Management and Therapy of Early Pregnancy Complications: First and Second Trimesters

14. Diabetes in Pregnancy

Reshama Navathe Sandro Gerli Elena Pacella  and Vincenzo Berghella 


Department of Obstetrics and Gynecology, Sidney Kimmel Medical College at Thomas Jefferson University, 833 Chestnut Street, Mezzanine, Philadelphia, PA 19146, USA


Department of Obstetrics and Gynecology, University of Perugia, Perugia, Italy


Department of Sense Organs, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy

Reshama Navathe (Corresponding author)


Sandro Gerli


Elena Pacella


Vincenzo Berghella


14.1 Pregestational Diabetes Mellitus

14.1.1 Diagnosis/Definition

Diabetes mellitus (DM) is defined as a metabolic abnormality characterized by elevated circulating glucose. The diagnoses of diabetes and impaired glucose tolerance outside of pregnancy are established on the basis of formal laboratory criteria (Table 14.1) [34].

Table 14.1

Criteria for the diagnosis of diabetes mellitus in the nonpregnant state

Normal values

Impaired fasting glucose or impaired glucose tolerance

Diabetes mellitus

FPG: < 100 mg/dL

75-g, 2-h OGTT: 2-h PG < 140 mg/dL

FPG: 100–125 mg/dL

75-g, 2-h OGTT: 2-h PG 140–199 mg/dL

Hemoglobin A1C 5.7–6.4 %

FPG:≥126 mg/dL (7.0 mmol/L)a

75-g, 2-h OGTT: 2-h PG ≥ 200 mg/dL (11.1 mmol/L)a

Hemoglobin A1C ≥ 6.5%a

Symptoms of hyperglycemia and PG (without regard to time since last meal) ≥ 200 mg/dL (11.1 mmol/L)

Source: ADA diabetes diagnosis guidelines [2]

The diagnosis of diabetes mellitus should be confirmed on a separate day by any of these three tests

AbbreviationsFPG fasting plasma glucose, OGTT oral glucose tolerance test, PG plasma glucose

aRepeat testing to confirm result unless unequivocal hyperglycemia is present

14.1.2 Basic Pathophysiology

The etiology of DM varies. Type I diabetics are insulin deficient, secondary to the autoimmune destruction of the pancreatic islet beta-cells [3]. These individuals develop disease early in life. They often present with significant weight loss, polydipsia, and polyuria. They are at risk of becoming acutely ill and developing ketoacidosis if no therapy is initiated. In contrast, type II diabetics produce insulin, but at diminished levels. Insulin resistance is the cardinal feature of type II diabetics and many exhibit insulin resistance at the level of the end-organ receptor. As a result, they are often hyperinsulinemic, at least in the early stages; relative hypoinsulinemia may develop later [3]. The onset of disease is usually later in life, the course is gradual but progressive, and the disease is linked to obesity [3]. As the obesity epidemic rises, type II diabetes is now being seen at earlier ages, including childhood and adolescence.

Both groups can be further subclassified on the basis of the presence of vascular complications, such as hypertension, renal disease, and retinopathy. The same physiologic changes of pregnancy that cause gestational diabetes also complicate the achievement of optimal glucose control in the pregestational diabetic. In a meta-analysis, women with type II diabetes had a 1.5× increased risk of perinatal mortality, decreased risk of diabetic ketoacidosis, and decreased cesarean delivery rate as compared to those with type I diabetes; however, there were no significant differences between the two groups in the frequency of major congenital malformation, stillbirth, or neonatal mortality [5].

14.1.3 Classification

The White classification has been used to categorize the severity of pregestational diabetes [6]. This system attempts to provide a standardized definition for describing pregnant women with diabetes and has some correlation with pregnancy outcome [78]. However, the White classes are not mutually exclusive, and therefore, some have argued that the classification of diabetes should be reassessed.

The classification criteria for diabetes are issued and updated by the American Diabetes Association (ADA) [3]. This provides a general classification system for diabetes (ADA). Including the presence/absence of vascular complications is a better predictor of adverse outcome than the specific White classification [9].

Vascular complications include nephropathy, retinopathy, hypertension, and arteriosclerotic disease.

As a result, the following system has been proposed [10]:

·               Type 1 diabetes, with or without vascular complications

·               Type 2 diabetes, with or without vascular complications

·               Gestational diabetes (diabetes diagnosed during pregnancy)

·               Other diabetes (e.g., genetic origin, drug or chemical induced)

14.2 Preconception Counseling

The care of the pregestational diabetic is best instituted in the preconception period. The frequency of maternal hospitalizations, length of NICU admission, congenital malformations, and perinatal mortality are reduced in women with DM who seek consultation in preparation for pregnancy; unfortunately, only about one third of these women receive such consultation [11].

The evaluation should emphasize the importance of tight glycemic controlwith normalization of the hemoglobin A1C (aim for <6 %) (Fig. 14.1) [1214]. Multiple studies, including RCTs, show that there is a decrease in spontaneous miscarriage, congenital anomalies, and other complications when optimal glucose control is attained via multiple daily insulin doses adjusted to glucose monitoring ≥4 times per day [1516].


Fig. 14.1

The image shows the red cell, on the left; the normal hemoglobin with adherent glucose (G), in the middle; and, on the right, the glycosylated hemoglobin, rich of glucose (G). α alpha globin chains, β beta globin chains

This consultation affords the opportunity to screen for end-organ damage and other comorbidities. Ophthalmologic evaluation, EKG, and renal evaluation via a 24-h urine collection for total protein and creatinine clearance will ascertain end-organ damage and determine ancillary pregnancy risks. As 40 % of young women with type 1 diabetes have hypothyroidism, thyroid-stimulating hormone (TSH) should be checked [17].

14.2.1 First Trimester

Ideally, women with pregestational diabetes have received preconceptional counseling and are optimized in their health status. Unfortunately, this is often not the case. Therefore, the first prenatal visit becomes the first opportunity to assess the patient’s baseline medical status and educate her about the management and potential complications of diabetes in pregnancy, as well as routine aspects of pregnancy care.

In the first trimester, emphasis should be placed on adherence to diet, exercise, and medication. Women who are not on insulin pumps should be counseled on frequent self-monitoring of blood glucose. Even in early pregnancy, women with pregestational diabetes are often seen more frequently than women with uncomplicated pregnancies. These extra visits can be used to review monitored blood glucose values, to discuss baseline testing results, and to manage comorbidities. A team-based approach, including the obstetrician, endocrinologist, nutrition, and primary care provider is often employed with these patients to provide the necessary expertise.

In addition to routine prenatal laboratory tests performed in the first trimester, there are several additional tests aimed at assessing diabetic disease control. Glycosylated hemoglobin reflects recent average glycemic control and can be used preconceptually or prenatally to aid in counseling regarding the risks of miscarriage, congenital malformations, and preeclampsia. If not performed preconceptually, testing should include the ophthalmologic evaluation, EKG, and renal evaluation via a 24-h urine collection for total protein and creatinine clearance to assess for comorbidities. TSH should be checked, especially in type 1 diabetics [17].

14.2.2 Miscarriage

First trimester ultrasound examination is often obtained to document viability, as the rate of miscarriage is higher in women with diabetes. This is especially true of those with poor glycemic control in the periconception period. In a 1984 study done looking at progressively severe White classification of diabetes, the rates of miscarriage for White classes C, D, and F were 25 %, 44 %, and 22 % respectively. This is compared to an approximate rate of 15 % in the nondiabetic population. Other studies on populations with better glycemic control reported miscarriage (Fig. 14.2) rates similar to those in the nondiabetic population.


Fig. 14.2

Image shows a spontaneous miscarriage in the first trimester in diabetic pregnant

First trimester ultrasound is also helpful in estimation of gestational age. Accurate estimation of gestational age is critical since many of these pregnancies undergo scheduled delivery.

14.2.3 Congenital Anomalies

There are many studies that have shown a higher risk of major congenital malformations (Fig. 14.3) and miscarriage associated with increasing first trimester glycosylated hemoglobin values (Table 14.2) [1820]. The risk of a structural anomaly in the fetus is increased three to eight times when compared to the 2 % risk for the general population. It is important to inform patients that elevated levels of glycosylated hemoglobin increase the risk of congenital anomalies, particularly neural tube and cardiac defects [21]. Miller and associates showed that women with a glycosylated hemoglobin level > 8.5 % was 22.4 % [19]. Another study comparing 1600 diabetic gravidas with 400,000 controls showed a threefold to sixfold increased risk of anomalies in the diabetic cohort.


Fig. 14.3

A major congenital malformation in diabetic pregnant, at 15 weeks of pregnancy

Table 14.2

Risk of congenital malformations based on hemoglobin A1c

HbA1c (%)


< 7

No increased risk


3–7 %


8–10 %

≥ 11

10–20 % or more

Source: Guerin, Diabetes Care 2007 [14]

The critical time for teratogenesis is during the period of 3–6 weeks after conception. As such, intervention should be planned for in the preconception period. This includes preconception optimization of glycemic control. Several trials of preconceptional metabolic care have demonstrated that malformation rates can be decreased to that of the general population with strict glycemic control. Additionally, in a 10-year case–control study, folic acid supplementation decreased the incidence of congenital heart defects by 20–25 % when compared with the general population [22]. The American College of Obstetricians and Gynecologists (ACOG) recommends preconception and first trimester pregnancy supplementation with 4 mg of folic acid (Fig. 14.4) for “women at high risk for neural tube defects” [23].


Fig. 14.4

Absorption of folic acid in the daily diet

14.2.4 Second Trimester

The most important aspect of diabetic care in the second trimester is management of blood glucose. As the placenta begins to secrete human placental lactogen, glucose control can become more and more difficult. It is in this trimester, once eating patterns have normalized after first trimester nausea has ended, that women tend to require increases in the medication to achieve optimal glucose control. Women should be seen by the obstetrical provider every two to four weeks to help them achieve glucose control. More frequent visits should be planed based upon the severity of the diabetes, the degree of glycemic control, and the presence of other pregnancy complications. Emphasis should be placed on reviewing the blood sugar log and modifying the treatment regimen as needed. This can also be done remotely via phone or email.

14.2.5 Aneuploidy

As diabetes does not increase the risk of fetal aneuploidy, patients should be offered standard genetic screening and testing options. However, several serum analytes are reduced in women with diabetes, and this can mimic Down syndrome. Second trimester maternal serum levels of AFP are significantly decreased in women with pregestational diabetes [24]. Levels of uE3 are modestly reduced (5–10 % lower), while beta-hCG and inhibin A levels are not significantly altered in this population [2526]. Therefore, reference values should be adjusted in women with diabetes.

14.2.6 Open Neural Tube Defects

The prevalence of neural tube defects (NTDs) (Fig. 14.5) is higher in women with pregestational diabetes mellitus. In a study from 2004, NTDs occurred in 0.19 % of pregnancies complicated by diabetes versus 0.07 % of pregnancies in women without diabetes [27].


Fig. 14.5

Ultrasonographic control of fetal neural tube defects

14.2.7 Cardiac Anomalies

Congenital heart disease occurs more frequently in the offspring of women with diabetes than in the general population and accounts for about one-half of diabetes-related major congenital anomalies [2128]. As an example, in a series of 535 pregnant women with preexisting diabetes, 30 (5.6 %) delivered an infant with confirmed congenital heart disease (Fig. 14.6); the risk was 8.3 % in women with A1C ≥ 8.5 % versus 3.9 % of those with an A1C below this level [29].


Fig. 14.6

Ultrasonographic detection of intrauterine congenital heart disease

Conotruncal and ventricular septal defects are the most common cardiac defects found in these fetuses.

Interventricular septal thickening may be noted in midtrimester fetuses of diabetic women with very poor control. Although this condition is usually mild and asymptomatic, congestive cardiomyopathy, which is a more diffuse process of hypertrophy and hyperplasia of the myocardial cells, can also occur. Both disorders are transient and managed with supportive care.

Fetal surveillance for the above is recommended in the second trimester of pregnancy. The nature of this surveillance is by convention and expert consensus rather than supported by well-performed trials (Table 14.3). Diabetic gravida should be offered alpha-fetoprotein screening at 16–18 weeks of gestation and targeted ultrasonography at 18–20 weeks. Because of the high risk of cardiac anomalies, some experts suggest fetal echocardiogram as well.

Table 14.3

Antepartum testing

A. Assessment of viability and exact GA: first trimester ultrasound

B. Detection of congenital malformations

 (a) If hemoglobin A1C is elevated, consider transvaginal ultrasound at about 14 weeks to rule out structural defects, including cardiac

 (b) Maternal serum alpha-fetoprotein level at 16 weeks

 (c) Level II ultrasound at 18–20 weeks

 (d) Fetal echocardiogram at 20–22 weeks

C. Assessment of fetal growth

 (a) Serial growth ultrasounds in third trimester every 3–4 weeks

D. Assessment of fetal well-being

 (a) Maternal assessment of fetal activity (“fetal kick counts”)

 (b) Weekly nonstress tests (NSTs) starting at 32 weeks; twice weekly NSTs at 36 weeks until delivery. Begin at 32 weeks if maternal glycemic control is satisfactory, fetal growth is appropriate, and there are no coexisting maternal medical or obstetric complications. Begin earlier (~28 weeks) and increase frequency if the above conditions are not met

Source: Mackeen, Evidence Based Medicine 2011 [75]

14.2.8 Third Trimester

In the diabetic patient, the major concerns of the third trimester include monitoring of complications necessitating premature delivery. Obstetrical management consists of reinforcement of good glycemic control, initiation of antenatal surveillance, estimation of fetal size, and monitoring for pregnancy complications such as preeclampsia (Table 14.3).

During the second trimester, generally only small changes in insulin doses are needed in women whose glucose control was stable by the end of the first trimester. In contrast, during the third trimester, insulin resistance due to the hormones produced by the placenta increases rapidly, and changes in insulin dose are commonly required to maintain euglycemia.

14.2.9 Fetal Death

Intrauterine fetal demise is now a rare complication of diabetic pregnancy (Fig. 14.7), primarily due to achievement of good glycemic control. The fetus of the diabetic mother is at risk for hypoxia primarily from fetal hyperglycemia and hyperinsulinemia leading to increased fetal oxygen consumption, which may induce fetal hypoxemia and acidosis [3033].


Fig. 14.7

Intrauterine fetal death is a complication of diabetic pregnancy

Additionally, maternal vasculopathy and hyperglycemia can lead to reduced uteroplacental perfusion, which may be associated with reduced fetal growth [34].

ACOG recommends antepartum fetal testing for pregnancies complicated by pregestational diabetes [12]. There are no data from large or randomized trials on which to make an evidenced-based recommendation as to which pregnancies complicated by diabetes should undergo fetal surveillance, when to start, what test to order, or how often to perform it [35].

As a result, management is largely based upon clinical experience and expert opinion. ACOG has suggested antepartum monitoring using fetal movement counting, biophysical profile, nonstress test (NST), and/or contraction stress test at “appropriate intervals” with initiation of testing generally at 32–34 weeks of gestation (Table 14.3) [12].

For women with good glycemic control, antepartum testing can start at 32 weeks with weekly NSTs and continue until delivery [12]. For women with poor glycemic control, antepartum testing may need to begin earlier. Any significant deterioration in maternal status necessitates reevaluation of the fetus. The frequency of intrauterine fetal death (excluding congenital malformations) with such protocols is approximately 3 per 1000 pregnancies in women with type 1 diabetes [36].

If non-reassuring fetal testing is related to a potentially reversible problem such as hyperglycemia or ketoacidosis, it is advisable to resuscitate the fetus in utero by treating the medical disorder. Pathologic fetal heart rate patterns will often revert to normal when the mother’s metabolic status is corrected.

14.2.10 Fetal Growth

Pregnancies complicated by maternal diabetes are commonly associated with accelerated growth but are also at increased risk of impaired fetal growth [37]. Serial ultrasounds in the third trimester to evaluate fetal growth and frequent prenatal visits to review glucose control are also advocated. These can begin at 28–32 weeks of gestation and then every 3–4 weeks thereafter until delivery.

Accelerated growth is most common among women whose diabetes is marked by insulin resistance; high insulin requirements are associated with accelerated fetal growth even in euglycemic pregnancies [38].

The term “large for gestational age” (LGA) usually refers to a fetus or newborn that is greater than the 90th centile for fetuses or infants of that gestational age (possibly including adjustments for fetal gender and ethnicity). At 40 weeks of gestation, the 90th percentile for birth weight in the United States is about 4060 g [39]. The term “macrosomia” refers to a fetus or infant that is greater than some defined weight regardless of gestational age, gender, or ethnicity. The American College of Obstetricians suggests a threshold of 4500 g because maternal and infant morbidity increases sharply above this level [40].

Maternal diabetes mellitus may double the incidence of LGA infants; it also changes the measurements of infants of diabetic mothers (IDMs) compared with offspring of women without diabetes [41]. Specifically, the chest-to-head and shoulder-to-head ratios are increased in IDMs. [42] LGA fetuses are at increased risk for a prolonged second stage of labor, shoulder dystocia, operative delivery, maternal and infant birth trauma, and perinatal death [43].

Maternal diabetes mellitus increases the likelihood of shoulder dystocia two- to sixfold compared to the population without diabetes and increases the likelihood of dystocia-associated fetal morbidity, such as brachial plexus injury (Fig. 14.8) [4445].


Fig. 14.8

Rubin maneuver in shoulder dystocia in diabetic patient. Shoulder dystocia, especially in patients with diabetes, is due to internal forces (IF) and external forces (EF). The IF comes from uterine contractions, whereas the EF, fetal macrosomia and inadequacy of the diameters of the pelvis and maneuvers

Although ultrasound is used to determine estimated fetal weight, it is evident that there is no highly reliable method for identifying LGA fetuses before delivery [4647]. This was illustrated in a review of studies of ultrasound for predicting EFW > 4000 g in women with diabetes [28]. Sensitivity ranged from 33 to 83 % and specificity ranged from 77 to 98 %. Given the limitations of fetal weight estimates, some investigators have used other measurements for predicting LGA and shoulder dystocia, such as enlarged abdominal circumference [4647]. Although this assessment can be somewhat predictive of LGA and shoulder dystocia, many of the measurements are difficult to obtain and reproduce accurately, and these formulas have not been validated in large studies or at a variety of sites.

Impaired growth is more common among women with diabetic vasculopathy and/or superimposed preeclampsia. It is associated with increased fetal and neonatal morbidity and mortality and has long-term health implications. If there is evidence of intrauterine growth restriction, tests of fetal well-being are initiated.

14.2.11 Polyhydramnios

Maternal diabetes is one of the most common etiologies of polyhydramnios, although the mechanism for the increased amniotic fluid volume has not been clearly defined. Possibilities include fetal polyuria secondary to maternal and fetal hyperglycemia, decreased fetal swallowing, or an imbalance in water movement between the maternal and fetal compartments [48]. Polyhydramnios is frequently associated with accelerated fetal growth. Fetal outcomes in pregnancies with diabetes-associated polyhydramnios may not be as poor as outcomes in pregnancies in which polyhydramnios is associated with fetal neurologic disease, twin to twin transfusion, or other syndromes. The antenatal surveillance that has been initiated for the diabetic gravida is sufficient in the setting of polyhydramnios.

14.2.12 Preterm Labor

Compared with controls without diabetes or hypertension, women with pregestational diabetes have significantly higher rates of both indicated preterm delivery and spontaneous preterm delivery [49]. Preterm delivery is primarily initiated because of preeclampsia, but both gestational and pregestational diabetes have been associated with indicated preterm delivery independent of preeclampsia [4950]. The reasons for an increased risk of spontaneous preterm delivery are not clear [5152].

The indications for inhibition of preterm labor are similar to those in the general obstetrical population. The preferred tocolytic therapy is nifedipine or indomethacin. These are preferred over beta-adrenergic receptor agonist therapy, as these drugs can cause severe hyperglycemia in women with diabetes. If preterm birth is anticipated or planned, administration of betamethasone improves neonatal outcome. It is important to manage the transient hyperglycemia induced by glucocorticoids [5354]. The hyperglycemic effect begins approximately 12 h after the first steroid dose and lasts for about five days [5556].

14.2.13 Maternal Complications

Women with pregestational diabetes are at risk for a number of obstetric and medical complications when compared to nondiabetic gravida, including worsening diabetic diseases, hypertension (Fig. 14.9), preeclampsia, cesarean delivery, and preterm delivery [57].


Fig. 14.9

An obese diabetic pregnant with hypertension

14.2.14 Retinopathy

In the White classification system, class R diabetes designates patients with proliferative diabetic retinopathy (Table 14.2). Diabetic retinopathy (Fig. 14.10) is the leading cause of blindness between the ages of 24 and 64 years [2]. Some form of retinopathy is present in 100 % of women who have had long-standing T1DM for 25 years or more, and approximately 20 % of these women are legally blind. Diabetic retinopathy progresses from mild nonproliferative abnormalities to proliferative diabetic retinopathy, which is characterized by growth of new blood vessels on the retina.


Fig. 14.10

Fluorescein angiography of eye suffering from type II diabetes retinopathy at the posterior pole shows numerous fluorescent-type aneurysmal and lock points for microhemorrhage areas of ischemia

Some studies have shown that progression of retinopathy in pregnancy occurs at an accelerated rate; this is usually in the setting of long-standing diabetes [58]. Other trials have failed to show accelerated progression when pregnant diabetes were compared to nonpregnant diabetics. Baseline retinopathy status was the only independent risk factor that predicted progression of retinopathy [59]. As stated earlier, screening for retinopathy is recommended, ideally in the preconception period. Patients with minimal disease should be examined yearly; those with significant pathology may need monthly exams during pregnancy [60]. Proliferative retinopathy is best treated with laser therapy, ideally before conception [61].

14.2.15 Nephropathy

Diabetes is the most common cause of end-stage renal disease (ESRD) and kidney failure in the United States [2]. The pathophysiology of diabetic renal disease is poorly understood. Duration and severity of hyperglycemia and the presence of other comorbidities such as hypertensive disease are thought to contribute to the deterioration of renal function.

Diabetic nephropathy is categorized by the presence and amount of urine protein excretion and can be detected by protein to creatinine ratio or 24-h urine collection. Progression of diabetic nephropathy is closely related to glycemic control; several studies have shown that pregnancy itself does not contribute to progressive of nephropathy. In fact, positing that pregnancy is a window of time for closer monitoring, and therefore potentially better glycemic control, well-controlled individuals may see a slowing of disease progression. In one prospective study that compared nonpregnant and pregnant diabetics with similar degrees of renal function, the pregnant diabetics were less likely to progress in their renal disease or their transition to ESRD.

14.2.16 Hypertensive Disorders

The diabetic gravida is at high risk of developing a hypertension spectrum disorder. In several studies of all types of diabetics, the incidence of hypertensive disorders during pregnancy varied from 15 to 30 %, more than four times the rate in the nondiabetic population. This appears to be related to pregestational hypertension and vascular and renal disease. Poor glycemic control also appears to play a role [62].

Chronic hypertension complicates 10–20 % of pregnancies in diabetic women and almost half of pregnancies with diabetes with vascular complications. The perinatal problems encountered with chronic hypertension including maternal stroke, preeclampsia, fetal growth restriction, and placental abruption. Women being treated for hypertension should be switched to beta blockers or calcium channel blockers to. Reasonable target blood pressure goals during pregnancy are systolic blood pressure of less than 140/90 mmHg, as pressures in this range may benefit long-term maternal health, and are unlikely to impair fetal growth [10].

In one review, the incidence of preeclampsia in diabetic women with and without vascular disease was 17 and 8 %, respectively, compared to a rate of 5–8 % in women without diabetes [42]. In another study, the risk of preeclampsia increased significantly with increasing A1C values above optimal levels [62]. Diagnosis and management of preeclampsia are similar to that in women without diabetes, except among those who enter pregnancy with preexisting nephropathy. In these women, diagnosing preeclampsia can be difficult and requires relying on deterioration of other markers.

14.2.17 Obesity

Whether obesity adds to the risks associated with diabetes in pregnancy is an area of ongoing investigation. Obesity itself is a risk factor for developing many of the later complications of pregnancy that are also associated with diabetes (Fig. 14.11). Obese women are at significantly increased risk of labor dysfunction, operative VD, shoulder dystocia, need for c-section, and subsequent increased risk of DVT and poor wound healing. Clinicians should be mindful of the patient’s weight gain and set goals for limited weight gain or even modest weight loss, and this should be brought up at every prenatal visit. The problem of obesity reflects also in epidural analgesia, for the difficulty to insert the needle in the right space of the column (Fig. 14.12).


Fig. 14.11

A severe obese pregnant in the delivery room


Fig. 14.12

The insertion of the needle in the correct column space is not always easy for the anesthetist, due to the abundant subcutaneous fat that restricts proper digital recognition of the correct spaces where to insert the needle

14.2.18 Heart Disease

Atherosclerotic heart disease may affect the diabetic gravida, especially those with long-term poorly controlled disease. Emphasis should be placed on preconception cardiac evaluation (history and electrocardiogram, consider echocardiogram). The prognosis is poor for these women with cardiac involvement, with a maternal mortality rate of 50 % or higher [63].

14.3 Special Considerations: Diabetic Ketoacidosis (DKA)

DKA is an uncommon but life-threatening disease that occurs as a result of absolute or relative insulin deficiency. It occurs in 0.5–3 % of diabetic pregnant women [64]. In gravidas with T1DM, DKA can occur in 5–10 %. Risk factors include type I diabetes, new onset diabetes, infections (e.g., urinary or respiratory tract infections), poor compliance, insulin pump failure, and treatment with betamimetics or steroids [12].

The presentation of DKA is similar in pregnant women to that in nonpregnant persons, with symptoms of nausea, vomiting, thirst, polyuria, polydipsia, abdominal pain, and, when severe, a change in mental status. Laboratory findings include hyperglycemia (usually >250 mg/dL [13.9 mmol/L]), acidemia (arterial pH < 7.30), an elevated anion gap (> 12 mEq/L), ketonemia, low serum bicarbonate (<15 mEq/L), elevated base deficit (> 4 mEq/L), and renal dysfunction [65]. Severe hyperglycemia can cause an osmotic diuresis resulting in maternal volume depletion. This, in turn, can result in reduced uterine perfusion and, in association with the metabolic abnormalities of DKA, produce life-threatening fetal hypoxemia and acidosis. Maternal mortality is less than 1 %, but fetal mortality rates of 9–36 % have been reported, as well as increased risks of preterm birth [64]. Thus, DKA is a true obstetrical emergency. During acute DKA, the fetal heart rate often has minimal or absent variability and absent accelerations, as well as repetitive decelerations [64]. These abnormalities usually resolve with resolution of DKA, but it may take several hours before the tracing is normal [66].

DKA is similarly managed in pregnant and nonpregnant patients. Aggressive hydration, intravenous insulin, and correction of the underlying etiology are the most important interventions, with close electrolyte (especially glucose and potassium) monitoring (Table 14.4) [1265]. It is important to determine the etiology of DKA, such as infection or insulin noncompliance. Glucocorticoids and betamimetics should be avoided during DKA, as they will worsen hyperglycemia.

DKA alone is generally not an indication for delivery. Emergent delivery before maternal stabilization should be avoided because it increases the risk of maternal morbidity and mortality and may result in delivery of a hypoxic, acidotic preterm infant for whom in utero resuscitation may have resulted in a better outcome. The timing of delivery needs to be individualized based on multiple factors including gestational age, maternal condition (whether the mother is responding to aggressive therapy or deteriorating), and fetal condition (whether the fetal heart rate pattern is improving or deteriorating). Fetal heart rate abnormalities resulting from maternal acidosis will often improve as DKA is treated and maternal condition improves [64].

Table 14.4

Management of diabetic ketoacidosis in pregnancy

IV hydration: use isotonic saline (0.9 % NS)

 First hour: give 1 L NS

 Hours 2–4: 0.5–1 L NS/h

 Thereafter (24 h): give 250 mL/h 0.45 % NS until 80 % deficit corrected

 Body water deficit = {[0.6 body weight (kg)] + [1–(140/serum sodium)]} ≈ 100 mL deficit/kg body weight

Insulin: mix 50 units of regular insulin in 500 mL of NS and flush IV tubing prior to infusion

 Loading: 0.2–0.4 units/kg

 Maintenance: 2–10 units/h

 Continue insulin therapy until bicarbonate and anion gap normalize

Potassium replacement: maintain serum K+ at 4–5 mEq/L

 If K+ is initially normal or reduced, consider an infusion of up to 15–20 mEq/h

 If K+ is elevated, do not add supplemental potassium until levels are within normal range and then add 20–30 mEq/L

Phosphate: consider replacement if serum phosphate < 1.0 mg/dL or if cardiac dysfunction present or patient obtunded

Bicarbonate: if pH is < 7.1, add one ampule (44 mEq) of bicarbonate to 1 L of 0.45 % NS

Laboratory tests: check arterial blood gas on admission; check serum glucose, ketones, and electrolytes every 1–2 h until normal

 Consider doubling insulin infusion rate if serum glucose does not decrease by 20 % within the first 2 h

 When blood glucose reaches 250 mg/dL, change IVF to D5NS

 Continue insulin drip until ketosis resolves and the first subcutaneous dose of insulin is administered

Source: Adapted from ACOG practice bulletin. Pregestational diabetes [12]

AbbreviationNS normal saline, IVF intravenous fluids, K+ potassium, kg kilograms

14.4 Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) is a diagnosis of diabetes first recognized or diagnosed during pregnancy [67]. It has been estimated that there is an overall 7 % incidence of GDM, representing one of the most common medical complications facing obstetricians [3]. Of cases of DM in pregnancy, 88 % are GDM [67]. The importance of screening for GDM, and treatment to optimize glycemic control to reduce hyperglycemia-associated complications, has been established [6869]. If GDM is diagnose in early pregnancy, then it is most likely preexisting diabetes and should be treated accordingly to minimize the complications of pregestational diabetes (above).

14.4.1 Pathophysiology

The pathophysiology of GDM is insulin resistance caused by circulating hormonal factors: increased maternal and placental production of human placental lactogen, progesterone, growth hormone, cortisol, and prolactin. As the placental mass increases, the circulating hormones increase; correspondingly, the incidence of GDM increases with increasing gestational age. Increased body weight and caloric intake also contribute to the insulin resistance associated with pregnancy and may offset the normally increased insulin production in the pregnant woman [70]. Women with GDM have been found to have lower basal islet cell function, in addition to insulin resistance, when compared to a nondiabetic cohort. The combination of the two factors contributes to the development of GDM. This insulin resistance and decreased insulin production persists in the postpartum state and can lead to the development of type II diabetes in this population.

14.4.2 Screening

Who, when, and how to screen and the diagnostic glucose cutoffs to establish the diagnosis of GDM are controversial.

The population who should be offered screening has not been uniformly identified [67]. Low-risk women in whom screening may not be necessary (selective screening) must meet all of the following criteria: age < 25 years, ethnic origin of low risk (not Hispanic, African, native American, south or east Asian, or Pacific Islander), BMI < 25, no previous personal or family history of impaired glucose tolerance, and no previous history of adverse obstetric outcomes associated with GDM [71]. However, universal screening is most commonly adopted. The risk of developing GDM is directly associated with prepregnancy BMI [72].

Screening is typically recommended at 24–28 weeks gestation [67]. Women with risk factors (Table 14.5) should be screened preconception or at first prenatal visit [71]. About 5–10 % of women with these risk factors will have early GDM, and these represent 40 % of all GDM diagnosed later at 24–28 weeks [73]. If the early screen is negative, a repeat screen should be performed at 24–28 weeks gestation. Typically, if a patient fails the early 1 h glucose screen and passes the early 3 h glucose tolerance test, the 3 h test should be repeated at 24–28 weeks. GDM is diagnosed with 2 abnormal values on the 3 h glucose test. Table 14.6 provides normal values.

Table 14.5

Risk factors for GDM

Prior unexplained stillbirth

Prior infant with congenital anomaly (if not screened in that pregnancy)

Prior macrosomic infant

History of gestational diabetes

Family history of diabetes


Chronic use of steroids

Age >35 years


Source: ACOG practice bulletin. Gestational diabetes mellitus [67]

Table 14.6

Criteria for standard 100-g glucose load to diagnose gestational diabetes


National Diabetes Data Group

Carpenter–Coustan criteria











1 h





2 h





3 h





Screening for GDM is somewhat controversial and can be performed in general either with a one-step or two-step process. One large trial has shown that two-step screening is more cost-effective than the one-step screening [74].

14.4.3 Complications

The incidence of complications is inversely proportional to glucose control. In poorly controlled DM, increased glucose in the mother causes abnormal metabolism, while in the fetus, it causes hyperinsulinemia and its consequences. However, treatment of even mild GDM reduced birth-weight percentiles and neonatal fat mass [75]. Other complications are hypertensive disorders and preeclampsia, macrosomia, operative delivery, and birth injury (see above, pregestational diabetes) [71]. Apart from transient neonatal hypoglycemia, no other metabolic derangement has been reported in the infant of the GDM mother. Long-term adult disorders, such as glucose intolerance and obesity, have been postulated to occur as frequently in these neonates as in neonates of women with pregestational diabetes, but this has not been verified by observational studies [76]. Approximately 50 % of women identified as having GDM will develop frank diabetes within 10 years, if followed longitudinally [77].

14.5 Treatment

Optimizing health outcomes and decreasing risk of the complications in both pregestational and gestational diabetes can be achieved by a combination of diet, exercise, glucose monitoring, and pharmacotherapy.

14.5.1 Diet

Nutritional requirements are adjusted on the basis of maternal body mass index (BMI); women with normal BMI require 30–35 kcal/kg/day. Individuals < 90 % of their ideal body weight (IBW) may increase this by an additional 5 kcal/kg/day, while those > 120 % of their IBW should decrease this value to 24 kcal/kg/day [12].

14.5.2 Exercise

Moderate exercise decreases the need for insulin therapy in type II diabetics by increasing the glucose uptake in skeletal muscle, and therefore, should be strongly encouraged for diabetic patient.

14.5.3 Glucose Monitoring

Preprandial and postprandial home glucose monitoring, have been associated with enhanced glucose control and shorter interval to achieve target blood sugars. Capillary blood glucose (“fingerstick”) measurements using a glucometer should be obtained at least four times a day—fasting and 2 h postprandial. Target levels are in Table 14.7 [78]. Though not in widespread use, continuous glucose monitoring is associated with decreased birth weight and incidence of macrosomia compared to routine monitoring [7980]. More recent studies showed no improvement in glycemic control or in maternal/fetal outcomes in women using continuous glucose monitoring versus four times per day glucometer use [8182].

Table 14.7

Target venous plasma glucose levels


60–90 mg/dL


60–100 mg/dL

One-hour postprandial

≤ 140 mg/dL

Two-hour postprandial

≤ 120 mg/dL

3 AM

60–90 mg/dL

Glycosylated hemoglobin A1c < 6 % is normal [83]. Hemoglobin A1c of 6 % reflects a mean glucose level of 120 mg/dL; each 1 % increment in hemoglobin A1c is equal to a change in mean glucose level of 30 mg/dL. There is evidence that blood sugars (and hemoglobin A1c measurements) should be maintained within normal limits throughout gestation and not just in a particular trimester to decrease the risk of poor pregnancy outcomes [84].

14.5.4 Oral Hypoglycemic Agents

There is insufficient evidence to assess the effectiveness of these agents on glucose control in the pregestational diabetic gravida. Therefore, even in women on oral hypoglycemic control before pregnancy, insulin therapy is suggested for glucose control. Occasionally, a woman well controlled on either glyburide or metformin prepregnancy, and a normal hemoglobin A1c, can be managed by continuing these medications (Fig. 14.13) [1685]. Newer evidence suggests that metformin is preferred over glyburide when oral hypoglycemic agents are employed (at least for GDM management) [86]. Improved maternal glycemic control and reduced neonatal hypoglycemia, respiratory distress syndrome, and NICU admission were noted when metformin was added to an insulin regimen in women with poor control despite high-dose insulin therapy [87].


Fig. 14.13

The administration of metformin reduces glycemia in diabetic pregnants

14.5.5 Insulin

Multiple-dose insulin (MDIinjection therapy is the mainstay in the management of pregestational diabetes. All subcutaneous insulin types have been approved during pregnancy.

A review of the types of insulin, their onset, and duration of action are listed in Table 14.8. Human insulin is preferred to animal insulin. Women, particularly those new to insulin therapy, need to be counseled about the differences in the various insulins in order to use them to their greatest efficacy. Close monitoring with at least weekly contact with a provider is suggested to maximize insulin adjustment. Hypoglycemia is a side effect of insulin treatment. Glucagon should be available for home use in emergency situations.

Table 14.8

Types of insulin and their pharmacokinetics






15–30 min

0.5–3 h

≤5 h


30 min

2.5–5 h

4–12 h


1–2 h

4–12 h

14–24 h


3–4 h

3–9 h

6–23 h (dose dependent)


3–4 h


24 h

Source: ACOG practice bulletin. Pregestational diabetes [12]

Satisfactory glucose control may be obtained solely with an intermediate-acting insulin rather than a short-acting insulin [88]. However, more optimal metabolic control is more likely achieved with one evening injection of long-acting insulin (e.g., insulin glargine), and meal-time injections of short-acting insulin (e.g., lispro or aspart). Glargine cannot be mixed in the same syringe with other insulins. Intermediate-acting insulin (e.g., Neutral Protamine Hagedorn [NPH]) twice daily can also be used, instead of insulin glargine. Studies have shown that short-acting insulin is as effective as regular insulin and may result in improved postprandial glucose control and less preterm deliveries [8990]. Insulin lispro should be given immediately before eating. As compared to two daily insulin injections, additional doses are associated with improved glycemic control [91]. A meta-analysis of cohort studies comparing insulin glargine to NPH did not reveal any significant differences in outcomes including infant birth weight, congenital anomalies, and respiratory distress [92]. A randomized trial including 310 pregnancies compared insulin detemir with NPH and found no differences between maternal hemoglobin A1c, the frequency of major hypoglycemic episodes, early fetal loss, congenital anomalies, and adverse events [8993].

Subcutaneous insulin pump therapy (continuous subcutaneous insulin infusion therapy (CSII)) may be continued in women already compliant with this mode of therapy. In nonpregnant adults, women compliant with insulin pumps have increased satisfaction, decreased episodes of severe hypoglycemia, and better control of hyperglycemia [12]. Basal infusion rates tend to increase and carbohydrate-to-insulin ratios decrease during the course of pregnancy [94]. There is currently insufficient evidence to recommend CSII versus MDI in pregnancy in women not already on pumps [9596]. Inhaled insulin has been tested in nonpregnant adults, but there are yet insufficient data for pregnancy management [97].

Carbohydrate counting and the use of an insulin-to-carbohydrate ratio of 1 unit of insulin for every 15 g of carbohydrate in early gestation can allow for greater flexibility in eating but have not been studied in a trial. As pregnancy advances with its concomitant increased insulin resistance, an increased ratio is required with 1 unit covering a lower amount of carbohydrates, for example, 1 unit/3 g of carbohydrate [94].



Lethbridge-Cejku M, Rose D, Vickerie J (2006) Summary health statistics for u.s. adults: national health interview survey, 2004. Vital Health Stat 10 (228):1–164


Greene MF, Creasy RK, Resnik R, Iams JD, Lockwood CJ, Moore T (2008) Creasy and Resnik’s Maternal-fetal medicine: principles and practice. Elsevier Health Sciences, Philadelphia, PA


American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33(Suppl 1):S62–S69. doi:10.2337/dc10-S062PubMedCentral


Alberti K, Davidson MB, DeFronzo RA et al (1998) Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 21:S5


Balsells M, Garcia-Patterson A, Gich I, Corcoy R (2009) Maternal and fetal outcome in women with type 2 versus type 1 diabetes mellitus: a systematic review and metaanalysis. J Clin Endocrinol Metab 94(11):4284–4291PubMed


White P (1978) Classification of obstetric diabetes. Am J Obstet Gynecol 130(2):228–230PubMed


Diamond MP, Salyer SL, Vaughn WK, Cotton R, Boehm FH (1987) Reassessment of White’s classification and Pedersen’s prognostically bad signs of diabetic pregnancies in insulin-dependent diabetic pregnancies. Obstet Gynecol 156(3):599–604


Bennett SN, Tita A, Owen J, Biggio JR, Harper LM (2015) Assessing white’s classification of pregestational diabetes in a contemporary diabetic population. Obstet Gynecol 125(5):1217–1223PubMedPubMedCentral


Cormier CM, Martinez CA, Refuerzo JS et al (2010) White’s classification of diabetes in pregnancy in the 21st century: is it still valid? Am J Perinatol 27(5):349–352. doi:10.1055/s-0029-1243307PubMed


Sacks DA, Metzger BE (2013) Classification of diabetes in pregnancy: time to reassess the alphabet. Obstet Gynecol 121(2, PART 1):345–348PubMed


Korenbrot CC, Steinberg A, Bender C, Newberry S (2002) Preconception care: a systematic review. Matern Child Health J 6(2):75–88PubMed


ACoP B (2005) ACOG practice bulletin. clinical management guidelines for obstetrician-gynecologists. number 60, march 2005. pregestational diabetes mellitus. Obstet Gynecol 105(3):675–685


Jensen DM, Korsholm L, Ovesen P et al (2009) Peri-conceptional A1C and risk of serious adverse pregnancy outcome in 933 women with type 1 diabetes. Diabetes Care 32(6):1046–1048. doi:10.2337/dc08-2061PubMedPubMedCentral


Guerin A, Nisenbaum R, Ray JG (2007) Use of maternal GHb concentration to estimate the risk of congenital anomalies in the offspring of women with prepregnancy diabetes. Diabetes Care 30(7):1920–1925, doi: dc07-0278 [pii]PubMed


Diabetes Control Complications Trial Research Group (1996) Pregnancy outcomes in the diabetes control and complications trial. Obstet Gynecol 174(4):1343–1353


Tieu J, Coat S, Hague W, Middleton P (2010) Oral anti‐diabetic agents for women with pre‐existing diabetes mellitus/impaired glucose tolerance or previous gestational diabetes mellitus. Cochrane Database Syst Rev (10):CD007724


Fischl AF, Herman WH, Sereika SM et al (2010) Impact of a preconception counseling program for teens with type 1 diabetes (READY-girls) on patient-provider interaction, resource utilization, and cost. Diabetes Care 33(4):701–705. doi:10.2337/dc09-1821PubMedPubMedCentral


Greene MF, Hare JW, Cloherty JP, Benacerraf BR, Soeldner JS (1989) First‐trimester hemoglobin A1 and risk for major malformation and spontaneous abortion in diabetic pregnancy. Teratology 39(3):225–231PubMed


Miller E, Hare JW, Cloherty JP et al (1982) Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers. Obstet Gynecol Surv 37(2):111–113


Ylinen K, Aula P, Stenman UH, Kesaniemi-Kuokkanen T, Teramo K (1984) Risk of minor and major fetal malformations in diabetics with high haemoglobin A1c values in early pregnancy. Br Med J (Clin Res Ed) 289(6441):345–346


Macintosh MC, Fleming KM, Bailey JA et al (2006) Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ 333(7560):177, doi: bmj.38856.692986.AE [pii]PubMedPubMedCentral


Van Beynum IM, Kapusta L, Bakker MK, Den Heijer M, Blom HJ, De Walle HE (2010) Protective effect of periconceptional folic acid supplements on the risk of congenital heart defects: a registry-based case-control study in the Northern Netherlands. Eur Heart J 31(4):464–471. doi:10.1093/eurheartj/ehp479PubMed


Cheschier N, ACOG Committee on Practice Bulletins-Obstetrics (2003) ACOG practice bulletin. neural tube defects. number 44, july 2003. (replaces committee opinion number 252, march 2001). Int J Gynaecol Obstet 83(1):123–133PubMed


Wald N, Cuckle H, Boreham J, Stirrat G, Turnbull A (1979) Maternal serum alpha‐fetoprotein and diabetes mellitus. BJOG 86(2):101–105


Huttly W, Rudnicka A, Wald NJ (2004) Second‐trimester prenatal screening markers for down syndrome in women with insulin‐dependent diabetes mellitus. Prenat Diagn 24(10):804–807PubMed


Evans MI, O’Brien JE, Dvorin E et al (1996) Similarity of insulin-dependent diabetics’ and non-insulin-dependent diabetics’ levels of beta-hCG and unconjugated estriol with controls: No need to adjust as with alpha-fetoprotein. J Soc Gynecol Investig 3(1):20–22PubMed


Ray JG, Vermeulen MJ, Shapiro JL, Kenshole AB (2001) Maternal and neonatal outcomes in pregestational and gestational diabetes mellitus, and the influence of maternal obesity and weight gain: the DEPOSIT study. Diabetes endocrine pregnancy outcome study in Toronto. QJM 94(7):347–356PubMed


Langer O (2005) Ultrasound biometry evolves in the management of diabetes in pregnancy. Ultrasound Obstet Gynecol 26(6):585–595PubMed


Starikov R, Bohrer J, Goh W et al (2013) Hemoglobin A1c in pregestational diabetic gravidas and the risk of congenital heart disease in the fetus. Pediatr Cardiol 34(7):1716–1722PubMed


Philipps AF, Porte PJ, Stabinsky S, Rosenkrantz TS, Raye JR (1984) Effects of chronic fetal hyperglycemia upon oxygen consumption in the ovine uterus and conceptus. J Clin Invest 74(1):279–286. doi:10.1172/JCI111412PubMedPubMedCentral


Cohn HE, Cohen WR, Piasecki GJ, Jackson BT (1992) The effect of hyperglycemia on acid-base and sympathoadrenal responses in the hypoxemic fetal monkey. J Dev Physiol 17(6):299–304PubMed


Shelley HJ, Bassett JM, Milner RD (1975) Control of carbohydrate metabolism in the fetus and newborn. Br Med Bull 31(1):37–43PubMed


Hay WW Jr, DiGiacomo JE, Meznarich HK, Hirst K, Zerbe G (1989) Effects of glucose and insulin on fetal glucose oxidation and oxygen consumption. Am J Physiol 256(6 Pt 1):E704–E713PubMed


Nylund L, Lunell N, Lewander R, Persson B, Sarby B, Thornstrom S (1982) Uteroplacental blood flow in diabetic pregnancy: measurements with indium 113m and a computer-linked gamma camera. Blood 144(3):298–302


Landon M, Vickers S (2002) Fetal surveillance in pregnancy complicated by diabetes mellitus: is it necessary? J Matern Fetal Neonatal Med 12(6):413–416PubMed


Siddiqui F, James D (2003) Fetal monitoring in type 1 diabetic pregnancies. Early Hum Dev 72(1):1–13PubMed


Lampl M, Jeanty P (2004) Exposure to maternal diabetes is associated with altered fetal growth patterns: a hypothesis regarding metabolic allocation to growth under hyperglycemic‐hypoxemic conditions. Am J Hum Biol 16(3):237–263PubMed


Menon RK, Cohen RM, Sperling MA, Cutfield WS, Mimouni F, Khoury JC (1990) Transplacental passage of insulin in pregnant women with insulin-dependent diabetes mellitus: its role in fetal macrosomia. N Engl J Med 323(5):309–315PubMed


Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M (1996) A United States national reference for fetal growth. Obstet Gynecol 87(2):163–168PubMed


American College of Obstetricians and Gynecologists (2000) Fetal macrosomia. ACOG Pract Bull 22:1–11


Acker DB, Barss VA (1995) Obstetrical complications. In: Brown FM, Hare JW (eds) Diabetes complication pregnancy, 2nd edn. Wiley-Liss, New York, p 153


Modanlou HD, Komatsu G, Dorchester W, Freeman RK, Bosu SK (1982) Large-for-gestational-age neonates: anthropometric reasons for shoulder dystocia. Obstet Gynecol 60(4):417–423PubMed


Benedetti TJ, Gabbe SG (1978) Shoulder dystocia A complication of fetal macrosomia and prolonged second stage of labor with midpelvic delivery. Obstet Gynecol 52(5):526–529PubMed


Langer O, Berkus MD, Huff RW, Samueloff A (1991) Shoulder dystocia: should the fetus weighing ≥ 4000 grams be delivered by cesarean section? Obstet Gynecol 165(4):831–837


Ecker JL, Greenberg JA, Norwitz ER, Nadel AS, Repke JT (1997) Birth weight as a predictor of brachial plexus injury. Obstet Gynecol 89(5):643–647PubMed


Scioscia M, Vimercati A, Ceci O, Vicino M, Selvaggi LE (2008) Estimation of birth weight by two-dimensional ultrasonography: a critical appraisal of its accuracy. Obstet Gynecol 111(1):57–65. doi:10.1097/01.AOG.0000296656.81143.e6PubMed


Combs CA, Rosenn B, Miodovnik M, Siddiqi TA (2000) Sonographic EFW and macrosomia: is there an optimum formula to predict diabetic fetal macrosomia? J Matern Fetal 9(1):55–61


Dashe JS, Nathan L, McIntire DD, Leveno KJ (2000) Correlation between amniotic fluid glucose concentration and amniotic fluid volume in pregnancy complicated by diabetes. Obstet Gynecol 182(4):901–904


Sibai BM, Caritis SN, Hauth JC et al (2000) Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies. Obstet Gynecol 183(6):1520–1524


Greene MF, Hare JW, Krache M et al (1989) Prematurity among insulin-requiring diabetic gravid women. Obstet Gynecol 161(1):106–111


Mimouni F, Miodovnik M, Siddiqi TA, Berk MA, Wittekind C, Tsang RC (1988) High spontaneous premature labor rate in insulin-dependent diabetic pregnant women: an association with poor glycemic control and urogenital infection. Obstet Gynecol 72(2):175–180PubMed


Reece EA, Sivan E, Francis G, Homko CJ (1998) Pregnancy outcomes among women with and without diabetic microvascular disease (white’s classes B to FR) versus non-diabetic controls. Am J Perinatol 15(9):549–555. doi:10.1055/s-2007-994059PubMed


Bedalov A, Balasubramanyam A (1997) Glucocorticoid-induced ketoacidosis in gestational diabetes: sequela of the acute treatment of preterm labor. A case report. Diabetes Care 20(6):922–924PubMed


Fisher JE, Smith RS, LaGrandeur R, Lorenz RP (1997) Gestational diabetes mellitus in women receiving beta-adrenergics and corticosteroids for threatened preterm delivery. Obstet Gynecol 90(6):880–883PubMed


Mathiesen ER, Christensen AL, Hellmuth E, Hornnes P, Stage E, Damm P (2002) Insulin dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: test of analgoritm. Acta Obstet Gynecol Scand 81(9):835–839PubMed


Refuerzo JS, Garg A, Rech B, Ramin SM, Vidaeff A, Blackwell SC (2012) Continuous glucose monitoring in diabetic women following antenatal corticosteroid therapy: a pilot study. Am J Perinatol 29(5):335–338. doi:10.1055/s-0031-1295642PubMed


Gary CF, Gant N, Leveno K, Gilstrap L, Hauth J, Wenstrom KD (2005) Williams obstetrics. Mc Grow–Hill, New York, pp 823–829


Temple R, Aldridge V, Sampson M, Greenwood R, Heyburn P, Glenn A (2001) Impact of pregnancy on the progression of diabetic retinopathy in type 1 diabetes. Diabet Med 18(7):573–577PubMed


Arun C, Taylor R (2008) Influence of pregnancy on long-term progression of retinopathy in patients with type 1 diabetes. Diabetologia 51(6):1041–1045PubMed


American Diabetes Association (2012) Standards of medical care in diabetes--2012. Diabetes Care 35(Suppl 1):S11–S63. doi:10.2337/dc12-s011


Klein BE, Moss SE, Klein R (1990) Effect of pregnancy on progression of diabetic retinopathy. Diabetes Care 13(1):34–40


Holmes VA, Young IS, Patterson CC et al (2011) Optimal glycemic control, pre-eclampsia, and gestational hypertension in women with type 1 diabetes in the diabetes and pre-eclampsia intervention trial. Diabetes Care 34(8):1683–1688. doi:10.2337/dc11-0244PubMedPubMedCentral


Gordon MC, Landon MB, Boyle J, Stewart KS, Gabbe SG (1996) Coronary artery disease in insulin-dependent diabetes mellitus of pregnancy (class H): a review of the literature. Obstet Gynecol Surv 51(7):437–444PubMed


Sibai BM, Viteri OA (2014) Diabetic ketoacidosis in pregnancy. Obstet Gynecol 123(1):167–178. doi:10.1097/AOG.0000000000000060PubMed


Carroll MA, Yeomans ER (2005) Diabetic ketoacidosis in pregnancy. Crit Care Med 33(10):S347–S353PubMed


Hagay ZJ, Weissman A, Lurie S, Insler V (1994) Reversal of fetal distress following intensive treatment of maternal diabetic ketoacidosis. Am J Perinatol 11(6):430–432. doi:10.1055/s-2007-994613PubMed


American College of Obstetricians and Gynecologists (2001) ACOG practice bulletin# 30: gestational diabetes. ACOG, Washington


Alwan N, Tuffnell DJ, West J (2009) Treatments for gestational diabetes. Cochrane Database Syst Rev (3):CD003395


Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS (2005) Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 352(24):2477–2486PubMed


American Diabetes Association (2004) Gestational diabetes mellitus. Diabetes Care 27(Suppl 1):S88–S90


Metzger BE, Buchanan TA, Coustan DR et al (2007) Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus. Diabetes Care 30(Suppl 2):S251–S260. doi:10.2337/dc07-s225PubMed


Torloni M, Betrán A, Horta B et al (2009) Prepregnancy BMI and the risk of gestational diabetes: a systematic review of the literature with meta‐analysis. Obes Rev 10(2):194–203PubMed


Meyer WJ, Carbone J, Gauthier DW, Gottmann DA (1996) Early gestational glucose screening and gestational diabetes. J Reprod Med 41(9):675–679PubMed


Meltzer S, Snyder J, Penrod J, Nudi M, Morin L (2010) Gestational diabetes mellitus screening and diagnosis: a prospective randomised controlled trial comparing costs of one‐step and two‐step methods. BJOG 117(4):407–415PubMed


Mackeen AD, Trauffer PM (2011) Gestational diabetes. In: Maternal-fetal evidence based guidelines. Informa Healthcare/Distributed in North America by Taylor & Francis, London/Boca Raton, p 247


Kim SY, England JL, Sharma JA, Njoroge T (2011) Gestational diabetes mellitus and risk of childhood overweight and obesity in offspring: a systematic review. Exp Diabetes Res 2011:541308. doi:10.1155/2011/541308PubMedPubMedCentral


Kim C, Newton KM, Knopp RH (2002) Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 25(10):1862–1868PubMed


Mackeen AD, Trauffer PM (2011) Pregestational diabetes. In: Maternal-fetal evidence based guidelines. Informa Healthcare/Distributed in North America by Taylor & Francis, London/Boca Raton, p 39


Murphy HR, Rayman G, Lewis K et al (2008) Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. BMJ 337:a1680. doi:10.1136/bmj.a1680PubMedPubMedCentral


Mclachlan K, Jenkins A, O’neal D (2007) The role of continuous glucose monitoring in clinical decision‐making in diabetes in pregnancy. Aust N Z J Obstet Gynaecol 47(3):186–190PubMed


Secher AL, Ringholm L, Andersen HU, Damm P, Mathiesen ER (2013) The effect of real-time continuous glucose monitoring in pregnant women with diabetes: a randomized controlled trial. Diabetes Care 36(7):1877–1883. doi:10.2337/dc12-2360PubMedPubMedCentral


Petrovski G, Dimitrovski C, Bogoev M, Milenkovic T, Ahmeti I, Bitovska I (2011) Is there a difference in pregnancy and glycemic outcome in patients with type 1 diabetes on insulin pump with constant or intermittent glucose monitoring? A pilot study. Diabetes Technol Ther 13(11):1109–1113PubMed


Gabbe SG, Graves CR (2003) Management of diabetes mellitus complicating pregnancy. Obstet Gynecol 102(4):857–868PubMed


Damm P, Mersebach H, Råstam J et al (2014) Poor pregnancy outcome in women with type 1 diabetes is predicted by elevated HbA1c and spikes of high glucose values in the third trimester. J Matern Fetal Neonatal Med 27(2):149–154PubMed


Tieu J, Crowther CA, Middleton P (2008) Dietary advice in pregnancy for preventing gestational diabetes mellitus. Cochrane Database Syst Rev (2):CD006674


Balsells M, Garcia-Patterson A, Sola I, Roque M, Gich I, Corcoy R (2015) Glibenclamide, metformin, and insulin for the treatment of gestational diabetes: a systematic review and meta-analysis. BMJ 350:h102. doi:10.1136/bmj.h102PubMedPubMedCentral


Ibrahim MI, Hamdy A, Shafik A, Taha S, Anwar M, Faris M (2014) The role of adding metformin in insulin-resistant diabetic pregnant women: a randomized controlled trial. Arch Gynecol Obstet 289(5):959–965PubMed


Ismail NAM, Nor NAM, Sufian SS, Mustafa N, Jamil MA, Kamaruddin NA (2007) Comparative study of two insulin regimes in pregnancy complicated by diabetes mellitus. Acta Obstet Gynecol Scand 86(4):407–408


Hod M, Mathiesen ER, Jovanovič L et al (2014) A randomized trial comparing perinatal outcomes using insulin detemir or neutral protamine hagedorn in type 1 diabetes. J Matern Fetal Neonatal Med 27(1):7–13PubMed


Mathiesen ER, Kinsley B, Amiel SA et al (2007) Maternal glycemic control and hypoglycemia in type 1 diabetic pregnancy: a randomized trial of insulin aspart versus human insulin in 322 pregnant women. Diabetes Care 30(4):771–776, doi: 30/4/771 [pii]PubMed


Nachum Z, Ben-Shlomo I, Weiner E, Shalev E (1999) Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. BMJ 319(7219):1223–1227PubMedPubMedCentral


Pollex E, Moretti ME, Koren G, Feig DS (2011) Safety of insulin glargine use in pregnancy: a systematic review and meta-analysis. Ann Pharmacother 45(1):9–16. doi:10.1345/aph.1P327PubMed


Mathiesen ER, Hod M, Ivanisevic M et al (2012) Maternal efficacy and safety outcomes in a randomized, controlled trial comparing insulin detemir with NPH insulin in 310 pregnant women with type 1 diabetes. Diabetes Care 35(10):2012–2017, doi: dc11-2264 [pii]PubMedPubMedCentral


Mathiesen JM, Secher AL, Ringholm L et al (2014) Changes in basal rates and bolus calculator settings in insulin pumps during pregnancy in women with type 1 diabetes. J Matern Fetal Neonatal Med 27(7):724–728PubMed


Farrar D, Tuffnell DJ, West J (2007) Continuous subcutaneous insulin infusion versus multiple daily injections of insulin for pregnant women with diabetes. Cochrane Database Syst Rev (3):CD005542


Mukhopadhyay A, Farrell T, Fraser RB, Ola B (2007) Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials. Obstet Gynecol 197(5):447–456


Hollander PA, Blonde L, Rowe R et al (2004) Efficacy and safety of inhaled insulin (exubera) compared with subcutaneous insulin therapy in patients with type 2 diabetes: results of a 6-month, randomized, comparative trial. Diabetes Care 27(10):2356–2362, doi: 27/10/2356 [pii]PubMed