21^st century, insulin was the sole medical option for GDM. After the introduction of glyburide and metformin, initiation of oral agents became the preferred first-line therapy, with addition or transition to insulin therapy if glycemic control remained suboptimal. In 2018, ACOG joined the ADA in endorsing insulin as first-line therapy, while the Society of Maternal-Fetal Medicine (SMFM) released a statement recommending metformin as a reasonable first-choice therapy.

Although there are few data from randomized controlled trials to determine the optimal therapeutic glycemic targets, the standard of care is that women who have fasting blood glucose levels >95 mg/dl, 1-hour postprandial glucose levels >140 mg/dl or 2-hour postprandial glucose levels >120 mg/dl be started on medical therapy. In 5 randomized trials it was demonstrated that if insulin therapy is started in women with GDM whose maternal glucoses are at target levels on diet alone but whose fetuses demonstrate excessive growth by an increased AC relative to the biparietal diameter (BPD) i.e. body to head disproportion, the rate of fetal macrosomia can be decreased (81). This fetal based strategy using ultrasound at 29-33 weeks to measure the AC in order dictate the aggressiveness of maternal glycemic control has been recommended by the Fifth International Workshop-Conference on Gestational Diabetes and the IADPSG (28,82,83). GDM can often be treated with twice daily injections of intermediate or long-acting insulin (NPH, glargine, detemir) and mealtime injections of lispro or aspart as necessary for postprandial hyperglycemia. Short acting insulin (lispro or aspart) is preferred over regular insulin due to time of onset and duration to better control postprandial glycemic excursions. See Endotext chapter “Pregestational Diabetes” for details regarding antepartum, intrapartum, and postpartum insulin dosing regimens.

FETAL SURVEILLANCE AND DELIVERY OPTIONS IN GESTATIONAL DIABETES

Individuals with GDM who require pharmacotherapy but do not have other comorbidities should initiate once or twice weekly antenatal fetal surveillance at 32 weeks gestation (110). There is no consensus regarding antepartum testing in women with diet-controlled GDM (1). For those individuals with diet-controlled GDM extending pregnancy beyond 40 weeks gestation, consideration could be made to initiate antenatal testing (110).

An ultrasound for growth to look for head to body disproportion (large abdominal circumference compared to the biparietal diameter) and evidence of LGA should be considered at ~29-32 weeks (1). The documented risks associated with attempted vaginal delivery with a fetal estimated weight >4500 gm in the setting of pregestational diabetes have resulted in a reasonable practice of offering cesarean delivery. This recommendation is extended to those with GDM and a fetal estimated weight >4500 gm (1). Nevertheless, a Cochrane review found insufficient evidence in using fetal biometry to assist in guiding the medical management of GDM to improve either perinatal or maternal health outcomes (111).

When GDM is well-controlled with either diet or medications, delivery <39 weeks gestation is not warranted. Delivery is usually recommended by 40 6/7 weeks for uncomplicated diet controlled GDM and by 39 6/7 weeks for well controlled GDM on medication (112). Earlier delivery should be considered with suboptimal glucose control or other complicating factors such as hypertension (112). The framework of evaluating the risks and benefits of induction of labor to expectant management in both high risk and low risk patients has shifted from a historical lens of induction of labor compared to spontaneous labor; multiple studies have demonstrated no increased risk of cesarean delivery with induction of labor <40 weeks gestation (113–115).

POSTPARUM ISSUES IN WOMEN WITH GESTATIONAL DIABETES

CONCLUSION

While some controversy remains regarding the screening and diagnostic criteria for GDM, it is undeniable that treatment with lifestyle or medication to achieve glycemic targets improves obstetric and perinatal outcomes. Due to the obesity epidemic, the incidence of GDM is only expected to rise, with subsequent or eventual T2DM diagnosis increasing accordingly.

The development of T2DM in women with a history of GDM as well as obesity and glucose intolerance in the offspring of women with preexisting DM or GDM set the stage for a perpetuating cycle that must be aggressively addressed with effective primary prevention strategies that begin in-utero. Pregnancy is clearly a unique opportunity to implement strategies to improve the mother’s lifetime risk for CVD in addition to that of her offspring and offers the potential to decrease the intergenerational risk of obesity, diabetes, and other metabolic derangements.

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