Diabetes in Pregnancy

GDM is characterized by hyperinsulinemia and insulin resistance.

In first trimester and early second trimester, increased insulin – due to high levels of estrogen.

In late second and early third trimesters, insulin resistance - due to a number of antagonistic hormones especially, placental lactogen, leptin, progesterone, prolactin and cortisol.

• Age >25years
• BMI >25kg/m²
• Increased weight gain during pregnancy (>90kg)
• Previous history of large for gestational age infants 4 kg or more
• History of GDM during previous pregnancies
• Previous stillbirth with pancreatic islet hyperplasia on autopsy
• Ethnic group (East Asian, Pacific Island ancestry)
• Elevated fasting or random blood glucose levels during pregnancy
• Family history of diabetes in first degree relatives
• History of metabolic X syndrome
• History of type I or type II Diabetes Mellitus
• Unexplained fetal loss
• Presence of polyhydramnios or recurrent vaginal candidiasis in present pregnancy
• Persistent glycosuria

While some advocate screening routinely to all pregnant mothers, others reserve it only for the potential candidates.

Screening strategy for detection of GDM are:

• Low risk —Absence of any risk factors as mentioned above →blood glucose testing is not routinely required.
• Average risk — some risk factors →perform screening test.
• High risk — Blood glucose test as soon as feasible.

The method employed is by using 50 gm oral glucose challenge test without regard to time of day or last meal, between 24 and 28 weeks of pregnancy.

A plasma glucose value of 140 mg percent (7.8mmol/l) or that of whole blood of 130 mg percent (7.2mmol/l) at 1 hour is considered as cut off point for consideration of a 100 gm (WHO – 75 gm) glucose tolerance test.

Who should be tested?

The first testing - first antenatal contact as early as possible.

The second testing - 24-28 weeks of pregnancy if the first test is negative.

At least 4 weeks gap between the two tests.

All Pregnant Women to be tested even if they come late in pregnancy.

If present beyond 28 weeks of pregnancy- only one test to be done

How to test

Single step testing - 75 gm oral glucose & measure plasma glucose 2 hour after ingestion.

75 gm glucose mixed with 300 ml water ingested whether in fasting or non-fasting state

A plasma standardized glucometer should be used to evaluate blood glucose 2 hours after the oral glucose load.

The threshold plasma glucose level of ≥140 mg/dl (7.8 mmol/l) is taken as cut off for diagnosis of GDM

• Increased perinatal loss is associated with fasting hyperglycemia.
• Fetal anomalies not increased due to the absence of metabolic disturbance during organogenesis.
• Increased incidence of macrosomia
• Polyhydramnios
• Birth trauma
• Recurrence of GDM in subsequent pregnancies is about 50 percent

The patient needs more frequent antenatal supervision with periodic checkup of fasting plasma glucose level which should be less than 90 mg percent.

Maintenance of mean plasma glucose level between 105 and 110 mg/dl is desirable for good fetal outcome.

The control of high blood glucose is done by restriction of diet, exercise with or without insulin.

Human insulin should be started if fasting plasma glucose level exceeds 90 mg/dl and 2 hours post-prandial value is greater than 120 mg/dl (repetitive) even on diet control.

Diet with 2000-2500 Kcal/day for normal weight woman and restriction to 1200-1800 Kcal/day for overweight woman is recommended

Exercise (aerobic, brisk walking) programs are safe in pregnancy and may obviate the need of insulin therapy

Obstetric management:

Women with good glycemic control and who do not require insulin may wait for spontaneous onset of labor.

However, elective delivery (induction or caesarean section) is considered in patients requiring insulin or with complications (macrosomia) at around 38 weeks.

Follow-up:

Women with fasting hyperglycemia have got worse prognosis to develop type-2 diabetes and cardiovascular complications.

Recurrence risk in subsequent pregnancy is more than 50%.

Originally used to assess the perinatal outcome and to formulate the obstetric management

Now mainly used for statistical correlation of different types of pregnant diabetics

Vasculopathy is given more importance to predict the outcome

Patients with poor glycemic control and vasculopathy are at increased risk of complication like IUD, IUGR, Pre-eclampsia and Ketoacidosis

It distinguishes between gestational diabetes (type A) and diabetes that existed before pregnancy (pre-gestational diabetes)

There are 2 classes of gestational diabetes (diabetes which began during pregnancy):

Difficult to stabilize the blood glucose during pregnancy due to altered carbohydrate metabolism and an impaired insulin action.

Insulin antagonism due to combined effect of human placental lactogen, estrogen, progesterone, free cortisol and degradation of the insulin by the placenta.

Insulin requirement increases as pregnancy advances.

With the “accelerated starvation” concept, there is rapid activation of lipolysis with short period of fasting.

Ketoacidosis can be precipitated during hyperemesis in early pregnancy, infection and fasting of labor.

It can be iatrogenically induced by β sympathomimetic and corticosteroids used in the management of preterm labor.

Insulin requirement falls significantly in puerperium.

Vascular changes, specially retinopathy, nephropathy, coronary artery disease and neuropathy may be worsened during pregnancy.

Complications of diabetes (Hyperglycemia and adverse pregnancy outcome):

• Maternal
• Fetal, and
• Neonatal

Maternal

During pregnancy:

Abortion: Recurrent spontaneous abortion may be associated with uncontrolled diabetes

Preterm labor (20%) may be due to infection or polyhydramnios

Infection: Urinary tract infection and vulvovaginitis

Increased incidence of pre-eclampsia (25%)

Polyhydramnios (25–50%) is a common association, probably because of

• Large baby
• Large placenta
• Fetal hyperglycemia leading to polyuria
• Increased glucose of liquor irritating the amniotic epithelium or increased osmosis

Maternal distress may be due to the combined effects of an oversized fetus and polyhydramnios

Diabetic retinopathy, microaneurysms, hemorrhages and proliferative retinopathy. Laser photocoagulation is the preferred treatment.

Diabetic nephropathy—may lead to renal failure

Ketoacidosis

During labor:

There is increased incidence of:

• Prolongation of labor due to macrosomia
• Shoulder dystocia - Shoulder dystocia is due to disproportionate growth with increased shoulder/head ratio
• Perineal injuries
• Postpartum haemorrhage
• Operative interventions

Puerperium

• Puerperal sepsis
• Lactation failure

Fetal complications

Fetal macrosomia (30–40%):

Maternal hyperglycemia →hypertrophy and hyperplasia of the fetal islets of Langerhans →increased secretion of fetal insulin →stimulates carbohydrate utilization and accumulation of fat Insulin like growth factors (IGF-I and II) are also involved in fetal growth and adiposity.With good diabetic control, incidence of macrosomia is markedly reduced.

Elevation of maternal free fatty acid (FFA) in diabetes leads to its increased transfer to the fetus →acceleration of triglyceride synthesis→ adiposity

Congenital malformation (6–10%)

Related to the severity of diabetes affecting organogenesis in the first trimester (both in type 1 and type 2 diabetes)

The factors associated with teratogenesis are multifactorial:

• Genetic susceptibility
• Hyperglycemia
• Arachidonic acid deficiency
• Ketone body excess
• Somatomedin inhibition
• Free oxygen radical excess (superoxide dismutase, an oxygen radical scavenging enzyme can protect excess malformation)
• Risks of fetal chromosomal abnormalities are not increased

Early detection of fetal anomalies

• Estimation of glycosylated hemoglobin A (HbA1c) before 14 weeks reflect the quality of diabetic control over the previous 3 months. Overall risk of fetal malformations are increased when the level of HbA1c is high (normal < 6 percent)
• Maternal serum α-fetoprotein level at 16 weeks and a detailed high resolution ultrasonography of the fetus.
• Comprehensive ultrasound examination (anomaly scan)—including fetal echocardiography is done at 20-22 weeks to detect any cardiac anomaly along with other structural malformation.
• Good glycemic control with preconceptional counselling can reduce the incidence to 0.8–2 percent
• Chance of major congenital malformation is about 8% and 23% when the values are 9.5 and 10 respectively

note

Major birth defects in infants of diabetic mothers

CNS and skeletal

• Neural tube defects
• Anencephaly
• Microcephaly
• Caudal regression Syndrome
• Sacral agenesis

Renal

• Renal agenesis
• Hydronephrosis
• Double ureter
• Polycystic kidneys

Cardiovascular

• VSD, ASD
• Coarctation of aorta
• Transposition of great vessels
• Situs inversus
• Fallot’s tetralogy

Gastrointestinal

• Duodenal atresia
• Anorectal atresia
• Omphalocoele
• Tracheoesophageal fistula

Others - Single umbilical artery

Birth injuries

For example, brachial plexus injury.

They are associated with prolonged labor and shoulder dystocia due to macrosomic baby.

Growth restriction

It is less commonly observed and is associated with maternal vasculopathy.

Placental amino acid transporters are involved in fetal macrosomia or IUGR in women with diabetes

Fetal death

It has multifactorial pathogenesis but the final event being hypoxia and lactic acidemia.

Observed more in patients with poor glycemic control, vasculopathy, pre-eclampsia, ketoacidosis and fetal macrosomia.

Fetal hyperglycemia and hyperinsulinemia increase fetal oxygen demand.

Glycosylated hemoglobin carries less oxygen molecule. It binds O2 more avidly and releases O2 less.

Other factors involved are fetal polycythaemia and hyperviscosity.

Neonatal complications

Hypoglycemia (< 37 mg/dl)

Respiratory Distress Syndrome

Hyperbilirubinemia

Polycythemia

Hypocalcaemia (< 7 mg/dl)

Hypomagnesaemia (< 7 mg/dl)

Cardiomyopathy

Perinatal mortality

The overall perinatal mortality is increased 2–3 times

The neonatal deaths are principally due to hypoglycemia, respiratory distress syndrome, polycythemia and jaundice.

Long-term effects

Childhood obesity,

Neuropsychological effects

Diabetes

Preconceptional counselling:

Goal is to achieve tight control of diabetes before the onset of pregnancy

All diabetic women are managed in a multidisciplinary combined obstetric and diabetic clinic with specialist obstetrician, diabetologist, specialist midwife, pediatrician and dietician.

Fetal congenital malformations are significantly low (0.8-2%) in women who receive preconceptional counselling.

Women are taught on self-glucose monitoring.

Appropriate advice about diet and insulin is given.

Chance of having a diabetic child is about 1-3% when the mother is only diabetic, 6% when father is only diabetic, rising to 20% if both the parents are diabetic.

Principles in the management are:

Careful antenatal supervision and glycemic control, so as to maintain the glucose level as near to physiological level as possible.

Determine optimum time and method of delivery

Arrangement for the care of the newborn

Antenatal care

Antenatal supervision should be at monthly intervals up to 20 weeks and thereafter at 2 weeks intervals.

At times patient needs admission for stabilization of blood glucose and for monitoring the fetus.

Diet—30 Kcal/kg for normal weight women, 24 Kcal/kg for overweight women and 12 Kcal/kg for morbidly obese women.

If values are exceeded even on diet, insulin therapy is suggested.

Diet should contain carbohydrate 50%, protein 20% and fat 25-30%.

Fat may be curtailed, if the patient is obese.

Fiber containing diet is increased.

Usually three meal regimen, with breakfast 25% of the total calorie intake, lunch 30%, dinner 30% and several snacks are quite suitable for most of the patients.

Frequent blood sugar estimation.

Monitoring of blood glucose by glucose meter can give an accurate idea about the control.

Glycosylated hemoglobin should be determined at the end of first trimester and trimonthly thereafter - HbAIc level of <6% is desirable.

Sonographic evaluation (Level II) in pregnancy (at 3-4 weeks interval) is extremely helpful, not only to diagnose varieties of congenital malformation of fetus but also to detect fetal macrosomia or growth restriction (rare).

Assessment of fetal well-being is to be made from 28 weeks onwards.

Biophysical profile and NST should be performed weekly.

Doppler umbilical artery velocimetry is useful in cases with vasculopathy.

Role of ultrasound

Preferably done in first trimester to confirm gestational age by dates.

Repeated at 18 to 20 weeks gestation to evaluate the fetus for congenital anomalies.

Particularly important in patients with pre-existing type 1 and 2 diabetes and elevated first trimester HbA1c (>6.5%)

Should be done at 30 to 32 weeks and 36-38 weeks of gestation to evaluate fetal size, amniotic fluid index, and to help ascertain the mode of delivery.

Tests of fetal wellbeing

Daily fetal movement counting: 32 weeks gestation and continue until delivery

Amniotic fluid index and biophysical profile

These tests are usually conducted twice weekly and are instituted at 32 to 34 weeks of gestation in women on insulin and can be done from 34-36 weeks of gestation in women whose diabetes is controlled by diet.

Some clinicians manage patients with dietary control without any additional testing.

Insulin Therapy

When diabetes is first detected during pregnancy and cannot be controlled by diet alone, it should be treated with insulin.

A post prandial (2 hours) plasma glucose level of more than 140 mg% even on diet control is an indication of insulin therapy.

There is frequent change in insulin need during pregnancy and changes in the dosage are made in small increments at a time.

Glycemic goals should be around 90 mg/dl before meals and not to exceed 120 mg/dl 2 hours after meals.

During the stabilization process of the insulin dose, frequent blood sugar estimation especially at night (2am– 6am) may be necessary using glucose meter (capillary whole blood, utilized for self-monitoring, is equivalent to venous plasma).

As pregnancy advances, “a double mixed regime” may be employed.

The patient should receive three to four daily injections of a regular (human Actrapid) and an intermediate acting insulin (Isophane), the latter is to be given before dinner.

The aim is to maintain the blood sugar level as near to normal as possible without causing troublesome hypoglycemia.

The total first dose of insulin is calculated according to the patient’s weight as follow:

• In the first trimester – weight x 0.7
• In the second trimester– weight x 0.8
• In the third trimester– weight x 0.9

Use of subcutaneous insulin infusion by insulin pump is preferred as it is more physiological.

Women are instructed on diet composition, insulin dose, recognition and treatment of hypoglycemia, hyperglycaemia and ketosis, adjusting insulin dose in relation to exercise, food and sick days.

Oral antidiabetic drug (metformin) is now safely used either alone or combined with insulin.

Admission

In uncomplicated cases, the patient is admitted at 34-36 weeks

Early hospitalization

• Facilitates stabilization of diabetes
• Minimizes the incidence of pre-eclampsia, polyhydramnios and preterm labor
• To select the appropriate time and method of delivery

Induction of labor

The indications are — 

• Diabetic women controlled on insulin (GDM or class B diabetes) are considered for induction of labor after 38 completed weeks.
• Women with vascular complications (pre-eclampsia, IUGR) often require induction after 37 weeks.

Prior to the day of induction of labor, the usual bed time dose of insulin is administered.

No breakfast and no morning dose of insulin is given on the day of induction.

Normal saline infusion is begun.

Induction is done by low rupture of the membranes.

Simultaneous oxytocin drip is started, if not contraindicated.

Cervical ripening can be done with prostaglandin followed by oxytocin infusion.

An intravenous drip of one liter of 5% dextrose is set up with 10 units of soluble insulin.

An infusion rate of 100-125 ml/hr (1-1.25 units/hr), will maintain a good glucose control to approximately 100 mg/dl (ACOG-2005).

Insulin may also be infused from a syringe pump (0.25-2 units/hr).

Blood glucose levels are estimated hourly with a glucose meter and the soluble insulin dose is adjusted accordingly.

Epidural analgesia is ideal for pain relief.

If the labor fails to start within 6-8 hours or if the labor progresses unsatisfactorily, caesarean section should be performed.

Caesarean Section

The indications are:

• Elderly primigravida
• Multigravida with a bad obstetric history
• Diabetes with complications or difficult to control
• Obstetric complications like pre-eclampsia, polyhydramnios, malpresentation
• Fetal macrosomia (> 4 kg)

As such, 50% of diabetic mothers are delivered by caesarean section

Procedure:

Caesarean section is scheduled for early morning

On the day of operation, breakfast and the insulin dose are omitted

A normal saline infusion is started

The administration of dextrose drip and the insulin dose are to be maintained as mentioned in induction until the patient is able to take fluids by mouth (ACOG-2005)

Continuous subcutaneous insulin infusion with insulin pump is preferred as it is more physiological

The insulin requirement suddenly falls following delivery and after stopping the drip, pre-pregnant dose of insulin is to be administered or adjusted from the blood glucose level

Epidural or spinal anesthesia is better than general anesthesia as oral feeding could be soon following the operation

To control blood glucose:

1. One liter of 5% dextrose drip is started with 10 units of soluble insulin
2. A general guideline for insulin infusion rate is, 1 unit per hour for blood glucose of 100-140 mg/dl, 2 units per hour for blood glucose of 141-180 mg/dl and 3 units per hour for blood glucose of 181-220 mg/dl. Use of motorized syringe pump for insulin infusion is convenient
3. Hourly estimation of blood glucose levels is done with glucose meter and the insulin dose is adjusted accordingly. The blood glucose level should be maintained between 80 and 100 mg per 100 ml

Spontaneous onset of labor at term

Pregnancy may be continued awaiting spontaneous onset of labor and vaginal delivery in:

• Young primigravida or multipara with good obstetric history
• Diabetes well controlled either by diet or insulin or without any obstetrical complication

However, in the absence of gadgets for assessment of fetal well-being, it is risky to continue the pregnancy in such cases up to the EDD.

In any case, the pregnancy should not be allowed to overrun the expected date.

Fetal monitoring:

• Constant watch to note the fetal condition is mandatory, preferably with continuous electronic fetal monitoring
• CTG using a scalp electrode is maintained
• Fetal scalp blood pH sampling is done whenever indicated
• The combination of fetal hyperglycemia and anoxia contribute not only to fetal distress but responsible for RDS
• Labor should not be allowed for more than an arbitrary 12 hours and should be augmented by low rupture of the membranes and oxytocin or delivered by caesarean section
• Shoulder dystocia may be a problem
• The cord should be clamped immediately after delivery to avoid hypervolemia

Pathology is insulin resistance →lipolysis →enhanced ketogenesis→fall in plasma HCO3– and pH (< 7.30)

It may be precipitated with the use of β mimetic agents (Isoxuprine) and corticosteroids

Management is done in an acute care unit where neonatal care is also available

Management

Parameters to assess are: degree of acidosis, alterations in the level of arterial blood gas, blood glucose, ketones and electrolytes

IV insulin

• 0.2 – 0.4 units/kg (loading dose)
• 2.0 – 10.0 units/hr (maintenance with frequent capillary glucose measurement)

Fluids

• Isotonic saline 4-6L in first 12 hours
• 5% Dextrose in normal saline when plasma glucose is 200 mg/dl

Potassium: if reduced or normal—infusion 15-20mEq/hr

Bicarbonate: if PH < 7.10, add 44 mEq of bicarbonate to 1L of 0.45 normal saline

Antibiotics should be given prophylactically to minimize infection

Insulin requirement falls dramatically following delivery

Revert to the insulin regime as was prior to pregnancy

A fresh blood glucose level after 24 hours will help to adjust the dose of insulin

Breastfeeding is encouraged

Women who breastfeed should have additional 500 Kcal daily in diet

In lactating women insulin dose is lower

Care of the baby

A neonatologist should be present at the time of delivery

The baby should preferably be kept in an intensive neonatal care unit and to remain vigilant for at least 48 hours, to detect and to treat effectively any complication likely to arise

Asphyxia is anticipated and be treated effectively

To look for any congenital malformation

Improvement in the care of diabetes in pregnancy has reduced perinatal mortality significantly (< 5%).

All babies should have blood glucose to be checked within 2 hours of birth to avoid problems of hypoglycemia (blood glucose < 35 mg/dl)

All babies should receive 1 mg vitamin K intramuscularly

Early breastfeeding within ½ – 1 hour is advocated and to be repeated at three to four hourly intervals thereafter to minimize hypoglycemia and hyperbilirubinemia

Contraception

Barrier method of contraceptives is ideal for spacing of births

Low dose combined oral pills containing third generation progestins are effective and have got minimal effect on carbohydrate metabolism

Main worry is their effect on vascular disease (thromboembolism and myocardial infarction)

Progestin only pill may be an alternative

IUCD may be used once diabetes is well controlled

Permanent sterilization is considered when family is completed

Postpartum management

In most women with GDM, hyperglycemia rapidly resolves shortly after delivery

It is reasonable to measure a single random or fasting blood glucose level before discharge from the hospital

Postpartum glucose tolerance testing is important for women who had GDM

Women with GDM have a 7-fold increased risk of developing type 2 diabetes mellitus compared with those who had a normoglycemic pregnancy

At 6 to 12 weeks postpartum, only one-third of women with persistent glucose intolerance have an abnormal fasting blood glucose level

Therefore, to detect all women with glucose intolerance, a 75-g, fasting, 2-hour, oral glucose tolerance test is recommended