ABSTRACT

The physiologic changes which occur during the reproductive cycle are vast and involve every body system. In this chapter, we will review the metabolic changes that occur during normal pregnancies and those affected by pre-gestational diabetes. Due to the significant overlap in maternal and perinatal risks secondary to pre-gestational diabetes and obesity, we will review the risks of maternal obesity and hyperglycemia on maternal, fetal, and neonatal outcomes. Management of preexisting diabetes in pregnancy will be reviewed in detail including up to date medications and diabetes technologies. Postpartum issues including changes in insulin sensitivity, breastfeeding and contraception for women with preexisting diabetes will be discussed. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

ROLE OF PRECONCEPTION AND INTERPREGNANCY COUNSELING/CARE

In recent years, increasing focus has been placed on improving preconception and inter-pregnancy care for reproductive aged individuals (1,2). Obstetric and perinatal outcomes are improved when an individual with pre-gestational diabetes enters the pregnancy in a medically-optimized state (3–6). Since roughly 50% of pregnancies are unplanned, it is in the patient’s best interest if their team begins discussing contraception and family planning during adolescence and early adulthood, as recommended by the ADA (7). Among those with pre-gestational diabetes, emphasis on importance of strict glycemic control, folic acid supplementation, discontinuation of potentially harmful medications (such as statins, angiotensin converting enzyme [ACE] inhibitors), encouraging weight loss in overweight/obese women and optimization of associated medical conditions, including complications of diabetes, are all important components of preconception care.

Hyperglycemia in the months leading up to conception and through the first trimester confers a significant “dose-dependent” risk of congenital anomalies, including cardiac and skeletal defects, as well as miscarriage (8–10). A hemoglobin A1c value ≤6.0% around the time of conception is associated with a risk for congenital anomalies of 1-3%, similar to the baseline population risk (9). Furthermore, if diabetes is poorly controlled or sequelae such as renal and cardiac disease are present at the time of conception, obstetric risks of preeclampsia, preterm delivery, and stillbirth are also increased (11,12).

We encourage health care providers to view every encounter with an individual of reproductive age as a pre-conception visit (figure 1). Socio-economic barriers including poor health literacy, smoking, being unmarried, lower family income, and poor relationship with their provider are associated with an absence of pre-pregnancy care, so increased efforts must be made to provide avenues to discuss family planning among these patients (13). Some suggested solutions include app-based platforms to engage patients and provide education on diet and lifestyle as well as pharmacy-based surveys to identify individuals who require folic acid supplements or other medication adjustments (14,15).

Figure 1.

Adapted from Wilkie, G. & Leftwich, H. (2020). Optimizing Care Preconception for Women With Diabetes and Obesity. Clinical Obstetrics and Gynecology.

NORMAL GLUCOSE LEVELS IN PREGNANCY

Understanding normal glucose levels in pregnancy is important for setting glycemic targets in women with diabetes. The first change that happens is a fall in fasting glucose levels, which occurs early in the first trimester. In the second and third trimesters, glucose levels rise slightly due to insulin resistance. A careful review of the literature including all available trials using continuous glucose monitors (CGM), plasma glucose samples, and self-monitored blood glucose (SMBG) demonstrated that pregnant women without diabetes (body mass index (BMI) 22-28 kg/m2) during the 3rd trimester (~34 weeks) have on average a fasting blood glucose (FBG) of 71 mg/dl; a 1 hour postprandial (PP) glucose of 109 mg/dl; and a 2 hour value of 99 mg/dl, much lower than the current targets for glycemic control for women with diabetes during pregnancy (16). (See figure 2). Increasing gestational age and maternal BMI affect "normal" glucose levels. A longitudinal study of 32 healthy, normal weight women between 16 weeks’ gestation to 6 weeks postpartum demonstrated a rise in mean glucose levels from 16 weeks (4.57 mmol/l (82.3 mg/dl) to 36 weeks (5.22 mmol/l (94.0 mg/dl) which was maintained at 6 weeks postpartum (5.20 mmol/l (93.7 mg/dl)) using CGM (17). Two-hour postprandial levels were increased rising from 95.7 mg/dl at 16 weeks to a peak of 110.6 mg/dl at 36 weeks. Although fasting blood levels are lower in pregnancy, postprandial glucose levels are slightly elevated which is likely related to the many impaired insulin actions; altered β cell secretion, hepatic gluconeogenesis and placenta derived circulating hormones (18).

Figure 2.

Glucose Levels During Pregnancy

REDUCING RISK OF CONGENITAL ANOMALIES

Hyperglycemia is a known teratogen whether occurring from T1DM or T2DM and can result in complex cardiac defects, CNS anomalies such as anencephaly and spina bifida, skeletal malformations, and genitourinary abnormalities (19,20). A systematic review of 13 observational studies of women with T1DM and T2DM demonstrated that poor glycemic control resulted in a pooled odds ratio of 3.44 (95%CI 2.3-5.15) of a congenital anomaly, 3.23 (CI 1.64- 6.36) of spontaneous loss, and 3.03 (1.87-4.92) of perinatal mortality compared to women with optimal glycemic control (21). Women with a normal A1c at conception and during the first trimester have no increased risk while women with a A1c of 10-12% or a fasting blood glucose >260 mg/dl have up to a 25% risk of major malformations (22,23). A recent analysis of 1,676 deliveries to women with preexisting diabetes between 2009-2018 found a similar significant rate of anomaly especially with increasing A1c taken at the first prenatal visit: women with A1c of 10% had a major congenital anomaly rate of 10% while women with A1c of 13% had a 20% major anomaly rate. The overall anomaly rate was 8% in this modern cohort. Most women in the cohort had T2DM (n=1,449) and fewer had T1DM (n=149), however more women with T1DM had infants with anomalies. The offspring of women with T1DM have higher prevalence of neonatal death (RR 4.56 [95% CI 3.42, 6.07], p < 0.0001) as well as infant death (RR 1.86 [95% CI 1.00, 3.46], p = 0.046) compared to offspring of women without diabetes (113). Periconception A1c >6.6% (adjusted odds ratio [aOR] 1.02 [95% CI 1.00, 1.04], p = 0.01), preconception retinopathy (aOR 2.05 [95% CI 1.04, 4.05], p = 0.04), and lack of preconception folic acid supplementation (aOR 2.52 [95% CI 1.12, 5.65], p = 0.03) were all independently associated with risk of neonatal and infant death (24). Most organizations recommend women achieve an A1c of less than 6.5% prior to conception (25,26). For women with hypoglycemia unawareness, less stringent glycemic targets may need to be used such as an A1c <7.0%. The A1C falls in pregnancy and if it is possible without significant hypoglycemia, an A1c of less than 6% is recommended.

The mechanism of glucose-induced congenital anomalies has not been fully elucidated (27). It has been shown that diabetes-induced fetal abnormalities may be mediated by a number of metabolic disturbances including elevated superoxide dismutase activity, reduced levels of myoinositol and arachidonic acid, and inhibition of the pentose phosphate shunt pathway. Oxidative stress appears to be involved in the etiology of fetal dysmorphogenesis and neural tube defects in the embryos of diabetic mice are also associated with altered expression of genes which control development of the neural tube (28).

Women with T2DM are more likely to be treated for dyslipidemia and hypertension. Chronic hypertension occurs in 13-19% of women with T2DM and many of these will be prescribed an ACE-inhibitor or Angiotensin receptor blocker (ARB) (29). The data on risk for first trimester exposure to ACE inhibitors is conflicting (see nephropathy section). Depending on the indication for use, an informed discussion on the benefits and risks of stopping these agents before pregnancy must occur but they should certainly be stopped as soon as a missed period occurs. The data on teratogenicity of statins for treatment of hypercholesterolemia is also conflicting and is based on animal, not human, studies (30). Pravastatin has had favorable effects on vascular endothelial growth factor in animal studies (31–33). A small multicenter pilot study examining pravastatin in prevention of preeclampsia in high-risk women found that pravastatin was safe when started between 12-16 weeks gestation. There is a large randomized clinical trial of 1,550 women evaluating pravastatin to prevent preeclampsia ongoing currently (ClinicalTrials.gov ID NCT03944512). At this time, current guidelines recommend that statins be stopped prior to pregnancy, but definitely at diagnosis of pregnancy.

INFLUENCE OF METABOLIC CHANGES IN PREGNANCY

Pregnancy is a complex metabolic state that involves dramatic alterations in the hormonal milieu in addition to changes in adipocytes and inflammatory cytokines. There are high levels of estrogen, progesterone, prolactin, cortisol, human chorionic gonadotropin, placental growth hormone, human chorionic somatomammotropin (human placental lactogen), leptin, TNFα, and oxidative stress biomarkers. In addition, decreases in adiponectin worsen maternal insulin resistance in the second trimester, in order to facilitate fuel utilization by the conceptus (34).

Metabolically, the first trimester is characterized by increased insulin sensitivity, which promotes adipose tissue accretion in early pregnancy. What mediates this increased insulin sensitivity remains unclear. Women are at increased risk for hypoglycemia, especially if accompanied by nausea and vomiting in pregnancy. Although most women show an increase in insulin sensitivity between 6-20 weeks’ gestation of pregnancy and report more frequent episodes of hypoglycemia, especially at night, there is a transient increase in insulin resistance very early in pregnancy (prior to 10 weeks), usually followed by increased insulin sensitivity up until 14-20 weeks (35).

In the fasting state, pregnant women deplete their glycogen stores quickly due to the fetoplacental glucose demands, and switch from carbohydrate to fat metabolism within 12 hours, resulting in increased lipolysis and ketone production (36–38). In women without diabetes, the second and third trimesters are characterized by insulin resistance with a 200-300% increase in the insulin response to glucose (39). This serves to meet the metabolic demands of the fetus, which requires 80% of its energy as glucose, while maintaining euglycemia in the mother. The placental and fetal demands for glucose are considerable and approach the equivalent of ~150 grams per day of glucose in the third trimester (37). In addition, the maternal metabolic rate increases by ~150-300 kcal/day in the third trimester, depending on the amount of gestational weight gain in pregnancy. These increased nutritional needs place the mother at risk for ketosis, which occurs much earlier than usual without adequate oral or intravenous nutrients, frequently referred to as "accelerated starvation of pregnancy" (36). See “Diabetic Ketoacidosis in Pregnancy” section for further details.

DIABETES COMPLICATIONS AND TREATMENT OPTIONS IN WOMEN WITH PREGESTATIONAL DIABETES AND THE ROLE OF PRECONCEPTION COUNSELING

Although historically, T1DM has been more prevalent than T2DM in women of child-bearing age, this is changing with increased obesity rates worldwide. The prevalence of prediabetes and diabetes is a burgeoning global epidemic (40,41). In the United States, the prevalence of diabetes among adults between 1980 and 2020 has quadrupled with an estimated 21.9 million adults living with diabetes, including reproductive aged women (41). There was higher prevalence of diabetes among non- Hispanic blacks and Mexican Americans (42). In Canada, the number of women with pre- existing diabetes has increased 50% between 1996 and 2001 with T2DM representing a growing proportion (43). There is limited data on the burden of diabetes during pregnancy in low and middle income countries around the world (44).

Both women with T1DM and T2DM are at increased risk of poor obstetrical outcomes, and both can have improved outcomes with optimized care (5,45). The White Classification (Table 1) was developed decades ago by Priscilla White at the Joslin Clinic to stratify risk of adverse pregnancy outcomes in women with T1DM according to the age of the patient, duration of diabetes, and presence of vascular complications of diabetes. Although recent evidence suggests that the classification does not predict adverse pregnancy outcomes better than taking into account the increased risk of micro- and macrovascular disease (e.g. retinopathy, nephropathy, hypertension, coronary artery disease, etc.), it is still often used in the U.S. to indicate level of risk for adverse pregnancy outcomes (46). Although it was developed to use in women with T1DM rather than T2DM, given the very low prevalence of T2DM in women of childbearing age decades ago when it was first established in 1949, many also apply it to this group of women. ACOG further modified it in 1986 and GDM was added to the classification and designated as A1 (controlled by diet alone) and A2 (controlled by medication). Women with T2DM are at least as high of a risk of pregnancy complications as women with T1DM. The reasons for this may include older age, a higher incidence of obesity, a lower rate of preconception counseling, disadvantaged socioeconomic backgrounds, and the co-existence of the metabolic syndrome including hyperlipidemia, hypertension, and chronic inflammation (29). Furthermore, the causes of pregnancy loss appear to differ in women with T1DM versus T2DM. In one series comparing outcomes, >75% of pregnancy losses in women with T1DM were due to major congenital anomalies or prematurity (47). In women with T2DM, >75% were attributable to stillbirth or chorioamnionitis, suggesting that obesity may play a role.

MANAGEMENT OF PRE-EXISTING DIABETES DURING PREGNANCY

DIABETES MICROVASCULAR AND MACROVASCULAR COMPLICATIONS

Women should be up-to-date on screening for complications of diabetes prior to conceiving. Diabetes care providers should discuss risk of progression of complications during pregnancy especially in women with retinopathy and nephropathy.

DIABETES AND AUTOIMMUNE DISORDERS

HYPERTENSIVE DISORDERS IN PREGNANCY

Individuals with pregestational diabetes are at increased risk of complications of pregnancy secondary to hypertensive disease (51,135). Serum creatinine, AST, ALT, and platelets as well as proteinuria (24-hour collection or random protein to creatinine ratio) should be collected as early as possible in pregnancy to establish a baseline and provide counseling on risks associated with significant proteinuria or renal failure. The updated ACC/AHA categorization of normal and abnormal blood pressure ranges outside of pregnancy have not been adopted in the obstetric population (136). Normal blood pressure values in pregnancy are defined as <140/90 mmHg; blood pressures ≥160/110 mmHg are considered severely elevated and warrant prompt treatment for maternal stroke prevention (137).

Although outside of pregnancy achieving a BP < 120/80 is renal-protective, there are no prospective trials that have demonstrated that achieving this goal improves pregnancy outcomes. Emerging evidence does suggest some elevated risk of preeclampsia, gestational diabetes, low birth weight, and preterm birth with increasing blood pressures >140/90 mmHg (138,139). Establishing blood pressure thresholds at which treatment should be initiated remains challenging due to the competing interests of the mother and fetus (137,140). Relative hypotension increases the risk for poor uteroplacental perfusion and fetal growth restriction, while poorly controlled hypertension is associated with increased risk of stroke, placental abruption and preterm delivery (141–143).

Among individuals with pregestational diabetes and pregestational (chronic or essential) hypertension, blood pressure treatment should be continued or initiated and titrated with a goal value of ~135/85 mmHg (108). A lower goal of 120/80 mmHg should be achieved in the setting of diabetic nephropathy (108). Women with diabetic nephropathy are at extremely high risk of developing preeclampsia which often leads to intrauterine growth restriction and prematurity. Even women with microalbuminuria are at a higher risk of preeclampsia than women without microalbuminuria. Blood pressure control is imperative to try to minimize the deterioration of renal function. Preferred anti-hypertensive agents in pregnancy include calcium channel blockers (Nifedipine, Amlodipine), select beta-blockers (Labetalol), and alpha-2 agonists (Methyldopa) (137). ACE-inhibitors and ARBs are contraindicated in all trimesters of pregnancy and diuretics are reserved for the treatment of pulmonary edema due to concerns that further decreasing the intravascular volume with diuretics could further compromise tissue and placental perfusion. All classes of hypertensive agents are safe in lactating mothers in the postpartum period (144).

After 20-24 weeks gestation, elevated blood pressure should prompt evaluation for preeclampsia. The etiology and pathophysiology of preeclampsia continues to be incompletely characterized, though evidence strongly suggests the microvascular disease may begin early in pregnancy at the time of implantation and manifest in the second or third trimesters (137,145). As a result, treatment of elevated blood pressure has not been shown to prevent preeclampsia. Since 2014, the US Preventative Task Force recommends low dose aspirin (81 mg) daily after 12 weeks’ gestation for those at high risk of preeclampsia who do not have a risk or contraindication to aspirin use (137,146,147). High risk factors include pregestational diabetes, chronic hypertension, history of preeclampsia, renal disease and should prompt low-dose aspirin initiation in the second trimester; ≥2 moderate risk factors such as nulliparity, obesity, age ≥35, family history of preeclampsia, or personal socioeconomic or poor obstetric history should also prompt use of low-dose aspirin (146,147).

FETAL SURVEILLANCE

Maternal hyperglycemia has temporal effects on the developing pregnancy based on gestational age at exposure (6,51,148). Hyperglycemia around the time of conception and early pregnancy is associated with increased risk of miscarriage, congenital anomalies, with cardiac malformations being most common, as well as placental dysfunction related to “end-organ damage” which could lead to growth-restricted fetuses (6). An early dating ultrasound in the first trimester is recommended to confirm gestational age of the fetus and to coordinate detailed anatomic survey at 18-20 weeks gestation. A fetal echocardiogram should be offered at 20-22 weeks if the A1c was elevated (>6.5-7.0) during the first trimester (148).

Later in pregnancy, hyperglycemia is associated with excessive weight gain in the fetus, with abdominal circumference and shoulder girth primarily measuring larger than expected for gestational age (149–151). Consideration can be made for serial ultrasound evaluation of fetal growth if there is suspicion of abnormal growth, though at minimum, a growth ultrasound in the third trimester should be performed (51). Serial ultrasounds are used to monitor growth and if the estimated fetal weight is less than the 10th percentile (small for gestational age (SGA)), umbilical artery Doppler velocimetry as an adjunct antenatal test is recommended to estimate the degree of uteroplacental insufficiency, predict poor obstetric outcome and assist in determining the optimal timing of delivery (152).

The association of pregestational diabetes and increased risk for stillbirth was documented as early as the 1950s, leading to a historical practice of intense monitoring with weekly contraction stress test and fetal lung maturity testing prior to delivery (153). Data emerged identifying congenital anomalies as a key factor in stillbirth; with increased focus on improved glycemic control in early pregnancy, stillbirth rates were reduced significantly (154,155). Contemporary practice typically consists of non-stress testing 1-2 times per week, with or without biophysical profile testing, with initiation around 32 weeks gestation (156). However, due to the increased risk of uteroplacental insufficiency and intrauterine fetal demise in patients with longstanding T1 DM, especially in those women with microvascular disease, diabetic nephropathy, hypertension, or evidence of poor intrauterine growth, fetal surveillance may be recommended earlier. While comorbidities such as poor glycemic control, vascular complications, hypertension, or nephropathy have a summative effect on risk for perinatal complications, antenatal testing is recommended for all patients with pregestational diabetes (156). A positive correlation between HbA1c and stillbirth is observed- the higher the HbA1c >6.5%, the higher the risk (157,158). Fetal hypoxia and cardiac dysfunction secondary to poor glycemic control are probably the most important pathogenic factors in stillbirths among pregnant women with diabetes (159).

LABOR AND DELIVERY

Delivery management and the timing of delivery is made according to maternal well-being, the degree of glycemic control, the presence of diabetic complications, growth of the fetus, evidence of uteroplacental insufficiency, and the results of fetal surveillance (160). A third trimester anesthesia consultation should be considered in the setting of concerns about cardiac dysfunction or ischemic heart disease, pulmonary hypertension from sleep apnea, hypertension, thromboembolic risks, potential desaturation while laying supine in women with severe obesity, or the possibility of difficult epidural placement or intubations.

Optimal delivery timing in the setting of pregestational diabetes requires a balance of perinatal risks, typically stillbirth versus risks of prematurity. In general, patients with reassuring fetal monitoring can continue a pregnancy until 39 weeks gestation, though expectant management beyond the estimated due date is not advised (161). Concurrent medical complications of mother or fetus may take precedent and require consideration for delivery prior to 39 weeks (161). When late preterm delivery is necessary, it should not be delayed for administration of corticosteroids for fetal lung maturity, as this practice has not been evaluated in pregnancies complicated by pregestational diabetes, and neonatal hypoglycemia may result (162).

With regards to route of delivery, a vaginal delivery is preferred for women with diabetes due to the increased maternal morbidity of cesarean delivery such as infection, thromboembolic disease, and longer recovery time. Nevertheless, when the estimated fetal weight is >4500g in the setting of diabetes, an elective cesarean delivery may be offered (163).

The target range for glycemic control during labor and at the time of delivery is 70-125 mg/dL; maintenance in this physiologic range aims to reduce to risk of neonatal hypoglycemia (164). To achieve this goal, most women with preexisting diabetes require management with an insulin drip and a dextrose infusion, though laboring individuals can eat and continue their home insulin regimen prior to admission. Ideally scheduled cesarean deliveries will occur in the morning, so that patients can simply reduce their morning long-acting insulin dosing by half on the day of surgery, though consideration can be made to skip it in a patient with well controlled T2DM who hadn’t required medication prior to pregnancy. An individual being admitted for scheduled induction of labor can be instructed to reduce long-acting insulin dosing for both the night before and morning of the induction (165). Once the patient is eating, the insulin drip can be discontinued and subcutaneous insulin resumed. Alternative management options include ongoing use of insulin pump or subcutaneous insulin, though both often pose logistic challenges due to the unpredictable length of labor. Prevention of neonatal hypoglycemia must be weighed against risk of maternal hypoglycemia during labor.

With the delivery of the placenta, insulin requirements drop in an acute and dramatic fashion, with most women needing roughly 10-30% less than their pre-pregnancy insulin doses or 1/2 to 1/3 of their third trimester insulin dosages; some women require no insulin for the first 24-48 hours (164). A glucose goal of 100-180 mg/dl postpartum seems prudent to avoid hypoglycemia given the high demands in caring for an infant and especially in nursing women as the increased caloric demands of lactation are known to reduce insulin requirements.

POSTPARTUM CARE AND CONCERNS FOR PREGESTATIONAL DIABETES

The postpartum care for mothers with diabetes should include counseling on a number of critical issues including maintenance of glycemic control, diet, exercise, weight loss, blood pressure management, breastfeeding, contraception/future pregnancy planning, and postpartum thyroiditis (for T1 DM). It has been demonstrated that the majority of women with pre-existing diabetes, even those who have been extremely adherent and who have had optimal glycemic control during pregnancy, have a dramatic worsening of their glucose control after the birth of their infant (178,179). Unfortunately, individuals utilizing public insurance often lose access as early as 6 weeks postpartum. Historically, the postpartum period has been relatively neglected, as both the new mother and her physician relax their vigilance. However, this period offers a unique opportunity to institute health habits that could have highly beneficial effects on the quality of life of both the mother and her infant and potentially achieve optimal glycemic control prior to a subsequent pregnancy.

Home glucose monitoring should be continued vigilantly in the postpartum period because insulin requirements drop almost immediately and often dramatically at this time, increasing the risk of hypoglycemia. Women with T1DM often need to decrease their third trimester insulin dosages by at least 50%, often to less than pre-pregnancy doses, immediately after delivery; they may have a "honeymoon" period for several days in which their insulin requirements are minimal. Some estimates of insulin requirements postpartum suggest that women may require as little as 60% of their pre-pregnancy doses, and requirements continue to be less than pre- pregnancy doses while breastfeeding (180). For women on an insulin pump, the postpartum basal rates can be discussed and preprogrammed prior to delivery to allow a seamless transition to the lower doses following delivery (181). If well controlled prior to pregnancy, pre- pregnancy insulin delivery settings can serve as an excellent starting point for the postpartum period, with an expected decrease in basal rates by 14% and increase in carb ratios by 10% (181).

Women with T1DM have been reported to have a between 3-25% incidence of postpartum thyroiditis (182). Hyperthyroidism can occur in the 2–4-month postpartum period and hypothyroidism may present in the 4–8-month period. Given the significance of this disorder, a TSH measurement should be offered at 3 and 6 months postpartum and before this time if a patient has symptoms (124).

CONTRACEPTION

Starting at puberty, it is recommended to provide women with diabetes preconception counseling including discussion of options for contraceptive use based on the Medical Eligibility Criteria (MEC) according to WHO and CDC (7,194). Counseling on contraceptive choices should be patient-centered and focused on the short- and long-term reproductive goals of the patient, taking into consideration the alternative-no contraception- and associated individualized risks of carrying a pregnancy to term. A meta-analysis found that low-income women with diabetes had low rates of postpartum birth control and more often were offered permanent contraception rather than reversible options (195).

Taken in isolation, a diagnosis of diabetes without vascular complications is compatible with all hormonal and non-hormonal contraception options: copper intrauterine device, levonorgestrel-releasing IUD, progestin implant, depo medroxyprogesterone acetate, progestin only pills, and combined estrogen-progestin methods (194). Evidence of vascular disease is a contraindication to combined hormonal contraception and depo medroxyprogesterone acetate (194). A large study recently found an overall low risk of venous thromboembolism among women with T1DM and T2DM (196). Concurrent conditions and habits such as poorly controlled hypertension, hypertriglyceridemia, or smoking increase the risk of venous thromboembolic events (197). Systematic reviews failed to find sufficient evidence to assess whether progestogen-only and combined contraceptives differ from non-hormonal contraceptives in diabetes control, lipid metabolism, and complications in women with pre-existing diabetes (198,199).

Long-acting reversible contraception (LARC) methods lasting 3-10 years include copper and hormonal intrauterine devices as well as progestin implants. There is no increase in pelvic inflammatory disease with the use of intrauterine devices in women with well controlled T1DM or T2DM after the post-insertion period. Immediate postpartum implants and IUDs are becoming increasingly available to patients who desire LARCs, and are effective in spacing pregnancies in high risk populations (200). For women who have completed childbearing and desire permanent sterilization, laparoscopic methods are safe and effective (201).

OBESITY IN PREGNANCY

Obesity alone or accompanied by Type 1 diabetes (T1DM), Type 2 diabetes (T2DM) or gestational diabetes (GDM) carries significant risks to both the mother and the infant, and obesity is the leading health concern in pregnant women (202–204). By the most recent NHANES statistics in women over age 20, 57% of black women, 44% of Hispanic or Mexican American women, and 40% of white women are obese (205). Independent of preexisting diabetes or GDM, obesity increases the maternal risks of hypertensive disorders, non-alcoholic fatty liver disease (NAFLD), proteinuria, gall bladder disease, aspiration pneumonia, thromboembolism, sleep apnea, cardiomyopathy, and pulmonary edema (203,206). In addition, it increases the risk of induction of labor, failed induction of labor, cesarean delivery, multiple anesthesia complications, postoperative infections including endometritis, wound dehiscence, postpartum hemorrhage, venous thromboembolism, postpartum depression, and lactation failure. Maternal obesity independently increases the risk of first trimester loss, stillbirth, recurrent pregnancy losses, and congenital malformations including central nervous system (CNS), cardiac, and gastrointestinal defects and cleft palate, shoulder dystocia, meconium aspiration, and impaired fetal growth including macrosomia. Most significantly, obesity increases the risk of perinatal mortality (202). Because so many women with T2DM are also obese, all of these complications increase the risk of poor pregnancy outcomes in this population. The majority (50-60%) of women who are overweight or obese prior to pregnancy gain more than the recommended amount of gestational weight by the Institute of Medicine guidelines (207,208). This results in higher weight retention postpartum and higher pre-pregnancy weight for subsequent pregnancies.

Obesity is an independent risk factor for congenital anomalies including spina bifida, neural tube defects, cardiac defects, cleft lip and palate, and limb reduction anomalies (209). Several reports have demonstrated an association of maternal BMI with neural tube defects and possibly other congenital anomalies (210). One study concluded that for every unit increase in BMI the relative risk of a neural tube defect increased 7% (210). In addition to an increased anomaly risk with maternal obesity, it is well known that detection of fetal anomalies in first and second trimester is reduced by 20% due to difficulty in adequate visualization in the setting of maternal obesity (211,212). There is conflicting evidence on the role of folic acid in these obesity-associated congenital anomalies (213–216).

Obese women with normal glucose tolerance on a controlled diet have higher glycemic patterns throughout the day and night by CGM compared to normal weight women both early and late in pregnancy (217, 218,219) The glucose area under the curve (AUC) was higher in the obese women both early and late in pregnancy on a controlled diet as were all glycemic values throughout the day and night. The mean 1-hour postprandial glucose during late pregnancy by CGM was 115 versus 102 mg/dl in the obese and normal weight women respectively and the mean 2-hour postprandial values were 107 mg/dl versus 96 mg/dl, respectively, both still much lower than current therapeutic targets (<140 mg/dl at 1 hour; < 120 mg/dl at 2 hours).

Women with Class III obesity (BMI>40) actually have improved pregnancy outcomes if they undergo bariatric surgery before becoming pregnant given such surgery decreases insulin resistance resulting in less diabetes, hypertension, and macrosomia compared to those who have not had the surgery (218,219). In any woman who has had prior bariatric surgery, it has been shown in systematic review to reduce the rate of gestational diabetes and preeclampsia in future pregnancies, however many studies are confounded given 80% of patients post bariatric surgery remain obese (220),. Following bariatric surgery, pregnancy should not be considered for 12-18 months post-operatively and after the rapid weight loss phase has been completed. Close attention to nutritional deficiencies must be maintained, especially with fat soluble vitamins D and K as well as folate, iron, thiamine, and B12. In a study of a cohort of infants born to obese women who had bariatric surgery, the offspring had improved fasting insulin levels and reduced measures of insulin resistance compared to siblings born prior to bariatric surgery (221).

MEDICAL NUTRITION THERAPY, EXERCISE AND WEIGHT GAIN RECOMMENDATIONS FOR WOMEN WITH DIABETES OR OBESITY

Currently, there is no consensus on the ideal macronutrient prescription for pregnant women or women with GDM, and there is concern that significant restriction of carbohydrate (33- 40% of total calories) leads to increased fat intake given protein intake is usually fairly constant at 15-20% (26,80,222). It is also important to asses intake along with energy requirements which is known to increase in pregnancy by approximately 200, 300, and 400 kcal/d in the first, second, and third trimesters, respectively, but these values vary depending on BMI, total energy expenditure, and physical activity (223). Women with pre-existing diabetes and GDM should receive individualized medical nutrition therapy (MNT) as needed to achieve treatment goals.

Pregravid BMI should be assessed and gestational weight gain (GWG) recommendations should be consistent with the current Institute of Medicine (IOM) weight gain guidelines (See Table 3) due to adverse maternal, fetal and neonatal outcomes (224). However, there are many trials which support no weight gain for women with a BMI of ≥30 kg/m2 with improved pregnancy outcomes and the lack of weight gain or even modest weight loss, did not increase the risk for small for gestational age (SGA) infants in the obese cohort. Further, targeting GWG to the lower range of the IOM guidelines (~11 kg or 25 lbs. for normal weight women; ~7 kg or 15 lbs. for overweight women; and 5 kg (11 lbs.) for women with Class 1 obesity (BMI 30-34 kg/m2).9 kg/m2) has been shown in many trials to decrease the risk of preeclampsia, cesarean delivery, GDM, and postpartum weight retention (225). This is an increasing public health concern given risks of excessive weight gain (greater than IOM recommendations) including cesarean deliveries, post-partum weight retention for the mother, large for gestational age infants, macrosomia, and childhood overweight or obesity for the offspring (223). Obese women are at increased risk of venous thromboembolism postpartum, and this risk is augmented in those who have had a cesarean section, resulting in ACOG’s recommendation for pneumatic sequential compression devices for those who have had cesarean section (226–228).

There is also increasing evidence that overweight or obese women with GDM may have improved pregnancy outcomes with less need for insulin if they gain weight less than the IOM recommendations without appreciably increasing the risk of SGA (229–231). For obese women, ~25 kcal/kg rather than 30 kcal/kg is currently recommended (232). However, other investigators would argue for a lower caloric intake (1600-1800 calories/day), which does not appear to increase ketone production (233).

The diet should be culturally appropriate and women should consume at least 150 grams of carbohydrate, primarily as complex carbohydrate and limit simple carbohydrates, especially those with high glycemic indices (80). Protein intake should be at least 1.1 g/kg/day (15-20% of total calories) unless patients have severe renal disease. Patients should be taught to control fat intake and to limit saturated fat to <10-15% of energy intake, trans fats to the minimal amount possible, and encourage consumption of the n-3 unsaturated fatty acids that supply a DHA intake of at least 200 mg/day (22). Diets high in saturated fat have been shown to worsen insulin resistance, provide excess TGs and FFAs for fetal fat accretion, increase inflammation, and have been implicated in adverse fetal programming effects on the offspring (see risk to offspring above). A fiber intake of at least 28 g/day is advised and the use of artificial sweeteners, other than saccharin, are deemed safe in pregnancy when used in moderation (23).

For normal weight women with T1DM with appropriate gestational weight gain, carbohydrate and calorie restriction may not be necessary as long as it is appropriately covered by insulin. Emphasizing consistent timing of meals with at least a bedtime snack to minimize hypoglycemia in proper relation to insulin doses is important. Many patients who dose prandial insulin based on an insulin to carbohydrate ratio are skilled at carbohydrate counting.

Exercise is an important component of healthy lifestyle and is recommended in pregnancy by ACOG, the ADA, and Society of Obstetricians and Gynecologists of Canada (25,234). The U.S. Department of Health and Human Services issued physical activity guidelines for Americans and recommend healthy pregnant and postpartum women receive at least 150 minutes per week of moderate-intensity aerobic activity (i.e., equivalent to brisk walking) (235). A large meta-analysis of all RCTs on diet and physical activity, which evaluated RCTs (using diet only n=13, physical activity n=18 or both n=13) concluded that dietary therapy was more effective in decreasing excess GWG and adverse pregnancy outcomes compared to physical activity (236). However, there was data suggesting that physical activity may decrease the risk of LGA infants (LGA, >90^th percentile). There was no increase in SGA infants (SGA; <10^th percentile) with physical activity. Submaximal exertion (≤70% maximal aerobic activity) does not appear to affect the fetal heart rate and although high intensity at maximal exertion has not been linked to adverse pregnancy outcomes, transient fetal bradycardia and shunting of blood flow away from the placenta and to exercising muscles has been observed with maximal exertion. Observational studies of women who exercise during pregnancy have shown benefits such as decreased GDM, cesarean and operative vaginal delivery and postpartum recovery time, although evidence from RCTs is limited (237,238).

Some data suggest that women who continued endurance exercise until term gained less weight and delivered slightly earlier than women who stopped at 28 weeks but they had a lower incidence of cesarean deliveries, shorter active labors, and fewer fetuses with intolerance of labor (239). Babies weighing less were born to women who continued endurance exercise during pregnancy compared with a group of women who reduced their exercise after the 20th week (3.39 kg versus 3.81 kg). Contraindications for a controlled exercise program include women at risk for preterm labor or delivery or any obstetric or medical conditions predisposing to growth restriction.

RISK TO OFFSPRING FROM AN INTRAUTERINE ENVIRONMENT CHARACTERIZED BY DIABETES OR OBESITY

CONCLUSION

The obstetric outlook for pregnancy in women with pre-existing diabetes has improved over the last century and has the potential to continue to improve as rapid advances in diabetes management, fetal surveillance, and neonatal care emerge. However, the greatest challenge health care providers face is the growing number of women developing GDM and T2DM as the obesity epidemic increases affecting women prior to pregnancy. In addition, the prevalence of T1DM is increasing globally. Furthermore, obesity-related complications exert a further deleterious effect on pregnancy outcomes. 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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