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ACOG Practice Bulletin No. 201: Pregestational Diabetes Mellitus

doi: 10.1097/AOG.0000000000002960
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Pregestational diabetes mellitus represents one of the most challenging medical complications of pregnancy because of the need for frequent monitoring and adjustment of medications as well as the potential for maternal and fetal complications. This document provides an overview of the current understanding of pregestational diabetes mellitus and suggests management guidelines during pregnancy. Because few well-designed studies have been performed, many of the guidelines are based on expert and consensus opinion. This document has been updated to reflect current data on pregestational diabetes. This Practice Bulletin is updated with summary information to counsel and manage women with pregestational diabetes before and during pregnancy, more recent literature reflecting experience with continuous subcutaneous insulin infusion during pregnancy, an expanded section on the role of oral hypoglycemic agents in pregnancy, and the option of long-acting reversible contraception during the postpartum period.

This information is designed as an educational resource to aid clinicians in providing obstetric and gynecologic care, and use of this information is voluntary. This information should not be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. It is not intended to substitute for the independent professional judgment of the treating clinician. Variations in practice may be warranted when, in the reasonable judgment of the treating clinician, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology. The American College of Obstetricians and Gynecologists reviews its publications regularly; however, its publications may not reflect the most recent evidence. Any updates to this document can be found on www.acog.org or by calling the ACOG Resource Center.

While ACOG makes every effort to present accurate and reliable information, this publication is provided “as is” without any warranty of accuracy, reliability, or otherwise, either express or implied. ACOG does not guarantee, warrant, or endorse the products or services of any firm, organization, or person. Neither ACOG nor its officers, directors, members, employees, or agents will be liable for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with this publication or reliance on the information presented.

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Number 201 (Replaces Practice Bulletin Number 60, March 2005)

Committee on Practice Bulletins—Obstetrics. This Practice Bulletin was developed by the American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics with the assistance of Aaron B. Caughey, MD, PhD; Anjali J. Kaimal, MD, MAS; and Steven G. Gabbe, MD.

Published online on November 20, 2018.

Copyright 2018 by the American College of Obstetricians and Gynecologists. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, posted on the Internet, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without prior written permission from the publisher.

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American College of Obstetricians and Gynecologists 409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920

Pregestational diabetes mellitus. ACOG Practice Bulletin No. 201. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;132:e228–48.

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Background

Definition and Prevalence

An estimated 14.9 million women in the United States have diabetes mellitus (1). The prevalence of diabetes mellitus in women of reproductive age has been reported to be from 3.1% to 6.8%, with pregestational diabetes observed in 1–2% of all pregnancies (2–4). Type 1 pregestational diabetes mellitus is characterized by an autoimmune process that destroys the pancreatic β cells, which leads to onset earlier in life, the need for insulin therapy, and the potential development of vascular, renal, and neuropathic complications. In contrast, type 2 diabetes mellitus, which has become the most common form of pregestational diabetes, is characterized by onset later in life, peripheral insulin resistance, relative insulin deficiency, and obesity. Although 90% of cases of diabetes encountered during pregnancy are gestational diabetes mellitus, more than one half of these women develop type 2 diabetes mellitus later in life. There are racial and ethnic disparities in women with pregestational diabetes. One study found higher rates in black, Native American, and Hispanic women and lower rates in non-Hispanic white and Asian women (4). Interestingly, type 1 and type 2 diabetes have both increased in recent years, and there are variations by race and ethnicity; non-Hispanic white women have had the greatest increase in type 1 diabetes, and Hispanic women have experienced the greatest increase in type 2 diabetes (5). The increasing incidence of type 2 pregestational diabetes mellitus is caused, in part, by increasing obesity in the United States (6, 7). Historically, any time diabetes was diagnosed during pregnancy, it was considered gestational diabetes. However, if diabetes is diagnosed in the first trimester or early second trimester with the standard diagnostic criteria of a hemoglobin A1c (HbA1c ) of 6.5% or greater, a fasting plasma glucose of 126 mg/dL or greater, or a 2-hour glucose of 200 mg/dL or greater on a 75-g oral glucose tolerance test, it is considered pregestational diabetes (8). There is little or no guidance regarding the diagnosis of pregestational diabetes in the late second trimester or third trimester.

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Management of Diabetes During Pregnancy

Pregnancy is broadly characterized by increased insulin resistance. Because placental-produced hormones increase through the second trimester and much of the third trimester, insulin resistance is greatest in the third trimester. This physiologic change is similar to the pathophysiology of type 2 diabetes and, thus, can increase insulin requirements and worsen glycemic control in women with either type 1 or type 2 diabetes (9). The increase in insulin resistance is primarily the result of the effects of several placental hormones, including human chorionic somatomammotropin (human placental lactogen), progesterone, prolactin, placental growth hormone, and cortisol. Additionally, tumor necrosis factor α and leptin have been implicated as contributors to the insulin resistant state of pregnancy and resultant maternal hyperglycemia (10, 11). The one exception to this is the late first trimester when relatively higher levels of estrogen may transiently enhance insulin sensitivity and increase the risk of maternal hypoglycemia especially when associated with nausea and vomiting.

Maternal glucose control should be maintained near physiologic levels before and throughout pregnancy to decrease the likelihood of complications of hyperglycemia, including spontaneous abortion, fetal malformation, fetal macrosomia, fetal death, and neonatal morbidity. The management of pregestational diabetes in pregnancy focuses on optimal glucose control, which is achieved using a careful combination of diet, exercise, and medical therapy (12–16). Self-monitoring of blood glucose using fingerstick glucose values recorded in glucose logs are commonly reviewed at least every 1–2 weeks during the first two trimesters and weekly after 24–28 weeks of gestation in order to adapt the treatment regimen to fluctuating insulin needs. In someone with excellent control, this can be individualized.

Similar to the management of gestational diabetes mellitus and diabetes mellitus in nonpregnant individuals, medical nutrition therapy with a carbohydrate-controlled diet is important (17). When possible, having a registered dietitian or certified diabetes educator involved in nutritional counseling is beneficial (18). Because of the physiologic changes that occur during pregnancy, caloric requirements are increased by approximately an additional 300 kcal/day during the second and third trimesters (19). Although the optimal dietary composition for pregnancy is unknown, wholesome food choices (including 40–50% from complex, high-fiber carbohydrates, 15–30% from protein, and 20–35% from primarily unsaturated fats) are commonly advised (20). Generally, the dietary approach to glycemic control is focused on careful carbohydrate counting and allocation of appropriate ratios of carbohydrates to meals and snacks. For example, typical carbohydrate allocation ranges might be 30–45 g at breakfast, 45–60 g at lunch and dinner, and 15-g snacks approximately 2–3 hours after each meal. Carbohydrate counting increases dietary flexibility and insulin dose can be tailored to the planned carbohydrate intake. Rather than simple carbohydrates, complex carbohydrates are recommended because they are digested more slowly and are less likely to produce significant postprandial hyperglycemia (21). It is thought that artificial sweeteners may be safely used in moderate amounts in pregnancy, though there are no large cohort or case–control studies to support this (22). Patients should be encouraged to keep a log of food intake with the specific carbohydrate counts so that this information can be correlated with insulin dosages, exercise, and glucose values.

Most insulin used in the treatment of pregestational diabetes mellitus is biosynthetic human insulin. Insulin requirements will increase throughout pregnancy, most markedly in the period between 28 weeks and 32 weeks of gestation (23). On average, insulin needs increase from a range of 0.7–0.8 units/kg actual body weight/day in the first trimester, to 0.8–1 units/kg/day in the second trimester, to 0.9–1.2 units/kg/day in the third trimester (14, 24). The goal of therapy is to achieve euglycemia in pregnancy without significant hypoglycemia because acute episodes of hypoglycemia can be unsafe. Glycemia goals generally include fasting and premeal glucose values of 95 mg/dL or less and either 1-hour postprandial levels of 140 mg/dL or less or 2-hour postprandial values of 120 mg/dL or less. During the night, glucose levels should not decrease to less than 60 mg/dL. Mean capillary glucose levels should be maintained at an average of 100 mg/dL (25, 26) to minimize fetal risk and complications of pregnancy (27, 28). In the second and third trimesters, an HbA1c less than 6% has the lowest risk of large-for-gestational-age infants (16). Importantly, because of the association of elevated glucose values and congenital anomalies, aggressive approaches to glycemic control early in the first trimester before or during embryogenesis may reduce the risk of fetal anomalies.

Short- or rapid-acting insulin analogues (eg, insulin lispro, insulin aspart) are administered before meals to reduce glucose elevations associated with eating (29, 30) (Table 1). Although regular insulin is considered a short-acting insulin, it is not interchangeable with the rapid-acting insulin analogues. Generally, insulin lispro and insulin aspart should be used preferentially instead of regular insulin because both have a more rapid onset of action, which enables the patient to administer her insulin right before the time of a meal rather than 10–15 minutes or longer before an anticipated meal (31). Although their rapid onset of action improves compliance, patient satisfaction, and glycemic control, insulin lispro or insulin aspart can cause significant hypoglycemia if administered inappropriately. However, it appears that, generally, there are fewer hypoglycemic episodes with lispro or aspart than with regular insulin (32). Because of improved outcomes and compliance when used subcutaneously, lispro and aspart insulin generally are preferred over regular insulin (33). A recent European study found a lower rate of congenital anomalies in fetuses when women were treated with insulin analogues, particularly the short acting agents, versus human insulin alone (34).

Table 1.

Table 1.

Longer acting or basal insulins (eg, neutral protamine Hagedorn [NPH], glargine, or detemir) are used to maintain euglycemia between meals and in the fasting state (Table 1). Usually, NPH is given before breakfast with a rapid-acting insulin and before the evening meal or at bedtime (29, 30). Bedtime administration is preferred because an injection given with the evening meal may increase the risks of nocturnal hypoglycemia.

Glargine and detemir are long-acting human insulin analogues produced with recombinant DNA. The absorption of these analogues is delayed, which creates a steady basal insulin state with minimal peak and generally a 24-hour duration (35). A meta-analysis from 331 pregnancies with glargine exposure showed no significant differences in maternal or neonatal outcomes between use of glargine and NPH during pregnancy (36). Detemir received approval from the U.S. Food and Drug Administration for reclassification to pregnancy category B from category C in 2012 based on a randomized trial that compared detemir to NPH in more than 300 pregnant women with type 1 diabetes mellitus. The study showed that detemir was noninferior to NPH in lowering HbA1c and preventing hypoglycemic episodes (37). A retrospective study of singleton pregnancies in women with type 1 diabetes who used either detemir or glargine from the start of the pregnancy showed comparable pregnancy outcomes and safety (38). There are few studies of these agents in pregnant women with type 2 diabetes, but the safety data should be similar, and they can be used when deemed to be clinically indicated. One recent study found lower rates of congenital anomalies in women treated with insulin analogues (34).

Frequent self-monitoring of blood glucose is assumed to be important to achieve euglycemia without significant hypoglycemia during pregnancy. However, no particular approach to blood glucose monitoring has been demonstrated to be superior to any other (39). A common approach is to check capillary glucose levels using a glucose meter in the fasting state, 1 or 2 hours after each meal, and before bed. If insulin dose is based on premeal values, premeal assessment should be integrated as well. Blood glucose meters indicate plasma glucose levels. Fasting glucose levels reflect the action of overnight basal insulin, whereas glucose concentrations before meals indicate daytime basal insulin activity (29). Levels after meals reveal the effect of the meal and recent insulin doses. In selected patients, especially those on insulin pumps, glucose determinations at 2–3 am may help detect nocturnal hypoglycemia, which can then cause elevated fasting blood glucose values through excessive carbohydrate intake to correct the low glucose level or through the Somogyi effect. Nocturnal hypoglycemia is caused by excessive basal insulin or an inadequate bedtime snack. Nocturnal hyperglycemia may be due to insufficient basal insulin or pump failure.

Increasingly, continuous glucose monitors are used to assess glucose control in individuals with diabetes mellitus. Continuous glucose monitors measure the glucose content of interstitial fluid through a needle sensor inserted subcutaneously. Occasional fingersticks are still necessary for calibration. A recent trial found that in comparison to offspring of pregnant women randomized to usual care with capillary blood glucose monitoring, the offspring of pregnant women randomized to continuous glucose monitors were less likely to experience neonatal hypoglycemia, be large for gestational age, or be admitted to the neonatal intensive care unit (40). Alternatively, another recent trial of continuous glucose monitoring found no difference in fetal macrosomia but did demonstrate lower rates of preeclampsia in women randomized to continuous glucose monitors (41). Closed loop systems that take the information from a continuous glucose monitor and actually change the insulin dose in an insulin pump are now available and, in one small case series in pregnant women, showed some promise with fewer hypoglycemic episodes (42).

Insulin doses generally are changed in response to a pattern of hyperglycemia or hypoglycemia. Hemoglobin A1c may be used as an integrated measure of glucose but may not fully capture hyperglycemia and hypoglycemia, therefore, it should be used as a secondary measure of glycemic control. Given the alteration in red blood cell turnover and physiologic changes in glucose parameters, HbA1c levels may need to be monitored more frequently in pregnancy than in the nonpregnant population (eg, monthly).

Because of the risk of diabetic ketoacidosis (DKA), women with pregestational diabetes should check urine ketones when their glucose levels exceed 200 mg/dL and immediately report positive test results to their health care teams. Historically, it was thought that women with type 2 diabetes could not develop DKA, but now there is evidence to the contrary, so these women should follow these recommendations just as women with type 1 diabetes do (43, 44). In particular, it appears that African-American women may more commonly present with ketosis-prone type 2 diabetes (45).

Even with meticulous monitoring, hypoglycemia is more frequent in pregnancy than at other times, particularly in women with type 1 pregestational diabetes mellitus. Patients should be questioned to determine if they can recognize when their glucose levels decrease to less than 60 mg/dL. Patients and their families should be taught how to respond quickly and appropriately to hypoglycemia. The best approach is to have glucose tablets available at all times. A drink of fruit juice or milk can be used if immediately available. In general, patients should be instructed to consume 15 g of carbohydrate and then wait 15 minutes for their glucose level to correct before taking in additional glucose (46). Patients should have glucagon on hand for severe hypoglycemia and loss of consciousness. Glucagon administration can be performed by nonmedical personnel, including family members, who should know where glucagon is kept and how to administer it. Patients also should wear a medical bracelet or necklace that indicates they have diabetes (47).

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Maternal Morbidity

Pregnancy has been associated with exacerbation of diabetes-related complications, particularly retinopathy and nephropathy (48, 49). Poorly controlled pregestational diabetes mellitus leads to serious end-organ damage that may eventually become life threatening. In turn, preexisting diabetes-related end-organ disease may have deleterious effects on obstetric outcomes.

Diabetic retinopathy is the leading cause of blindness in the United States in individuals aged 24–74 years and is classified as nonproliferative retinopathy (which is characterized by retinal microaneurysms and dot-blot hemorrhages) and proliferative retinopathy (which is marked by neovascularization) (50). It appears that retinopathy commonly progresses in pregnancy. In two studies, retinopathy progression is seen in about one fourth of patients and associated with chronic hypertension (51, 52). In another study, one third of women experienced retinopathy progression that was associated with the rapid institution of strict glycemic control early in pregnancy and hypertensive disorders of pregnancy (53). This is consistent with nonpregnant diabetic individuals who experience progression with improved glycemic control, although the long-term benefits of glycemic control appear to outweigh the harms (54). Proliferative retinopathy is best treated with pan-retinal photocoagulation, ideally before the patient becomes pregnant (55). Women with diabetes who become pregnant should have a comprehensive eye examination in the first trimester and should be monitored closely throughout pregnancy at the physician’s discretion depending on the results of the first trimester examination (56).

Diabetic nephropathy is estimated to be present in 5–10% of diabetic pregnancies (57–59). Most studies have failed to demonstrate permanent deterioration in renal function associated with pregnancy in women with mild-to-moderate diabetic nephropathy (60, 61). However, progression to end stage renal disease has been reported in women with serum creatinine levels exceeding 1.5 mg/dL or severe proteinuria (more than 3 g per 24 hours) at baseline (48, 57). Women with preexisting diabetic nephropathy are at significantly higher risk for several adverse obstetric complications, including hypertensive disorders, uteroplacental insufficiency, and iatrogenic preterm birth because of worsening renal function (59, 62, 63). Before becoming pregnant, a baseline evaluation of renal function by serum creatinine and assessment of urinary protein excretion (urine protein-to-creatinine ratio or 24-hour protein excretion) are recommended with follow-up measurements at regular intervals throughout pregnancy (64). If a 24-hour collection for creatinine clearance has not been done in the year before pregnancy, it is common for this assessment to be done early in pregnancy to establish a baseline.

Chronic hypertension is observed in approximately 5–10% of pregnant patients with pregestational diabetes mellitus (65). Hypertension, especially in the presence of nephropathy, increases the risk of preeclampsia, uteroplacental insufficiency, and stillbirth (66). At least one study found that tighter control of blood pressures in women with type 1 diabetes may be beneficial (67). Ideally, hypertension should be controlled before pregnancy. In nonpregnant patients, treatment is likely to include an angiotensin-converting enzyme inhibitor or an angiotensin II receptor blocker. Because of their adverse fetal effects, these medications should be discontinued before becoming pregnant and should not be used during pregnancy (68).

Pregestational diabetes is a risk factor for acute myocardial infarction during pregnancy (69, 70). Symptomatic coronary artery disease in women with pregestational diabetes mellitus is most commonly seen in those with long-standing disease, nephropathy, and hypertension (71). Preexisting coronary artery disease may be a contraindication to pregnancy because of the pregnancy-associated hemodynamic changes that may result in myocardial infarction and death (72). It is common to assess women with pregestational diabetes with a baseline electrocardiogram, particularly in those with longstanding diabetes (eg, Class D) or any vascular complications.

Diabetic neuropathy is not well-studied in pregnancy but may manifest as recalcitrant nausea and vomiting secondary to gastroparesis (73). It does not appear that pregnancy increases the risk of diabetic neuropathy, but it can affect the pregnancy (74, 75). Women with gastroparesis secondary to an autonomic neuropathy are at increased risk of hyperemesis and may require total parenteral nutrition during pregnancy (76). Gastroparesis affects the interaction between diet and diabetes management, further complicates the control of diabetes itself, and increases the risk of hypoglycemic episodes. In women with this diagnosis, metoclopramide, a pro-kinetic agent, can be used in pregnancy.

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Diabetic Ketoacidosis

Diabetic ketoacidosis is a life-threatening emergency observed in 5–10% of all pregnancies complicated by pregestational diabetes mellitus (77–79). Because diabetic ketoacidosis is caused by an absolute or relative insulin deficiency, it is most commonly observed in women with type 1 pregestational diabetes mellitus, but it also can be seen in those with type 2 diabetes. Enhanced insulin resistance probably plays a role in the higher incidence of diabetic ketoacidosis observed during pregnancy, as well as the propensity for diabetic ketoacidosis to develop more rapidly and at less severe levels of hyperglycemia and even with normal glucose levels (80). Common risk factors for diabetic ketoacidosis during pregnancy include new onset diabetes; infections, such as influenza and urinary tract infection; poor patient compliance; insulin pump failure; and treatment with β-mimetic tocolytic medications and antenatal corticosteroids (81).

Typical clinical presentation of diabetic ketoacidosis in pregnancy includes abdominal pain, nausea and vomiting, and altered sensorium. Abnormal laboratory findings commonly include a low arterial pH (less than 7.3), a low serum bicarbonate level (less than 15 mEq/L), an elevated anion gap, and positive serum ketones (65). Continuous fetal heart rate monitoring commonly demonstrates minimal variability and may have late decelerations in the setting of contractions. However, this pattern usually resolves as the maternal condition improves, and delivery is rarely indicated.

For laboratory assessment, obtain arterial blood gases to document degree of acidosis present, measure glucose (in addition to hourly capillary blood glucose ketones), and serum ketones electrolyte levels obtained at 1- to 2-hour intervals. Treatment regimens are based on aggressive hydration and intravenous insulin (see Box 1). As opposed to subcutaneous insulin, there appears to be no advantage to the insulin lispro or insulin aspart as compared with regular insulin, which is the most common form of intravenous insulin. Because hypoglycemia and hypokalemia are frequent complications of diabetic ketoacidosis therapy, glucose and potassium concentrations should be monitored closely. Maternal mortality is rare, and many of these cases resolve quickly with appropriate medical management (79). Historically, fetal mortality has ranged from 10% to 35% of cases, but mortality has decreased considerably in recent years (78, 79, 82, 83).

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Perinatal Morbidity and Mortality

The perinatal mortality rate in pregnancies complicated by pregestational diabetes mellitus decreased markedly in the twentieth century (84), and one study from the United Kingdom found that it has continued to decrease (85). Overall perinatal outcomes are best when glucose control is achieved before a woman becomes pregnant and in the absence of maternal vascular or hypertensive disease (13, 86, 87). The relationship between maternal end-organ disease and adverse pregnancy outcome was first described by a study that used a classification system that attempted to predict perinatal risk according to the age at onset of diabetes; duration of diabetes; and the presence of vasculopathy, renal (Class F), proliferative retinal (Class R), and cardiac (Class H) complications (88, 89). This system still appears to be valuable in predicting pregnancy complications, with those who have had diabetes for a longer time having a higher rate of problems (87, 90). Complications also are more significant in the presence of chronic hypertension (90, 91).

Major congenital anomalies are the leading cause of perinatal mortality in pregnancies complicated by pregestational diabetes mellitus, and they occur in 6–12% of infants of women with diabetes (92–94). Studies have linked the increased rate of congenital malformations, as well as spontaneous abortion, to poor prepregnancy glucose control (85, 95, 96). Hyperglycemia during organogenesis (5–8 weeks after the last menstrual period) is thought to play a critical role in abnormal development (97, 98), and in animal models has been shown to affect gene expression (99, 100). There is a concern that the increase in hypoglycemic episodes seen with tighter glycemic control may have a negative effect on the pregnancy, but clinical studies have not demonstrated an association between hypoglycemic episodes and adverse fetal outcomes (101, 102). Glycosylated hemoglobin levels correlate directly with the frequency of anomalies. In classic studies, a level less than 1% higher than the upper limit of normal, or approximately 5–6%, is associated with a fetal malformation rate close to that observed in normal pregnancies (2–3%). However, an HbA1c concentration near 10% is associated with a fetal anomaly rate of 20–25% (92, 103). More recent studies support these findings with higher rates of all anomalies and cardiac anomalies in women with elevated HbA1c levels (104–106). Complex cardiac defects; central nervous system anomalies, such as anencephaly and spina bifida; and skeletal malformations, including sacral agenesis, are most common (26, 93, 94, 107, 108).

Women with pregestational diabetes mellitus, particularly those who receive scant or late prenatal care (109), more often experience adverse perinatal outcomes (26). Stillbirths are higher in women with diabetes and are associated with higher HbA1c values (110) and with delayed or absent prenatal care (109). Facilitated diffusion of glucose across the placenta leads to transient fetal hyperglycemia. Subsequent stimulation of the fetal pancreatic β cells results in fetal hyperinsulinemia with several fetal and neonatal consequences. Because insulin is a potent growth hormone, excessive fetal growth occurs, particularly in adipose tissue (111). The fetus of a woman with poorly controlled diabetes is at increased risk of fetal death and is more likely to weigh more than 4,000 g with a disproportionate concentration of fat around the shoulders and chest, which more than doubles the risk of shoulder dystocia at vaginal delivery (26). Fetal macrosomia is strongly associated with HbA1c values in the pregnancy (112), and there is a suggestion that elevated postprandial values may be most closely related to the risk of macrosomia (113, 114).

The neonatal consequences of poorly controlled pregestational diabetes mellitus during pregnancy include profound hypoglycemia, a higher rate of respiratory distress syndrome, polycythemia, organomegaly, electrolyte disturbances, and hyperbilirubinemia. Long-term outcomes for offspring of women with type 1 diabetes mellitus include obesity and carbohydrate intolerance (115–118). These long-term effects are likely due to fetal programming and lead to increases in metabolic syndrome and cardiac disease in adult life (119). In one study, there was an association between higher HbA1c in women and lower primary school achievement in their offspring, but the exact causal mechanism of this finding is unclear (120). In a systematic review and meta-analysis of 33 observational studies, pregnant women with type 2 diabetes mellitus were found to have similar rates of congenital malformations, stillbirth, and neonatal mortality, and increased rates of perinatal mortality compared with pregnant women with type 1 diabetes mellitus (83). A recent study also demonstrated an association between pregestational diabetes mellitus in pregnancy and subsequent autism spectrum disorder in these children with adjusted hazard ratios of 2.33 (95% CI, 1.29–4.21) for type 1 diabetes mellitus and 1.39 (95% CI, 1.18–1.62) for type 2 diabetes mellitus (121).

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Obstetric Complications

Women with pregestational diabetes mellitus have a greater risk of a wide range of obstetric complications. For these women, the rate of primary cesarean delivery is increased (65, 122); spontaneous preterm labor appears to be more common (123, 124); and for some women—particularly those with poor glycemic control—the increased incidence of polyhydramnios may be a cause of preterm labor (65). Improvements in HbA1c from greater than 7% to 6–7% to less than 6% demonstrate better obstetric outcomes (28).

Preeclampsia is observed in 15–20% of pregnancies complicated by type 1 diabetes mellitus without nephropathy and in approximately 50% with nephropathy (90, 123, 125). Preeclampsia is more likely to occur in women with hypertension and poor glucose control (57, 58, 62, 90, 91).

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Clinical Considerations and Recommendations

Is there a role for prepregnancy counseling?

Prepregnancy counseling for women with pregestational diabetes mellitus has been reported to be beneficial and cost effective and should be encouraged (2, 126). Because less than one third of women with diabetes mellitus seek prepregnancy counseling (127), any visit to a health care provider should be used as an opportunity to review the aspects of diabetes management during pregnancy and if a pregnancy is not being planned, opportunities for contraception. Prepregnancy counseling should focus on the importance of euglycemic control before pregnancy, as well as the adverse obstetric and maternal outcomes that can result from poorly controlled diabetes. The specific risk of fetal embryopathy related to glycemic control is an important outcome to counsel patients about in order to emphasize the importance of prepregnancy glycemic control (128). Additionally, because the recommended glucose levels are usually lower in pregnancy and glycemic management changes frequently throughout gestation because of the effect of placental hormones, these differences should be discussed with patients who are considering pregnancy. Evaluating for underlying vasculopathy is generally advised, including a retinal examination by an ophthalmologist, a 24-hour urine collection for protein excretion and creatinine clearance, lipid assessment, and electrocardiography. Because up to 40% of young women with type 1 diabetes mellitus also may have thyroid dysfunction, thyroid function studies should be obtained as well (129). At least 400 micrograms of folic acid should be prescribed to all women contemplating pregnancy (130). This is particularly important in women with diabetes given their increased risk of neural tube defects. Higher doses of folic acid may be beneficial in high-risk patients and doses of 800 micrograms or 1 mg have been prescribed, especially in the presence of other risk factors for neural tube defects. However, there is not specific, prospective evidence that supports this recommendation. Additionally, because pregestational diabetes is considered a high-risk factor for the development of preeclampsia, the American College of Obstetricians and Gynecologists recommends that low-dose aspirin (81 mg/day) prophylaxis should be initiated between 12 weeks and 28 weeks of gestation (optimally before 16 weeks of gestation) and continued until delivery (131) (Box 2).

Is there a role for continuous subcutaneous insulin infusion during pregnancy?

With continuous subcutaneous insulin infusion therapy (the insulin pump), insulin can be delivered in a pattern that closely resembles physiologic insulin secretion (132–134). A rapid-acting insulin, such as insulin lispro, is most appropriate for infusion pumps (135). Usually 50–60% of the total daily dose is administered at a continuous basal rate; boluses before meals and snacks comprise the rest (40–50%) of the total daily dose (134). Patients who use continuous subcutaneous insulin infusion must be highly motivated and compliant. Potential advantages of the insulin pump include a decrease in episodes of severe hypoglycemia, better control of hyperglycemia, and a more flexible lifestyle. Although improved glycemic control had been demonstrated in a systematic review in individuals with type 1 diabetes (136, 137), it was only recently demonstrated in individuals with type 2 diabetes (138, 139). Potential disadvantages include the increased cost of the pump and pump supplies. In addition, adverse events with the insulin pump occur approximately three times per 1 year of use and of these approximately 38% are pump malfunctions (140). If the delivery of insulin is interrupted or impaired by battery failure or infection at the infusion site, DKA may develop rapidly; 9.8% of pump adverse events lead to high ketones or DKA (140, 141). Despite potential advantages and modest evidence that glycemic control may be improved (142, 143), in a recent meta-analysis of five small randomized trials of the insulin pump versus injectable insulin, there were no statistically significant differences in outcomes (144). Thus, in women who have euglycemia with multiple dose injectable insulin, they can be maintained on that insulin dosage approach. However, in those women without good control, conversion to a subcutaneous insulin pump before pregnancy may improve glycemic control, particularly in those with type 1 diabetes (136).

Is there a role for oral hypoglycemic agents in pregnancy?

Oral hypoglycemic agents are not generally used in patients with type 1 diabetes. Although they are used widely in the treatment of nonpregnant patients with type 2 diabetes, they have not been well studied in the treatment of women with pregestational diabetes during pregnancy. However, although there are little data on women with pregestational diabetes, glyburide (a second-generation sulfonylurea) and metformin (a biguanide) have been used to treat gestational diabetes in the third trimester. Glyburide acts to increase insulin release from the beta cells of the pancreas, and its onset of action is approximately 4 hours and its duration of action is approximately 10 hours. Initial studies of glyburide demonstrated no difference when compared with insulin, but recent meta-analyses have identified some adverse neonatal outcomes in women with gestational diabetes managed on glyburide (145–148). Metformin, a category B drug, has been used as a hypoglycemic agent and a treatment for infertility in polycystic ovary syndrome (149, 150). In a randomized trial of 751 women with gestational diabetes mellitus treated between 20 weeks and 33 weeks of gestation, metformin (alone or with supplemental insulin) was not associated with increased diabetes-related perinatal complications compared with insulin, with no significant differences in glucose control (151). A recent network meta-analysis found that metformin had the greatest probability of reducing complications in women with gestational diabetes compared with glyburide and insulin (152). In a recent cohort study, metformin was associated with congenital anomalies compared with a population with no metformin use (153). However, when the analysis was stratified between those on metformin for diabetes versus other indications, it was only the women with diabetes who had an increased risk of congenital anomalies (odds ratio, −3.95; 95% CI, 1.77–9.41), not the other indications (odds ratio, −0.83; 95% CI, 0.18–2.81). In another recent study of the use of oral agents by women with pregestational diabetes, there was no increase in the risk of miscarriage, anomalies, or stillbirth in women who used oral hypoglycemic medications during pregnancy (154). Similarly, a recent case–control study found no statistically significant increased risk of nongenetic congenital anomalies in women exposed to metformin in the first trimester (155). Despite increasing data on metformin’s use in pregnancy, there is limited long-term safety information on the infants of these women. The use of all oral hypoglycemic agents for control of pregestational type 2 diabetes mellitus during pregnancy should be limited and individualized until data regarding the safety and efficacy of these drugs become available. Thus, insulin is the preferred treatment for pregestational diabetes in pregnancy not controlled by diet and exercise. Women with type 2 diabetes who are stable on oral agents before pregnancy and become pregnant should be counseled that insulin is the preferred therapy in pregnancy and that oral antidiabetic medications are not approved by the U.S. FDA for treatment of diabetes during pregnancy because they cross the placenta and lack long-term neonatal safety data. For those women with type 2 diabetes who decline insulin, those who their obstetricians or obstetric care providers believe will be unable to safely administer insulin, or those who cannot afford insulin, metformin (and rarely glyburide) is a reasonable alternative choice in the context of discussing with the patient the limitations of the safety data and a high rate of treatment failure, which requires insulin supplementation (156).

What fetal assessment is appropriate in women with pregestational diabetes mellitus?

An ultrasound examination early in gestation can be used not only to demonstrate fetal viability but to accurately date the pregnancy as well (157). Most major anomalies can be detected at 18–20 weeks of gestation by a detailed ultrasound examination that includes a carefully performed assessment of fetal cardiac structures, including the great vessels (158, 159). Echocardiography may be indicated in cases of suspected cardiac defects or when the fetal heart and great vessels cannot be visualized adequately by routine anatomical ultrasonography or in patients at increased risk of cardiac anomalies (eg, elevated HbA1c) (105, 160). Because fetal echocardiography is not routinely available in all settings, some practices may choose to refer for this evaluation only in those with increased risk, whereas other practices will obtain the fetal echo routinely in all women with pregestational diabetes. Neonates delivered to women with pregestational diabetes are at increased risk of macrosomia and, depending on concomitant risk factors, also may be at increased risk of fetal growth restriction (91, 161). Certainly, screening with fundal height measurements is recommended, but it is also common for ultrasonography to be used to assess fetal weight in the third trimester. If abnormal fetal growth is suspected, ultrasound examinations should be used to approximate fetal growth. There is no particular approach that has been demonstrated as superior to another, but when fetal macrosomia or large for gestational age is of concern, it is common to obtain a fetal growth ultrasound examination before delivery, commonly at 34 0/7 weeks to 38 6/7 weeks of gestation. If there is a concern for fetal growth restriction, additional, earlier ultrasound examinations during the third trimester may be used.

Maternal assessment of fetal movements is a potentially simple method for monitoring fetal well-being. However, most practitioners obtain formal antenatal testing. Antepartum fetal monitoring, including the nonstress test, the biophysical profile, or the modified biophysical profile when performed at appropriate intervals (usually once or twice per week), is a valuable approach and can be used to monitor the pregnancies of women with pregestational diabetes mellitus (162–165). Initiation of testing is appropriate for most women at 32 weeks of gestation. However, testing at earlier gestational ages may be warranted in some pregnancies complicated by additional high-risk conditions. In response to a report of an increased stillbirth rate in patients with a reactive nonstress test within 1 week of delivery, twice weekly testing has been widely adopted (166); however, the optimal timing or frequency of testing has not been ascertained (167) and such testing has not been found to be specifically predictive of impending fetal demise in women with pregestational diabetes. However, if maternal glucose control deteriorates, the fetal condition may deteriorate as well, and increased testing for fetal well-being may be indicated. Doppler velocimetry of the umbilical artery may be useful in monitoring pregnancies with growth restriction (165, 168).

When, where, and how should delivery occur for women with pregestational diabetes?

Optimal timing of delivery relies on balancing the risk of fetal death with the risks of preterm birth. Early delivery (36 0/7 weeks to 38 6/7 weeks of gestation, or even earlier) may be indicated in some patients with vasculopathy, nephropathy, poor glucose control, or a prior stillbirth (169, 170). In contrast, women with well-controlled diabetes with no other comorbidities may be managed expectantly to 39 0/7 weeks to 39 6/7 weeks of gestation as long as antenatal testing remains reassuring (171, 172). Expectant management beyond 40 0/7 weeks of gestation generally is not recommended. Delivery of women with pregestational diabetes should occur at institutions with health care providers experienced in caring for such individuals. For example, because such patients may require intravenous insulin drips and their offspring may have neonatal hypoglycemia, it is important that the patients give birth at a hospital that can provide such care.

The planned approach to delivery is often based on estimated fetal weight. Although the diagnosis of fetal macrosomia is imprecise, in order to prevent traumatic birth injury to the fetus, prophylactic cesarean delivery may be considered if the estimated fetal weight is at least 4,500 g in women with diabetes (164, 173). Although an ultrasonography estimate of fetal weight may help in this clinical decision, ultrasonography has not proved to be more accurate than clinical assessment in determining the size of the large fetus (174–176). Induction of labor in pregnant women with fetuses with suspected macrosomia has not been found to reduce birth trauma in diabetic women. Historically, there were thought to be no improvements in outcomes of pregnancies induced prophylactically with large for gestational age infants (177). Recently, in one trial and in meta-analyses that did not include women with pregestational diabetes, induction of labor in the setting of suspected large for gestational age infants was associated with a reduction in birth trauma without increasing the risk of cesarean delivery (178–180). However, before becoming routinely adopted, this practice needs further study, particularly in women with pregestational diabetes. During labor, women with pregestational diabetes generally should undergo continuous intrapartum electronic fetal monitoring and typically are excluded from consideration for intermittent auscultation (181).

Women with diabetes have a higher risk of experiencing a shoulder dystocia than women without diabetes even when controlling for birth weight (182). As such, the health care provider should have heightened awareness for shoulder dystocia in the setting of pregestational diabetes and may wish to consider other clinical factors (eg, estimated fetal weight, prolonged second stage of labor, and indication for intervention) that could modify this risk. When considering an operative vaginal delivery, one should carefully consider the relative maternal and neonatal risks. Judicious use of operative vaginal delivery is reasonable even in the presence of risk factors for shoulder dystocia.

How should glucose control be managed in the hospital and during labor?

Health care providers generally hospitalize women with diabetes in pregnancy who have experienced frequent episodes of hyper- or hypoglycemia to improve glycemic control. In women who appear to need further education and a consistent, regimented approach to insulin delivery and diet, the current dosage regimen can be used and rapidly adjusted to improve blood glucose values. For those individuals in whom it is unclear how well the glucose values are controlled or for those whose glucose values are very high (eg, greater than 200 mg/dL), an intravenous infusion of insulin may be started to ascertain the total daily insulin needs of the patient. Additionally, if corticosteroids are administered to accelerate lung maturation in the setting of an obstetric complication, an increased insulin requirement during the next 5 days should be anticipated, and the patient’s glucose levels should be closely monitored (183).

During induction of labor, maternal glycemia can be controlled with an intravenous infusion of short-acting (commonly regular) insulin, an “insulin drip,” titrated to maintain hourly readings of blood glucose levels less than 110 mg/dL (13, 25, 184) (Box 3). Avoiding intrapartum maternal hyperglycemia may prevent fetal hyperglycemia and reduce the likelihood of subsequent neonatal hypoglycemia (118). During active labor, blood glucose levels should be checked at regular intervals, generally hourly. Insulin may not be needed in women with type 2 diabetes. However, insulin is always required in those with type 1 diabetes; if patients become hypoglycemic, intravenous dextrose should be given and the insulin infusion rate reduced. Alternatively, patients who are using an insulin pump may, instead, continue their basal infusion during labor, though approaches to having patients use their pumps vary from hospital to hospital.

Insulin requirements decrease rapidly after delivery. One third to one half of the predelivery dose of intermediate or long-acting insulin should be started after delivery as basal insulin. After starting regular food intake, one third to one half of the short or rapid acting insulin dosages can be started as well (25). Similarly, for women on insulin pumps, the continuous basal infusion generally should be reduced by approximately 50% to avoid hypoglycemic episodes.

Are special postpartum considerations necessary?

Breastfeeding should be encouraged in women with pregestational diabetes mellitus. An additional 500 kcal/d more than the prepregnancy caloric intake is recommended with breastfeeding. Small snacks before breastfeeding may reduce the risks of hypoglycemia (185). It is common for women with diabetes mellitus to have greater difficulties with lactation than the general population, and there should be a low threshold for consultation with a lactation specialist (186).

For women who do not choose permanent contraception with tubal ligation, long-acting reversible contraception with an intrauterine device or implantable progestin are the most effective forms of contraception and should be recommended (187). The long-acting reversible contraception methods do not appear to affect glycemic control postpartum (188, 189). Limited data suggest no increased complications for intrauterine device use in women with diabetes (190, 191). Other second-line options include low-dose combination oral contraceptives for women without vasculopathy who do not smoke, whereas progestin-only pills can be prescribed for women with vascular disease (192). Barrier methods, although less effective, will not affect glucose control or vasculopathy. Because of their increased mortality risk, sterilization is commonly discussed with women with serious vasculopathy or other end-organ complications and for those who have completed their families.

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Summary of Recommendations and Conclusions

The following recommendations and conclusions are based on limited or inconsistent scientific evidence (Level B):

  • Maternal glucose control should be maintained near physiologic levels before and throughout pregnancy to decrease the likelihood of complications of hyperglycemia, including spontaneous abortion, fetal malformation, fetal macrosomia, fetal death, and neonatal morbidity.
  • The dietary approach to glycemic control is focused on careful carbohydrate counting and allocation of appropriate ratios of carbohydrates to meals and snacks.
  • Patients and their families should be taught how to respond quickly and appropriately to hypoglycemia.
  • Prepregnancy counseling for women with pregestational diabetes mellitus has been reported to be beneficial and cost effective and should be encouraged.
  • Because pregestational diabetes is considered a high-risk factor for the development of preeclampsia, the American College of Obstetricians and Gynecologists recommends that low-dose aspirin (81 mg/day) prophylaxis should be initiated between 12 weeks and 28 weeks of gestation (optimally before 16 weeks of gestation) and continued until delivery.
  • The use of all oral hypoglycemic agents for control of pregestational type 2 diabetes mellitus during pregnancy should be limited and individualized until data regarding the safety and efficacy of these drugs become available.
  • Insulin is the preferred treatment for pregestational diabetes in pregnancy not controlled by diet and exercise.
  • Antepartum fetal monitoring, including the nonstress test, the biophysical profile, or the modified biophysical profile when performed at appropriate intervals (usually once or twice per week), is a valuable approach and can be used to monitor the pregnancies of women with pregestational diabetes mellitus.

The following recommendations are based primarily on consensus and expert opinion (Level C):

  • Prepregnancy counseling should focus on the importance of euglycemic control before pregnancy, as well as the adverse obstetric and maternal outcomes that can result from poorly controlled diabetes.
  • Although the diagnosis of fetal macrosomia is imprecise, in order to prevent traumatic birth injury to the fetus, prophylactic cesarean delivery may be considered if the estimated fetal weight is at least 4,500 g in women with diabetes.

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For More Information

The American College of Obstetricians and Gynecologists has identified additional resources on topics related to this document that may be helpful for ob-gyns, other health care providers, and patients. You may view these resources at www.acog.org/More-Info/PregestationalDiabetes.

These resources are for information only and are not meant to be comprehensive. Referral to these resources does not imply the American College of Obstetricians and Gynecologists’ endorsement of the organization, the organization’s website, or the content of the resource. These resources may change without notice.

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References

1. Centers for Disease Control and Prevention. National diabetes statistics report, 2017: estimates of diabetes and its burden in the United States. Atlanta (GA): CDC; 2017. (Level II-3)
2. Peterson C, Grosse SD, Li R, Sharma AJ, Razzaghi H, Herman WH, et al. Preventable health and cost burden of adverse birth outcomes associated with pregestational diabetes in the United States. Am J Obstet Gynecol 2015;212:74.e1–9. (Level II-3)
3. Lawrence JM, Contreras R, Chen W, Sacks DA. Trends in the prevalence of preexisting diabetes and gestational diabetes mellitus among a racially/ethnically diverse population of pregnant women, 1999–2005. Diabetes Care 2008;31:899–904. (Level II-3)
4. Britton LE, Hussey JM, Crandell JL, Berry DC, Brooks JL, Bryant AG. Racial/ethnic disparities in diabetes diagnosis and glycemic control among women of reproductive age [preprint]. J Womens Health (Larchmt) 2018; DOI: 10.1089/jwh.2017.6845. (Level II-3)
5. Peng TY, Ehrlich SF, Crites Y, Kitzmiller JL, Kuzniewicz MW, Hedderson MM, et al. Trends and racial and ethnic disparities in the prevalence of pregestational type 1 and type 2 diabetes in Northern California: 1996-2014. Am J Obstet Gynecol 2017;216:177.e1–8. (Level II-3)
6. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK [published erratum appears in Lancet 2011;378:1778]. Lancet 2011;378:815–25. (Level II-3)
7. Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA 2003;290:1884–90. (Level II-3)
8. Classification and diagnosis of diabetes: standards of medical care in diabetes-2018. American Diabetes Association. Diabetes Care 2018;41:S13–27. (Level III)
9. Zagury RL, Rodacki M, Mello de Oliveira L, Saunders C, de Carvalho Padilha P, Zajdenverg L. Carbohydrate counting during pregnancy in women with type 1 diabetes: are there predictable changes that we should know? Ann Nutr Metab 2017;70:140–6. (Level III)
10. Ryan EA. Hormones and insulin resistance during pregnancy. Lancet 2003;362:1777–8. (Level III)
11. Lowe LP, Metzger BE, Lowe WL Jr, Dyer AR, McDade TW, McIntyre HD. Inflammatory mediators and glucose in pregnancy: results from a subset of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study. HAPO Study Cooperative Research Group. J Clin Endocrinol Metab 2010;95:5427–34. (Level II-3)
12. Gabbe SG, Mestman JH, Freeman RK, Goebelsmann UT, Lowensohn RI, Nochimson D, et al. Management and outcome of pregnancy in diabetes mellitus, classes B to R. Am J Obstet Gynecol 1977;129:723–32. (Level II-2)
13. Jovanovic L, Peterson CM. Management of the pregnant, insulin-dependent diabetic woman. Diabetes Care 1980;3:63–8. (Level II-3)
14. Jovanovic L, Druzin M, Peterson CM. Effect of euglycemia on the outcome of pregnancy in insulin-dependent diabetic women as compared with normal control subjects. Am J Med 1981;71:921–7. (Level II-2)
15. Garner P. Type I diabetes mellitus and pregnancy. Lancet 1995;346:157–61. (Level III)
16. Management of diabetes in pregnancy: standards of medical care in diabetes-2018. American Diabetes Association. Diabetes Care 2018;41:S137–43. (Level III)
17. Asbjornsdottir B, Akueson CE, Ronneby H, Rytter A, Andersen JR, Damm P, et al. The influence of carbohydrate consumption on glycemic control in pregnant women with type 1 diabetes. Diabetes Res Clin Pract 2017;127:97–104. (Level II-3)
18. Gurau J, Cronk A, Pelliccia M, Vandenbussche K. Role of the nutrition professional in high-risk obstetrics inpatient teams. Can J Diet Pract Res 2013;74:75–9. (Level III)
19. Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A, et al. Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications. American Diabetes Association. Diabetes Care 2003;26(suppl 1):S51–61. (Level III)
20. American Diabetes Association. 4. Lifestyle management: standards of medical care in diabetes-2018. Diabetes Care 2018;41(suppl 1):S38–50. (Level III)
21. Moses RG, Barker M, Winter M, Petocz P, Brand-Miller JC. Can a low-glycemic index diet reduce the need for insulin in gestational diabetes mellitus? A randomized trial. Diabetes Care 2009;32:996–1000. (Level I)
22. Hueston WJ, Eilers GM, King DE, McGlaughlin VG. Common questions patients ask during pregnancy. Am Fam Physician 1995;51:1465–70. (Level III)
23. Steel JM, Johnstone FD, Hume R, Mao JH. Insulin requirements during pregnancy in women with type I diabetes. Obstet Gynecol 1994;83:253–8. (Level II-3)
24. Langer O, Anyaegbunam A, Brustman L, Guidetti D, Levy J, Mazze R. Pregestational diabetes: insulin requirements throughout pregnancy. Am J Obstet Gynecol 1988;159:616–21. (Level II-3)
25. Landon MB, Catalano PM, Gabbe SG. Diabetes mellitus complicating pregnancy. In: Gabbe SG, Niebyl JR, Simpson JL, Landon MB, Galan HL, Jauniaux ER, et al, editors. Obstetrics: normal and problem pregnancies. 7th ed. Philadelphia (PA): Elsevier; 2017. p. 862–98. (Level III)
26. Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 2003;102:857–68. (Level III)
27. Jensen DM, Korsholm L, Ovesen P, Beck-Nielsen H, Moelsted-Pedersen L, Westergaard JG, et al. Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care 2009;32:1046–8. (Level II-3)
28. Maresh MJ, Holmes VA, Patterson CC, Young IS, Pearson DW, Walker JD, et al. Glycemic targets in the second and third trimester of pregnancy for women with type 1 diabetes. Diabetes and Pre-eclampsia Intervention Trial Study Group. Diabetes Care 2015;38:34–42. (Level II-3)
29. DeWitt DE, Hirsch IB. Outpatient insulin therapy in type 1 and type 2 diabetes mellitus: scientific review. JAMA 2003;289:2254–64. (Level III)
30. DeWitt DE, Dugdale DC. Using new insulin strategies in the outpatient treatment of diabetes: clinical applications. JAMA 2003;289:2265–9. (Level III)
31. Holleman F, Hoekstra JB. Insulin lispro [published erratum appears in N Engl J Med 2003;349:1487]. N Engl J Med 1997;337:176–83. (Level III)
32. Anderson JH Jr, Brunelle RL, Koivisto VA, Pfutzner A, Trautmann ME, Vignati L, et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment. Multicenter Insulin Lispro Study Group. Diabetes 1997;46:265–70. (Level II-3)
33. Rys P, Pankiewicz O, Łach K, Kwaskowski A, Skrzekowska-Baran I, Malecki MT. Efficacy and safety comparison of rapid-acting insulin aspart and regular human insulin in the treatment of type 1 and type 2 diabetes mellitus: a systematic review. Diabetes Metab 2011;37:190–200. (Systematic Review)
34. Wang H, Wender-Ozegowska E, Garne E, Morgan M, Loane M, Morris JK, et al. Insulin analogues use in pregnancy among women with pregestational diabetes mellitus and risk of congenital anomaly: a retrospective population-based cohort study. BMJ Open 2018;8:e014972. (Level II-2)
35. Bolli GB, Owens DR. Insulin glargine. Lancet 2000;356:443–5. (Level III)
36. Lepercq J, Lin J, Hall GC, Wang E, Dain MP, Riddle MC, et al. Meta-analysis of maternal and neonatal outcomes associated with the use of insulin glargine versus NPH insulin during pregnancy. Obstet Gynecol Int 2012;2012:649070. (Meta-Analysis)
37. Mathiesen ER, Hod M, Ivanisevic M, Duran Garcia S, Brondsted L, Jovanovic L, et al. Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Detemir in Pregnancy Study Group. Diabetes Care 2012;35:2012–7. (Level I)
38. Callesen NF, Damm J, Mathiesen JM, Ringholm L, Damm P, Mathiesen ER. Treatment with the long-acting insulin analogues detemir or glargine during pregnancy in women with type 1 diabetes: comparison of glycaemic control and pregnancy outcome. J Matern Fetal Neonatal Med 2013;26:588–92. (Level II-3)
39. Moy FM, Ray A, Buckley BS, West HM. Techniques of monitoring blood glucose during pregnancy for women with pre-existing diabetes. Cochrane Database of Systematic Reviews 2017, Issue 6. Art. No.: CD009613. DOI: 10.1002/14651858.CD009613.pub3. (Meta-Analysis and Systematic Review)
40. Feig DS, Donovan LE, Corcoy R, Murphy KE, Amiel SA, Hunt KF, et al. Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial. CONCEPTT Collaborative Group [published erratum appears in Lancet 2017;390:2346]. Lancet 2017;390:2347–59. (Level I)
41. Voormolen DN, DeVries JH, Sanson RME, Heringa MP, de Valk HW, Kok M, et al. Continuous glucose monitoring during diabetic pregnancy (GlucoMOMS): A multicentre randomized controlled trial. Diabetes Obes Metab 2018;20:1894–902. (Level I)
42. Stewart ZA, Wilinska ME, Hartnell S, O'Neil LK, Rayman G, Scott EM, et al. Day-and-night closed-loop insulin delivery in a broad population of pregnant women with type 1 diabetes: a randomized controlled crossover trial. Diabetes Care 2018;41:1391–9. (Level I)
43. Newton CA, Raskin P. Diabetic ketoacidosis in type 1 and type 2 diabetes mellitus: clinical and biochemical differences. Arch Intern Med 2004;164:1925–31. (Level II-3)
44. Barski L, Nevzorov R, Harman-Boehm I, Jotkowitz A, Rabaev E, Zektser M, et al. Comparison of diabetic ketoacidosis in patients with type-1 and type-2 diabetes mellitus. Am J Med Sci 2013;345:326–30. (Level II-3)
45. Vellanki P, Umpierrez GE. Diabetic ketoacidosis: a common debut of diabetes among African Americans with type 2 diabetes. Endocr Pract 2017;23:971–8. (Level III)
46. Slama G, Traynard PY, Desplanque N, Pudar H, Dhunputh I, Letanoux M, et al. The search for an optimized treatment of hypoglycemia. Carbohydrates in tablets, solution, or gel for the correction of insulin reactions. Arch Intern Med 1990;150:589–93. (Level II-1)
47. Glycemic targets: standards of medical care in diabetes-2018. American Diabetes Association. Diabetes Care 2018;41(suppl 1):S55–64. (Level III)
48. Purdy LP, Hantsch CE, Molitch ME, Metzger BE, Phelps RL, Dooley SL, et al. Effect of pregnancy on renal function in patients with moderate-to-severe diabetic renal insufficiency. Diabetes Care 1996;19:1067–74. (Level III)
49. Temple RC, Aldridge VA, Sampson MJ, Greenwood RH, Heyburn PJ, Glenn A. Impact of pregnancy on the progression of diabetic retinopathy in Type 1 diabetes. Diabet Med 2001;18:573–7. (Level II-2)
50. Frank RN. Diabetic retinopathy. N Engl J Med 2004;350:48–58. (Level III)
51. Vestgaard M, Ringholm L, Laugesen CS, Rasmussen KL, Damm P, Mathiesen ER. Pregnancy-induced sight-threatening diabetic retinopathy in women with Type 1 diabetes. Diabet Med 2010;27:431–5. (Level II-2)
52. Egan AM, McVicker L, Heerey A, Carmody L, Harney F, Dunne FP. Diabetic retinopathy in pregnancy: a population-based study of women with pregestational diabetes. J Diabetes Res 2015;2015:310239. (Level II-3)
53. Rosenn B, Miodovnik M, Kranias G, Khoury J, Combs CA, Mimouni F, et al. Progression of diabetic retinopathy in pregnancy: association with hypertension in pregnancy. Am J Obstet Gynecol 1992;166:1214–8. (Level II-3)
54. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group [published erratum appears in Arch Ophthalmol 1998;116:1469]. Arch Ophthalmol 1998;116:874–86. (Level I)
55. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 1990;13:34–40. (Level II-2)
56. Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy in diabetes. American Diabetes Association. Diabetes Care 2004;27(suppl 1):S84–7. (Level III)
57. Gordon M, Landon MB, Samuels P, Hissrich S, Gabbe SG. Perinatal outcome and long-term follow-up associated with modern management of diabetic nephropathy. Obstet Gynecol 1996;87:401–9. (Level II-3)
58. Miodovnik M, Rosenn BM, Khoury JC, Grigsby JL, Siddiqi TA. Does pregnancy increase the risk for development and progression of diabetic nephropathy? Am J Obstet Gynecol 1996;174:1180–9; discussion 1189–91. (Level II-2)
59. Ekbom P, Damm P, Feldt-Rasmussen B, Feldt-Rasmussen U, Molvig J, Mathiesen ER. Pregnancy outcome in type 1 diabetic women with microalbuminuria. Diabetes Care 2001;24:1739–44. (Level II-3)
60. Rossing K, Jacobsen P, Hommel E, Mathiesen E, Svenningsen A, Rossing P, et al. Pregnancy and progression of diabetic nephropathy. Diabetologia 2002;45:36–41. (Level II-3)
61. Young EC, Pires ML, Marques LP, de Oliveira JE, Zajdenverg L. Effects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes. Diabetes Metab Syndr 2011;5:137–42. (Level II-3)
62. Combs CA, Rosenn B, Kitzmiller JL, Khoury JC, Wheeler BC, Miodovnik M. Early-pregnancy proteinuria in diabetes related to preeclampsia. Obstet Gynecol 1993;82:802–7. (Level III)
63. Khoury JC, Miodovnik M, LeMasters G, Sibai B. Pregnancy outcome and progression of diabetic nephropathy. What's next? J Matern Fetal Neonatal Med 2002;11:238–44. (Level II-2)
64. Preconception care of women with diabetes. American Diabetes Association. Diabetes Care 2004;27(suppl 1):S76–8. (2004A) (Level III)
65. Reece EA, Coustan DR, Gabbe S, editors. Diabetes in women: adolescence, pregnancy, and menopause. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004. (Level III)
66. Simpson LL. Maternal medical disease: risk of antepartum fetal death. Semin Perinatol 2002;26:42–50. (Level III)
67. Nielsen LR, Damm P, Mathiesen ER. Improved pregnancy outcome in type 1 diabetic women with microalbuminuria or diabetic nephropathy: effect of intensified antihypertensive therapy? Diabetes Care 2009;32:38–44. (Level II-3)
68. Pucci M, Sarween N, Knox E, Lipkin G, Martin U. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits. Expert Rev Clin Pharmacol 2015;8:221–31. (Level III)
69. Ladner HE, Danielsen B, Gilbert WM. Acute myocardial infarction in pregnancy and the puerperium: a population-based study. Obstet Gynecol 2005;105:480–4. (Level II-3)
70. James AH, Jamison MG, Biswas MS, Brancazio LR, Swamy GK, Myers ER. Acute myocardial infarction in pregnancy: a United States population-based study. Circulation 2006;113:1564–71. (Level II-3)
71. Gordon MC, Landon MB, Boyle J, Stewart KS, Gabbe SG. Coronary artery disease in insulin-dependent diabetes mellitus of pregnancy (class H): a review of the literature. Obstet Gynecol Surv 1996;51:437–44. (Level III)
72. Coustan DR, editor. Prepregnancy counseling, assessment and management of women with preexisting diabetes or previous gestational diabetes. In: Medical management of pregnancy complicated by diabetes. 5th ed. Alexandria (VA): American Diabetes Association; 2013. p. 5–26. (Level III)
73. Airaksinen KE, Anttila LM, Linnaluoto MK, Jouppila PI, Takkunen JT, Salmela PI. Autonomic influence on pregnancy outcome in IDDM. Diabetes Care 1990;13:756–61. (Level II-2)
74. Verier-Mine O, Chaturvedi N, Webb D, Fuller JH. Is pregnancy a risk factor for microvascular complications? The EURODIAB Prospective Complications Study. Diabet Med 2005;22:1503–9. (Level II-2)
75. Hagay Z, Weissman A. Management of diabetic pregnancy complicated by coronary artery disease and neuropathy. Obstet Gynecol Clin North Am 1996;23:205–20. (Level III)
76. Kitzmiller JL, Block JM, Brown FM, Catalano PM, Conway DL, Coustan DR, et al. Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care. Diabetes Care 2008;31:1060–79. (Level III)
77. Rodgers BD, Rodgers DE. Clinical variables associated with diabetic ketoacidosis during pregnancy. J Reprod Med 1991;36:797–800. (Level III)
78. Cullen MT, Reece EA, Homko CJ, Sivan E. The changing presentations of diabetic ketoacidosis during pregnancy. Am J Perinatol 1996;13:449–51. (Level III)
79. Bryant SN, Herrera CL, Nelson DB, Cunningham FG. Diabetic ketoacidosis complicating pregnancy. J Neonatal Perinatal Med 2017;10:17–23. (Level II-3)
80. Dalfra MG, Burlina S, Sartore G, Lapolla A. Ketoacidosis in diabetic pregnancy. J Matern Fetal Neonatal Med 2016;29:2889–95. (Level III)
81. Schneider MB, Umpierrez GE, Ramsey RD, Mabie WC, Bennett KA. Pregnancy complicated by diabetic ketoacidosis: maternal and fetal outcomes. Diabetes Care 2003;26:958–9. (Level III)
82. Chauhan SP, Perry KG Jr, McLaughlin BN, Roberts WE, Sullivan CA, Morrison JC. Diabetic ketoacidosis complicating pregnancy. J Perinatol 1996;16:173–5. (Level II-3)
83. Balsells M, Garcia-Patterson A, Gich I, Corcoy R. Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab 2009;94:4284–91. (Systematic Review and Meta-Analysis)
84. Feig DS, Hwee J, Shah BR, Booth GL, Bierman AS, Lipscombe LL. Trends in incidence of diabetes in pregnancy and serious perinatal outcomes: a large, population-based study in Ontario, Canada, 1996-2010. Diabetes Care 2014;37:1590–6. (Level II-3)
85. Bell R, Bailey K, Cresswell T, Hawthorne G, Critchley J, Lewis-Barned N. Trends in prevalence and outcomes of pregnancy in women with pre-existing type I and type II diabetes. Northern Diabetic Pregnancy Survey Steering Group. BJOG 2008;115:445–52. (Level II-3)
86. Pregnancy outcomes in the Diabetes Control and Complications Trial. The Diabetes Control Complications Trial Research Group. Am J Obstet Gynecol 1996;174:1343–53. (Level I)
87. Sibai BM, Caritis S, Hauth J, Lindheimer M, VanDorsten JP, MacPherson C, et al. Risks of preeclampsia and adverse neonatal outcomes among women with pregestational diabetes mellitus. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol 2000;182:364–9. (Level I)
88. White P. Pregnancy complicating diabetes. Am J Med 1949;7:609–16. (Level III)
89. Hare JW, White P. Gestational diabetes and the White classification [commentary]. Diabetes Care 1980;3:394. (Level II-2)
90. Bennett SN, Tita A, Owen J, Biggio JR, Harper LM. Assessing White's classification of pregestational diabetes in a contemporary diabetic population. Obstet Gynecol 2015;125:1217–23. (Level II-3)
91. Yanit KE, Snowden JM, Cheng YW, Caughey AB. The impact of chronic hypertension and pregestational diabetes on pregnancy outcomes. Am J Obstet Gynecol 2012;207:333.e1–6. (Level II-3)
92. Kitzmiller JL, Buchanan TA, Kjos S, Combs CA, Ratner RE. Pre-conception care of diabetes, congenital malformations, and spontaneous abortions. Diabetes Care 1996;19:514–41. (Level III)
93. Agha MM, Glazier RH, Moineddin R, Booth G. Congenital abnormalities in newborns of women with pregestational diabetes: a time-trend analysis, 1994 to 2009. Birth Defects Res A Clin Mol Teratol 2016;106:831–9. (Level II-3)
94. Leirgul E, Brodwall K, Greve G, Vollset SE, Holmstrom H, Tell GS, et al. Maternal diabetes, birth weight, and neonatal risk of congenital heart defects in Norway, 1994-2009. Obstet Gynecol 2016;128:1116–25. (Level II-3)
95. Mills JL, Simpson JL, Driscoll SG, Jovanovic-Peterson L, Van Allen M, Aarons JH, et al. Incidence of spontaneous abortion among normal women and insulin-dependent diabetic women whose pregnancies were identified within 21 days of conception. N Engl J Med 1988;319:1617–23. (Level II-2)
96. Rosenn B, Miodovnik M, Combs CA, Khoury J, Siddiqi TA. Glycemic thresholds for spontaneous abortion and congenital malformations in insulin-dependent diabetes mellitus. Obstet Gynecol 1994;84:515–20. (Level II-3)
97. Freinkel N. Diabetic embryopathy and fuel-mediated organ teratogenesis: lessons from animal models. Horm Metab Res 1988;20:463–75. (Level III)
98. Baack ML, Wang C, Hu S, Segar JL, Norris AW. Hyperglycemia induces embryopathy, even in the absence of systemic maternal diabetes: an in vivo test of the fuel mediated teratogenesis hypothesis. Reprod Toxicol 2014;46:129–36. (Animal Study)
99. Liang J, Gui Y, Wang W, Gao S, Li J, Song H. Elevated glucose induces congenital heart defects by altering the expression of tbx5, tbx20, and has2 in developing zebrafish embryos. Birth Defects Res A Clin Mol Teratol 2010;88:480–6. (Animal Study)
100. Zhao J, Hakvoort TB, Willemsen AM, Jongejan A, Sokolovic M, Bradley EJ, et al. Effect of hyperglycemia on gene expression during early organogenesis in mice. PLoS One 2016;11:e0158035. (Animal Study)
101. Rosenn BM, Miodovnik M, Holcberg G, Khoury JC, Siddiqi TA. Hypoglycemia: the price of intensive insulin therapy for pregnant women with insulin-dependent diabetes mellitus. Obstet Gynecol 1995;85:417–22. (Level II-3)
102. ter Braak EW, Evers IM, Willem Erkelens D, Visser GH. Maternal hypoglycemia during pregnancy in type 1 diabetes: maternal and fetal consequences. Diabetes Metab Res Rev 2002;18:96–105. (Level III)
103. Greene MF, Hare JW, Cloherty JP, Benacerraf BR, Soeldner JS. First-trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 1989;39:225–31. (Level II-3)
104. Wender-Ozegowska E, Wroblewska K, Zawiejska A, Pietryga M, Szczapa J, Biczysko R. Threshold values of maternal blood glucose in early diabetic pregnancy—prediction of fetal malformations. Acta Obstet Gynecol Scand 2005;84:17–25. (Level II-3)
105. Starikov R, Bohrer J, Goh W, Kuwahara M, Chien EK, Lopes V, et al. Hemoglobin A1c in pregestational diabetic gravidas and the risk of congenital heart disease in the fetus. Pediatr Cardiol 2013;34:1716–22. (Level II-3)
106. Ludvigsson JF, Neovius M, Söderling J, Gudbjörnsdottir S, Svensson A, Franzén S, et al. Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden. BMJ 2018;362:k2638. (Level II-2)
107. Sheffield JS, Butler-Koster EL, Casey BM, McIntire DD, Leveno KJ. Maternal diabetes mellitus and infant malformations. Obstet Gynecol 2002;100:925–30. (Level II-3)
108. Wren C, Birrell G, Hawthorne G. Cardiovascular malformations in infants of diabetic mothers. Heart 2003;89:1217–20. (Level II–3)
109. Allen AJ, Snowden JM, Lau B, Cheng Y, Caughey AB. Type-2 diabetes mellitus: does prenatal care affect outcomes? J Matern Fetal Neonatal Med 2018;31:93–7. (Level II-3)
110. Tennant PW, Glinianaia SV, Bilous RW, Rankin J, Bell R. Pre-existing diabetes, maternal glycated haemoglobin, and the risks of fetal and infant death: a population-based study. Diabetologia 2014;57:285–94. (Level II-3)
111. Modanlou HD, Komatsu G, Dorchester W, Freeman RK, Bosu SK. Large-for-gestational-age neonates: anthropometric reasons for shoulder dystocia. Obstet Gynecol 1982;60:417–23. (Level II-3)
112. Cyganek K, Skupien J, Katra B, Hebda-Szydlo A, Janas I, Trznadel-Morawska I, et al. Risk of macrosomia remains glucose-dependent in a cohort of women with pregestational type 1 diabetes and good glycemic control. Endocrine 2017;55:447–55. (Level II-3)
113. Jovanovic-Peterson L, Peterson CM, Reed GF, Metzger BE, Mills JL, Knopp RH, et al. Maternal postprandial glucose levels and infant birth weight: the Diabetes in Early Pregnancy Study. The National Institute of Child Health and Human Development—Diabetes in Early Pregnancy Study. Am J Obstet Gynecol 1991;164:103–11. (Level II-2)
114. Combs CA, Gunderson E, Kitzmiller JL, Gavin LA, Main EK. Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy. Diabetes Care 1992;15:1251–7. (Level II-2)
115. Silverman BL, Rizzo T, Green OC, Cho NH, Winter RJ, Ogata ES, et al. Long-term prospective evaluation of offspring of diabetic mothers. Diabetes 1991;40(Suppl 2):121–5. (Level II-2)
116. Silverman BL, Metzger BE, Cho NH, Loeb CA. Impaired glucose tolerance in adolescent offspring of diabetic mothers. Relationship to fetal hyperinsulinism. Diabetes Care 1995;18:611–7. (Level II-2)
117. Sobngwi E, Boudou P, Mauvais-Jarvis F, Leblanc H, Velho G, Vexiau P, et al. Effect of a diabetic environment in utero on predisposition to type 2 diabetes. Lancet 2003;361:1861–5. (Level II-2)
118. Oh W. Neonatal outcome and care. In: Reece EA, Coustan DR, Gabbe SG, editors. Diabetes in women: adolescence, pregnancy, and menopause. 3rd ed. Philadelphia (PA): Lippincott Williams & Wilkins; 2004. p. 451–9. (Level III)
119. Mitanchez D, Yzydorczyk C, Siddeek B, Boubred F, Benahmed M, Simeoni U. The offspring of the diabetic mother—short- and long-term implications. Best Pract Res Clin Obstet Gynaecol 2015;29(2):256–69. (Level III)
120. Knorr S, Clausen TD, Vlachova Z, Bytoft B, Damm P, Beck-Nielsen H, et al. Academic achievement in primary school in offspring born to mothers with type 1 diabetes (the EPICOM Study): a register-based prospective cohort study. Diabetes Care 2015;38:1238–44. (Level II-3)
121. Xiang AH, Wang X, Martinez MP, Page K, Buchanan TA, Feldman RK. Maternal type 1 diabetes and risk of autism in offspring. JAMA 2018;320:89–91. (Level II-2)
122. Remsberg KE, McKeown RE, McFarland KF, Irwin LS. Diabetes in pregnancy and cesarean delivery. Diabetes Care 1999;22:1561–7. (Level II-3)
123. Reece EA, Sivan E, Francis G, Homko CJ. Pregnancy outcomes among women with and without diabetic microvascular disease (White's classes B to FR) versus non-diabetic controls. Am J Perinatol 1998;15:549–55. (Level II-2)
124. Sibai BM, Caritis SN, Hauth JC, MacPherson C, VanDorsten JP, Klebanoff M, et al. Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies. The National institute of Child health and Human Development Maternal- Fetal Medicine Units Network. Am J Obstet Gynecol 2000;183:1520–4. (Level II-2)
125. Siddiqi T, Rosenn B, Mimouni F, Khoury J, Miodovnik M. Hypertension during pregnancy in insulin-dependent diabetic women. Obstet Gynecol 1991;77:514–9. (Level II-3)
126. Rosenn B, Miodovnik M, Combs CA, Khoury J, Siddiqi TA. Pre-conception management of insulin-dependent diabetes: improvement of pregnancy outcome. Obstet Gynecol 1991;77:846–9. (Level II-3)
127. Janz NK, Herman WH, Becker MP, Charron-Prochownik D, Shayna VL, Lesnick TG, et al. Diabetes and pregnancy. Factors associated with seeking pre-conception care. Diabetes Care 1995;18:157–65. (Level II-2)
128. Guerin A, Nisenbaum R, Ray JG. Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care 2007;30:1920–5. (Level III)
129. Umpierrez GE, Latif KA, Murphy MB, Lambeth HC, Stentz F, Bush A, et al. Thyroid dysfunction in patients with type 1 diabetes: a longitudinal study. Diabetes Care 2003;26:1181–5. (Level II-3)
130. Neural tube defects. Practice Bulletin No. 187. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;130:e279–90. (Level III)
131. Low-dose aspirin use during pregnancy. ACOG Committee Opinion No. 743. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;132:e44–52. (Level III)
132. Coustan DR, Reece EA, Sherwin RS, Rudolf MC, Bates SE, Sockin SM, et al. A randomized clinical trial of the insulin pump vs intensive conventional therapy in diabetic pregnancies. JAMA 1986;255:631–6. (Level II-1)
133. Carta Q, Meriggi E, Trossarelli GF, Catella G, Dal Molin V, Menato G, et al. Continuous subcutaneous insulin infusion versus intensive conventional insulin therapy in type I and type II diabetic pregnancy. Diabete Metab 1986;12:121–9. (Level II-1)
134. Gabbe SG, Holing E, Temple P, Brown ZA. Benefits, risks, costs, and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus. Am J Obstet Gynecol 2000;182:1283–91. (Level II-3)
135. Continuous subcutaneous insulin infusion. American Diabetes Association. Diabetes Care 2004;27(suppl 1):S110. (Level III)
136. Yeh HC, Brown TT, Maruthur N, Ranasinghe P, Berger Z, Suh YD, et al. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and meta-analysis. Ann Intern Med 2012;157:336–47. (Systematic Review and Meta-Analysis)
137. Rys PM, Ludwig-Slomczynska AH, Cyganek K, Malecki MT. Continuous subcutaneous insulin infusion vs multiple daily injections in pregnant women with type 1 diabetes mellitus: a systematic review and meta-analysis of randomised controlled trials and observational studies. Eur J Endocrinol 2018;178:545–63. (Systematic Review)
138. Reznik Y, Cohen O, Aronson R, Conget I, Runzis S, Castaneda J, et al. Insulin pump treatment compared with multiple daily injections for treatment of type 2 diabetes (OpT2mise): a randomised open-label controlled trial. OpT2mise Study Group. Lancet 2014;384:1265–72. (Level I)
139. Aronson R, Reznik Y, Conget I, Castaneda JA, Runzis S, Lee SW, et al. Sustained efficacy of insulin pump therapy compared with multiple daily injections in type 2 diabetes: 12-month data from the OpT2mise randomized trial. OpT2mise Study Group. Diabetes Obes Metab 2016;18:500–7. (Level II-3)
140. Ross P, Gray AR, Milburn J, Kumarasamy IM, Wu F, Farrand S, et al. Insulin pump-associated adverse events are common, but not associated with glycemic control, socio-economic status, or pump/infusion set type. Acta Diabetol 2016;53:991–8. (Level II-3)
141. Lindenbaum C, Menzin A, Ludmir J. Diabetic ketoacidosis in pregnancy resulting from insulin pump failure. A case report. J Reprod Med 1993;38:306–8. (Level III)
142. Kallas-Koeman MM, Kong JM, Klinke JA, Butalia S, Lodha AK, Lim KI, et al. Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes. Diabetologia 2014;57:681–9. (Level II-3)
143. Kekalainen P, Juuti M, Walle T, Laatikainen T. Continuous subcutaneous insulin infusion during pregnancy in women with complicated type 1 diabetes is associated with better glycemic control but not with improvement in pregnancy outcomes. Diabetes Technol Ther 2016;18:144–50. (Level II-3)
144. Farrar D, Tuffnell DJ, West J, West HM. Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database of Systematic Reviews 2016, Issue 6. Art. No.: CD005542. DOI: 10.1002/14651858.CD005542.pub3. (Systematic Review and Meta-Analysis)
145. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134–8. (Level I)
146. Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I, Corcoy R. Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 2015;350:h102. (Systematic Review and Meta-Analysis)
147. Poolsup N, Suksomboon N, Amin M. Efficacy and safety of oral antidiabetic drugs in comparison to insulin in treating gestational diabetes mellitus: a meta-analysis. PLoS One 2014;9:e109985. (Meta-Analysis)
148. Song R, Chen L, Chen Y, Si X, Liu Y, Liu Y, et al. Comparison of glyburide and insulin in the management of gestational diabetes: a meta-analysis. PLoS One 2017;12:e0182488. (Meta-Analysis)
149. Heard MJ, Pierce A, Carson SA, Buster JE. Pregnancies following use of metformin for ovulation induction in patients with polycystic ovary syndrome. Fertil Steril 2002;77:669–73. (Level III)
150. Glueck CJ, Goldenberg N, Pranikoff J, Loftspring M, Sieve L, Wang P. Height, weight, and motor-social development during the first 18 months of life in 126 infants born to 109 mothers with polycystic ovary syndrome who conceived on and continued metformin through pregnancy. Hum Reprod 2004;19:1323–30. (Level II-3)
151. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. MiG Trial Investigators [published erratum appears in N Engl J Med 2008;359:106]. N Engl J Med 2008;358:2003–15. (Level I)
152. Farrar D, Simmonds M, Bryant M, Sheldon TA, Tuffnell D, Golder S, et al. Treatments for gestational diabetes: a systematic review and meta-analysis. BMJ Open 2017;7:e015557. (Systematic Review and Meta-Analysis)
153. Panchaud A, Rousson V, Vial T, Bernard N, Baud D, Amar E, et al. Pregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services. Br J Clin Pharmacol 2018;84:568–78. (Level II-2)
154. Cea-Soriano L, García-Rodríguez LA, Brodovicz KG, Masso Gonzalez E, Bartels DB, Hernández-Díaz S. Safety of non-insulin glucose-lowering drugs in pregnant women with pre-gestational diabetes: a cohort study. Diabetes Obes Metab 2018;20:1642–51. (Level II-2)
155. Given JE, Loane M, Garne E, Addor M, Bakker M, Bertaut-Nativel B, et al. Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study. BMJ 2018;361:k2477. (Level II-2)
156. Gestational diabetes mellitus. ACOG Practice Bulletin No. 190. American College of Obstetricians and Gynecologists. Obstet Gynecol 2018;131:e49–64. (Level III)
157. Methods for estimating the due date. Committee Opinion No. 700. American College of Obstetricians and Gynecologists. Obstet Gynecol 2017;129:e150–4. (Level III)
158. Greene MF, Benacerraf BR. Prenatal diagnosis in diabetic gravidas: utility of ultrasound and maternal serum alpha-fetoprotein screening. Obstet Gynecol 1991;77:520–4. (Level II-3)
159. Albert TJ, Landon MB, Wheller JJ, Samuels P, Cheng RF, Gabbe S. Prenatal detection of fetal anomalies in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1996;174:1424–8. (Level II-3)
160. Davey BT, Seubert DE, Phoon CK. Indications for fetal echocardiography high referral, low yield? Obstet Gynecol Surv 2009;64:405–15. (Level III)
161. Hammoud NM, Visser GH, Peters SA, Graatsma EM, Pistorius L, de Valk HW. Fetal growth profiles of macrosomic and non-macrosomic infants of women with pregestational or gestational diabetes. Ultrasound Obstet Gynecol 2013;41:390–7. (Level II-3)
162. Kjos SL, Leung A, Henry OA, Victor MR, Paul RH, Medearis AL. Antepartum surveillance in diabetic pregnancies: predictors of fetal distress in labor. Am J Obstet Gynecol 1995;173:1532–9. (Level II-3)
163. Landon MB, Gabbe SG. Fetal surveillance and timing of delivery in pregnancy complicated by diabetes mellitus. Obstet Gynecol Clin North Am 1996;23:109–23. (Level III)
164. Rouse DJ, Owen J, Goldenberg RL, Cliver SP. The effectiveness and costs of elective cesarean delivery for fetal macrosomia diagnosed by ultrasound. JAMA 1996;276:1480–6. (Level III)
165. Antepartum fetal surveillance. Practice Bulletin No. 145. American College of Obstetricians and Gynecologists. Obstet Gynecol 2014;124:182–92. (Level III)
166. Barrett JM, Salyer SL, Boehm FH. The nonstress test: an evaluation of 1,000 patients. Am J Obstet Gynecol 1981;141:153–7. (Level II-3)
167. Signore C, Freeman RK, Spong CY. Antenatal testing-a reevaluation: executive summary of a Eunice Kennedy Shriver National Institute of Child Health and Human Development workshop. Obstet Gynecol 2009;113:687–701. (Level III)
168. Landon MB, Langer O, Gabbe SG, Schick C, Brustman L. Fetal surveillance in pregnancies complicated by insulin-dependent diabetes mellitus. Am J Obstet Gynecol 1992;167:617–21. (Level II-3)
169. Spong CY, Mercer BM, D'alton M, Kilpatrick S, Blackwell S, Saade G. Timing of indicated late-preterm and early-term birth. Obstet Gynecol 2011;118:323–33. (Level III)
170. Caughey AB, Valent AM. When to deliver women with diabetes in pregnancy? Am J Perinatol 2016;33:1250–4. (Level III)
171. Kjos SL, Henry OA, Montoro M, Buchanan TA, Mestman JH. Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management. Am J Obstet Gynecol 1993;169:611–5. (Level I)
172. Medically indicated late-preterm and early-term deliveries. Committee Opinion No. 560. American College of Obstetricians and Gynecologists. Obstet Gynecol 2013;121:908–10. (Level III)
173. Fetal macrosomia. Practice Bulletin No. 173. American College of Obstetricians and Gynecologists. Obstet Gynecol 2016;128:e195–209. (Level III)
174. Miller JM Jr, Brown HL, Khawli OF, Pastorek JG II, Gabert HA. Ultrasonographic identification of the macrosomic fetus. Am J Obstet Gynecol 1988;159:1110–4. (Level II-3)
175. Johnstone FD, Prescott RJ, Steel JM, Mao JH, Chambers S, Muir N. Clinical and ultrasound prediction of macrosomia in diabetic pregnancy. Br J Obstet Gynaecol 1996;103:747–54. (Level II-3)
176. Chauhan SP, Hendrix NW, Magann EF, Morrison JC, Kenney SP, Devoe LD. Limitations of clinical and sonographic estimates of birth weight: experience with 1034 parturients. Obstet Gynecol 1998;91:72–7. (Level II-2)
177. Sanchez-Ramos L, Bernstein S, Kaunitz AM. Expectant management versus labor induction for suspected fetal macrosomia: a systematic review. Obstet Gynecol 2002;100:997–1002. (Meta-Analysis)
178. Boulvain M, Senat MV, Perrotin F, Winer N, Beucher G, Subtil D, et al. Induction of labour versus expectant management for large-for-date fetuses: a randomised controlled trial. Groupe de Recherche en Obstetrique et Gynecologie, (GROG). Lancet 2015;385:2600–5. (Level I)
179. Magro-Malosso ER, Saccone G, Chen M, Navathe R, Di Tommaso M, Berghella V. Induction of labour for suspected macrosomia at term in non-diabetic women: a systematic review and meta-analysis of randomized controlled trials. BJOG 2017;124:414–21. (Systematic Review and Meta-Analysis)
180. Boulvain M, Irion O, Dowswell T, Thornton JG. Induction of labour at or near term for suspected fetal macrosomia. Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD000938. DOI: 10.1002/14651858.CD000938.pub2. (Systematic Review and Meta-Analysis)
181. Intrapartum fetal heart rate monitoring: nomenclature, interpretation, and general management principles. ACOG Practice Bulletin No. 106. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;114:192–202. (Level III)
182. Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol 1998;179:476–80. (Level II-3)
183. Mathiesen ER, Christensen AB, Hellmuth E, Hornnes P, Stage E, Damm P. Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: test of an algorithm [correction of analgoritm. Acta Obstet Gynecol Scand 2002;81:835–9. (Level II-2)
184. Garber AJ, Moghissi ES, Bransome ED Jr, Clark NG, Clement S, Cobin RH, et al. American College of Endocrinology position statement on inpatient diabetes and metabolic control. American College of Endocrinology Task Force on Inpatient Diabetes Metabolic Control. Endocr Pract 2004;10(suppl 2):4–9. (Level III)
185. Coustan DR, editor. Use of insulin during pregnancy in preexisting diabetes. In: Medical management of pregnancy complicated by diabetes. 5th ed. Alexandria (VA): American Diabetes Association; 2013. p. 105–16. (Level III)
186. Matias SL, Dewey KG, Quesenberry CP Jr, Gunderson EP. Maternal prepregnancy obesity and insulin treatment during pregnancy are independently associated with delayed lactogenesis in women with recent gestational diabetes mellitus. Am J Clin Nutr 2014;99:115–21. (Level II-3)
187. Parks C, Peipert JF. Eliminating health disparities in unintended pregnancy with long-acting reversible contraception (LARC). Am J Obstet Gynecol 2016;214:681–8. (Level III)
188. Goldstuck ND, Steyn PS. The intrauterine device in women with diabetes mellitus type I and II: a systematic review. ISRN Obstet Gynecol 2013;2013:814062. (Systematic Review)
189. Kiley JW, Hammond C, Niznik C, Rademaker A, Liu D, Shulman LP. Postpartum glucose tolerance in women with gestational diabetes using levonorgestrel intrauterine contraception. Contraception 2015;91:67–70. (Level III)
190. Kimmerle R, Weiss R, Berger M, Kurz KH. Effectiveness, safety, and acceptability of a copper intrauterine device (CU Safe 300) in type I diabetic women. Diabetes Care 1993;16:1227–30. (Level II-2)
191. World Health Organization. Medical eligibility criteria for contraceptive use. 5th ed. Geneva: WHO; 2015. (Level III)
192. Garg SK, Chase HP, Marshall G, Hoops SL, Holmes DL, Jackson WE. Oral contraceptives and renal and retinal complications in young women with insulin-dependent diabetes mellitus. JAMA 1994;271:1099–102. (Level II-2)
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