Diabetic pregnancy is pregnancy associated with diabetes mellitus. The term “diabetic pregnancy” may refer to a pregnancy in a woman with pre-existing diabetes, or to diabetes that develops during pregnancy; in the latter case, the condition is known as gestational diabetes. Women with established diabetes can have a normal pregnancy provided that the diabetes is well controlled.
Careful control of blood glucose levels must begin well before conception. Poor control may affect the baby’s growth, and increase the risk of fetal malformations and complications during pregnancy. In gestational diabetes, the mother does not produce enough insulin to keep blood glucose levels normal.
The condition is usually detected in the second half of pregnancy, when urine tests reveal the presence of glucose. Treatment is the same as for women who have pre-existing diabetes mellitus. Gestational diabetes disappears after the birth, but it is associated with an increased risk of the woman developing Type 2 diabetes in later life.
Diabetes in pregnancy in detail - technical
Topics covered:
- Essentials
- Introduction
- Historical perspective
- Classification
- Epidemiology
- Aetiology, genetics, pathogenesis, and pathology
- Screening
- Diagnosis
- Towards new diagnostic criteria for diagnosing GDM-The HAPO Study
- Effects of diabetes in pregnancy
- Treatment
- Fetal assessment
- Timing and mode of delivery
- Postpartum considerations
- Further reading
Essentials
Diabetes is one of the most common medical complications in pregnancy: 0.4 to 2% of all births are complicated by pregestational diabetes; about 3% of pregnancies are complicated by gestational diabetes mellitus, with substantially more in some populations.
Preconceptional evaluation—this should include evaluation of glycaemic control, blood pressure, retinal disease, renal status, thyroid function, peripheral and autonomic neuropathy, peripheral vascular disease, and hypoglyacemic symptoms.
Pregnancy outcome—(1) Pregnancy complicated by diabetes is associated with increased perinatal mortality. (2) Early growth delay, major congenital malformations, and abortions are related to poor glycaemic control around the time of conception and in the first trimester. (3) Macrosomia may be associated with significant obstetrical morbidity such as shoulder dystocia, which may result in severe birth trauma.
Screening and diagnosis—selective or universal screening for gestational diabetes mellitus should be determined by population characteristics. The most commonly accepted method of diagnosis of gestational diabetes mellitus is the 100-g oral glucose tolerance test, using either the National Diabetes Data Group criteria or Carpenter and Coustan criteria.
Medical management—the key to improving pregnancy outcome in women with diabetes is strict glycaemic control. Proper diet has a very important function unique to maternal diabetes: it must assure adequate nourishment to the developing fetus without risking significant and prolonged hyperglycemia. Medical therapy with pharmacological agents should be reserved for those who fail to achieve desired level of glycaemic control despite diet therapy, and for those who are not appropriate candidates for diet therapy alone. Glibenclamide is safe and effective for the treatment of gestational diabetes mellitus.
Obstetric management—important aspects include: (1) Measurement of the fetal abdominal circumference early in the third trimester may identify infants at risk for macrosomia in the absence of maternal pharmacological therapy. (2) The timing of delivery of the patient with diabetes is a balancing act between potential intrauterine death, shoulder dystocia and the consequences of premature delivery—expectant management beyond the estimated due date is not recommended generally, although an ultrasound estimate of fetal weight may help to rule out macrosomia. Cesarean delivery to prevent traumatic birth injury may be considered if the estimated fetal weight is greater than 4000 to 4500 g. (3) Poor glycaemic control in late pregnancy is a significant risk factor for fetal distress and neonatal asphyxia—a team of professionals (physicians, neonatal nurse practitioners, midwives, and/or respiratory therapists) trained in the paediatric management of complicated deliveries should be present in the delivery room.
Postpartum management—at 6 to 8 weeks a 75-g oral glucose tolerance test should be administered to all women with gestational diabetes mellitus. The test should be repeated on a regular basis every 1 to 3 years, depending upon the patient’s risk factors for developing type 2 diabetes.
Introduction
Diabetes is one of the most common medical complications in pregnancy, affecting 4 to 10% of women worldwide and even more highly prevalent in specific geographic regions and ethnic populations. In the United States of America and Europe, about 135 000 to 200 000 women are diagnosed annually with gestational diabetes (GDM), adding to the number of women who have diabetes (type 1 or type 2) before pregnancy. The increasing prevalence of type 2 diabetes in general, and in younger people in particular, has led to an increasing number of pregnancies with this complication.
During normal pregnancy, a marked reduction of insulin sensitivity is compensated by a reciprocal increase in β-cell secretion, hence pregnancy is characterized as a state of hyperinsulinaemia and insulin resistance in response to diabetogenic effects of normal carbohydrate metabolism. The increased risk for maternal hyperglycaemia and the resultant fetal hyperinsulinaemia are central to the pathophysiology of diabetic complications. All types of diabetes have increased risk for stillbirth, deviant fetal growth (macrosomia, growth restriction), metabolic (e.g. hypoglycaaemia, hypocalcaemia), haematological (e.g. hyperbilirubinaemia, polycythaemia) and respiratory complications that increase neonatal intensive care unit admission rates; also a greater incidence of birth trauma (e.g. shoulder dystocia). The most significant fetal complications in type 1 and type 2 diabetes are congenital anomalies; there is also a high risk of spontaneous abortion.
Historical perspective
Before the discovery of insulin, diabetes was an affliction with a dismal prognosis. A successful pregnancy was virtually impossible when compromised by untreated diabetes. Pregnancy worsened the disease and shortened the lives of these women, many of whom died either during or shortly after the pregnancy. Poor interventional obstetric care with increased risk of puerperal sepsis further compromised the pregnancies. The link between congenital malformations and maternal diabetes in pregnancy is of more recent concern.
With the discovery and use of insulin, a new hope arose for diabetic women and their reproductive potential. With the introduction of insulin, maternal mortality fell dramatically, and perinatal mortality decreased over time. However, the introduction of insulin did not ameliorate the problems of macrosomia and associated traumatic injury to mother and fetus, as well as continuing complications such as neonatal hypoglycaemia, congenital malformations, pre-eclampsia, and infection. By the 1940s insulin had made pregnancy relatively safe for the diabetic mother, but it also complicated the problem because physicians saw patients with severe diabetes who in the pre-insulin era would never have become pregnant. During this period, several attempts were made to ameliorate fetal death due to diabetes. It was observed that there was a significant stillbirth rate beyond 36 weeks of gestation, hence diabetic patients were routinely delivered at or before 36 weeks by caesarean section or by induction of labour if fetal death had not already occurred, or if maternal complications had not mandated an earlier delivery. At the Joslin Clinic in Boston, under the leadership of Priscilla White, new clinical recommendations for the care of pregnant diabetic women consisted of strict glycaemic control, long-term hospitalization, and sound obstetrical management.
Gestational diabetes (GDM)—a term first used by O’Sullivan in 1961—is defined as ‘carbohydrate intolerance of varying severity with onset or first recognition during pregnancy’. At about the same time, others reported increased perinatal mortality associated with abnormal oral glucose tolerance during pregnancy, but gestational diabetes as a clinical entity was slow to win converts, partly because of the relatively short phase of hyperglycaemia during the latter part of pregnancy and partly on account of its disappearance after the delivery. However, it has become increasingly accepted as a disease, not only for its implications on the immediate outcome of pregnancy, but also for long-term effects on child and mother (maternal development in later life of type 2 diabetes).
Classification
Patients with pregestational diabetes are categorized according to length of disease and the presence of microvascular or other end-organ complications (Table 1). GDM—defined as stated above as carbohydrate intolerance of varying severity with onset or first recognition during pregnancy—is further stratified by fasting plasma glucose and treatment modality to A1 and A2 (Table 1).
Epidemiology
GDM is a problem with major public health implications and one that is growing in magnitude as its incidence climbs. The principal sources of epidemiological information are national and local statistics, hospital and ambulatory medical records, and research studies and specialized registries. These epidemiological data vary as to their specificity, population size, criteria for ascertainment, and definition of disease. Estimates that diabetes (type 1, type 2, and GDM) occurs annually in 1% to 14% of all pregnancies are based on both national birth statistics and small community studies.
Since the prevalence of type 1 and type 2 diabetes varies by both race and age, it is difficult to differentiate the number of births complicated by type 1 diabetes from those complicated by type 2 diabetes in the population as a whole or in any of its components. However, it is estimated that between 0.4% and 2% of all births are complicated by pregestational diabetes. Moreover, it is assumed that the prevalence of pregnancies complicated by pregestational diabetes will increase. This is based on several factors that have emerged in recent years: (1) increased incidence in type 2 diabetes among adolescents and women less than 25 years of age; (2) increased birth rate among adolescents; (3) population growth (due to immigration and higher birth rate) among groups with higher risk of diabetes (specifically Hispanic and Asian-American); (4) increased incidence of obesity in women of childbearing age.
The epidemiology of GDM is subject to substantial limitations due to disagreement over: (1) who should be screened; (2) when screening should occur; (3) screening test criteria; and, (4) diagnostic test criteria. Screening recommendations for GDM range from the inclusion of all pregnant women (universal) to the exclusion of all women except those with very specific risk factors (selective), the latter being estimated to omit more than 5% of women with the condition. Based on the United States Vital Statistics database in 2002, GDM occurred in the pregnancies resulting in live births of 3.4% Hispanic women, 2.7% African-American women, and 2.8% white women. However, the situation is still complicated by disagreement as to diagnostic criteria for GDM. For example, there is a controversy as to whether the 75-g 2-h oral glucose tolerance test (OGTT) should be considered in place of the 100 g 3-h OGTT, and the interpretation of OGTT criteria is also subject to debate. Some advocate that one abnormal value on the OGTT has the same risk of adverse perinatal outcome as does two abnormal values, hence the true prevalence of GDM in a studied population is still a matter of definition and classification.
| Table 1 Classification of diabetes in pregnancy |
|---|
| Class | Onset | Fasting plasma glucose | Therapy |
| A1 | Gestational | <105 mg/dl (5.8 mmol/litre) | Diet |
| A2 | Gestational | >105 mg/dl (5.8 mmol/litre) | Pharmacological |
| Class | Age of onset (years) | Duration (years) | Vascular complication | Insulin |
| B | >20 | <10 | None | Insulin |
| C | 10–19 | 10–19 | None | Insulin |
| D | <10 | >20 | Benign retinopathy | Insulin |
| F | Any | Any | Nephropathy | Insulin |
| R | Any | Any | Proliferative retinopathy | Insulin |
| H | Any | Any | Heart | Insulin |
As pregnancy advances the increasing tissue resistance to insulin creates a demand for more insulin, which is readily met in most women such that normoglycaaemia is maintained. Hyperglycaemia develops if insulin secretion is inadequate to overcome insulin resistance: in most cases this happens in the last half of pregnancy, with insulin resistance increasing progressively until delivery, when in most cases it rapidly disappears.
Aetiology, genetics, pathogenesis, and pathology
GDM is characterized by carbohydrate intolerance of variable severity, with onset or first recognition during pregnancy. This definition applies whether or not there is a need for insulin and whether or not it disappears after pregnancy: it does not apply to gravid patients with previously diagnosed diabetes. Pregnancy can be viewed as a progressive condition of insulin resistance, hyperinsulinaemia, and postprandial hyperglycaemia. Glucose is transferred through the placenta by facilitated diffusion, with postprandial elevation increasing nutrient availability (glucose) to the fetus. In addition, peripheral insulin resistance is more pronounced in skeletal muscle than in the adipose tissue, resulting in ingested nutrients being shunted towards the adipose tissue. This promotes maternal anabolism and energy storage needed in late pregnancy when fetal growth is maximal.
The physiological changes responsible for insulin resistance in pregnancy appear to be related to the metabolic effects of several hormones and other factors that are elevated in the maternal circulation during gestation. The development of insulin resistance and GDM during pregnancy tends to parallel the growth of the fetomaternal unit and the levels of hormones secreted by the placenta. Progesterone signalling may play a vital role in insulin release and pancreatic function and may affect susceptibility to diabetes; moreover progesterone prohibits normal adaptation of the pancreatic β-cell reserve during pregnancy and is a major contributor to increased insulin resistance. Human placental lactogen (hPL) levels increase at the onset of the second trimester, causing a decrease in phosphorylation of insulin receptor substrate-1 and intense insulin resistance. In addition cortisol and prolactin increase insulin resistance and alter insulin function.
Leptin is a 16-kDa protein encoded by the ob/ob (obesity) gene, secreted by adipocyte tissue, and also produced by a number of other tissues including the stomach, intestine, and placenta in humans. It acts on hypothalamic receptors to decrease food intake and increase energy expenditure. Fasting insulin and leptin concentrations correlate closely with body fat, making leptin a good marker of obesity and insulin resistance. The serum leptin levels in women with GDM are significantly higher than in women whose pregnancies are not compromised by this condition.
Adiponectin is an adipose tissue hormone secreted by adipocytes that may facilitate the regulation of glucose and lipid metabolism. It decreases hepatic glucose production and insulin resistance by up-regulating fatty acid oxidation. Adiponectin may emerge as a significant factor in carbohydrate-fat metabolism and in the development of insulin resistance during pregnancy because of data suggesting that there are decreased adiponectin levels in women with GDM compared with healthy control subjects.
Risk factors for the development of GDM are specified in Table 2.
Screening
There is considerable controversy concerning who should be screened for GDM. The American Diabetes Association proposed that all pregnant women undergo risk assessment for GDM at the first office visit as early as possible, with the recommendation that they need not be screened for GDM if they have none of the risk factors described in Table 2, but they should be screened if any risk factors are present. If they are found to not have GDM on the initial screening (negative screening results), they should be retested between 24 to 28 weeks of gestation. By contrast, the American College of Obstetricians and Gynecologists recommends that all pregnant women be screened for GDM between 24 and 28 weeks of gestation, except women who meet all the low risk criteria.
The 4th Workshop Conferences on GDM recommended screening with a 50-g oral glucose load followed 1 h later with a blood glucose determination, with those found to have a value of 130 mg/dl (7.2 mmol/litre) followed up with a 100-g OGTT. Using their data, this approach had a sensitivity of 79% and specificity of 87% for the diagnosis of GDM by the OGTT. To account for plasma determination, the cut-off was modified to 140 mg/dl (7.8 mmol/litre) and this threshold has been widely applied as the indication for a follow-up OGTT. Coustan et al. studied 6000 women using a 50-g oral glucose challenge test: using an abnormal threshold designated as 130 mg/dl (7.2 mmol/litre) had a sensitivity of nearly 100%, with 23% requiring a 3-h OGTT; by contrast, the use of a threshold of 140 mg/dl (7.8 mmol/litre) resulted in sensitivity of 80 to 90%, with 15% requiring a 3-h OGTT. Hence, lowering the threshold from 140 mg/dl (7.8 mmol/litre) to 130 mg/dl (7.2 mmol/litre) resulted in an 11% increase in test sensitivity, but there was a significant increase in the numbers of women requiring an OGTT. About 10% of individuals with screening results between 130 and 139 mg/dl (7.2–7.8 mmol/litre) will manifest GDM if tested with a 3-h OGTT. Because the precise cost–benefit ratio for diagnosing GDM remains unresolved, either threshold is acceptable, hence the selection should be decided mainly by demographic/geographic considerations. In regions with a high prevalence of GDM/type 2 diabetes, it is reasonable to use the lower threshold (130 mg/dl or 7.2 mmol/litre—increasing sensitivity); in an area of lower prevalence, cost-effectiveness may dictate the choice of a higher threshold (140 mg/dl or 7.8 mmol/litre).
| Table 2 Risk factors for GDM |
|---|
| Risk factor | Description |
| Age | >25 years |
| Obesity | Prepregnancy BMI> 30 kg/m2 |
| Ethnicity | Hispanic, Native American, Asian American, African-American |
| Family history | First degree relative with type 2 diabetes |
| Previous GDM | |
| Previous infant large for gestational age |
Diagnosis
The ideal diagnostic test for gestational diabetes has not yet been developed. The limitations of the OGTT include test duration, time of performance (morning only, after nocturnal fast), patient discomfort, especially during the first trimester with potential nausea and vomiting, as well as the supraphysiological glucose load unrelated to body weight. Finally, the issue of reproducibility remains a limitation. The most commonly accepted method of diagnosis of GDM is the 100-g 3-h OGTT, using either the National Diabetes Data Group or the Carpenter and Coustan criteria. Both diagnostic criteria require two or more abnormal values for the diagnosis of GDM (Table 3). Despite repeated reports of the association between one abnormal value on the OGTT results and adverse outcome in pregnancy, the use of one abnormal value for the diagnosis of GDM remains controversial.
There is no consensus on the glucose load concentration that should be used for the glucose test. Several clinical studies have attempted to test if the 75-g load (recommended by the World Health Organization and by the American Diabetes Association) will be more convenient and provide greater accuracy than the 100-g load, while others have suggested that some GDM women will not be identified with the lower load. Some advocate that the 75-g load be used in the diagnosis of GDM using the threshold suggested by the Carpenter–Coustan criteria, i.e. fasting 95 mg/dl (5.3 mmol/litre), 1 h 180 mg/dl (10 mmol/litre), 2 h 155 mg/dl (8.6 mmol/litre). This recommendation eliminated the 3-h sample and used two or more abnormal values for diagnosis. The result was a one-step approach in which the OGTT is performed without prior plasma or serum glucose screening, which may be cost-effective for high-risk patients.
Recently, the Hyperglycemia & Adverse Pregnancy Outcome (HAPO) study has collected data from around 25 000 pregnancies to examine the relationships between maternal glycaemia and pregnancy outcome in a setting where both caregivers and subjects were masked or blinded to glucose tolerance test results. It is anticipated that the results of the HAPO study will provide data that lead to criteria for the diagnosis of GDM that are linked to risk of adverse outcome.
| Table 3 Diagnostic criteria for GDM |
|---|
| Status | Carpenter and Coustan | NDDG |
| Fasting | 95 mg/dl (5.3 mmol/litre) | 105 mg/dl (5.8 mmol/litre) |
| 1 h after GTT | 180 mg/dl (10 mmol/litre) | 190 mg/dl (10.6 mmol/litre) |
| 2 h after GTT | 155 mg/dl (8.6 mmol/litre) | 185 mg/dl (10.3 mmol/litre) |
| 3 h after GTT | 140 mg/dl (7.8 mmol/litre) | 145 mg/dl (8.0 mmol/litre) |
|
NDDG, National Diabetes Data Group. |
Towards new diagnostic criteria for diagnosing GDM - The HAPO Study
The HAPO Study was an investigator initiated project, planned as a prospective, observational, multicentre, blinded study. The study was held in a multinational, multi cultural, ethnically diverse population, from various countries. It was designed to find if, and what is the correlation between adverse pregnancy outcomes to maternal glucose intolerance, that fall short of overt diabetes values. Also, it was meant to set the evidence-based criteria for diagnosis and classification of GDM, to be based upon the correlation between glycaemic levels and perinatal outcome. The preliminary hypothesis of the study was that gestational hyperglycaemia, even below the threshold for diabetes, will be associated with increased maternal, fetal and neonatal morbidities
A total of 23 316 women completed the course of the study, not being lost to follow-up, and remaining with their data blinded. The results of the HAPO study demonstrate an association between increasing levels of fasting, 1-h and 2-h plasma glucose post a 75 g OGTT, to the four primary endpoints of the study: birth weight above the 90th percentile, cord blood serum C-peptide level above the 90th percentile, primary caesarean delivery and clinical neonatal hypoglycaemia. Although significant correlations were present for the two latter outcomes, they were not as strong as those with the two former endpoints. Positive correlations were also found between increasing plasma glucose levels to the five secondary outcomes: premature delivery, shoulder dystocia or birth injury, intensive neonatal care admission, hyperbilirubinaemia, and pre-eclampsia. Adjustments were made for field centre, maternal BMI, blood pressure, height, parity, baby gender, and ethnic group—these reduced the observed associations, but they generally remained valid. This validates the results for all age groups, countries, and ethnic origin—thus, eliminating the proposed impacts of some speculated confounders.
Additional analyses examined the issue of neonatal adiposity. Out of the total HAPO participants, cord serum C-peptide results were available for 19 885 newborns and skin-fold measurements for 19 389. These measurements were used to determine the relationship between neonatal adiposity (defined as the sum of skin folds higher than 90th percentile or body fat percentage over 90th percentile) to maternal glucose levels. There is a statistically significant correlation between increasing values of maternal glycemia, on all OGTT values, and cord serum C-peptide to neonatal adiposity. The pattern is similar to the correlation between maternal glucose values and birth weight above the 90th percentile, and was held true also for fat free mass (derived by subtracting fat mass from total body weight).
The HAPO study therefore demonstrates that fasting glucose levels and post 75 g OGTT are correlated to maternal, perinatal, and neonatal outcomes and this is essentially in a linear manner. Glucose has an impact on pregnancy outcome, even at levels below the current, commonly accepted range. There seems to be no apparent threshold, but rather a continuum of glucose levels. These results now provide the evidence base for developing perinatal outcome-based standards to diagnose and classify GDM, that are valid and therefore applicable worldwide Furthermore, these associations between adverse outcomes and ‘nondiabetic’ hyperglycaemia, suggest the need to lower current diagnostic thresholds for GDM. It is anticipated that the International Association of Diabetes and Pregnancy Study Groups (IADPSG) will shortly publish its recommended criteria for GDM which are based on the findings from the HAPO study.
Effects of diabetes in pregnancy
All types of diabetes have increased risk for stillbirth, deviant fetal growth (macrosomia, growth restriction), metabolic complications (e.g. hypoglycaemia, hypocalcaemia), haematological complications (e.g. hyperbilirubinaemia, polycythaemia), respiratory complications that increase neonatal intensive care unit admission, and birth trauma (e.g. shoulder dystocia). It has been demonstrated in both randomized and cohort studies that lack of treatment for GDM is associated with increased risk of these serious perinatal morbidities.
Treatment
Preconception care for pregestational diabetes
About 50% of all pregnancies are unplanned and do not have the advantages of preconception care. Congenital anomalies and spontaneous abortions are more serious complications in pregestational diabetes than in GDM. Preconception counselling for women with pregestational diabetes mellitus has been reported to be beneficial and cost-effective and should be encouraged. A search for underlying vasculopathy is advisable and, in selected patients, may include a retinal examination, estimation of urinary protein excretion (albumin creatinine ratio or protein creatinine ratio or 24-h urinary collection) and renal function (eGFR or creatinine clearance), and electrocardiography. Due to comorbidity with type 1 diabetes mellitus, thyroid function studies also should be obtained. Folic acid should be prescribed to all women contemplating pregnancy, which is particularly important in women with diabetes given their increased risk of neural tube defects.
Intensified therapy in pregnancy
Intensified therapy in the management of GDM and pregestational diabetes is aimed at achieving best possible levels of glycaemic control. It involves frequent self-monitoring of blood glucose (SMBG), diet, oral hypoglycaemic drugs, multiple injections of insulin or its equivalent, and a multidisciplinary team effort. This approach often makes the difference between success and failure in diabetes management. Regardless of the treatment modality used, the purpose is to achieve glycaemic control that diminishes the rate of hypoglycaemia and ketosis and maximizes perinatal outcome. Although there is ample evidence that there is an association between glycaemic control and the occurrence of maternal/fetal complications, this association does not prove cause and effect. It does, however, provide the rationale to attempt to control blood glucose levels, the accepted glycaemic metabolic goals being specified in Table 4.
Diet and exercise
For all types of diabetes, the underlying foundation of treatment is diet. Two approaches are currently recommended: decreasing the proportion of carbohydrates to 35 to 40% in a daily regimen of three meals and three or four snacks, and lowering glycaemic index carbohydrates for approximately 60% of daily intake. The assignment of daily caloric intake is similar for gestational and pregestational diabetes and is calculated based on prepregnancy body mass index (20–25 kcal/kg for obese women and 35 kcal/kg for nonobese women, of actual pregnancy weight). An appropriate exercise programme may improve postprandial blood glucose levels and insulin sensitivity for pregnant diabetic women who are not only willing but also able (socioeconomic limitations, obesity, multiparity) to participate. Patients with GDM who fail to achieve the desired level of glycaemic control should be treated with pharmacological agents.
Oral hypoglycaemic agents
Historically, oral antidiabetic agents were contraindicated in pregnancy. The early-generation sulfonylureas crossed the placenta and had the potential to stimulate the fetal pancreas, leading to fetal hyperinsulinaemia, and they were potentially associated with fetal malformations. Of the sulfonylurea family of drugs, only glibenclamide has been shown to have minimal (4%) transfer across the human placenta and has not been associated with excess neonatal hypoglycaemia in clinical studies. Moreover, it has been demonstrated to be safe and as efficient as insulin for the treatment of GDM in both randomized and prospective studies. Dosing must be carefully balanced with meals and snacks to prevent maternal hypoglycaemia (as with insulin therapy).
Metformin does cross the placenta and should not be used for treatment of GDM except in clinical trials, which should include long-term follow-up of infants. Patients with pregestational diabetes that requires pharmacological treatment should be treated exclusively with insulin.
Insulin treatment
There is a gradual increase in insulin requirement throughout pregnancy: 0.7 units/kg per day in the first trimester; 0.8 units/kg per day at week 18, 0.9 units/kg per day at week 26, and 1.0 units/kg per day from week 36 until delivery. Women with pregestational diabetes need adjustment of insulin dose for each trimester in addition to frequent assessment and individualization of dosage. Mounting evidence of the beneficial effects of insulin lispro in type 1 and type 2 nonpregnant diabetic women includes decreased frequency of severe hypoglycaemic episodes, limited postprandial glucose excursions, and a possible decrease in glycosylated haemoglobin when the drug is administered by continuous subcutaneous infusion. Insulin lispro also provides greater convenience in the timing of administration (analogues administered up to 15 min after the start of a meal, compared to soluble insulin taken 30 min before a meal). Insulin Aspart has been shown to be superior to human insulin for postprandial glycaemic control. As far as is known, maternal safety profile and fetal/perinatal outcomes with respect to fetal loss, perinatal mortality, congenital malformation, and child health are not affected by choice of insulin.
| Table 4 Recommended glycaemic metabolic goals in the treatment of diabetes in pregnancy |
|---|
| Plasma glucose | |
| Fasting | 60–95 mg/dl (3.3–5.3 mmol/litre) |
| Before a meal | <95 mg/dl (<5.3 mmol/litre) |
| 1 h after a meal | <140 mg/dl (<7.8 mmol/litre) |
| 2 h after a meal | <120 mg/dl (<6.7 mmol/litre) |
| Mean blood glucose | <95 mg/dl (<5.3 mmol/litre) |
Experience of the use of insulin pumps in pregnancy has been limited. For patients treated with an insulin pump or intensified conventional therapy, comparable maternal/fetal outcomes and metabolic control have been achieved. However, improvement in patient lifestyle and success after difficulties achieving acceptable levels of metabolic control with conventional therapy may justify the use of a pump.
When should treatment be intensified?
Measurement of the fetal abdominal circumference above the 70 to 75th percentile early in the third trimester may identify infants at risk for macrosomia in the absence of maternal insulin therapy. Studies primarily in pregnancies with maternal fasting glucose levels of <105 mg/dl (<5.8 mmol/litre) have evaluated this approach. The measurement of both maternal and fetal factors may eventually enhance fetal outcome in a subset of patients with GDM.
Fetal assessment
The main contributor to perinatal mortality and morbidity for the offspring of the patient with pregestational diabetes is congenital malformations of the fetus. Abnormalities commonly affect the central nervous system, heart, and genitourinary and gastrointestinal systems. Detection of congenital anomalies should be initiated as early as the first trimester of pregnancy and repeated in the second trimester. If possible, early anomaly scan using transvaginal ultrasonography may be helpful (14–16 weeks); a basic examination is mandatory in the second trimester of pregnancy.
Antepartum fetal monitoring—including fetal movement counting, the nonstress test, the biophysical profile, and the contraction stress test—can be used to monitor women with pregnancy complicated by diabetes. Initiation of testing is appropriate for most patients at 32 to 34 weeks of gestation, but testing at earlier gestational ages may be warranted in some pregnancies complicated by additional high-risk conditions. The primary clinical value of current antepartum fetal monitoring tests is their low false-negative rate and ability to reassure the clinician that the fetus with normal test results is unlikely to die in utero. In a metabolically stable patient such testing therefore allows prolongation of pregnancy with continued fetal maturation.
Timing and mode of delivery
The care provider’s decision on the optimum time to deliver the infant in the pregnancy complicated by diabetes needs to balance between the perceived risk of late intrauterine death and shoulder dystocia and the consequences of unnecessary prematurity and caesarean section delivery. The indications for planned delivery of a patient with diabetes include macrosomia or fetus large for gestational age, previous stillbirth, prevention of fetal demise, and reduction in potential shoulder dystocia. Maternal indications for planned delivery include hypertension, diabetic vasculopathy, and poor compliance to the diabetic management resulting in adverse glycaemic control.
Rouse et al. calculated the probability of shoulder dystocia based on birth weight in diabetic and nondiabetic pregnancies. For birth weights of 4500 g or more there was a 52% probability in diabetic compared to 14% in nondiabetic pregnancies, and the mean probability that a neonatal brachial plexus injury would persist was 6.7% (range 0–19%). Thus, to prevent one case of permanent brachial plexus injury in babies weighting 4500 g or more would necessitate performing 153 caesarean deliveries in diabetic mothers and 419 in nondiabetic mothers. If a cut-off of 4000 g is used, then 169 caesarean sections would be required in diabetic women compared to 654 in nondiabetic women. However, Erb’s palsy should not be the only consideration in evaluation of morbidity prevention by caesarean delivery. Although Erb’s palsy is a severe complication, bone fractures, asphyxia, respiratory complications requiring neonatal intensive care admission, and neonatal and fetal demise should be considered when calculating the cost of caesarean sections performed to prevent shoulder dystocia and adverse outcome.
When diabetes is well controlled and gestational age is well documented, respiratory distress syndrome at or beyond 39 weeks of gestation is rare enough that routine amniocentesis for pulmonary maturity is not necessary. At earlier gestational ages, or when control is poor or undocumented, pulmonary maturity should be assessed before induction. However, when early delivery is planned because of maternal or fetal compromise, the urgency of the indication should be considered in the decision to perform amniocentesis.
Postpartum considerations
Immediate postpartum management for patients with pregestational diabetes should include adjustment of insulin dosage. Usually, due to substantial decrease in insulin resistance shortly after delivery, insulin dose should be reduced by 50%.
In women with GDM, diabetes will be diagnosed in some women soon after pregnancy, suggesting they had pre-existing diabetes that was not diagnosed before pregnancy. The estimate of long-term risk for developing diabetes among women who have had GDM depends on the diagnostic test used, the duration of follow-up, age, and other characteristics of the population studied. It is recommended that all women with GDM should be screened for type 2 diabetes 6 weeks postpartum using a 75-g OGTT. Factors identifiable during or shortly after pregnancy that increase the risk for subsequent diabetes include the degree of abnormality of the diagnostic OGTT, the presence or absence of obesity, the gestational age at diagnosis of GDM, and the degree of abnormality of the postpartum OGTT. Individuals at increased risk should be counselled regarding diet, exercise, and weight reduction or maintenance to forestall or prevent the onset of type 2 diabetes. Further reading