Following the immediate postprandial period, unused glucose is stored in muscle and liver tissue as glycogen. The release of this stored energy is regulated by glucagon. Glucagon normally serves as the body's major defense against hypoglycemia. Its role is to maintain blood glucose levels between meals and during the fasting state. When blood glucose levels are high, such as after eating, the secretion of glucagon by the pancreas is inhibited.

Many of the more recent therapies developed for the treatment of type 2 diabetes have been incretin-based. One class of medication, the incretin mimetic, mimics the action of the incretin hormones GLP-1 and GIP, leading to an increase in insulin secretion from the pancreas. An additional beneficial effect of these medications is delayed gastric emptying, which increases satiety and promotes weight loss.

Diabetes encompasses a relatively large and somewhat diverse group of metabolic diseases. The ADA has identified four different clinical classes of diabetes based on etiology: type 1, type 2, gestational, and other types. In addition, the ADA has defined categories of increased risk for diabetes, collectively known as "prediabetes." Many of the types of diabetes identified by the ADA are not commonly encountered in nursing practice and are related to rare genetic and immune-mediated syndromes; these fall into the "other types" class. The common pathologic factors that categorize all these diseases as diabetes relate to abnormal insulin production, impaired insulin utilization, or both [5].

Formerly known as juvenile-onset diabetes, type 1 diabetes usually has its onset in people younger than 30 years of age. It is most often seen in people with a lean body type, although it can occur in people who are older and overweight. Type 1 diabetes results when a person's pancreas cannot produce any of its insulin for use by the body. If the individual with type 1 diabetes does not receive insulin from an outside source, he or she is likely to develop a life-threatening condition known as ketoacidosis. Patients with type 1 diabetes require insulin from an exogenous source to stay alive.

As discussed, GDM refers to diabetes that develops during pregnancy and complicates approximately 2% to 10% of all pregnancies [144]. It occurs more frequently among American Indian, Asian American, Hispanic/Latina, and Pacific Islander populations. Other risk factors for GDM include age older than 25 years, overweight/obesity, and personal history of GDM or a family history of diabetes [9,144].

Pregnancy is a time of hormonal fluctuation, altering a woman's metabolism of carbohydrates, fats, and protein. Placental hormones that help the fetus develop naturally cause some insulin resistance in the mother. Normally, these changes in pregnancy result in a mild increase in maternal glucose levels, which provides the fetus with a continuous, increased supply of glucose for its growth. Most of the time, the mother's body can overcome excessive glycemia by increasing insulin production. In a healthy pregnancy, the mother's insulin secretion doubles by the third trimester [4,10,11,12].

In late pregnancy, anabolic hormones responsible for fetal growth and development increase dramatically. Insulin-opposing hormones, such as human placental lactogen, prolactin, estrogen, and progesterone, cause an even greater degree of resistance. As a result, maternal basal insulin levels are high and eating produces two to three times more insulin output than in the prepregnancy state. However, insulin sensitivity decreases by as much as 50% of that seen in the first trimester. Most cases of GDM occur early in the third trimester because of these metabolic changes.

Maternal diabetes during pregnancy increases the risk of preterm labor [14]. Some of this risk may be due to increased uterine volume caused by macrosomia and/or polyhydramnios, which are associated with GDM. Maternal hypertension and urinary tract infections are also associated with GDM and increase the risk of preterm labor. Women with pre-existing diabetes who have vascular symptoms also have a higher risk for preterm labor.

Polyhydramnios occurs in about 18% of patients with GDM and is diagnosed when the amniotic fluid volume is greater than 2,000 mL. The excess amniotic fluid can distend the amniotic sac and cause premature rupture of the membranes. Fetal hyperglycemia that leads to increased fetal diuresis is the most likely cause of polyhydramnios. Therapeutic amniocentesis can relieve the pressure of polyhydramnios and prevent premature rupture of the membranes, but it is associated with risks as well [15].

HELLP syndrome is a severe form of pre-eclampsia occurring in approximately 5% to 12% of cases [17]. It can lead to liver hemorrhage, disseminated intravascular coagulation, pulmonary edema, kidney failure, and placental abruption. HELLP syndrome may develop after giving birth in women who had pre-eclampsia.

Possible anomalies of the heart include asymmetric septal hypertrophy, transposition of the great vessels, ventricular septal defects, and/or cardiomyopathy. Approximately 30% of infants of mothers with diabetes present with one or more of these cardiac conditions [27].

Possible birth trauma injuries in cases of macrosomia include shoulder dystocia, brachial plexus trauma, facial nerve injuries, and asphyxia. Shoulder dystocia is potentially catastrophic. While it occurs in fewer than 3% of all vaginal deliveries, 22% of infants weighing greater than 4,500 grams experience shoulder dystocia [31]. Shoulder dystocia occurs during birth when the infant's head is delivered, but the shoulder is unable to completely pass through the birth canal due to a discrepancy between the size of the fetal shoulders and the size of the pelvic inlet. Obstruction may affect one or both shoulders. Infants delivered after shoulder dystocia may experience brachial plexus injury, hypoxia, and even death. In addition to macrosomia, maternal obesity is also a risk factor for shoulder dystocia [31].

The fetal origins theory hypothesizes that developmental overnutrition and metabolic programming play important roles in the early development of disease. This theory provides an explanation of why exposure to hyperglycemia in the womb would predispose offspring to excess adiposity and metabolic disease later in life [36].

The patient's recent glycemic control should be evaluated prior to pregnancy. In a 2016 position statement, the ADA recommended that women have an A1C of less than 6.5%, or as close to normal as possible, before attempting conception [40]. Hemoglobin A1c (HgbA1c) levels should be assessed monthly in those who are planning pregnancy. Maintaining hemoglobin A1c levels closer to a target of 6.5% is likely to reduce the risk of congenital malformations [157]. The recommended preconceptual blood glucose targets are ≤90 mg/dL fasting, ≤130–140 mg/dL one hour postprandial, and ≤120 mg/dL two hours postprandial [40]. However, these strict targets pose a very real risk for severe hypoglycemia. Therefore, it is vital to educate patients and their support person(s) on the prevention, signs, symptoms, and treatment of hypoglycemia. It is also advisable to provide glucagon and education regarding how to use it. Monitoring blood ketone levels is also recommended for those who are hyperglycemic or feeling unwell, especially those with type 1 diabetes [157].

Healthcare providers should carefully evaluate patients' medications prior to conception. Medications that may be contraindicated in pregnancy include statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and some oral antidiabetic agents [40].

As such, a dilated retinal exam by an ophthalmologist is an important part of preconception care. If a patient has preproliferative retinopathy or macular edema, she should have laser photocoagulation to stabilize her retinal status before pregnancy [41]. In women with proliferative or severe non-proliferative retinopathy, the ADA recommends slowly lowering the blood glucose levels to near-normal over a six-month period before pregnancy is attempted [25].

When used as directed, oral contraceptives are 98% effective [13]. The oral agent of choice in women with diabetes is a low-dose combined estrogen plus progestin pill. These agents have not been associated with increasing insulin resistance, as the higher dose pills have. For postpartum women who are breastfeeding, it is safe to start low-dose contraceptives six to eight weeks after delivery [13].

The ADA's goals for glycemic control during pregnancy are to achieve and maintain near normal glycemia while minimizing hypoglycemia throughout the pregnancy. Glycemic targets are [25,40]:

Postprandial glucose levels are most strongly associated with excess birth weight and are the best guide to SMBG during pregnancy [16]. In women with diabetes, postprandial glucose peaks approximately 90 minutes after beginning a meal. However, there is considerable individual and day-to-day variability in this. The postprandial sample should be taken one hour after the beginning of the meal to best measure the peak glucose following the meal. Patients who use rapid-acting insulin before meals should also test their blood glucose before eating so they can adjust their insulin dose appropriately.

Ketoacidosis can develop rapidly in a pregnancy complicated by diabetes due to the physiologic insulin resistance, increased fat metabolism, and rapid depletion of insulin stores that occurs naturally in the pregnant state [25]. Diabetic ketoacidosis (DKA) is usually associated with type 1 diabetes but can also occur in type 2 diabetes and can develop at lower levels of hyperglycemia in pregnant women with either type of diabetes. DKA during pregnancy is associated with a high fetal mortality rate. Maternal fasting ketonemia is associated with decreased intelligence and poor development of fine motor skills in the offspring.

Insulin is the treatment of choice for pregnant and nonpregnant patients with type 1 diabetes. It is also the recommended agent for women with type 2 diabetes during pregnancy, as oral agents do not usually provide adequate glycemic control [25]. Additionally, insulin does not cross the placenta, easing concern that the drug may cause harm to the fetus [52]. The primary goal of insulin replacement during pregnancy is to achieve plasma glucose concentrations nearly identical to those observed in nondiabetic women. However, achieving the goal of rigid glycemic control is less important than avoiding symptomatic hypoglycemia [16].

From a physiologic standpoint, the risk for hypoglycemia increases during early pregnancy. Additionally, insulin-induced hypoglycemia is more pronounced in pregnancy and is more dangerous to the fetus. Blood glucose control that is too tight is associated with growth restriction and can result in microsomia and other neonatal and developmental problems.

According to the ADA, the goals of medical nutritional therapy during pregnancy are to provide adequate energy and nutrients needed for optimal outcomes. In its 2023 guideline, the ADA recommends that nutrition counseling for pregnant patients should endorse a balance of macronutrients, including nutrient-dense fruits, vegetables, legumes, whole grains, and healthy fats with omega-3 fatty acids that include nuts and seeds and fish in the eating pattern [150]. General guidelines for the nutritional management of pre-existing diabetes are to [63]:

Although the future risk to the mother's renal status is low, diabetic nephropathy during pregnancy poses other serious risks to both the mother and the fetus. Impaired renal function is a strong risk factor for fetal growth restriction, pre-eclampsia, and premature delivery. Even early nephropathy is associated with an increased risk for fetal growth restriction. There is usually a decline in the renal function of pregnant women with underlying diabetic nephropathy. As renal blood flow and the glomerular filtration rate increase by 30% to 50% during pregnancy, the risk for proteinuria increases.

Not many cholesterol-lowering medications are safe for use during pregnancy. While statin medications are used in patients with diabetes, they are not safe during pregnancy. Bile acid-binding resins, such as cholestyramine, are the only approved lipid-lowering medications for use in pregnancy. The ADA recommends using fibric acids and niacin as secondary strategies in pregnant women who have triglyceride levels greater than 1,000 mg/dL [10].

Hashimoto disease, also known as autoimmune thyroiditis, is characterized by antibodies reacting against proteins in the thyroid gland and causing destruction of the gland itself, resulting in hypothyroidism. This can adversely affect glycemic control and lipid metabolism during pregnancy. Furthermore, maternal hypothyroidism can inhibit brain development and is associated with pregnancy loss and premature delivery [70].

Propylthiouracil (PTU) is the safest anti-thyroid medication for use in pregnant women. Healthcare providers should closely monitor the effects of PTU and adjust dosages accordingly, as this drug can affect the fetal thyroid gland. Although radioactive iodine is a very effective treatment for other patients with hyperthyroidism, it is a contraindicated treatment during pregnancy [71].

One study showed that the risk for GDM increased with the number of pregravid cardiometabolic risk factors [84]. According to this study, cardiometabolic risk profile could predict the risk for GDM as early as seven years before pregnancy. Obesity appears to be the single greatest risk factor. The combination of obesity with mild hyperglycemia was associated with the greatest overall risk. The study concluded that the pregravid cardiometabolic risk profile might help clinicians to identify high-risk women for primary prevention and early management of GDM [84].

The potential for agreement on diagnostic criteria for GDM came in 2008, upon publication of the findings from a landmark study on the effects of hyperglycemia and pregnancy. Known as the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, this research data generated a flurry of controversy that continues today. The major finding from the HAPO study was that even mild elevations of blood glucose in pregnant women could have detrimental effects on both mother and child [89]. This prompted a movement for enhanced diagnostic criteria to identify and treat lower levels of blood glucose in pregnant women than previously considered.

In pregnant women not known to have diabetes, the ADA recommends screening at 24 to 28 weeks' gestation using a 75-gram two-hour OGTT that should be performed in the morning after an overnight fast of at least eight hours. The test is diagnostic for GDM if any of the following values result [100,147]:

The glycemic index appraises the effect of specific foods on blood glucose. Foods that are high on the glycemic index tend to increase blood glucose more than foods low on the index. High-glycemic foods include white bread, pasta, rice, low-fiber cereals, and baked goods; low-glycemic foods include fruits, vegetables, whole grains, and legumes.

Among women giving birth in the United States in 2014, 25.6% were overweight and 24.8% were obese [110]. A significant percentage of women who are overweight or obese will develop GDM when they become pregnant. Data from the HAPO study reveal that women with GDM who are obese have a significantly higher risk for adverse pregnancy outcomes, including macrosomia, fetal hyperinsulinemia, and pre-eclampsia. Greater weight gain during pregnancy also increases the likelihood of the need for insulin and the incidence of preterm delivery, although it reduces the risk for low birth weight. Furthermore, the combination of both GDM and obesity together has a greater impact on health outcomes than either one alone. The obesity epidemic has spurred interest in the effects of calorie restriction for obese women who are pregnant, including those with GDM. Calorie restriction during pregnancy raises concerns regarding the consequences of limited maternal weight gain on the growth of the fetus [111,112,113].

As discussed, the pregnancy weight gain recommendations from the IOM were revised in 2009 [64]. While these guidelines recommend less gestational weight gain for overweight and obese women, some experts feel that selected obese women should gain even less weight than the IOM suggests. Studies suggest that some obese women can gain less than 15 pounds, or even lose up to 10 pounds during pregnancy, without adverse outcomes. In these women, research indicates that moderate caloric restriction does not seem to impair fetal growth and may prevent macrosomia [114,115,116].

Several other studies suggest that calorie restriction in obese women during pregnancy can result in positive outcomes. Obese pregnant women restricting calories by 30% to 33% appears to be safe, with no associated increase in perinatal morbidity. Calorie restriction may increase a woman's insulin sensitivity, resulting in a decreased need for injections. Even so, continued research is necessary to determine the effects of calorie restriction during pregnancy on the future health of the child [16].

Although evidence-based guidelines for the optimal management of maternal obesity during pregnancy are lacking, the ACOG published a practice bulletin on obesity during pregnancy in 2015. The bulletin addresses clinical management questions about appropriate interventions before and during pregnancy, recommendations for weight gain, potential alterations to antepartum and intrapartum care, labor and delivery considerations, and the most effective postpartum care and strategies [117]. Additionally, experts recommend that pregnant women avoid excessive gestational weight gain, exercise moderately, and eat a healthy diet. Women should only attempt weight loss during pregnancy under the supervision of a qualified healthcare provider [16,25,113].

In pregnancy, metformin crosses the placenta in significant amounts. This raises the concern that it could affect fetal physiology or cause congenital anomalies. However, congenital malformations take place during the first nine weeks of pregnancy, while the diagnosis of GDM usually takes place at 24 to 28 weeks. Nevertheless, even if safe regarding organogenesis, it will be important to study metformin's effect on the offspring during the growth years and later in life. Metformin may slightly increase the risk of prematurity [25].

The Metformin in Gestational diabetes (MiG) trial was an important study that assessed the efficacy and safety of metformin in pregnancy. It included 751 women with GDM at 22 to 33 weeks' gestation and compared the use of insulin to metformin on measures of neonatal hypoglycemia, respiratory distress, neonatal jaundice, birth trauma, Apgar scores, and prematurity [121]. The trial results indicated that almost half of patients using metformin ended up requiring supplemental insulin to meet blood glucose targets [25]. Neonatal complications did not differ significantly between the two groups, and there were no serious adverse events associated with use of metformin. Women who used metformin reported a higher rate of satisfaction compared to insulin. While the results of MiG are promising, guidelines recommend avoiding metformin as routine therapy for GDM pending further clinical trials [10,25,75].

The MiG Trial Offspring Follow-Up (MiG TOFU) continued to follow the offspring of mothers with GDM who used metformin during pregnancy [123]. The focus of the 2011 MiG TOFU was to examine the body composition of these children at 2 years of age. Results suggest that metformin exposure in utero might lead to improved insulin sensitivity in the fetus and result in a metabolically healthier pattern of growth in early childhood, including less development of visceral fat (central adiposity), a significant component of metabolic syndrome [123]. A 2018 MiG TOFU report showed no significant differences between offspring of those treated with metformin versus insulin at 7 years of age. However, at 9 years of age, metformin offspring were larger by measures of BMI, weight, and arm and waist circumferences. Levels of fasting glucose, triglyceride, insulin, insulin resistance, A1C, cholesterol, liver transaminases, leptin, and adiponectin were similar, as were body fat percentage and abdominal fat percentages [124]. The results of MiG TOFU, while promising at first, now suggest that in utero exposure to metformin may lead to negative implications for the prevention of diabetes in the offspring of women with GDM later in life.

Other studies have shown that metformin may help decrease the risk for macrosomia in the offspring, but it does not appear to help obese mothers lose weight [122]. More follow-up studies and longitudinal research are needed to clarify these results.

A mother's diet before pregnancy appears to influence her metabolism during pregnancy, which may have important associations with a child's health at birth and later in life. Data from more than 13,000 women enrolled in the Nurses' Health Study II indicated that a prepregnancy diet high in animal fat and cholesterol could increase the risk of developing GDM. Those with the highest intake of animal fat had an increased risk for GDM compared to those with the lowest percentage. Women whose diets were high in other types of fats, such as plant-based oils, did not have an increased risk. This research suggests that reducing the amount of animal fat and cholesterol in the diet prior to pregnancy may help prevent GDM [134]. A systematic review of 14 randomized controlled trials were analyzed to determine whether dietary intervention in pregnant women could prevent GDM [133]. Three of the trials compared diet with standard antenatal care in 455 women (mean age 27.7 years in the diet group vs 29.0 years in the standard care group). All three studies reported a statistically significantly lower incidence of GDM with dietary intervention compared to standard care. Meta-analysis of two of the studies also showed a statistically significant lower incidence of gestational hypertension with dietary intervention [133].

Fetal ultrasound can detect major anatomic abnormalities in the fetus, assess fetal growth status, and provide an estimate of fetal weight. It can also detect polyhydramnios, a common finding in pregnancies complicated by diabetes. The ADA recommends fetal ultrasound to screen for congenital anomalies when the pregnant woman has an A1C greater than 7% or a fasting plasma glucose greater than 120 mg/dL, as these values are associated with a greater risk for congenital malformations [13,16].

Postpartum weight loss should be a gradual loss of the weight gained during pregnancy, in some cases in addition to excess prepregnancy weight. The aim should be to lose 0.5 to 1 pound per week [16]. A more rapid weight loss may lead to fatigue and nutrient depletion.

Hypoglycemia in the newborn is defined as blood glucose of 45 mg/dL or less, usually without any other signs. It tends to be more severe in infants of mothers with pre-existing type 1 or type 2 diabetes and occurs in 25% to 40% of these births [138]. Elevated maternal glucose levels prior to birth stimulate overproduction of insulin by the infant's pancreas, leading to hypoglycemia in the early postpartum period. Macrosomic and preterm infants are at the greatest risk for hypoglycemia.

Breastfeeding offers many health benefits to women, including those with diabetes. Furthermore, it offers immediate and future benefits to both mother and child. Healthcare providers who work with patients with diabetes should advocate for breastfeeding and support institutional policies that facilitate breastfeeding.

Lactation increases the caloric needs of the mother [141]. The initial energy demands of breastfeeding exceed the prepregnancy demand by approximately 650 calories per day. This decreases by about 100 calories in the second half of the first year of breastfeeding. The ADA recommends that breastfeeding mothers with diabetes consume at least 1,800 calories per day to meet the requirements for lactation while allowing for gradual weight loss [16]. Stored fat meets some of this need, providing about 150 calories per day. Therefore, an increase of about 500 calories per day over the prepregnancy allowance may be needed [16].

In addition, the insulin requirements for nursing mothers are about 25% lower during lactation. In GDM, breastfeeding may be associated with lower rates of postpartum diabetes and lower fasting glucose levels [13,141]. In fact, lactation results in more favorable cardiometabolic profile among postpartum women in general, including women with GDM. This may protect against metabolic syndrome later in life [141].

As noted, the hormonal fluctuations of pregnancy can increase the risk for depression, and severe depression is associated with poor glycemic control and ultimately poor pregnancy outcomes. Psychotherapy is the first line of treatment for depression during pregnancy. Referral to a mental health professional is appropriate. The safety of antidepressant medications during pregnancy is questionable, as some have been linked to congenital anomalies and infantile withdrawal syndrome. In the most severe cases, the benefits of using antidepressant medication may outweigh the risks, as fetal exposure to untreated major depressive disorder is significant. Balancing the risks to the fetus exposed to severe maternal depression and to the medications to treat depression is necessary [10].