Diabetes and Reproduction

9th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

D. Rouiller
Geneva

Introduction

Diabetes mellitus is estimated to be present in ˜ 4% of all pregnancies , thus representing the most frequent endocrine disorder, if not the most frequent complication, of pregnancy. Gestational diabetes (GDM), i.e. diabetes discovered during pregnancy, accounts for 88% of cases, preexisting type 2 diabetes for 8%, and preexisting type 1 diabetes for 4%.

Because offspring of mothers who experience both fasting (>5.8 mM) and postprandial (>6.7 mM) hyperglycemia are at greatest risk for intrauterine death or neonatal mortality, careful antepartum fetal surveillance is mandatory . The greatest risk of child malformations is during organogenesis in the first 8 weeks of pregnancy , often before the mother even knows she is pregnant. Despite the results of prospective studies demonstrating that tight diabetic control before conception is effective in reducing the risk of malformations, only 1 out of 4 pregnancies in diabetic women is properly planned .

Offspring of patients with gestational diabetes are at significant risk for fetal macrosomia and other neonatal morbidities, including hypoglycemia, hypocalcemia, polycythemia, and hyperbilirubinemia .

The aims of this discussion are to detail the effect of diabetes on the outcome of pregnancy for both mother and child, and to stress the importance of 1) planning pregnancies in case of preexisting diabetes, 2) detecting women with gestational diabetes, and 3) providing multidisciplinary care to all women with diabetes during pregnancy.

Glucose homeostasis during normal pregnancy

By the end of the second trimester of pregnancy, the mother's blood glucose rises sharply after meals, to levels 1-2 mM higher than in non pregnant controls . The peak is followed by an exaggerated trough. The rise in glucose is paralleled by a peak in insulin levels about 4-fold higher than in control women. Considering that insulin metabolism is not changed during pregnancy, the best interpretation of the results is a marked insulin resistance in muscle and fat, which was ultimately proven by insulin tolerance tests. The ensuing hypoglycemia is attributed to accelerated extraction of glucose by the fetoplacental unit.

The cellular mechanism causing insulin resistance is not fully understood. Possible explanations include decreased numbers of insulin receptors and of glucose transporters at the surface of insulin target cells.

Possible relationship between hormonal changes in pregnancy and insulin resistance

Regardless of the cellular mechanism of insulin resistance, evidence is accumulating that the production of placental counter-regulatory hormones is the primary cause of the resistance.

The kinetics of hCG, showing a peak level of secretion during the first trimester, makes it an unlikely contributor to insulin resistance which increases mainly towards the end of pregnancy.

During the second and third trimester, however, there is a progressive increase in placental chorionic sommatotropins, known to exert anti-insulin action. This rise is paralleled by suppression of maternal pituitary growth hormone, even in response to hypoglycemia. Placental growth hormones belong to a family of homologous hormones, which have evolved from a precursor GH gene . hGH-V and hCS account for 85% and 12% of GH hormones during pregnancy, respectively, and are the primary metabolic regulators of pregnancy. In gestational diabetes mellitus, growth hormone binding protein (GHBP) levels are elevated. Since GHBP is generated from proteolytic cleavage of the GH receptor, it is suggested that GH receptors are elevated, thus increasing GH sensitivity, resulting in increased insulin resistance and risk of macrosomia. GH-V, IGF-1, and IGFBP do correlate with birth weight.

Progesterone also rises continuously during pregnancy, and has been shown to cause insulin resistance in laboratory animals . It may contribute to the resistance observed in human pregnancy. Cortisol levels also increase over pregnancy, but so does the cortisol binding globulin . A role of cortisol in the insulin resistance of pregnancy remains therefore to be proven.

In conclusion, placental hormones of the growth hormone family induce insulin resistance, thus promoting hypertriglyceridemia and hyperglycemia during the fed state and lipolysis during fasting. Furthermore, facilitated transport of glucose, active transport of amino-acids, and a relative impermeability to fat of the placenta result in accelerated starvation, with hypoglycemia and lipolysis on the mother's side .

The teleological purpose of these adaptations is to preferentially drive glucose and certain amino acids to the fetus while forcing the mother to use fat as a source of fuel. This hypothesis remains to be proven.

Gestational Diabetes

Physiopathology

Although the exact cause of gestational diabetes is not known, the most commonly accepted hypothesis is derived from the metabolic changes of pregnancy described above. As the placenta grows, more of the counter-regulatory hormones are produced, and insulin resistance becomes greater. In normal pregnancy, the pancreas is able to make additional insulin to overcome the resistance. When the pancreas is unable to produce enough insulin, gestational diabetes results. The resulting hyperglycemia leads to fetal hyperinsulinemia, itself thought to be responsible for most complications in the offspring . Increased sensitivity to hCS has been recently proposed as a cause of increased insulin resistance in women with gestational diabetes and a risk factor for fetal macrosomia .

Women at risk

It is important to rapidly detect women with GDM because of the increased risk of perinatal mortality and with birth trauma related to macrosomia . Risk factors include:

Age 25 or older.
Age < 25 but obese.
Polycystic ovary syndrome
Family history of diabetes
Problems in a previous pregnancy
Previous gestational diabetes (66% risk)
High blood pressure
Ethnicity (Indians, Hispanics, Africans, Pacific Islanders)
Presence of hydramnios

For economical reasons, it has been recently proposed that women with low risk profile do not need to be screened for GDM . Women at low risk are younger that 25 years, have no family history of diabetes, have a normal body weight (BMI <27 kg/m²), and are not member of an ethnic group known to be at risk of diabetes. This attitude is controversial. A recent study showed that although few women with GDM were missed using the proposed criteria (4%), the number of women fulfilling all the exclusion criteria was quite limited (10%). Screening all pregnant women has the advantage of simplicity, while applying complicated criteria, that will exclude only a small number of women from the screening test, may not be that cost effective.

GDM Screening

The screening test is applied at 24-28 weeks of pregnancy. A 50-g oral glucose challenge in the non fasting state is followed by a plasma glucose measurement at 1 hr . If the 1-hr glucose level is = 7.8 mM (140 mg/dL), a full 100-g oral glucose tolerance test is performed in the fasting state. If a random glucose is = 11.1 mM (200 mg/dL), the diagnosis is made, and the full test is not necessary.

Although there is no consensus, it may be worth screening women at high risk at 12-14 weeks. If the test is normal, a second test is performed at 24-28 weeks.

GDM Diagnosis

There is also little consensus about the upper limits of normality for glycemia during the 3-h 100g oral glucose tolerance test. The values proposed by the National Diabetes DataGroup are closest to the original whole blood values of O'Sullivan after correction for measurements in plasma samples and for improved specificity of newer glucose assays:

Fasting <5.8 mM (105 mg/dL);
1-hour <10.6 mM (190 mg/dL);
2-hour <9.2 mM (165 mg/dL);
3-hour <8.1 mM (145 mg/dL).

The test is performed after an overnight fast of a least 8 hours but no more than 14 hours. Two values out of these limits are diagnostic of Gestational Diabetes. If only one value is abnormal, some practitioners apply the same dietary recommendations as for gestational diabetes, and follow for the development of macrosomia with 32-week ultrasonography; others repeat the test 2 weeks later.

Diet

Unless fasting glucose levels are frankly elevated (> 6.7 mM), requiring immediate insulin treatment, treatment with diet alone should be tried first, associated with self monitoring of blood glucose.

Total calories are limited to 30 kcal/Kg with ± 6 kcal/Kg adjustments when bodyweight is outside 80-120% desired body weight limits. They are divided into 3 meals and 3 snacks. Since insulin resistance is higher in the morning, carbohydrate content should ideally be limited at breakfast. The goals are to obtain in the majority of measurements performed at the same time point:

Fasting capillary blood sugar < 5.5 mM
postprandial levels < 7.8 mM
No ketones in the urine

It is most often difficult to obtain these goals unless the proportion of carbohydrates in the diet is kept <50% of total calories.

Exercise

Although there is no consensus about its benefits, exercise using leg muscles while recumbent, arm muscles, but not trunk muscles may be proposed when there are no obstetrical contraindications. This may help maintain postprandial glycemia within targets and avoid the need for exogenous insulin .

Insulin

Human insulin therapy is initiated if, despite good adherence to diet recommendations:

Fasting glucose >5.0 mM (90), or
Glucose 1 hr after a particular meal > 6.7 mM (120)
for more than 4 days in a week . Convenient starting doses are 10 Units NPH in the morning and 6 Units in the evening. Regular insulin is added before breakfast and dinner as required, starting with 4 Units.

Neonatal morbidity

Women with GDM are at increased risk of hypertension in late pregnancy, with the resulting higher prevalence of preeclampsia and hydramnios.

Most neonatal complications are the consequence of B-cell hyperplasia and increased influx of gluconeogenetic amino-acids. Macrosomia, because of increased thoracic diameter, is associated with an increased risk of trauma at delivery both to the mother (vaginal, perineal, and rectal injury), and the fetus (shoulder dystocia and brachial plexus injury) . It should be stressed that good glycemic control during pregnancy does not definitively decrease the risk of macrosomia .

The risk of stillbirth is increased in GDM . Other neonatal morbidities observed with increased frequency in GDM include RDS, polycythemia, cardiomyopathy, hyperbilirubinemia, and hypoparathyroidism (hypocalcemia) .

Weekly biophysical profiles are recommended early in the third trimester in case of gestational complications (hydramnios, suspected macrosomia, hypertension) or poorly controlled diabetes. Monitoring is advised from at least week 36 in patients requiring insulin, and from week 40 when diabetes is adequately controlled with diet only. Delivery is recommended at 37-38 weeks in poorly controlled diabetes and at 40 weeks in patients on insulin but with good diabetic control. Elective caesarian section is generally performed when estimated fetal weight is over 4300-4500g.

GDM Postpartum follow up

women with gestational diabetes are at increased risk of developing the condition in subsequent pregnancies, and up to 60 percent may develop type 2 diabetes within 20 years . If they were diagnosed with gestational diabetes earlier than the 24th week of gestation or present other risk factors for type 2 diabetes, including obesity, they may face a higher risk of developing diabetes. To formulate a diabetes prognostic to the mother, we would recommend a 2-h oral glucose tolerance test with a 75-g glucose load, performed at least 6 weeks after delivery, since a fasting value alone was recently shown not to provide sufficient sensitivity . If the test reveals impaired glucose tolerance (2h post-glucose = 7.8 mM/140 mg/dL), even if values are not diagnostic of diabetes (2h post-glucose = 11.1 mM/200 mg/dL), the risk of developing type 2 diabetes within the next five years is high. Follow up glucose tests should therefore be performed every six to twelve months to detect incipient type 2 diabetes as early as possible. Patients should be informed that the risk of developing diabetes may be reduced by lifelong weight surveillance and physical activity.

Preexisting diabetes and pregnancy

Planning of pregnancy in women with diabetes

Until the dawn of the era of tight control of blood glucose, women with diabetes who became pregnant commonly experienced serious problems such as miscarriage, stillbirth or a baby with birth defects . Today, women with diabetes usually have healthy pregnancies, provided that a pluridisciplinary health care team is involved.

Counseling incorporates discussion of the following:

Effect of pregnancy on the progression of diabetic complications
Risk of congenital anomalies and means of prevention
Fetal and neonatal complications
Practice of home capillary blood glucose self monitoring
Cost implications of care and prevention of complications

Diabetes control (glycated hemoglobin) should be optimized and complications treated (see below) before conception. Appropriate dietary adherence (including sufficient intake of folic acid, other vitamins, and iron) is enforced.

Any concomitant disease, as indicated by physical exam or history, should also be investigated and treated. Thyroid function tests including thyroid-stimulating hormone and free thyroxin levels are mandatory because of a 5-10% overlap of type 1 diabetes with hypo- or hyperthyroidism .

Conception should be deferred until this initial evaluation is completed, and specific goals of therapy have been achieved. Appropriate counseling for contraception is then mandatory.

Effect of pregnancy on the mother's diabetes

In case of preexisting type 1 or type 2 diabetes, pregnancy may have adverse effects on the progression of the mother's diabetic complications.

Nephropathy :

Baseline assessment of renal function by creatinine clearance and 24-h microalbumin excretion (microalbumin/creatinine ratios and other methodologies for measuring glomerular filtration rates are acceptable) should be undertaken before conception and followed at regular intervals because of the impact of pregnancy on proteinuria and the impact of renal insufficiency on fetal growth and development. Fortunately, <5% of diabetic women who become pregnant have overt nephropathy. Proteinuria generally increases during pregnancy but returns to prepregnancy levels afterwards. Women with renal failure (creatinine clearance <50 ml/min) should be counseled to avoid pregnancy unless renal function can be stabilized by renal transplantation. In subjects with less severe nephropathy, renal function worsens during pregnancy in only 8-30% and at a rate no different than background; therefore, it should not serve as a contraindication to conception and pregnancy; Hypertension, however might become a problem, and should be kept below 130/85 to reduce the rate of progression of diabetic nephropathy, retinopathy and macrovascular disease, and to decrease the risk of preeclampsia and hydramnios.

Retinopathy:

Diabetic retinopathy is likely to accelerate during pregnancy , probably because of the rapid enforcement of near normoglycemia is known to favor neovascularization . Baseline assessment with a dilated pupil exam is necessary. Preconception laser therapy of proliferative retinopathy will reduce the risk of worsening. Repeated ophthalmologic examination should be anticipated during pregnancy for women with background retinopathy, which might deteriorate during pregnancy, but usually returns to the pre-pregnancy status after delivery.

Neuropathy

The presence of autonomic neuropathy, including gastroparesis, urinary retention, hypoglycemic unawareness, or orthostatic hypotension may complicate the management of diabetes in pregnancy. Gastroparesis may cause intractable vomiting, which may require hospitalization for parenteral nutrition and hydratation . These complications should be identified, and taken care of before conception. Peripheral neuropathy, especially compartment syndromes such as carpal tunnel syndrome, may be exacerbated by pregnancy.

Macrovascular complications

Historically, women with prior heart disease have been at considerable risk of maternal death during pregnancy . However, cardiac concerns should not be a problem in those who have no history of heart disease, are under 45, do not smoke, and have a normal electrocardiogram.

The presence of coronary artery disease (CAD) carries a high maternal mortality rate during pregnancy. Evidence of CAD should be sought in any woman who has had diabetes for more than 10 years or in the presence of complications. Severe CAD is a contraindication to pregnancy, and should be adequately addressed before conception. Bypass surgery may be required.

Preexisting diabetes and risk to the baby

In case of preexisting diabetes, the most important risk to the fetus is congenital malformations, related to hyperglycemia and ketosis during organogenesis. Elevated HbA1c at the time of conception has been shown to be associated with a marked increase in congenital malformations, and 30 to 50 % of perinatal mortality in diabetic pregnancy is due to fetal malformations. Sacral agenesis and caudal dysplasia are 400 times more frequent in diabetic than in normal pregnancies. Other anomalies associating with diabetes during first trimester include open spina bifida, anencephaly, renal agenesis, ventricular septal defects, and great vessels transposition. Offspring of diabetic women also face specific risks during late pregnancy, mostly related to deficits in placental exchanges of oxygen and nutrients. Delivery before 37 weeks is associated with an increased risk of RDS, while delivery after 40 weeks carries an unacceptable risk of fetal demise. Women with poorly controlled diabetes should therefore probably be delivered at 37-38 weeks, after testing for lung maturity.

Long-term effect of diabetic pregnancy on the child

More recent studies suggest that exposure to maternal diabetes of the fetus may present long-term health problems, that may arise either during childhood or even up to 40 to 50 years later . Children whose mothers had diabetes during pregnancy tend to be overweight, to have impaired glucose tolerance, and also may have slightly elevated blood pressure, all of which put them at increased risk of cardiovascular disease as adults, If the mother's diabetes was poorly controlled during pregnancy, the youngsters also may have an increased risk of learning disabilities.

Surveillance during delivery

Because glucose turnover is increased 4-fold during labor, the morning insulin is not administered before an elective induction. It is however important to avoid maternal hyperglycemia to reduce the risk of neonatal hypoglycemia. Every effort should therefore be made to keep blood sugar between 3.9 and 6.1 mM (70 and 110 mg/dL). Glucose levels are measured at least hourly. If glycemia is below 3.9 mM (70 mg/dL), a 5% glucose infusion is started (100 ml/h). Below 3.3 mM (60 mg/dL), a 10% Glucose infusion is substituted. If glucose values are higher than 6.1 mM (110 mg/dL), an insulin pump is started (1U/h.). Over 8.3 mM (150 mg/dL), the insulin dose is doubled (2 U/h).

During postpartum, the need for tight control is reduced, and values of glycemia up to 11 mM are acceptable pending discharge from the hospital.

Prediction of Diabetes in offspring

Prediction of type 1 diabetes mellitus

Genetic markers may be helpful in assessing the risk of type 1 diabetes in close relatives of a patient with type 1 diabetes. The risk of diabetes is markedly increased in close relatives of type 1 diabetics, averaging about 4 and 6% in offspring of a diabetic mother and father, respectively, and five percent in siblings, versus 0.4% in subjects with no family history of diabetes. The risk in siblings is influenced by the degree of genetic similarity, reaching 33% in identical twins. The risk falls to 12.9, 4.5, and 1.8%, respectively, if the siblings share two, one, or no haplotypes. Sharing two haplotypes with a DR3/DR4 proband, however, increase the risk to 19% .

Prediction of type 2 diabetes mellitus

Although people with a family history of type 2 diabetes mellitus have a 5-10x increase in lifetime risk of developing type 2 diabetes, the risk is greatly influenced by ethnic background and environmental factors such as obesity . Precise prediction is therefore more difficult than for type 1 diabetes.