Curr Diab Rep (2012) 12:33–42 DOI 10.1007/s11892-011-0249-0

DIABETES AND PREGNANCY (CJ HOMKO, SECTION EDITOR)

Management of Diabetes in Pregnancy Jerasimos Ballas & Thomas R. Moore & Gladys A. Ramos

Published online: 3 December 2011 # Springer Science+Business Media, LLC 2011

Abstract The link between diabetes and poor pregnancy outcomes is well established. As in the non-pregnant population, pregnant women with diabetes can experience profound effects on multiple maternal organ systems. In the fetus, morbidities arising from exposure to diabetes in utero include not only increased congenital anomalies, fetal overgrowth, and stillbirth, but metabolic abnormalities that appear to carry on into early life, adolescence, and beyond. This article emphasizes the newest guidelines for diabetes screening in pregnancy while reviewing their potential impact on maternal and neonatal complications that arise in the setting of hyperglycemia in pregnancy. Keywords Diabetes mellitus . Gestational diabetes mellitus . Metformin . Glyburide . Pregnancy; diabetes management

Introduction: Classification of Diabetes in Pregnancy The most recent criteria for diagnosis and classification of diabetes were issued by the American Diabetes Association (ADA) in 2010 [1••]. The classification includes four clinical types: 1. Type 1 diabetes (DM1), formerly referred to as insulindependent or juvenile-onset diabetes. 2. Type 2 diabetes (DM2), formerly referred to as non– insulin-dependent or adult-onset diabetes. 3. Other specific types of diabetes related to a variety of genetic-, drug-, or chemical-induced diabetes 4. Gestational diabetes mellitus (GDM).

Type 1 Diabetes Clinical Trial Acronyms ACHOIS Australian Carbohydrate Intolerance Study in Pregnant Women DCCT Diabetes Control and Complications Trial HAPO Hyperglycemia and Adverse Pregnancy Outcomes MiG Metformin in Gestational Diabetes

J. Ballas : T. R. Moore : G. A. Ramos (*) Reproductive Medicine Department, University of California San Diego, 200 West Arbor Drive, San Diego, CA, USA e-mail: [email protected]

DM1 accounts for approximately 5% to 10% of patients diagnosed with diabetes in the general population. However, DM1 may represent a slightly greater fraction of reproductiveaged women, due to the relatively earlier age of onset compared with DM2. Markers of the immune response responsible for the pancreatic islet cell destruction pathognomonic of DM1 include autoantibodies directed to pancreatic islet cells, insulin, glutamic acid decarboxylase (GAD65), and tyrosine phosphatase IA-2 and IA-2β. One or more of these autoantibodies are usually present in 85% to 90% of individuals with DM1 and elevated fasting glucose. Most evidence indicates a genetic predisposition related to an individual’s HLA associations with linkage to DQA and DQB genes.

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Type 2 Diabetes DM2 comprises 90% to 95% of those with diabetes and encompasses individuals who have insulin resistance with relative (rather than absolute) insulin deficiency. These patients, upon diagnosis and for most of their lifetime, do not require insulin therapy for survival. The specific etiology of DM2 is not known, but autoimmunity is not implicated as in DM1. Often associated with obesity or an increase in fat deposition in the abdominal region, the hyperglycemia in these patients is gradual and progressive, making ketoacidosis a rare event compared with DM1. Until recently, diagnosis of DM2 during pregnancy has been difficult due to the overlap with GDM. However, in 2008 to 2009, the International Association of Diabetes in Pregnancy Study Groups (IADPSG) and the ADA issued guidelines that state in high-risk women presenting for their first prenatal visit, DM2 may be diagnosed by the same criteria as outside of pregnancy [1••, 2••]. The new guidelines for diagnosing DM2 are as follows: 1. Hemoglobin A1c (HbA1c) >6.5%, performed in a laboratory using a method that is NGSP (National Glycohemoglobin Standardization Program) certified and standardized to the DCCT assay.* OR 2. Fasting plasma glucose of ≥126 mg/dL, with fasting defined as no caloric intake for at least 8 h.* OR 3. 2-hour plasma glucose ≥200 mg/dL during a 75-g oral glucose tolerance test (OGTT) as prescribed by the World Health Organization.* OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL. *In the absence of unequivocal hyperglycemia, criteria 1 to 3 should be confirmed by repeat testing.

Gestational Diabetes Mellitus New Diagnostic Criteria for GDM The HAPO study was a multicenter prospective cohort trial that aimed to correlate newborn outcomes and glucose parameters in “normal” women defined as those who underwent a 75-g OGTT between 28 and 32 weeks and had fasting plasma glucose ≤105 mg/dL and 2-hour plasma glucose level ≤200 mg/dL [3]. When maternal glucose levels were correlated with measures of newborn adiposity and birth weight greater than 90th percentile, the investigators found a linear relationship between increasing

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glucose levels and elevated umbilical cord C-peptide, increased percent body fat, and neonatal birth weight [3, 4•]. Considering these findings of excess neonatal obesity in women with “normal” OGTT results, the IADPSG recommended new guidelines for the diagnosis of GDM. They selected an increased odds ratio of 1.75 for the outcomes of the 90th percentile for cord C-peptide, birth weight, and percent neonatal body fat. This translated to the following threshold values based on a 75-g 2-hour OGTT: & & &

Fasting plasma glucose of ≥92 mg/dL 1-hour value of ≥180 mg/dL 2-hour value of ≥153 mg/dL

A single abnormal value would be diagnostic of GDM. Applying these new thresholds, a total of 17.8% of the HAPO cohort would be diagnosed with GDM. The committee also agreed with the ADA position recommending screening of all pregnant women at first prenatal visit to identify those with overt DM2. The IADPSG recommended that women with a fasting glucose value greater than 92 mg/dL but less than 126 mg/dL upon first trimester testing would be diagnosed with GDM. All those with normal fasting glucose values at the time of the first prenatal visit would then undergo 75-g 2-hour OGTT at 24 to 28 weeks. If adopted widely, this new protocol represents a new paradigm for diagnosing GDM based on reducing fetal and childhood morbidity rather than maternal disease as formerly. Why Should GDM Be Treated? The US Preventative Services Task Force recently concluded that, based on available evidence, screening or treatment for GDM cannot be justified [5]. However, two recent randomized controlled trials have demonstrated improved outcomes of neonates in GDM pregnancy whose mothers were treated with diet and/or insulin, compared with no treatment. Crowther et al. [6], in the ACHOIS, randomized 1,000 women with GDM to treatment or no therapy between 16 and 30 weeks of gestation. Criteria for entry into the trial were a fasting glucose less than 140 mg/dL, and a 2-hour postprandial level between 140 and 200 mg/dL, therefore excluding people with overt diabetes. Women randomized to the treatment arm monitored glucose four times daily and dietary counseling was provided. Plasma glucose targets were premeal values less than 99 mg/dL and 3-hour postprandial levels less than 126 mg/dL. Approximately 20% in the treatment arm required insulin to achieve glycemic goals. The birth weight in the intervention group was lower (3,335±551 g vs 3,482±660 g; P<0.001) and perhaps more importantly, the rate of large for gestational (LGA) infants (13% vs 22%; P<0.001) and the rate of macrosomia (10% vs 21%; P<0.001) were reduced by

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approximately half. Serious perinatal complications were significantly lower among the infants in the treatment group when compared with the routine care group (adjusted RR: 0.33 [0.14–0.75]). Umbilical cord leptin, a protein linked to the development of fetal adiposity, was significantly lower (P=0.02). In 2009, a randomized controlled trial reported by the National Institute of Child Health and Development Maternal-Fetal Medicine Network evaluated the effects of treating mild GDM [7••]. Women were included if they had two abnormal values on a 3-hour OGTT (100 mg/dL) between 24 and 31 weeks and excluded if the fasting plasma glucose was greater than 95 mg/dL. The treatment group received medical nutritional therapy and insulin as needed to maintain fasting glucose values below 95 mg/dL and 2-hour postprandial levels below 120 mg/dL. Approximately 8% of the intervention group required insulin. Among those in the treatment arm, there was a significant reduction in mean birth weight (3,302±502 g vs 3,408± 589 g), and neonatal fat mass (427±198 g vs 464±222 g). The frequency of LGA (7.1% vs 14.5%), and macrosomic infants (4,000 g; 5.9% vs 14.3%) was reduced by approximately half. The rates of shoulder dystocia (1.5% vs 4.0%), and cesarean delivery (26.9% vs33.8%) were also significantly lower among the treated women.

Treatment of Diabetes During Pregnancy Timing of Capillary Glucose Monitoring Postprandial glucose values have the strongest correlation with fetal growth. The Diabetes in Early Pregnacy study reported that when postprandial glucose values averaged 120 mg/dL, approximately 20% of infants were macrosomic, whereas a modest 30% rise in postprandial glucose levels to a mean of 160 mg/dL resulted in a 35% macrosomia rate [8]. Similarly, de Veciana et al. [9] randomized diabetic women to use of preprandial or postprandial blood glucose levels for dietary and insulin management. In women managed with postprandial blood glucose levels, the mean (± SD) decrease in the glycated hemoglobin during treatment was greater (−3%±2.2% vs 0.6%±1.6%; P<0.001), birth weights were lower (3,469± 668 g vs 3,848±434 g; P=0.01), and the rates of neonatal hypoglycemia (3% vs 21%; P=0.05) and macrosomia (12% vs 42%; P=0.01) were lower. Therefore, a typical glucose monitoring schedule involves capillary glucose checks at fasting, 1, or 2 h after each meal and at bedtime. For patients taking intermediate- or long-acting medication at bedtime, a capillary glucose level between 3 AM and 4 AM (the glucose nadir of the day) can aid with interpretation of the glucose values obtained in the morning.

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Target Capillary Glucose Levels Parretti et al. [10] profiled glucose variation in normal pregnant women twice monthly during the third trimester, monitoring pre- and postprandial glucose values. The 95th percentiles of the plasma glucose excursions are shown in Fig. 1. It can be seen that fasting and premeal plasma glucose levels are usually below 80 mg/dL and often below 70 mg/dL. Peak postprandial plasma glucose values rarely exceed 110 mg/dL. Accordingly, the Fifth International Workshop Conference on Gestational Diabetes currently recommends the following target glucose values [11]: 1. Fasting plasma glucose 90 to 99 mg/dL (5.0–5.5 mmol/L) and 2. 1-hour postprandial plasma glucose less than 140 mg/dL (7.8 mmol/L) Or 3. 2-hour postprandial plasma glucose less than 120 to 127 mg/dL (6.7–7.1 mmol/L)

Oral Medications in Diabetic Pregnancy Historically, insulin has been the mainstay of therapy for GDM because it does not cross the placenta into the fetus and has many decades of proven efficacy. However, use of insulin during GDM pregnancy, which may comprise as few as 3 to 6 weeks of treatment, requires extensive teaching and monitoring. Injection of insulin at multiple times in the day may be inconvenient. Thus oral agents, if effective, would be a welcome substitute for insulin for many women. Unfortunately, most of the oral agents used in the nondiabetic population have not been tested for safety in pregnancy. Further, early reports of use of oral hypoglycemic drugs (eg, sulfonylureas) in pregnancy indicated increased fetal anomalies and prolonged neonatal hypoglycemia [12]. More recently however, when Towner et al. [13] evaluated the frequency of birth defects in patients who took oral hypoglycemic agents during the periconceptional period, they concluded that the risk of fetal anomalies was strongly associated with the first-trimester HbA1c level and duration of diabetes but not with the use of oral hypoglycemic medications. Glyburide Glyburide, a second-generation sulfonylurea, has been shown to cross the placenta minimally in both laboratory studies and a large clinical trial [14]. A prospective randomized trial, conducted by Langer et al. [15], compared glyburide with insulin in 404 women with GDM and showed equivalently excellent maternal glycemic control and perinatal outcomes.

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Fig. 1 Diurnal plasma glucose profile in normoglycemic third trimester gravidas. The numbers represent the 95th percentile values. (Adapted from Parretti E, Mecacci F, Panini M, et al.: Third trimester maternal glucose levels from diurnal profiles in nondiabetic pregnancies: Correlation with

sonographic parameters of fetal growth. Diabetes Care 24:1317, 2001) [61]. (Copyright American Diabetes Association. Reprinted with permission from the American Diabetes Association)

Chmait et al. [16], reporting experience with 69 patients with gestational diabetes who were given glyburide, found a failure rate of 19% (>10% glucose values above target). Glyburide failure rate was higher in women diagnosed earlier in pregnancy (20 vs 27 weeks; P<0.003) and whose average fasting glucose in the week prior to starting glyburide was higher (126 vs 101 mg/dL). Following the publication of the randomized control trial, several retrospective series have been published comprising 504 glyburide-treated patients, summarized recently by Moore [17]. Jacobson et al. [18] performed a retrospective cohort comparison of glyburide and insulin treatment of gestational diabetes. The insulin group (n=268) consisted of those diagnosed in 1999 through 2000 and the glyburide group (n=236) was diagnosed in 2001 through 2002. There were no statistically significant differences in gestational age at delivery, mode of delivery, birth weight, LGA, or percent macrosomia. The rate of preeclampsia doubled in the glyburide group (12% vs 6%; P<0.02). The glyburide group was also superior in achieving target glycemic levels (86% vs 63%; P<0.001). The failure rate (transfer to insulin) was 12%. At present there is a growing acceptance of glyburide use as a primary therapy for GDM [19]. A significant concern is the documented transfer of glyburide across the placenta. Recently, a study of the pharmacokinetics of glyburide in pregnancy demonstrated a ratio of umbilical cord/maternal plasma glyburide (ng/mL) concentration of 0.7±0.4 [20].

fertility [21]. The safety profile of metformin in the first trimester and apparent lack of teratogenicity has been well documented in patients where pregnancy is achieved while undergoing treatment. Older studies evaluating the efficacy and safety of the treatment of women with pregestational and gestational diabetes with metformin raised concerns regarding a higher perinatal mortality, higher rate of preeclampsia, and failure of therapy [22, 23]. However, the metformin-treated women in these early studies were older, more obese, and treated later in pregnancy. A more recent cohort study of metformin in pregnancy was reported by Hughes and Rowan [24] including 93 women with metformin treatment (only 32 continued until delivery) and 121 controls. There was no difference in perinatal outcomes between the groups. Recently, a large randomized controlled trial was performed comparing metformin to insulin for the treatment of gestational diabetes (MiG trial) [25•]. This study was powered to detect a 33% increase in composite outcome (neonatal hypoglycemia, respratory distress, need for phototherapy, birth trauma, 5-minute Apgar of <7, or prematurity). A total of 751 women with GDM between 20 and 30 weeks of gestation were randomized to metformin or insulin. Fortysix percent of women receiving metformin required the addition of insulin to obtain glycemic control. There were no differences in the rate of the primary composite outcome, a lower rate of severe neonatal hypoglycemia, and no differences in neonatal anthropometric measurements in the metformin-treated group. However, there was a higher rate of prematurity in the metformin-treated group (12.1%) versus the insulin group (7.6%). The authors acknowledge that the rate of preterm births was due to a

Metformin Metformin is frequently used in patients with polycystic ovary syndrome and DM2 to improve insulin resistance and

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higher number of spontaneous preterm births, which may be due to chance alone or some as-yet undetermined effect of metformin. However, other data published by the same author and other authors do not reflect this finding. Goh et al. [26] performed a prospective study of 1,269 women with GDM. In their study, 371 women were treated with diet, 399 with insulin, and 465 with metformin (250 metformin alone, 215 metformin plus insulin). In their insulin group, there were more preterm births (attributed to iatrogenic preterm births—there was no difference in rates of spontaneous preterm births between groups) than in the diet and metformin-treated groups. In subanalysis, when comparing women treated with metformin plus insulin versus insulin alone, there were fewer preterm births in women treated with metformin plus insulin (12.8% vs 19.2%; P=0.04). The rate of preterm birth in the metformin group was no different from that of women treated with diet. A follow-up study is currently underway to assess the offspring of the women enrolled in the MiG trial at 2 years of age. In summary, using metformin in pregnancy for women with GDM or DM2, either alone or as an adjunct to insulin therapy, appears to be safe and efficacious. In the setting of women being treated with metformin for polycystic ovary syndrome alone, it may be beneficial to discontinue treatment to properly screen and diagnose for GDM and then treat accordingly.

Principles of Insulin Therapy in Pregnancy No available insulin delivery protocol approaches the precise secretion of the hormone from the human pancreas, but the therapeutic goal of exogenous insulin therapy during pregnancy is to achieve diurnal glucose excursions similar to those of nondiabetic pregnant women. Normal pregnant women maintain postprandial blood glucose excursions within a relatively narrow range (70–120 mg/dL). As pregnancy progresses, the fasting and between-meal blood glucose levels drop progressively lower as a result of the continual uptake of maternal glucose by the growing fetus. Insulin regimens for pregnant women must be designed to avoid excessive unopposed insulin action during the fasting or interprandial periods while ensuring adequate insulin dosing during the highly insulin resistant morning hours. Insulin type and dosage frequency should be individualized. Use of short-acting regular insulin or rapid-acting insulin (eg, lispro or aspart) before each major meal helps limit postprandial hyperglycemia. To provide safe but not excessive basal glucose levels between meals, intermediate and longer-acting preparations may be necessary, such as isoprotane insulin (NPH) or insulin glargine (Lantus),

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respectively. Typical subcutaneous insulin dosing regimens deliver two thirds of total insulin in the morning, two thirds of which are intermediate-acting and one third of which is regular insulin. The remaining one third of the total insulin dose is given in the evening, with 50% as short-acting insulin prior to dinner and 50% as intermediate-acting given after 10 PM. The use of a subcutaneous insulin infusion with a portable pump for DM1 during pregnancy has become more widespread [27]. An advantage of this approach is the more physiologic insulin release pattern that may be achieved with the pump. Recent metanalysis of six randomized controlled trials comparing multiple insulin injections to the insulin pump did not find any significant differences in pregnancy outcomes or glycemic control [28].

Maternal and Fetal Complications in Diabetic Pregnancies Hypertension and Preeclampsia Pregnant women with pregestational diabetes have a fourfold increased risk of hypertension during pregnancy compared with nondiabetic pregnant women [29]. A significant portion of this risk is attributed to the increased rate (10% to 20%) of pre-existing chronic hypertension in such populations. Longer duration of disease, poor glycemic control, co-existing maternal obesity, and pre-existing renal compromise increase the likelihood of hypertensive complications in diabetic pregnancies [30]. Similarly, the risk of developing preeclampsia in pregestational diabetic pregnancy is elevated approximately fourfold compared with nondiabetic pregnancy, reaching as high as 40% to 50% when co-existing chronic hypertension or renal disease are present [31]. Recent trials have shown increased risk of gestational hypertension and preeclampsia with a diagnosis of GDM only [3, 4•, 32]. Chronic hypertension in a diabetic patient should be suspected when blood pressures exceed 130/80 mm Hg prior to or during the first trimester. If this is found, supporting blood work may include blood urea nitrogen (>10 mg/dL), serum creatinine (>1 mg/dL), and creatinine clearance (<100 mL/min). If blood pressure exceeds 140/ 90 mm Hg after 20 weeks, workup for preeclampsia should be initiated, including a complete blood count and liver function tests in addition to the aforementioned blood work. If preeclampsia is ruled out, and chronic hypertension is suspected, initiating pharmacotherapy for blood pressures greater than 150/100 mm Hg is warranted to reduce maternal morbidities, including stroke and placental abruption, although benefit to the fetus beyond preventing iatrogenic prematurity has not been established.

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Renal Impairment and Nephropathy Diabetes can have profound effects on the kidneys, evidenced by the fact that it remains the single most common cause of end-stage renal disease in the United States. Pregnancy also impacts the kidney, with significant increases in renal perfusion (30%) and glomerular filtration rate (50% to 100%) occurring over the course of a normal pregnancy. Women with underlying preexisting moderate-to-severe nephropathy (urine albumin:creatinine ratio ≥300) or renal impairment (serum creatinine >1.4 mg/dL) are at the greatest risk for deterioration of renal function, profound proteinuria, exacerbation of coexisting hypertension, fetal growth restriction, and preeclampsia. These risks are significantly increased in the setting of poor glycemic control and uncontrolled chronic hypertension [33]. Pregnant women with DM2 of any duration, all who have DM1 with a diagnosis more than 5 years, and those with comorbidities such as chronic hypertension should be screened for nephropathy prior to 20 weeks gestation. Either a spot protein-to-creatinine ratio (30–299 μg/mg for microalbuminuria and ≥300 μg/mg for macroalbuminuria) or 24-hour urine collection for both total protein and creatinine clearance should be performed (>300 mg/24 hours is diagnostic of proteinuria). Improved glucose management and appropriate antihypertensive therapy are the mainstays of therapy, having been shown to have a modest improvement on pregnancy outcomes and renal protection [33–36, 37•]. Diabetic Retinopathy Retinopathy is noted in almost 80% of women who have had diabetes for 20 years or more, and virtually all patients with DM1 after 25 years have some form of retinopathy [29, 30]. Pregnancy, which was once thought to globally exacerbate and potentially accelerate the process, seems to primarily affect women who are at high risk for proliferation at baseline—namely women with diabetes for greater than 10 years, pre-existing moderate-to-severe retinopathy, and poor glycemic control as evidenced by high initial HbA1c levels (HbA1c >6 SDs). Concomitant hypertension and preeclampsia are also risk factors for progression in pregnancy [38]. Laser coagulation has been shown to be safe and efficacious in pregnancy for the treatment of the pre-proliferative stages of retinopathy and has allowed for improved outcomes in a subset of patients in which pregnancy was once contraindicated [39]. Screening for retinopathy is recommended in all women with pre-existing diabetes for more than 5 years, ideally before pregnancy or as early in a pregnancy as possible. In rare cases of severe disease that may be refractory to laser coagulation, termination of pregnancy can be considered given the high risk of permanent blindness. Stable diabetic retinopathy is not considered a contraindication to vaginal

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delivery; however, elective cesarean delivery may be considered to avoid increased intraocular pressure in cases that necessitated, or were refractory to, laser coagulation. Diabetic Ketoacidosis The prevalence of diabetic ketoacidosis (DKA) in diabetic pregnancies is extremely low (1% to 2%); however, it presents one of the true medical emergencies in pregnancy that still carries a significant amount of maternal and fetal morbidity and mortality. It is overwhelmingly observed in women with DM1, although cases in women with DM2 and GDM have also been reported [29, 33]. As in non-pregnant women, DKA is often brought on by an inciting factor such as infection, dehydration, and poor compliance with medication. Pregnancy, unfortunately, puts women at an increased risk for DKA given the increased rates of urinary tract infections, pyelonephritis, vomiting, dehydration, insulin insensitivity, lipolysis, ketosis, and exposure to drugs such as steroids or β-sympathomimetic drugs compared with a non-pregnant population [29, 30, 33]. The workup and treatment protocols do not differ between pregnant and non-pregnant patients; however, it should be understood that up to one third of pregnant women in DKA could present with minimally elevated blood glucose (>200 mg/dL) given the baseline level of pregnancy-induced insulin insensitivity. Therefore, additional criteria should be sought, including a fall in serum bicarbonate below 18 mg/dL, a pH less than 7.30, positive serum ketones at a 1:4 dilution, or a blood gas with a base excess of −4 or lower, indicating a metabolic acidemia [40, 41]. Once the diagnosis is made, the inciting factor should be identified and treated in conjunction with standard DKA treatment protocols, which include rapid rehydration, continuous urine output assessment, correction of glycemic derangement with intravenous insulin and glucose, and the appropriate replenishment of electrolytes, namely potassium to prevent cardiac arrhythmias and bicarbonate to mitigate acidemia. Fetal status may be assessed periodically in gestations ≤24 weeks, and continuously in all gestations greater than 24 weeks, with the understanding that the vast majority of fetal heart rate abnormalities will normalize with improvement of maternal status. Emergent delivery should be avoided unless impending fetal compromise becomes apparent despite treatment of DKA [42]. Diabetic Gastropathy The diagnosis of gastroparesis is established by gastric emptying scintigraphy, in which food is retained in the stomach for more than 12 h. Gastroparesis is considered a relative contraindication to pregnancy given the significant maternal morbidity and poor reported perinatal outcomes [35]. Gastroparesis is exceedingly difficult to manage

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considering the decreased gastric motility and the increased gastroesophageal reflux and vomiting that accompanies pregnancy. It can be differentiated from classic hyperemesis in that nausea and vomiting are alternatively associated with bloating, postprandial fullness, severe abdominal pain, and cramping separate from episodes of vomiting. For women with gastroparesis treatment is mainly supportive. Correcting for electrolyte disturbances, maintaining hydration, providing comfort measures for gastric pain, and relief of nausea with centrally acting antiemetics and prokinetic agents that aim to improve gastric motility are goals of therapy [43, 44]. If oral nutrition proves impossible or signs of maternal malnutrition or fetal growth restriction are seen, parenteral feeds, jejunal feeds, or gastrostomy tubes may be needed, although all of these present challenges and risks for an as-yet determined overall benefit.

Fetal and Neonatal Complications in Diabetic Pregnancies Although the overall incidence of fetal loss in diabetic pregnancies has decreased 30-fold since the introduction of insulin in the 1920s, the rate of perinatal mortality in diabetic pregnancies still remains twice that of the nondiabetic population [29]. The largest contributor to this mortality rate, as well as significant ongoing morbidity, is structural fetal anomalies [30]. Additionally, the incidence of fetal overgrowth and accompanying endocrine derangement is significantly increased in these offspring, leading to increased risk for intrauterine and neonatal demise, birth trauma, neonatal hypoglycemia and its sequelae, and long-term risk for metabolic syndrome in childhood and adolescence. Birth Defects Population studies have consistently shown a two- to sixfold increase in major malformations in infants born to diabetic mothers [30]. Although the precise mechanism leading to fetal malformations is poorly understood, it has long been established that poor glycemic control at time of conception, duration of disease, and the presence of vascular comorbidities are associated with the risk of malformations [13, 45]. Cardiac defects, whether isolated or combined with other defects, are the most prevalent and consistently associated malformations. Other anomalies include intracranial anomalies, spinal defects, limb deficiencies, facial clefts, and distal gastrointestinal atresias [46, 47]. While maternal obesity is increasingly being seen as an independent risk factor for many of these anomalies, its role as a positive risk modifier in diabetic women has also been established [47, 48]. Women with pregestational diabetes should undergo preconception counseling that stresses the importance of

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good glycemic control, with a goal of HbA1c of less than 7% to decrease the risk of birth defects. Once pregnant, women with diabetes should have a detailed anatomy ultrasound performed between 18 and 20 weeks. If the patient has received low-risk results from serum screening for aneuploidy and the anatomic images, including cardiac views, can be completely cleared as normal at that time, no further screening for congenital anomalies is necessary. However, if cardiac views are inadequate for any reason, a fetal echocardiogram is warranted. Fetal Overgrowth and Associated Complications Fetal macrosomia (birth weight >90th percentile or 4,000 g) has been found to occur at a 10-fold higher rate in diabetic pregnancies compared with a normal population [30]. It is this weight disparity that is felt to contribute to greater risk of birth trauma and cesarean deliveries in diabetic pregnancies. When compared with nondiabetic pregnancies, the rate of shoulder dystocia is increased two to four times in diabetic pregnancies, whereas a woman’s risk of cesarean delivery may increase as high as sixfold [49–52]. Maternal fasting blood glucose levels have been viewed as the strongest predictor of fetal macrosomia, particularly in the second and third trimester [29, 30]. Recent data from the HAPO study show that in a population with insulin insensitivity that would otherwise screen negative for GDM there is a significant, linear relationship between elevated blood glucose value (>1 SD) on a 2-hour glucose test and higher rates of macrosomia, cesarean deliveries, and newborn morbidity [3]. Conversely, improved blood glucose monitoring and strict control have been associated with improvement of all of these outcomes [4•, 6, 7••]. Co-existing maternal obesity may serve as strong confounder as well as an independent factor for fetal overgrowth in diabetic pregnancies, particularly in women diagnosed with GDM [53, 54]. Ultrasound evaluation to assess the fetal growth is an important part of the treatment paradigm in diabetic pregnancies. Fetal overgrowth is most reliably identified in the second and third trimesters, with accelerated abdominal circumference growth beginning at approximately 32 weeks being one of the most consistent findings [55]. This correlates with newborn biometric studies that show excess fetal weight tends to be disproportionally deposited along the abdomen and interscapular region, which likely relates clinically to increased risk of shoulder dystocia and labor abnormalities [56]. Because the American College of Obstetricians and Gynecologists recommends offering elective cesarean delivery in diabetic pregnancies with an estimated fetal weight exceeding 4,500 g, typically an ultrasound is performed between 36 and 37 weeks in all diabetic pregnancies to plan for mode of delivery [57]. Although macrosomia is strongly associated with suboptimal glucose control in diabetic

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pregnancies, the risk of intrauterine growth restriction must always be considered in diabetic patients in whom disease has been long-standing and there is known cardiovascular or renal compromise. If growth restriction is found, close monitoring of interval growth with Doppler assessments of uteroplacental function and vigilant screening for preeclampsia should be implemented. Fetal lung development is delayed in diabetic pregnancies, likely due to elevated fetal insulin interfering with endogenous glucocorticoid-induced pulmonary maturation at the level of the pulmonary fibroblasts [30]. This delayed maturation likely leads to the disproportionate excess of respiratory distress in near-term infants from diabetic pregnancies [58]. Clinically, this may pose a challenge to timing delivery at term. Although 99% of normal infants at 37 weeks were found to have mature lung phospholipid profiles, in diabetic pregnancies such high proportions are not reached until 38.5 weeks, which should be taken into account before induction of labor, and certainly cesarean delivery, is planned prior to 39 weeks [59].

Conclusions Diabetes in pregnancy is a condition associated with significant morbidity for both mother and offspring. Owing to the global rise in obesity, managing pregnancies to minimize these morbidities will be increasingly challenging. Although significant advances have been achieved, improving maternal, fetal, and neonatal morbidity and mortality, our understanding of this ancient disease continues to be challenged. With the growing body of research linking in utero exposure to abnormal glucose levels with the development of childhood and adult metabolic syndrome, aggressive diagnosis and treatment of diabetes during pregnancy appears warranted [60].

Disclosure No potential conflicts of interest relevant to this article were reported.

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