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. 

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

Treatment Options in Achieving Glycemic Control

All women with T1DM and T2DM should target an A1c of <6.5% preconception when possible. For women with T2DM on oral or noninsulin injectable agents, consider switching to insulin prior to pregnancy, even in women with goal glycemic control.

ORAL AND NON-INSULIN INJECTABLE GLYCEMIC LOWERING AGENTS

No oral hypoglycemics are approved for pre-existing diabetes in pregnancy although glyburide and metformin have been used in multiple RCTs for GDM. (Please see Endotext Gestational Diabetes chapter). There is no evidence that exposure to glyburide or metformin in first trimester are teratogenic, but both do cross the placenta, metformin substantially more than glyburide (48–50).  There appear to be no metformin receptors in the embryo but there are metformin receptors in the fetus. There is minimal data on thiazolidinediones or meglitinides and no data on incretin-based therapies (dipeptidyl peptidase [DPP]-4 inhibitors and glucagon-like peptide [GLP]-1 analogues). It is recommended that women with T2DM who are actively trying to become pregnant should be switched from oral or noninsulin injectable hypoglycemic agents to insulin prior to conception if possible. This rationale is based on the fact that it may take some time to determine the ideal insulin dose prior to the critical time of embryogenesis. Furthermore, oral hypoglycemic agents alone are likely to fail to control glucoses during pregnancy given the insulin resistance of pregnancy. However, women who conceive on any oral agents should not stop them until they can be switched effectively to insulin because hyperglycemia is potentially much more dangerous than any of the current available therapies to treat diabetes (51). There are potential concerns for sodium-glucose cotransporter-2 (SGLT2) inhibitors in pregnancy based on a case of profound polyuria in a pregnant patient with familial renal glycosuria (mutation in gene encoding SGLT2 transporter) (52).  Furthermore, pregnancy causes polyuria and glycosuria normally due to increased glomerular filtration rate, and it is unknown whether SGLT2-inhibitors would provide additional efficacy. Metformin is sometimes used preconception and throughout the first trimester in women with polycystic ovary syndrome (PCOS) not for glycemic control but to improve fertility and prevent early miscarriage. Recent guidelines do not recommend metformin as a first line agent for ovulation induction in women with PCOS and infertility, but rather letrozole. There is no known teratogenic effect of metformin when used in women with PCOS (50,53,54).

Oral agents may be considered if insulin is not a possible treatment in special situations, such as patient declining insulin therapy due to injection phobia, history of intravenous drug use, or cost. For women with preexisting diabetes who decline insulin therapy, oral agents are preferable to no therapy. Their use is unlikely to result in adverse outcomes from the agents themselves unless hyperglycemia is inadequately controlled. There are few studies looking at metformin use among pregnant women with T2DM (55,56).  One study of 106 women with T2DM receiving metformin during pregnancy compared to insulin alone treatment found a large failure rate of metformin monotherapy (84.9% of metformin only group required addition of insulin), less neonatal hypoglycemia (p=<0.01), less NICU stay >24 hours (p=o.o1), less maternal weight gain (p<0.01), less gestational hypertension (p=0.029); however, SGA infants were more common in the metformin group compared to the insulin only group (p<-0.01) (55).  In a small randomized pilot study of 19 pregnant women with T2DM (8 receiving metformin and 11 receiving insulin), there was no significant difference in glycemic control, NICU stay, cesarean section, need for neonatal dextrose between the two groups (56). The Metformin in Women with Type 2 Diabetes in Pregnancy Trial (MiTy) is currently enrolling pregnant women with T2DM who are on insulin, randomizing them to metformin or placebo, and should be a very helpful in evaluation of maternal and neonatal outcomes (57).

INSULIN USE IN PREGNANCY

Given lack of long-term safety data on metformin use in pregnancy, the American Diabetes Association (ADA) and American College of Obstetricians and Gynecologists (ACOG) recommend insulin as the first line agent for treatment of diabetes in pregnancy, including preexisting diabetes and GDM (25,26).  Insulin therapy must be individualized for women with preexisting diabetes in pregnancy.

Basal Insulin

Basal insulin is given 1-2 times daily or via a continuous insulin infusion pump. Although there are less safety data on the use of long-acting insulin analogues in pregnancy, they do appear to be safe. There were early concerns that glargine may have a more pronounced mitogenic effect due to the higher affinity to the IGF-1 receptor. A recent meta-analysis did not demonstrate any difference in maternal or fetal outcomes in pregnancies exposed to glargine vs. NPH (58).  Early case reports raised concern over progression of retinopathy with glargine, however recent studies in the non-pregnant population have not shown this. The efficacy and safety of detemir has been confirmed in a multinational RCT involving 371 women, approximately half of whom were enrolled prior to pregnancy (59,60).  There were no differences in any of the maternal or neonatal outcomes. Overall glycemic control was slightly better with detemir compared to NPH, with lower fasting glucose, less risk of maternal hypoglycemia and slightly reduced A1c levels. There have been no studies looking at safety of newer basal insulins such as degludec (Tresiba), glargine U300 (Toujeo), and the biosimilar glargine (Basaglar). Basal insulin may be provided as two doses of NPH or with one of the long-acting analogues - detemir preferred over glargine. The absence of a peak with glargine and detemir may result in inadequate control of fasting glucoses, which can often be ameliorated by the use of NPH before bedtime to take advantage of its 8-hour peak. The evening dose of NPH usually needs to be moved to bedtime to avoid nocturnal hypoglycemia and prevent fasting hyperglycemia.  A recent study evaluating detemir vs NPH in 108 women with type 2 diabetes during pregnancy found improved neonatal and maternal outcomes with use of detemir. Women using detemir compared to NPH had improved composite outcome of adverse neonatal outcomes, shoulder dystocia, large for gestational age, neonatal intensive care unit stay, respiratory distress, or hypoglycemia as well as improved maternal outcomes, including less hypoglycemia and fewer hypertensive disorders.  Although women with T2DM may sometimes achieve adequate glycemic control with twice-daily injections, perinatal outcomes were better with four times daily compared to twice-daily regimens in both women with T2DM and GDM in a randomized study (61).

Bolus Insulin

Bolus insulin dosing is provided with short acting insulin with doses calculated based on pre-meal glucose and carbohydrate intake using a correction factor and insulin to carbohydrate ratio (62). For women that do not know how to count carbohydrates, fixed meal-time insulin dosing can be prescribed. Lispro and aspart have been used in multiple trials in pregnancy, and their safety and efficacy are well-established. Lispro and aspart are preferred  to regular insulin due to improvement in postprandial glycemia and reduced hypoglycemia, while fetal outcomes were similar (63,64). Patient satisfaction has also been higher for patients using lispro or aspart compared to regular insulin. There are no data on short acting insulin glulisine, ultra-fast acting aspart, nor the recently FDA approved ultra-fast acting insulin lispro in pregnancy. Lispro or aspart insulin may be especially helpful in women with hyperemesis or gastroparesis because they can be dosed after a successful meal and still be effective. It has been demonstrated that rapid acting insulins may take longer to reach maximal concentrations (49 [37-55] vs 71 [52-108] min) in late gestation (65).  Thus, for some women it may be necessary to take mealtime insulin 15-30 minutes prior to the start of a meal (termed pre-bolusing).

CONTINUOUS SUBCUTANEOUS INSULIN INFUSION (CSII) OR INSULIN PUMP THERAPY

Many patients with T1DM or long-standing T2DM require multiple daily injections (4-5 injections per day) or an insulin pump to achieve optimal glycemic control during pregnancy. Many women with T1DM use continuous insulin infusion pumps and CGM during pregnancy (66).  CGM will be reviewed in detail below. There have been several studies showing insulin pump use is safe in pregnancy. In a large multicenter trial of women with T1DM during pregnancy, there was improved A1c both in the first trimester as well as in the third trimester and no difference in rates of diabetic ketoacidosis (DKA) or severe hypoglycemia compared to women with T1DM treated with multiple daily injections during pregnancy (67).  Most studies have shown improvement in glycemic control, but not all (68–70).  Most studies have shown similar maternal and perinatal outcomes (71). An analysis of data from 248 women with T1DM enrolled in the Continuous Glucose Monitoring in Women With Type 1 Diabetes in Pregnancy Trial (CONCEPTT) showed that women using MDI therapy versus insulin pump therapy had similar first trimester glycemia but MDI users had lower glycemia at 34 weeks than insulin pump users and were more likely to achieve target A1c. MDI users were more likely to achieve target A1c (p = 0.009 and p = 0.001, respectively).  In this analysis, pump users had lower hypoglycemia fear but increased NICU admissions, neonatal hypoglycemia, and hypertensive disorders compared to MDI users. There are no definitive studies favoring continuous subcutaneous insulin infusion (insulin pump) over multiple daily injections (70,72,73).  RCTs of multiple daily injections versus the insulin pump generally showed equivalent glycemic control and perinatal outcomes. Insulin pumps can be especially useful for patients with nocturnal hypoglycemia, gastroparesis, or a prominent dawn phenomenon(72). 

Disadvantages of insulin pump therapy include cost and the risk for marked hyperglycemia or DKA as a consequence of insulin delivery failure from a kinked catheter or from infusion site problems, although rare (74). Patients should be educated on how to quickly recognize and manage insulin pump failure. Therefore, it may be optimal to begin pump therapy before pregnancy due to the steep learning curve involved with its use and the need to continually adjust basal and bolus settings due to the changing insulin resistance in pregnancy. However, in motivated pregnant patients with a multidisciplinary team of diabetes education specialists and pump trainers, insulin pump initiation is safe in pregnancy. Several studies demonstrate the significant changes in bolus more than basal insulin requirements during pregnancy which should be understood to achieve optimal glycemic control (71,75). 

A recently published paper on the use of a closed loop pump in pregnancy was very favorable but a pregnancy–specific algorithm was required (76).  There are currently two FDA-approved hybrid closed loop systems on the market in the United States, the Medtronic 670G with recent upgrade to the 770G and the Tandem T-slim X2 with Control IQ technology. Neither semi closed loop system is approved for use in pregnancy, partly due to the lack of large safety trials and that each has an algorithm that fixes the target glucose at higher levels than goal glycemia in pregnancy. With the rise in popularity of these automated insulin pump systems, women are becoming pregnant using these automated insulin pumps and using off label in pregnancy. A discussion needs to occur with their diabetes care team about continuing to use the pump off-label in pregnancy or switching to manual (or non-automated) mode. A case series of three women using the Medtronic 670G in pregnancy in auto mode at varying times and durations has shown some improvement in time in range when in auto mode although the women did not achieve the A1c target in pregnancy (<6%). This case series is too small to evaluate obstetric or neonatal outcomes and highlights the need for larger trials on automated insulin delivery systems in pregnancy. Well-designed randomized clinical trials with appropriate glycemic control outcomes (using CGM) and adequate power to examine obstetric and neonatal outcomes are needed to make strong recommendations regarding the benefits of hybrid closed loop insulin pump therapy in pregnancy. However, recruitment to such trials is challenging. The next generation of closed loop pumps that allow for customized lower targets for pregnancy and are responsive to the fairly rapid changes in insulin sensitivity from week to week are anticipated in the near future (77). There have been few studies evaluating hybrid closed loop insulin delivery systems in pregnancy. A randomized study evaluating hybrid closed loop therapy in women with T1DM during pregnancy vs sensor-augmented pump therapy (SAPT) showed that hybrid closed loop insulin pump therapy achieved a higher percentage of glucose time in range compared to patients using SAPT alone (76). This study included a subset of women who continued closed loop therapy through labor and delivery, and these women achieved a high percentage of glucose in range during hospitalization and delivery. In this study, there were no significant differences in time in hypoglycemic range or adverse outcomes between the hybrid closed loop group and SAPT group. In one study using intermittent blinded CGM in which the information was used by the health care team to adjust insulin treatment, there was improved glycemic control in the third trimester and a reduction in macrosomia rates (78). In another study of intermittent use of real time CGM (where glucose results are simultaneously displayed) there was no improvement of glycemic control or macrosomia (79).

With the burgeoning technology options for management of diabetes during pregnancy, research on hybrid closed loop insulin pump technologies during pregnancy is needed. There are currently a couple of studies of hybrid closed loop systems in pregnancy, the Pregnancy Intervention with a Closed Loop System and the Automated Insulin Delivery Among Pregnant women with T1D.

Importance of Glycemic Control

Failure to achieve optimal control in early pregnancy may have teratogenic effects in the first 3- 10 weeks of gestation or lead to early fetal loss. Poor glycemic control later in pregnancy increases the risk of intrauterine fetal demise, macrosomia, cardiac septal enlargement in the fetus, perinatal death, and metabolic complications such as hypoglycemia in the newborn. Target glucose values for fasting and postprandial times should be discussed with the patient. Current guidelines are that fasting and premeal blood glucose should be <95 mg/dl, the 1 hour postprandial glucose <130-140mg/dl and the 2-hour postprandial glucose <120mg/dl (80).

Although a review of the literature suggests that the mean FPG, 1-hour PP, and 2-hour PP +/- 1 SD glucoses are significantly lower in normal weight women in the 3rd trimester (FPG ~71 +/- 8 mg/dl; 1-hour PP ~109 +/- 13 mg/dl; 2-hour PP 99 +/- 10 mg) than current therapeutic targets, (19), no RCTs have been completed to determine whether lowering the therapeutic targets results in more favorable pregnancy outcomes or decreases large for gestation age (LGA). A prospective study in pregnant women with T1DM showed less preeclampsia with glucose targets of fasting <5.1 mmol/L (92 mg/dl), preprandial <6.0 mmol/L (108 mg/dl) and 1 hour postprandial <7.8 mmol/L (140 mg/dl) (81). An A1c should be done at the first visit and every 1-3 months thereafter depending on if at target or not (<6% if possible with minimal hypoglycemia) (25,51).  Additional labs and exams recommended for women with preexisting diabetes during pregnancy are summarized in Table 2.

The risk of maternal hypoglycemia needs to be weighed with the risk of maternal hyperglycemia. Maternal hypoglycemia is common and often severe in pregnancy in women with T1DM.  During the first trimester, before the placenta increases the production of hormones, nausea and increased insulin sensitivity may place the mother at risk for hypoglycemia. Women must be counseled that their insulin requirements in the first trimester are likely to decrease by 10-20% (82). This is especially true at night when prolonged fasting and continuous fetal-placental glucose utilization places the woman at even a higher risk for hypoglycemia. One of the highest risk periods for severe hypoglycemia is between midnight and 8:00 a.m. Pregnant women with diabetes complicated by gastroparesis or hyperemesis gravidarum are at the greatest risk for daytime hypoglycemia. In a series of 84 pregnant women with T1DM, hypoglycemia requiring assistance from another person occurred in 71% of patients with a peak incidence at 10-15 weeks gestation (83).  One third of subjects had a least one severe episode resulting in seizures, loss of consciousness, or injury. There are also data to suggest that the counterregulatory hormonal responses to hypoglycemia, particularly growth hormone and epinephrine, are diminished in pregnancy (84,85). This risk of hypoglycemia may be ameliorated if efforts are made to achieve good glycemic control preconception, by the use of analogue insulins, and with the use of CGM (86,87) Insulin pumps with or without CGM may help achieve glycemic targets without increasing hypoglycemia (67,76,88). 

Use of CGM especially with real-time sensor glucose data shared with a partner or loved one has been shown to reduce fear of hypoglycemia in pregnancy. The risk of hypoglycemia is also present in pregnant women with T2DM, but tends to be less so than in women with T1DM (89). The risk of hypoglycemia to the fetus is difficult to study but animal studies indicate that hypoglycemia is potentially teratogenic during organogenesis, which would translate into a gestational age between 3-10 weeks in the human (90). Exposure to hypoglycemia in utero may have long-term effects on the offspring including neuropsychological defects, so intensive efforts must be made to avoid it (90). To help reduce risk of nocturnal hypoglycemia, women with T1DM especially if using NPH insulin may need a small bedtime snack and/or reduce overnight basal insulin doses. The patient should have a glucagon emergency kit and carry easily absorbed carbohydrate with her at all times. Education of patients and care providers to avoid hypoglycemia can reduce the incidence of hypoglycemia unawareness. The incidence of severe hypoglycemia in pregnant women with T1DM can be reduced often without significantly increasing A1c levels and is a priority given hypoglycemic unawareness worsens with repeated episodes and can result in maternal seizures and rarely maternal death (91).

By 18-20 weeks of gestation, peripheral insulin resistance increases resulting in increasing insulin requirements so that it is not unusual for a pregnant woman to require 2-3 times as much insulin as she did prior to pregnancy depending on baseline insulin resistance, carbohydrate intake, and body mass index. In a study of 27 women with T1DM on an insulin pump, the carbohydrate-to-insulin ratio intensified 4-fold from early to late pregnancy (e.g. 1 unit for every 20 grams to 1 unit for every 5 grams), and the basal insulin rates increased 50% (71).

Glucose Monitoring Timing and Frequency

Pregnant women with diabetes must frequently self-monitor their glucose in order to achieve tight glycemic control. Since fetal macrosomia (overgrowth) is related to both the fasting and postprandial glucose excursions, pregnant women with diabetes need to monitor their post-meal and fasting glucoses regularly and women with T1DM or T2DM using a flexible intensive insulin regimen also need to monitor their pre-meal glucoses (92).

Postprandial glucose measurements determine if the insulin to carbohydrate ratios are effective in meeting glycemic targets as optimal control is associated with less macrosomia, metabolic complications in the fetus, and possibly preeclampsia (81,93).  Due to the increased risk of nocturnal hypoglycemia with any intensive insulin therapy, glucose monitoring during the night is often necessary given the frequent occurrence of recurrent hypoglycemia and resulting hypoglycemic unawareness with the achievement of tight glycemic control.

CONTINUOUS GLUCOSE MONITORING

CGM may help identify periods of hyper- or hypoglycemia and certainly confirm glycemic patterns and variability (78,94).  The ADA and ACOG recommend that CGM may be used as adjunctive therapy with self-monitored blood glucose (SMBG) values in pregnancy especially in those with frequent or severe hypoglycemia. In pregnancy, the mean sensor glucose may be better at estimating glycemic control than A1c. For women with T1DM, the International Consensus on Time in Range recommends increasing time in range in pregnancy quickly and safely with a pregnancy goal sensor glucose range of 63 to 140 mg/dl (3.5-7.8 mmol/L) with >70% time in range, <25% time above range (>140 mg/dl [>7.8 mol/L], <4% of time below 63 mg/dl (<3.5 mmol/L), and <1% time below 54 mg/dl (<3 mmol/L). The expert guidance did not recommend time in range goals for patients with T2DM or gestational diabetes due to lack of clear evidence in these populations.

CGM has been an advancing technology with tremendous improvements in accuracy, comfort, longer duration, convenience, and insurance coverage over the past decade. Some newer CGM devices are factory calibrated and do not require fingerstick glucose calibrations. There are also flash CGM systems on the market which require scanning of the sensor with a receiver to display the sensor glucose. Although CGM is currently not approved for use during pregnancy, many women with T1DM and some with T2DM use the technology preconception and continue to do so during pregnancy, or are started on CGM during pregnancy off-label. Pregnant women with diabetes may use CGM either in conjunction with an insulin pump or with MDI therapy to help achieve glycemic control. Sensor-augmented pump therapy (SAPT) and hybrid closed loop pump therapy have growing data in pregnancy. The Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT) trial was a large multicenter trial examined CGM use in women planning pregnancy as well as pregnant women with T1DM using either MDI or insulin pump therapy (94). This study found statistically significantly lower incidence of large for gestational age (LGA) infants, less neonatal intensive care unit stays more than 24 hours, and less neonatal hypoglycemia. This study found a small difference in A1c among the pregnant women using CGM, less time spent in hyperglycemia range, and more time spent in range. Importantly this was the first study to show improvement in non-glycemic outcomes for CGM use in pregnancy (94). A follow-up study to the CONCEPTT trial found that pregnant women using real time CGM compared to capillary glucose monitoring were more likely to achieve ADA and NICE (National Institute of Clinical Excellence) guidelines for A1c targets by 34 weeks gestation.

Sensor glucose values from CGM may not be as accurate at extremes of hypo- or hyperglycemia or with rapid changes in glucose, so patients should always check fingerstick glucose if the patient feels the glucose is different than the displayed sensor glucose. CGM values may have a lag time behind actual plasma glucose values.

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.

Retinopathy

Diabetic retinopathy may progress during pregnancy and throughout the first year postpartum. However, pregnancy does not cause permanent worsening in mild retinopathy (95,96). The cause for progression in moderate and especially severe proliferative retinopathy is likely due to a combined effect of the rapid institution of tight glycemic control, increased plasma volume, anemia, placental angiogenic growth factors, and the hypercoagulable state of pregnancy (97,98). In 179 pregnancies in women with T1DM DM who were followed prospectively, progression of retinopathy occurred in 5% of women. Risk factors for progression were duration of diabetes >10 years (10% versus 0% in the <10-year duration of diabetes group), moderate to severe background retinopathy (30% versus 3.7% in the no or background diabetic retinopathy group), and a trend for those women who had the greatest fall in A1c (97). The risk of progression of retinopathy is most pronounced in women with more severe pre-existing proliferative retinopathy, chronic hypertension, preeclampsia, development of hypertension during pregnancy, and poor glycemic control prior to pregnancy and dilated retinal exams during pregnancy are indicated (99). Proliferative retinopathy may also progress during pregnancy, especially in women with hypertension or poor glycemic control early in pregnancy (100).  Pregnancy can also contribute to macular edema, which is often reversible following delivery (101).

Therefore, women with T1DM and T2DM should have ophthalmological assessments before conception. All guidelines recommend that women have a comprehensive eye exam or fundus photography before pregnancy and in the first trimester. Laser photocoagulation for severe non-proliferative or proliferative retinopathy prior to pregnancy reduces the risk of vision loss in pregnancy and should be done prior to pregnancy (26). Women with low-risk eye disease should be followed by an ophthalmologist during pregnancy, but significant vision-threatening progression of retinopathy is rare in these individuals. For vision-threatening retinopathy, laser photocoagulation can be used during pregnancy (101).  Safety of bevacizumab injection during pregnancy is not clear with some case reports of normal pregnancy after bevacizumab injections for macular edema in pregnancy, and other early pregnancy loss following bevacizumab injection. In women with severe untreated proliferative retinopathy, vaginal delivery with the Valsalva maneuver has been associated with retinal and vitreous hemorrhage. Little data exist to guide mode of delivery in women with advanced retinal disease and some experts have suggested avoiding significant Valsalva maneuvers—instead offering assisted second-stage delivery or cesarean delivery (23).

Diabetic Nephropathy/Chronic Kidney Disease

Microalbuminuria and overt nephropathy are associated with increased risk of maternal and fetal complications (102–105). Although proteinuria increases during pregnancy in women with preexisting nephropathy, those with a normal glomerular filtration rate (GFR) rarely have a permanent deterioration in renal function provided blood pressure and blood glucose are well controlled (106–108). Those with more severe renal insufficiency (creatinine >1.5 mg/dl) have a 30-50% risk of a permanent pregnancy-related decline in GFR (109). Among pregnant women with diabetes, nephropathy significantly increases the risk of preeclampsia which is seen in 35-64% of women with baseline nephropathy and 9-17% of women with diabetes without nephropathy.  Factors which may contribute to worsening nephropathy in pregnancy include the hyperfiltration of pregnancy, increase in protein intake, hypertension, and withdrawal of ACE Inhibitors or ARBs. More stringent control of blood pressure in pregnancy may reduce the likelihood of increasing protein excretion and reduced GFR. In a series of 36 women with T1DM and nephropathy, maternal and obstetric outcomes were strongly dependent on the degree of maternal renal function (110). In women with a creatinine clearance of >80 cc/min, the prematurity rate was 19% and the mean birth weight was 2670 grams in comparison to women with a creatinine clearance of 30-80 cc/min in whom 60% of the infants were premature and the mean birth weight was only 1640 grams. Overall, ~50% of the patients developed nephrotic range proteinuria, 97% of the patients required antihypertensive treatment, and 20% of the children had neurodevelopmental delays. In normal pregnancy, urinary albumin excretion increases up to 30 mg/day and total protein excretion increases up to 300 mg/day. Women with pre-existing proteinuria often have a significant progressive increase in protein excretion, frequently into the nephrotic range, in part due to the 30-50% increase in GFR that occurs during pregnancy.

Prior to conception, women should be screened for chronic kidney disease. Dipstick methods are unreliable and random urine protein/creatinine ratios are convenient but not as accurate as methods to carefully quantify proteinuria using 24-hour urine excretions in pregnancy. There have not been studies looking at spot urine albumin to creatinine ratio versus 24-hour urine protein assessment in pregnant women with diabetes. In hypertensive pregnant women, one study found that the spot urine albumin to creatinine ratio had higher diagnostic accuracy than 24-hour urine protein assessment (111). It is reasonable to collect a spot urine albumin to creatinine ratio in patients who have not followed through with collection of 24-hour urine specimens.

There is conflicting information on whether first-trimester exposure to ACE inhibitors and ARBs is associated with an increased risk of congenital malformations. A meta-analysis, limited by small study size (786 exposed infants), demonstrated a significant risk ratio (relative risk [RR] 1.78, 95% confidence interval [CI] 1.07–2.94) for increased anomalies in infants exposed to first-trimester ACE inhibitors and ARBs compared to the normal population (112). However, the increased risk of congenital anomalies appears to be more related to hypertension itself, rather than drug exposure. There was no statistically significant difference (RR 1.41, 95% confidence interval (CI) 0.66–3.04) when ACE inhibitor and ARB exposed pregnancies were compared to other hypertensive pregnancies. A large cohort study of women with chronic hypertension including over 4100 pregnant women exposed to ACE inhibitors during the first trimester of pregnancy found no significant increase in major congenital anomalies (113).  Exposure in the second and third trimesters is clearly associated with a fetal renin-angiotensin system blockade syndrome, which includes anuria in the 2nd and 3rd trimester, which may be irreversible. However, one recent case report of a pregnant women with anhydramnios who had ARB exposure at 30 weeks’ gestation had normalization of amniotic fluid volume after cessation of the medication. Furthermore, there were no apparent renal abnormalities at birth or 2 year follow up (114). Women who are taking ACE-inhibitors or ARBs should be counseled that these agents are contraindicated in the 2nd and 3rd trimester of pregnancy. Women who are actively trying to get pregnant should be switched to calcium channel blockers (such as nifedipine or diltiazem), methyldopa, hydralazine, or selected B-adrenergic blockers such as labetalol.

Women who are considering pregnancy but not likely to become pregnant in a short time and who are receiving renal protection from ACE inhibitors or ARBs due to significant underlying renal disease can be counseled to continue these agents. However, they should closely monitor their menstrual cycles and stop these agents as soon as pregnancy is confirmed.

Women with severe renal insufficiency should be counseled that their chances for a favorable obstetric outcome may be higher with a successful renal transplant. Women with good function of their renal allografts who have only mild hypertension, do not require high doses of immunosuppressive agents, and are 1-2 years out from their renal transplant have a much better prognosis than women with severe renal insufficiency and who are likely to require dialysis during pregnancy. Successful pregnancy outcomes have been reported in 89% of these successful renal transplant patients (115). Timing of conception in relation to transplant is controversial and should be individualized. Pre-pregnancy graft function can help predict risk of adverse pregnancy outcomes, especially preeclampsia, and postpartum graft function (116).

Cardiovascular Disease

Although infrequent, cardiovascular disease (CVD) can occur in women of reproductive age with diabetes. The increasing prevalence of T2DM with associated hyperlipidemia, hypertension, obesity, advanced maternal age, and inflammation is further increasing the prevalence of CVD. CVD most often occurs in women with long-standing diabetes, hypertension, and nephropathy (117). Because of the high morbidity and mortality of coronary artery disease in pregnancy, women with pre-existing diabetes and cardiac risk factors such as hyperlipidemia, hypertension, smoking, advanced maternal age (>35), or a strong family history should have their cardiac status assessed with functional testing prior to conception (51,118). There are limited case reports of coronary artery disease events during pregnancy, but with the increased oxygen demand from increased cardiac output, events do occur and need to be treated similarly to outside of pregnancy, trying to minimize radiation exposure to the fetus (117,119,120).  In a recent study of 79 women with history of coronary artery disease prior to pregnancy of which 22.8% had preexisting diabetes, there were low rates of cardiac events during pregnancy in all women with and without diabetes but more frequent poor obstetric and neonatal outcomes including small for gestational age, preeclampsia, and preterm delivery. This study confirms the need for preconception counseling and cardiac testing for women with risk of or known coronary artery disease.

Due to the increased cardiac output of pregnancy, decrease in systemic vascular resistance, and increase in oxygen consumption, the risk of myocardial ischemia is higher in pregnancy. Myocardial oxygen demands are even higher at labor and delivery, and activation of catecholamines and stress hormones can cause myocardial ischemia. Coronary artery dissection is also more common in pregnancy and typical chest pain should be appropriately evaluated. An EKG should be considered preconception for any woman with diabetes older than 35 years (23). Women with longstanding diabetes and especially those with other risk factors for coronary artery disease (hyperlipidemia or hypertension) should be evaluated for asymptomatic coronary artery disease before becoming pregnant. Women with atypical chest pain, significant dyspnea, or an abnormal resting EKG should also have a cardiology consultation for consideration of a functional cardiac stress test before pregnancy. Statins should be discontinued before conception since there is inadequate data about their safety during pregnancy. However, if a woman has severe hypertriglyceridemia with random TG >1000 or fasting >400, placing her at high risk for pancreatitis, it may be necessary to continue fibrate therapy if a low-fat diet, fish oil, or niacin therapy is not effective or tolerated. Triglycerides typically double to quadruple in pregnancy placing women at high risk for this condition. There is inadequate data on the use of ezetimibe in pregnancy. (See Endotext chapter on Lipid and Lipoproteins during Pregnancy).

Neuropathy

There are limited data on diabetic neuropathy during pregnancy. Neuropathy may manifest as peripheral neuropathy, gastroparesis, and cardiac autonomic neuropathy. Gastroparesis may present as intractable nausea and vomiting, and it can be particularly difficult to control both the symptoms and glucoses in women with gastroparesis during pregnancy. For patients with gastroparesis, timing of insulin delivery in relation to the meal needs to carefully be weighed against the risk of hypoglycemia as discussed previously.

DIABETES AND AUTOIMMUNE DISORDERS

Associated Autoimmune Thyroid Disease

Up to 30-40% of young women with T1DM have accompanying thyroid disease, and women with T1DM have a 5-10% risk of developing autoimmune thyroid disease first diagnosed in pregnancy (most commonly Hashimoto's thyroiditis) (121). TSH should be checked prior to pregnancy since the fetus is completely dependent on maternal thyroid hormone in the first trimester (122,123). Women with positive TPO antibodies should have their TSH checked each trimester (Table 2) since the demands of pregnancy can unmask decreased thyroid reserve from Hashimoto’s thyroiditis. Thyroid hormone requirements increase by 30-50% in most pregnant women, often early in pregnancy due to increase in thyroid binding globulin stimulated by estrogen. For most women on thyroid hormone replacement prior to pregnancy, the American Thyroid Association (ATA) and ACOG recommend TSH be within the trimester-specific reference range for pregnancy at a particular lab, or if not provided, preconception and first trimester TSH <2.5 mU/L and second and third trimester TSH goals <3 mU/L, and thyroid hormone replacement should be adjusted to achieve these goals (124,125). For diagnosis of hypothyroidism during pregnancy, recent recommendations from the ATA recommend new reference ranges for TSH during pregnancy and screening in women with history of T1DM each trimester with reference range being 0.4 from the lower limit of the nonpregnant TSH reference range and 0.5 from the upper non-pregnant range which results in a new TSH range of ~0.1-4mUl/L(124,126). This recommendation is based on the TSH range in pregnant women in the Maternal Fetal Medicine Units Network, and there was no benefit in treating women with levothyroxine with TSH <4.

Other Autoimmune Conditions

Other autoimmune conditions are also more common among women with T1DM compared to women without T1DM. Celiac disease has been estimated to have a prevalence of 3-9% in individuals with T1DM and is more common among females than males (127,128). This can often lead to vitamin D deficiency and iron deficiency and it is reasonable to screen women with T1DM for vitamin D deficiency in pregnancy if they have not been previously screened.  Autoimmune gastritis and pernicious anemia are also more common among individuals with T1DM than patients without diabetes with prevalence approximating 5-10% and 1-3%, respectively (129). Addison’s disease is also seen in 0.5-1% of patients with T1DM (129).

DIABETIC KETOACIDOSIS IN PREGNANCY

Pregnancy predisposes the mother to accelerated starvation with enhanced lipolysis, which can result in ketonuria after an overnight fast. DKA may therefore occur at lower glucose levels (~200 mg/dl or ~11 mmol/l), often referred to as "euglycemic DKA" of pregnancy, and may develop more rapidly than it does in non-pregnant individuals (130,131). Up to 30% of episodes of DKA in pregnant women with diabetes have occurred with glucose values <250 mg/dl (13.9 mmol/L).  Women also have a lower buffering capacity due to the progesterone-induced respiratory alkalosis resulting in a compensatory metabolic acidosis. Furthermore, euglycemic DKA is not uncommon in pregnancy due to increased propensity to ketosis in pregnant women and glomerular hyperfiltration in pregnancy which causes glycosuria at lower serum glucoses. Any pregnant woman with T1DM with unexplained weight loss or unable to keep down food or fluids should check urine ketones at home and if positive, a chemistry panel should be ordered to rule out an anion gap even if the maternal glucose is <200 mg/dl. It should also be recommended to check urine ketones with any glucose >200 mg/dL.

Maternal DKA is associated with significant risk to the fetus and poor neonatal outcomes including morbidity and mortality.  Cardiotography of the fetus during maternal DKA suggests fetal distress (as evidenced by late decelerations) and in one study improved with correction of maternal acidosis. In a study of 20 consecutive cases of DKA, only 65% of fetuses were alive on admission to the hospital (131). Once the patient was hospitalized and treated, the risk of fetal loss declined dramatically. Risk factors for fetal loss included DKA presenting later in pregnancy (mean gestational age 31 weeks versus 24 weeks); glucose > 800 mg/dl; BUN > 20 mg/dl; osmolality > 300 mmol/L; high insulin requirements; and longer duration until resolution of DKA. The fetal heart rate must be monitored continuously until the acidosis has resolved. There was no maternal mortality in this small series. In another case series of DKA in pregnancy, almost all women presented with nausea and vomiting (97%) and the majority had improvement of hyperglycemia to <200 mg/dL within 6 hours of admission and resolution of acidosis within 12 hours (132). Causes of DKA in pregnancy vary widely with infection less common as a precipitant (133). Of the infectious causes, pyelonephritis was the most common. However, there is often no precipitant other than emesis in the pregnant woman who can develop starvation ketosis very quickly. In a series of 37 pregnant women with DKA, emesis alone accounted for 42% of the cases (60% of these women had gastroparesis), and 17% were non- compliant with prescribed insulin dosing. Beta agonist therapy, insulin pump failure, infection, undiagnosed pregnancy, and new onset diabetes each accounted for 8% of the cases.

Prolonged fasting is a common precipitant for DKA and it has been shown that even women with GDM can become severely ketotic if they are given B-mimetic tocolytic medications or betamethasone (to accelerate fetal lung maturity) in the face of prolonged fasting (134). It is imperative to remember that the pregnant woman unable to take glucose orally requires an additional 100-150 grams of intravenous glucose to meet the metabolic demands of the pregnancy in the 2nd and 3rd trimester. Without adequate carbohydrate (often a D10 glucose solution is needed), fat will be burned for fuel and the patient in DKA will remain ketotic. Diabetic ketoacidosis carries the highest risk of fetal mortality in the third trimester thought in part due to the extreme insulin resistance in these patients and insulin requirements to treat DKA that are nearly twice as high as in the second trimester (131).

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 glycemiccontrol, 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 womenneeding roughly 10-30% less than their pre-pregnancy insulin doses or 1/2 to 1/3 of their third trimester insulindosages; 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.

Immediate Risks to Newborn

The immediate neonatal period is characterized by the transition from in-utero to independent physiology, with unique risks in neonates born to individuals with diabetes.  Glycemic control throughout the entire gestation as well as in the hours before birth both influence this transition. As previously described, hyperglycemia early in pregnancy may result in congenital anomalies, such as cardiac anomalies, which complicate the transition to post-natal circulation. Glycemic control in the second and third trimester may result in a macrosomic infant with increased adiposity in the shoulders and abdomen. And finally, hyperglycemia during labor exacerbates the adjustment of the neonatal pancreas when glucose delivery via the placenta abruptly ceases.

Even with aggressive management of diabetes, the incidence of neonatal complications ranges from 12-75% (166) In a large analysis of nearly 200,000 neonates, severe neonatal morbidity was increased in neonates born to women with pregestational diabetes compared to those with gestational diabetes or no diabetes at an odds ratio of 2.27 and 1.96 respectively (167).  Driving this relationship was the increased risks of respiratory distress syndrome, mechanical ventilation, and neonatal death (167).  Additionally, neonates were more likely to be large for gestational age and require neonatal intensive care unit admission (167).  In the setting of poor glycemic control, respiratory distress syndrome may occur in up to 31% of infants due to known insulin antagonism of cortisol on fetal pneumocytes and surfactant production (168). The estimated odds ratio between pregestational diabetes and neonatal respiratory distress syndrome is 2.66 (169). With extremely poor glucose control, there is also an increased risk of fetal mortality due to fetal acidemia and hypoxia. One study found higher rates of neonatal hypoglycemia in women managed with continuous insulin infusion pump during pregnancy compared to multiple daily injection therapy, although confounders including early maternal BMI and duration of an insulin infusion play a role (170).

Macrosomia places the mother at increased risk of requiring a cesarean section and the infant at increased risk for shoulder dystocia. Shoulder dystocia can result in Erb’s palsy, Klumpke palsy, clavicular and humeral fractures, and hypoxic ischemic encephalopathy, with overall neonatal injury rate of 5.2% (171,172). Shoulder dystocia occurs nearly 20% of the time when a 4500-gram infant is delivered vaginally. Nevertheless, shoulder dystocia remains challenging to predict, with 60% of shoulder dystocias occur in neonates weighing <4000g (173). There are a number of conflicting studies regarding induction versus cesarean section for suspected macrosomia (174–176).  A large RCT performed in France, Switzerland, and Belgium compared induction of labor at 39 weeks gestation to expectant management among individuals with LGA fetuses, though insulin-dependent diabetes was an exclusion factor (176).  Induction of labor was associated with a significant reduction in the composite primary outcome (significant shoulder dystocia, fracture of the clavicle or long bone, brachial plexus injury, intracranial hemorrhage, or neonatal death), with a RR of 0.32 (95% CI 0.15-0.71)(176). While a small but significant difference in spontaneous vaginal delivery was noted between groups, rates of operative vaginal delivery and cesarean deliveries were not significantly different (176). Current guidelines from ACOG do not recommend delivery prior to 39 weeks for suspected macrosomia (177).

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).

Breastfeeding

Both the benefits of breastfeeding- and conversely, the risks of failing to do so- are profound and well documented for both mother and child (183).  Pregestational diabetes and obesity have been identified as an independent risk factors for low milk supply, raising the question whether the metabolic milieu during lactogenesis I in mid-pregnancy or during the transition to lactogenesis II and III after delivery may be contributing (184).  Additional challenges emerge at the time of delivery, with considerable separation of mothers and infants due to NICU admission and treatment for prematurity, respiratory distress syndrome, and hyperglycemia (167).  Dyads can be set up for success with policies and procedures that encourage antenatal colostrum collection, early initiation of pumping if unable to directly breastfeed, and ample lactation consultant support. Women with both T1 DM and T2DM have lower rates of breastfeeding despite good intentions (185,186).  When women have stopped breastfeeding, most stop due to low milk supply rather than diabetes specific reasons (187).

When individuals with diabetes are successful in breastfeeding their infants, benefits include reduction in postpartum weight retention and reduced risk for obesity and insulin resistance in offspring(188). Conflicting data exists on the relationship between breastfeeding and the incidence of type 1 diabetes in offspring of women with pregestational diabetes, though breastmilk induction at the time of complementary food introduction is linked to reduced risk of islet autoimmunity and type 1 diabetes (189,190).

Additional considerations must be made for individuals with Type 2 diabetes as they consider oral agents in the postpartum period. Acceptable levels of metformin have been identified in breastmilk, rendering it a safe medication for lactating women (191,192). A small study suggested that glyburide and glipizide do not appreciably cross into breast mild and may be safe (193). There are no adequate data on the use of thiazolidinediones, meglitinides, or incretin therapy in nursing mothers.

Statins should not be started if the woman is nursing due to inadequate studies in breastfeeding mothers. Women who are candidates for an ACE-inhibitor can be started on one of these agents at this time as they have not been shown to appear significantly in breast milk (144).

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 isreduced 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 preeclampsiain 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 atleast 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^thpercentile) 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

Early Life Origins of Metabolic Diseases

Given the strong associations between maternal diabetes and obesity and the risk of childhood obesity and glucose intolerance, the metabolic milieu of the intrauterine environment is a critical risk factor for the genesis of adult diabetes and cardiovascular disease (203,240–243).  The evidence of this fetal programming and its contribution to the developmental origins of human disease (DoHAD) is one of the most compelling reasons why optimizing maternal glycemic control, identifying other nutrients contributing to excess fetal fat accretion, emphasizing weight loss efforts before pregnancy, ingesting a healthy low-fat diet, and avoiding excessive weight gain are so critical and carry long term health implications to both the mother and her offspring. The emerging field of epigenetics has clearly shown in animal models and non-human primates that the intrauterine environment, as a result of maternal metabolism and nutrient exposure, can modify fetal gene expression (244,245).

Maternal hyperglycemia in early pregnancy has been associated with childhood leptin levels at 5 years of age, even when adjusted for maternal BMI and other confounders (β=0.09 ± 0.04, p=0.03) (246). In this study, higher maternal glucose levels post-75-gram glucose tolerance test in the second trimester were associated with greater total body fat percentage as measured by DXA in the children at 5 years of age.

There are data, especially in animal and non-human primate models, to support that a maternal high fat diet andobesity can influence mesenchymal stems cells to differentiate along adipocyte rather than osteocyte pathways, invoke changes in the serotonergic system resulting in increased anxiety in non-human primate offspring, affect neural pathways involved with appetite regulation, promote lipotoxicity, regulate gluconeogenic enzymes in the fetal liver generating histology consistent with NAFLD, alter mitochondrial function in skeletal muscle, and program beta cell mass in the pancreas (242,247–254).  These epigenetic changes are being substantiated in human studies with evidence of differential adipokine methylation and gene expression in adult offspring of women with diabetes in pregnancy and through alterations in fetal placental DNA methylation of the lipoprotein lipase gene which are associated with the anthropometric profile in children at 5 years of age (255). These findings further support the concept of fetal metabolic programming through epigenetic changes (256). As a result, the intrauterine metabolic environment may have a transgenerational influence on obesity and diabetes risk in the offspring, influencing appetite regulation, beta cell mass, liver dysfunction, adipocyte metabolism, and mitochondrial function.

Offspring of mothers with type 2 diabetes and gestational diabetes have higher risk of childhood obesity, young adult or adolescent insulin resistance and diabetes, nonalcoholic fatty liver disease, hypertension, and cardiovascular disease (257–262) . The risk of youth onset diabetes is higher in offspring of mothers born with pregestational type 2 diabetes than with gestational diabetes (14-fold compared to 4-fold risk) (263). These epigenetic changes are not isolated to maternal BMI alone but it has also been demonstrated that paternal factors impact offspring risk of obesity and diabetes (264,265). Offspring of women with T1DM have a risk of developing T1DM of about 1-3%. The risk is higher in the offspring if the father has T1DM rather than the mother (~3-6%) and if both parents have T1DM, the risk is ~20% (266,267).

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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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.

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).

α: Note that while most international and national guidelines have moved toward universal testing, the United Kingdom’s National Institute for Health and Care Excellence continues to recommend risk-based GDM testing (33)

β: Cutoff of 140mg/dL results in sensitivity of 70–88% and specificity of 69–89% and requires GTT in ~15% patients; cutoff of 130mg/dL results in sensitivity of 88–99% and specificity of 66–77% specific and requires GTT in ~25% patients.

¥: ACOG allows for consideration of diagnosis with ≥1 criteria met

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).

Screening Prior to 24 Weeks Gestation- Who, Why, and How?

Several factors have contributed to newer recommendations to consider early screening for diabetes:  the rising incidence of Type 2 diabetes (T2DM) as a result of the obesity epidemic, in addition to a better understanding of the risks associated with hyperglycemia early in pregnancy, such as congenital anomalies and miscarriage (41). In an obstetric setting, the best time to screen for and diagnose pregestational diabetes is as early as possible in the pregnancy, ideally in the first trimester before the placental effects causing insulin resistance have begun. There is not a recognized lower gestational age cutoff at which insulin resistance can be attributed to placental effects, though this likely occurs prior to the GDM screening range of 24-28 weeks.

The 2021 ADA guidelines recommend screening individuals at the first prenatal visit if BMI >25 kg/m² (or >23 kg/m² in Asian Americans) and one or more risk factors (Table 2). The IADPSG/ADA recommends that women diagnosed for the first time in pregnancy should be considered as having overt diabetes following the same criteria for diabetes outside of pregnancy (Table 3) (28,32).

ACOG recommends that high risk individuals be screened on their first prenatal visit with a 50g glucose load and if the value at 1 hour exceeds 130-140 mg/dl, a diagnostic 3-hour 100g OGTT be performed. The 1-hour test does not have to be performed during a fasting state but a serum sample must be drawn exactly 1-hour after administering the oral glucose.

The options given by the ADA to diagnose overt diabetes in early pregnancy has resulted in some opponentsunderscoring that some high-risk women with only impaired glucose tolerance (by a GTT) will be missed early using the IADPSG criteria since a practitioner can choose whether to obtain an A1c, fasting glucose, or 75 gm 2-hour GTT early in pregnancy. Some practitioners are recommending that an A1c of 5.7-6.4% be used to diagnose “early GDM” since this level diagnoses prediabetes outside of pregnancy (42,43). However, an A1c of 5.7-6.4% or greater was not given as an optional criterion by either IADPSG or the ADA to diagnose GDM but a recommendation to screen. Further, studies outside of pregnancy have demonstrated that the A1c is the least sensitive test to diagnose either prediabetes or diabetes, especially given that anemia is common in pregnancy and the A1c will be falsely low in conditions of high red blood cell turnover (44,45). Further, it has been demonstrated that the FBG is less sensitive than the post glucose load value on a 75 gm 2-hour GTT for diagnosing prediabetes or diabetes, especially for Asian women who have been shown to typically have normal FBGs. There is a profound difference amongst different ethnic populations studied in the HAPO trial in regards to the sensitivity of a FBG versus a 1- or 2-hour 75 gm glucose value in diagnosing GDM (36).  In Hong Kong, of all of the women in the HAPO trial who were diagnosed as having GDM using the new criteria, only 26% had an abnormal FBG and the remainder were diagnosed by either a 1-hour post glucose value (45%) or abnormal 2-hour value (29%) (25). Thus, guidelines recommended lower BMI criteria/stricter criteria for screening in the Asian American population. Both ACOG and the ADA agree that if initial testing does not result in a diagnosis of diabetes, routine screening for GDM should occur at 24 to 28 weeks gestation (1,32).

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 andreduce 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 thepostprandial 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.

Metformin

One of the largest experiences with metformin in the setting of GDM was with metformin initiated later in pregnancy (84). In this randomized, controlled Metformin in Gestation (MIG) trial, 751 individuals with GDM were randomized to metformin versus insulin. Individuals that did not get adequate glycemic control on metformin received insulin. There was no difference in both groups concerning the primary composite outcome (neonatal hypoglycemia, respiratory distress, need for phototherapy, birth trauma, 5-minute APGAR <7), or premature birth. As such, metformin did not appear to increase any adverse outcomes, although it was associated with a slight increase in preterm birth; however, this did not appear to be clinically relevant.

Importantly, 46% of the women in the metformin group required supplemental insulin to achieve adequate glycemic control. This study demonstrated interesting metformin benefits including: reduced maternal weight gain, improved patient satisfaction, and reduced incidence of gestational hypertension. In a smaller RCT, Ijas et al demonstrated metformin had a 32% failure rate. They also noted metformin failures were more likely to be obese, have higher fasting blood glucose levels, and initiated pharmacotherapy earlier (85). Spaulonci et al randomized 47 women to metformin or insulin and also demonstrated significant metformin benefits including: less gestational weight gain, lower mean glucose levels, and lower rates of neonatal hypoglycemia (86). Overall, meta-analyses have demonstrated largely reassuring outcomes for metformin compared to insulin and glyburide (87–91).

Metformin should be avoided in patients with renal insufficiency. It is typically prescribed in divided doses starting with 500 mg once or twice daily for 1 week and then increasing to a maximum dose of 2500 mg daily in divided doses with meals. Common side effects include gastrointestinal complaints (occurring in 2.5-45.7% of pregnant patients in studies) (87). These randomized trials have shown short term efficacy and safety of metformin use in pregnancy for GDM treatment.

Until recently, long-term safety data of in-utero metformin exposure has been lacking, though several studies have been published commenting on infant and childhood weight, BMI, cardiovascular health, IQ and developmental outcomes. The earliest follow-up studies in metformin-exposed infants suggested they had larger measures of subcutaneous fat when compared to those exposed to insulin (88).  Another study in PCOS women comparing metformin to placebo showed that although women randomized to metformin gained less weight during pregnancy, at 1 year postpartum the women who used metformin in pregnancy lost less weight and their infants were heavier than those in the placebo group (91). These fetal and neonatal results are likely because metformin is concentrated in the fetal compartment with umbilical artery and vein levels being up to twice those seen in the maternal serum (92,93).Hypothetically if metformin increases insulin sensitivity in the fetus, it might be possible for excess nutrient flux across the placenta to result in increased fetal adipogenesis. More recent studies also identified increased weight in metformin-exposed infants, a relationship that may no longer be present after 4 years of age (94,95).  Long-term follow up of BMI is conflicting (94,95). A very large study in New Zealand evaluated outcomes at 4 years of age in nearly 4000 individuals, with no differences in growth and development assessments compared to insulin-exposed children (96). The metabolic and weight differences warrant further investigation since similar patterns of low birth weight followed by accelerated growth are associated with adverse long-term outcomes (97). At least one study has failed to demonstrate such a relationship in this population (98).  A study of 211 women with GDM randomized to insulin versus metformin during pregnancy found similar developmental outcomes by 2 years of age (90).

In review, the ADA and ACOG note that insulin is the first line agent for treatment of GDM if lifestyle changes have not achieved glycemic targets (1,32). The ADA notes that although individual RCTs have shown short term benefits and safety of metformin and glyburide, long- term safety data are lacking (99). Both organizations acknowledge that 20-45% of women fail metformin monotherapy necessitating that insulin be added (1). Counseling is necessary to explain to women that although current data do not demonstrate any adverse short-term outcomes, there are concerns about placental transfer of metformin, potential increased preterm birth, and lack of data on long term outcomes of fetuses exposed to metformin in-utero, metformin’s effect on fetal insulin sensitivity, hepatic gluconeogenesis, and the long-term fetal programming implications are unknown.

Glyburide and Other Agents

Glyburide is the only sulfonylurea that has been studied in a large randomized trial in GDM women. It was approved by the 5th International Workshop and IADPSG as a possible alternative to insulin in GDM women due to a number of randomized controlled trials (100–102).  The dose ranges from 2.5-20 mg daily in divided doses.

Glyburide exposure in most RCTs is limited to the second and third trimesters, so the effect on embryogenesis was not studied, but there are no convincing reports that it is a teratogen.  Due to its peak at 3-4 hours, many women have inadequate control of their 1- or 2-hour postprandial glucoses and then become hypoglycemic 3-4 hours later and data suggest that serum concentrations with usual doses are lower in pregnant women. If used, it should be given 30 mins-1-hour before breakfast and dinner and should not be given before bedtime due to the risk of nocturnal or early morning hypoglycemia in light of its 3–4-hour peak (similar to regular insulin). For women unwilling to administer multiple daily insulin injections who have postprandial glucoses well controlled by glyburide but have fasting hyperglycemia, adding intermediate or long-acting insulin before bedtime to the glyburide can sometimes be useful. If both postprandial and fasting glucoses remain elevated, the patient should be switched to insulin.

The earliest RCTs offered glyburide as a safe alternative to insulin, without significant differences in outcomes (101). In the last 20 years, mounting evidence has suggested there is increased risk of both maternal and neonatal hypoglycemia with glyburide use (87,103–105). In some trials, maternal glycemic control, macrosomia, neonatal hypoglycemia, and neonatal outcomes were not different between groups although in others, there was a significantly greater rate of macrosomic infants in the glyburide group (101,106–108). In a meta-analysis examining metformin versus insulin versus glibenclamide (glyburide) treatment for women with GDM, there were significant increases in macrosomia (risk ratio 2.62) and neonatal hypoglycemia (risk ratio 2.04) among women treated with glibeclamide compared to insulin (87). This is the same publication reviewed above that showed the increased risk of preterm birth in the group of women treated with metformin compared to insulin. This meta-analysis in addition to a second meta-analysis show statistically significantly worse neonatal outcomes among offspring of women with GDM treated with glyburide compared to insulin during pregnancy (87,106). There were higher rates of neonatal hypoglycemia, respiratory distress syndrome, macrosomia, and birth injury without significant differences in glycemic control (106).

A RCT compared the efficacy of metformin with glyburide for glycemic control in gestational diabetes (102). In the patients who achieved adequate glycemic control, the mean glucose levels were not statistically different between the two groups. However, 26 patients in the metformin group (34.7%) and 12 patients in the glyburide group (16.2%) did not achieve adequate glycemic control and required insulin therapy (p=.01). Thus, in this study, the failure rate of metformin was twice as high as the failure rate of glyburide when used in the management of GDM (102). Thesefindings are consistent with the general finding that approximately, 15% of patients will fail maximum dose glyburide therapy and need to be switched to insulin, especially if dietary restriction is not carefully followed.

Although it was initially thought not to appreciably cross the placenta or significantly affect fetal insulin levels, examination using HPLC mass spectrometry suggested a modest amount of glyburide does cross (92).

There is not sufficient information available on thiazolidinediones, meglitinides, DPP-4 inhibitors, GLP-1 agonists and such agents should only be used in the setting of approved clinical trials as their teratogenic potential is unknown. Acarbose was studied in two very small studies in GDM women and given its minimal GI absorption is likely to be safe but GI side effects are often prohibitive (109).

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

Re-evaluating Glucose Tolerance Postpartum and Future Risk of Diabetes

Identification of poor glycemic control in pregnancy as a means to predict risk for T2DM was present in the earliest screening and diagnostic strategies. Up to 70% of individuals with GDM are estimated to ultimately develop T2DM within 20-30 years of delivery. Differentiation of GDM from previously undiagnosed T2DM should be performed via a 75 gm 2h GTT within 4-12 weeks postpartum as recommended by the ADA, Canadian Diabetes Association (CDA), Fifth International Workshop, and ACOG since most women with impaired glucose intolerance will be missed if only a FBG is checked (116).  A 2-hour value of at least 200 mg/dl establishes a diagnosis of diabetes and a 2-hour value of at least 140 mg/dl but less than 200 mg/dl makes the diagnosis of impaired glucose tolerance.

An attractive alternative approach is to perform the 75 gm GTT on postpartum day 2 prior to hospital discharge, since completion of postpartum screening is historically low. A large series of ~23,000 women who received lab testing through Quest diagnostics suggested that only 19% of women receive postpartum diabetes testing within a 6 month period (117). Waters et al demonstrated a negative GTT prior to hospital discharge excluded T2DM diagnosis at 4-12 weeks postpartum (118). Individuals with normal testing in this time period should be instructed to screen for T2DM at least every 3 years (119).

A weight loss program consisting of diet and exercise should be instituted for women with GDM in order to improve their insulin sensitivity and hopefully to prevent the development of T2DM (120). Hyperglycemia generally resolves inthe majority of patients during this interval but up to 10% of patients will fulfill criteria for T2DM. At the minimum, a fasting blood glucose should be done to determine if the woman has persistent diabetes (glucose >125 mg/dl) or impaired fasting glucose tolerance (glucose ≥ 100 mg/dl). Of note, breastfeeding has been shown to improve insulin resistance and glucose values in postpartum women with recent GDM (121,122).

Utility of using the A1c postpartum to predict the subsequent occurrence of T2DM in women with a history of GDM has not been studied extensively, and may be affected by glycemic control during pregnancy if done before 3 months postpartum (123). A study looking at utility of using A1c vs 2h GTT vs FPG for screening of women with recent GDM showed that A1c and A1c plus FPG did not have the sensitivity and specificity to diagnosis impaired carbohydrate metabolism postpartum (124,125). The importance of diagnosing impaired glucose intolerance lies in its value in predicting the future development of T2DM. In one series which mainly studied Latino women, a diagnosis of impaired glucose tolerance was the most potent predictor of the development of T2DM in women with a history of GDM; 80% of such women developed diabetes in the subsequent 5-7 years (126).  Intensified efforts promoting diet, exercise and weight loss should be instituted in these patients.

Other studies have shown other risk factors for development of prediabetes and/or T2DM after GDM including earlier diagnosis of GDM in pregnancy, insulin therapy during pregnancy, and BMI (127–129). A study in Italy showed pre-pregnancy BMI and PCOS as strong predictors of postpartum impaired glucose tolerance (130). A1c within 12 months postpartum may be useful in addition to GTT to diagnose some women with history of GDM and normal glucose tolerance. A study of 141 women in Spain with recent GDM found that 10% had normal glucose tolerance, normal FPG, and isolated A1c 5.7-6.4% suggesting that A1c is a useful tool to diagnose prediabetes in women with a history of GDM with normal glucose tolerance postpartum (131). Interestingly, in this study the group of women with isolated A1c 5.7-6.4% with normal glucose tolerance and normal FPG were more likely to be Caucasian and more likely had higher LDL-C values. A1c is a sensitive test in detecting prediabetes and overt diabetes in postpartum women with history of GDM (132).

The TRIPOD study demonstrated that the use of a thiazolidinedione postpartum in women with a history of GDM and persistent impaired glucose intolerance decreased the development of T2DM. The rate of T2DM in the 133 women randomized to troglitazone was 5.4% versus 12.1% in the 133 women randomized to placebo at a median follow-up of 30 months (133). The protection from diabetes was closely related to the degree of reduction of insulin secretion three months after randomization and persisted 8 months after the medication was stopped. In the PIPOD study, use of Pioglitazone to the same high-risk patient group stabilized previously falling β-cell function and revealed a close association between reduced insulin requirements and low risk of diabetes (5,134). However, using thiazolidinediones for the purpose of preventing the development of T2DM in women with a history of GDM has not been recommended. The Diabetes Prevention Trial analyzed their data in women with a history of GDM (54). A total of 349 subjects had a history of GDM, and such a history conferred a 74% hazard rate for the development of T2DM compared to women without a history of GDM. In the placebo arm, women developed T2DM at an alarming rate of 17% per year but this rate was cut in half by either use of metformin or diet and exercise.

The DPP, TRIPOD, and PIPOD studies support clinical management that focuses on identifying women who meet criteria for metabolic syndrome, achieving postpartum weight loss, and instituting aggressive interventions beginning with lifestyle changes to decrease insulin resistance for the primary prevention of T2DM. Women with a history of GDM who display normal testing postpartum should undergo lifestyle interventions for postpartum weight reduction and receive repeat  testing at least every 3 years (32).  For women who may have subsequent pregnancies, screening more frequently has the advantage of detecting abnormal glucose metabolism before the next pregnancy to ensure preconception glucose control (1).

Breastfeeding

Breastfeeding should be encouraged in all individuals with a history of gestational diabetes for maternal and offspring health outcomes. Lactation completes the reproductive cycle and is associated with significant short and long term benefits for both mother and infant, with most demonstrating a dose-dependent relationship (135).  ACOG and the AAP recommend exclusive breastfeeding for the first 6 months of life, then ongoing breastfeeding with complementary foods through the first year or as long as desired by both mother and child; the WHO has similar recommendations though 2 years of life (135–137).

Initially the correlation between breastfeeding and reduced incidence of T2DM were based on self-reported lactation status and diabetes diagnoses. Subsequent larger studies have confirmed this relationship.  Over 1200 individuals who had at least 1 live birth and reported lactation duration were followed in a community-based prospective study over 30 years, with diabetes screening performed up to 7 times (CARDIA study) (138).  Not only was there a three-fold increased incidence of T2DM in those with no breastfeeding compared to any breastfeeding, the relative hazard was graded based on duration of breastfeeding (138). These findings are also reported in the most recent meta-analysis evaluating the relationship between lactation and maternal risk of T2DM (139).

For children, breastmilk intake also appears to decrease the risk of developing obesity and impaired glucose tolerance (140,141). In the large EPOCH study (Exploring Perinatal Outcomes Among Children Study), offspring of women with diabetes (primarily GDM) who were breast fed for at least 6 months had a slower BMI growth trajectory during childhood and a lower childhood BMI than those who were not breastfed for this time period (142). There is a growing literature suggesting that some of the protective benefits on childhood obesity and programming the infant immune system from breast milk may be influenced by appetite regulatory hormones, biomarkers of oxidative stress and inflammation, and the milk microbiome (143–146).

Contraception

Discussing contraception and family planning during pregnancy is an effective way to promote safe pregnancy interval, with optimal outcomes observed when delivery and conception are at least 18 months apart (147).  For individuals with GDM, the postpartum and inter-pregnancy periods offer a tremendous opportunity to employ diet and lifestyle changes to reduce the risk of subsequent GDM or Type 2 DM (147).  All pharmacologic options for contraception are considered safe in the setting of recent or remote GDM, though estrogen-containing methods should be delayed until ≥21 days postpartum to reduce the risk of thromboembolism (148). Estrogen may negatively impact breast milk production, so consideration of infant feeding method should also be weighed against initiation. We recommend a patient-centered approach to counseling and selecting a contraceptive method.

There is limited data on the influence of various contraceptive methods on long-term risk of Type 2 DM, insulin sensitivity, glycemic control, weigh gain, and hypercholesterolemia(149).  Extensive research evaluating these relationships concludes the adverse outcomes observed with methods such as Depo-provera in the GDM population are more closely associated with initial BMI and pregnancy weight gain than the GDM diagnosis itself.

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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