Maternal complications of GDM

Gestational diabetes mellitus (GDM) is defined as any carbohydrate intolerance first diagnosed during pregnancy. It is associated with adverse outcome not only for the mother, but also for the child, whether as a fetus, a neonate, a child or an adult. Maternal consequences include increased rate of operative and cesarean delivery, hypertensive disorders during pregnancy and future risk for type 2 diabetes mellitus as well as other aspects of the metabolic syndrome, such as obesity, cardiovascular morbidities and recurrent GDM. Also, there are maternal implications secondary to a delivery of a macrosomic or a large for gestational age fetus, such as an increased rate of cesarean delivery, postpartum hemorrhage, birth trauma and shoulder dystocia. In this entry we shall review maternal complications of gestational diabetes mellitus, during and following gestation: hypertensive disorders in pregnancy, increased risk of cesarean and operative deliveries, postpartum type 2 diabetes mellitus and macrosomia related complications

Hypertensive disorders during pregnancy

Gestational diabetes mellitus (GDM) is defined as any carbohydrate intolerance first diagnosed during pregnancy[1]. Women with GDM are at an increased risk for hypertensive disorders during pregnancy compared to those without GDM. A portion of this risk is related to co-existing mutual risk factors, such as obesity, increased maternal age and family history. However, it is evident from several studies that GDM per se is an independent risk factor for hypertensive disorders during pregnancy, with an increased relative risk ranging from 1.4 to 2.5[2][3][4].

What is the role of insulin resistance? Insulin resistance plays an important role in the pathogenesis of hypertensive disorders during pregnancy. Available data suggest that insulin resistance, already linked to the pathogenesis of essential hypertension, contributes to the development of hypertension during pregnancy as well, be it gestational hypertension or pre-eclampsia. However, the exact association between insulin resistance and hypertensive disorders, and the mechanism involved are poorly understood [5]. Several studies [6][7]have assessed insulin resistance by homeostatic model assessment (HOMA) during gestation, particularly in the first trimester, and found it to be associated with the occurrence of hypertension later in pregnancy. Moreover, conditions associated with increased insulin resistance, such as gestational diabetes, polycystic ovary syndrome and obesity were also found to be risk factors for developing hypertension during pregnancy [8]. Laboratory parameters, associated with the metabolic syndrome of insulin resistance, are also observed more frequently in women with hypertension during pregnancy, such as: hyperinsulinemia, hyperlipidemia and elevated levels of Plasminogen Activator Inhibitor-1, Leptin and Tumor Necrosis Factor-α [8].

What is the risk for women with GDM to develop hypertensive disorder? Multiple studies have investigated the risk of gestational hypertension and pre-eclampsia to occur in women with GDM. Casey et al. [2] compared 61,209 non-diabetic pregnant women to 874 women with diet treated GDM. They documented a higher risk for hypertensive disorders reaching 17% in the GDM population vs. 12% in non-diabetic women. Joffe et al.[3] in the Calcium for Pre-eclampsia Prevention (CPEP) trial followed 4589 nulliparous women. They demonstrated that among women with GDM there is and increased risk for pre-eclampsia specifically as well as for all hypertensive disorders - relative risk 1.67 (95% confidence interval (CI) 0.92-3.05) and 1.54 (95% CI 1.28-2.11), respectively. Similar results were reported by Yogev et al. [4] who studied 1813 patients with GDM and demonstrated that preeclampsia in GDM subjects is diagnosed at a younger age, usually during the first pregnancy, in more obese women and in those with a higher gestational weight gain. The rate of pre-eclampsia is correlated to the severity of GDM at diagnosis and to the level of glycemic control - 7.8% vs. 13.8%, (relative risk 1.81, 95%CI 1.3-2.51), when comparing patients with Fasting Plasma Glucose (FPG) <105 and FPG >105 on the diagnostic OGTT and 9.8% vs. 18% (relative risk 2.56, 95%C.I. 1.5-4.3), in those with FPG <115 and FPG >115 on the glycemic control indices.

What is the contribution of the HAPO study? Recently, this data was strengthened by results of the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. This was an observational multicenter study of approximately 25,000 women. The study results demonstrated that the risk of adverse pregnancy outcome is continuously increased in relation to elevated maternal levels of glucose, on a 75g Oral Glucose Tolerance Test (OGTT) preformed at 24–28 weeks, even with glucose levels below those considered previously as diabetes. Specifically, the odds ratio for pre-eclampsia associated with an increase in FPG of 1 SD, (6.9 mg/dl), 1-hour plasma glucose level of 1 SD (30.9 mg/dl) and 2-hour plasma glucose level of 1 SD (23.5 mg/dl), following a 75g OGTT, was 1.21 (95% CI 1.13-1.29), 1.28 (95% CI 1.2-1.7) and 1.28 (95% CI 1.2-1.7), respectively. After adjustment for BMI and fasting C-peptide the associations remained significant but weaker [9][10].

Cesarean Section and Instrumental Deliveries

GDM is a risk factor for cesarean sections and operative deliveries, and is independent of birth weight, associated with cesarean delivery rate of up to approximately 30%[2] [11][12]. In the Tri-hospital GDM study from 1996[11] the rate of cesarean delivery was studied in relation to birth weight and gestational glucose tolerance, in women with treated GDM, untreated borderline GDM and in normal controls without glucose intolerance. The results of the study demonstrate that untreated women with borderline GDM had an increased rate of cesarean delivery compared to controls (29.6% vs. 20.2%, P=.02), as did had women with treated GDM compared to controls (adjusted OR=2.1; 95% CI 1.3-3.6). Women with treated GDM, even though birth weight was normalized, remained at a higher risk for cesarean delivery of approximately 33%. This suggests that diagnosis of GDM leads to a lower threshold for intervention by cesarean delivery, independent of birth weight. Similar rates of cesarean deliveries were reported by Casey et al. [2] who concluded that women with GDM had a 30% rate of cesarean delivery, compared to 17% in the general population. The risk is increased not solely for cesarean deliveries, but similarly and independently increased for operative deliveries. Compared with non-diabetics, women with GDM are prone to higher risk of vaginal operative deliveries. The degree of glucose intolerance (determined by FPG > 105mg/dl) and maternal weight are independent variables that significantly increase the risk for operative delivery[12].

GDM and Postpartum type 2 diabetes mellitus

GDM usually resolves following delivery, however, some women with GDM actually have T2DM not previously diagnosed. Also, women who had a pregnancy complicated by GDM remain at an increased risk to develop future T2DM. This risk varies according to co-existing risk factors; some of them are treatable, while others are not. Prevention of postpartum diabetes should first recognize such risk factors, and focus on modifiable targets. The diagnosis of postpartum T2DM can be made shortly after delivery, suggesting it to be pre existing overt diabetes and not GDM, or weeks, months and years after delivery [13][14].

What is the incidence of postpartum T2DM in women with past GDM? The prevalence of abnormal carbohydrate tolerance following a pregnancy with GDM was evaluated in numerous studies [15][16][17][18][19]. In a 28 year follow up of the original cohort from O'sullivan’s work [20]that determined the OGTT cutoffs for GDM, nearly half of the women with GDM had T2DM later in life [15]. Kjos et al. [16] performed an early 75g OGTT, as early as 5-8 weeks after delivery, in 246 women with GDM. They reported that 19% had an abnormal OGTT - 10% of which were diagnosed with impaired glucose tolerance (IGT) and 9% had T2DM. Vambergue et al. [17] in the Diagest 2 study reported that women with GDM had an 18%, 13.4% and 8.5% incidence of T2DM, IGT and impaired fasting glucose (IFG), respectively, when followed up 6.75 years after delivery. Sivaraman et al. [18] reported that the risk of developing diabetes was 6.9% at five years and 21.1% at ten years following the initial diagnosis of GDM. Chodick et al. [19] reported that the risk of T2DM among women with prior GDM was 15.7% up to 10 years of follow-up. O'sullivan, in 1991, summarized available data and reported a large variance in the risk of postpartum T2DM, ranging from 6% to 60% when evaluated from early as 6 week after delivery to as late as 10 year afterwards[21]. Similar and more recent meta-analysis followed, also recording a large variation in the occurrence of postpartum T2DM. The range of postpartum T2DM was 2.6-70%, in a follow up period of 6 week to 28 years. The cumulative incidence of T2DM increased markedly in the first 5 years after delivery and plateaued after 10 years [22].

What are the risk factors for postpartum T2DM? The large variance in the risk of postpartum T2DM is attributed to the existing risk factors in the studied population. Numerous studies have focused on the factors that determine those at risk to develop future T2DM following a pregnancy with GDM [13-19][23][24][25]. The reported risk factors are summarized in table 1.

Table 1: Risk factor for post partum diabetes
Ethnicity (e.g. African-American, Latino, Native American, Asian American, Pacific Islander)
Age at delivery ≥ 33-35 years
High Parity
Family history of diabetes
Duration of follow up after pregnancy
Testing modality for diagnosing diabetes (e.g. Oral glucose tolerance test, Fasting plasma glucose, Random plasma glucose or Hemoglobin A1C)
Early Diagnosis of gestational diabetes mellitus (< 22-24 weeks)
Severity of gestational diabetes mellitus:
- Degree of hyperglycemia in pregnancy and immediately postpartum
- Total area under the diagnostic Oral glucose tolerance test
- Number of abnormal Oral glucose tolerance test values
- Level of fasting blood glucose on the Oral glucose tolerance test
- Need for pharmacological therapy to achieve glycemic control
- Elevated fasting glucose level during pregnancy
Lifestyle parameters:
- Limited physical activity
- Consumption of dietary fat
- Smoking
Maternal Weight:
- Pre-pregnancy weight and Body Mass Index
- Gestational weight gain
- Postpartum weight retention
Metabolic syndrome parameters at early postpartum:
- Waist circumference of 88cm or higher
- High-density lipoprotein cholesterol > 50mg/dL

How and when to test for postpartum T2DM? Since some cases of GDM are actually T2DM not previously detected and due to the fact that GDM is a risk factor for future onset of T2DM, women with a history of GDM should be screened for diabetes in the early postpartum period and periodically thereafter. Screening for postpartum diabetes can be performed at the time of postpartum follow up, when the maternal metabolic adaptations of pregnancy have subsided. Although there are no long term randomized trials to prove the benefit of such screening it is still advocated for. Studies have evaluated the 75g OGTT vs. FPG as screening tools for postpartum T2DM, consistently finding in favor of the OGTT, suggesting that a postpartum FPG measurement alone is not sensitive enough to classify glucose tolerance status accurately, and that the OGTT identifies a higher proportion of women with diabetes and impaired glucose tolerance[26]. Other tools, such as RPG and A1C have not been evaluated as to their efficacy for postpartum screening. Several organizations have published recommendations for postpartum T2DM screening after a pregnancy complicated by GDM. The American Diabetes Association (ADA)[27] recommends routine postpartum diabetes screening for all women with a history of GDM. Screening may be achieved by hemoglobin A1C, FPG or a 75g OGTT. Screening is recommended 6-12 weeks after delivery, and lifelong screening should be continued at least every 3 years. In contrast to the ADA's recommendations, the American Congress of Obstetricians and Gynecologists (ACOG) [28]support the use of the OGTT, rather than FPG or A1C, as the initial screening immediately after delivery. If initial screening is negative, the long term screening than may be performed by FPG.

Do physicians and patients adhere to post partum testing for T2DM? The short answer to this question is that these guidelines are poorly executed, both by caregivers and patients. Timely testing for diabetes may provide an opportunity to prevent or delay the onset of T2DM, through lifestyle modifications and pharmacologic intervention. Nevertheless, women in the postpartum period are preoccupied with neonatal care and recovery from the delivery, thus, little attention is devoted to testing for T2DM. Although postpartum screening has increased over the last decade, it is still far from ideal. Most estimates of postpartum screening are that approximately third to half of women preform it. In numerous studies [29][30][31][32][33][34][35][36][37][38] estimate that 15% to 80% of the caregivers provide orders to preform postpartum screening. Patient compliance to undergo screening is even more unsatisfactory ranging from 4% to 60%. The screening tools that were used included a wide variety of tests, such as OGTT, FPG, Random plasma glucose (RPG) and HbA1C. Some received no orders for screening but rather referred to primary care physicians for counseling. Only 25-50% of the screening tests were performed in the 6-12 weeks postpartum timeframe[35], and the median time from delivery to the first such testing was 428 days [31]. Older age, nulliparity, Asian or Hispanic ethnicity, higher education, earlier GDM diagnosis, use of diabetes medications during pregnancy and more provider contacts after delivery were positive predictors of postpartum screening. Obesity, higher parity, poor prenatal care and lack of postpartum examinations were associated with lower screening rates [32][33]. These finding have promoted several programs to improve postpartum glucose screening, including staff education, patient care protocols, electronic orders for lab test and computerized reminder systems. These strategies have indeed led to an improvement in postpartum screening [29][39][40][41].

Macrosomia Related Complications

Macrosomia is an absolute definition of a birth weight above 4000-4500g, regardless of the gestational age. In contrast, large for gestational age (LGA) is relative definition of a birth weight above the 90th percentile for a given gestational age, based on sex adjusted growth curves. Maternal diabetes is an independent risk factor for fetal macrosomia and LGA. Even without GDM increasing levels of maternal glycemia, predispose for an increased fetal birth weight, LGA and macrosomia [9][42]. Fetal macrosomia complicates as many as 50% of pregnancies in women with GDM, and a delivery of an infant weighing greater than 4500g occurs 10 times more often in women with diabetes. The rate of macrosomia in women with untreated borderline GDM may be as high as 20% compared to 6% in treated GDM vs. only 2% in those without diabetes [11]. Compared to non-diabetic macrosomia, the macrosomic fetus of a diabetic mother has a higher body fat percentage, thicker skin folds, greater shoulder circumference and smaller head-to-abdominal circumference ratio – all of this suggests that an altered body shape and body composition occurs in GDM related macrosomia[43][44]. This factor may contribute to the higher rate of shoulder dystocia and birth trauma observed in these infants.

Maternal morbidity associated with macrosomia include: increased risk of operative and cesarean deliveries, postpartum hemorrhage, birth trauma and shoulder dystocia. The risk for a cesarean delivery is doubled in cases of macrosomia, and it is attributed mainly to arrested or protracted labor[45]. Although induction of labor at term is successful in diabetic pregnancies in approximately 82% of patients, it is not a useful measure to prevent macrosomia or cesarean delivery, and yields a significantly higher cesarean delivery rate compared to uncomplicated pregnancies[12].The risk for post partum hemorrhage in the presence of macrosomia is also doubled[46].

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