Endocrine disorders in pregnancy

1. Endocrine disorders in pregnancy By Dr. Khattab KAEO Prof. of Obstetrics and Gynaecology Faculty of Medicine, Al-Azhar University, Damietta

2. Diabetes mellitus (DM)

3. Physiology: In the nonpregnant state the ingested glucose is: 1- through the enterohepatic circulation, and with the aid of insulin, is deposited in the liver as glycogen. 2- through the general circulation: A- a proportion is metabolised directly by the tissues; B- some is converted to depot fat; C- A proportion is stored as muscle glycogen (with the aid of insulin). Blood glucose is maintained between 4.5 and 5.5 mmol/L Placental and cerebral glucose uptake is independent of insulin.

4. Physiological glycosuria of pregnancy This is the commonest cause of glycosuria during pregnancy. It occurs in 15% of healthy pregnant women due to increased glomerular filtration rate and due to higher postprandial glucose levels. False glycosuria: Women with more than usual glycosuria in pregnancy may have sustained renal damage from earlier untreated UTI.

5. Definition and classification Using 75 g oral glucose WHO defined normal glucose tolerance as fasting venous plasma glucose level of <6 mmol/L and 2-h level of <8 mmol/L. "Impaired glucose tolerance" (IGT) in non-pregnant women as: fasting glucose 7.8 mmol/L or 2-h glucose 8-11 mmol/L. DM is defined if: fasting glucose is >7.8 mmol /L and/or 2-h glucose >11 mmol/L.

6. Overt or clinical DM: Abnormal 2 values of a 3-h GTT with polyphagia, poly-uria, polydipsia & other related sympt If symptoms are absent, the condition is then called "chemical DM". Now, “type I” DM has replaced the term “IDDM”. It usually results from a cell-mediated autoimmune destruction of the  cells. This destruction is marked by auto-antibodies to insulin, to islet cells & to glutamic acid decarboxylase. One, and usually more, of these antibodies are present in 85-90% of cases. In type II DM, insulin receptors are deficient.

7. Gestational Impaired Glucose Tolerance & Gestational DM: GDM is defined as “carbohydrate intolerance with onset or first recognition during pregnancy”. GDM & GIGT occur as a consequence of the increased insulin resistance that develops du-ring pregnancy due to the secretion of placental hormones, particularly progesterone & hPL. GDM in the 1st ½ of pregnancy may suggest glucose intolerance before pregnancy. There may be marked weight gain, particularly in the abdominal region. There may be oedema early in pregnancy. There is no evidence that GIGT is associated with excess fetal mortality, or maternal or fetal morbidity. The main risks of GDM are fetal macrosomia.

8. Screening: At booking whether or not there is any risk factor. Again at 24-28 w or earlier if there is risk factor(s). Indeed, screening is repeated because glucose intolerance becomes worse during pregnancy. Screening may be not recommended in women under 25 years, with normal weight, no personal or family history of DM, no history of poor obstetric outcome & does not belong to an ethnic group predis-posed to DM. Currently recommended screening procedure in North America is a two step procedure i.e. screening by a 50g glucose challenge; if 1-h serum glucose 140 mg/dl (7.8mmol/L), a 3-h 100g GTT (sensitivity = 80% & specificity = 80%) is indicated. But it is costly and may not be justified in population with a low prevalence of DM or in a developing country population. Whole blood glucose values are lower than plasma levels due to glucose uptake by haemoglobin. A screening system based on assaying random blood sugar (RBS) in the early third trimester is less sensitive and specific but may be more convenient for the above-mentioned population. Alternatively, if glycosuria is detected, RBS is done. If >6 mmol/L while the patient was fasting or >2 h postprandial, or 7 mmol/L up to 2 h after meal, a 75 g GTT is performed. RBS >11 mmol/L = abnormal glucose tolerance; a GTT is not needed. A one step screening procedure proposed by the WHO and is mostly used in Europe is a two hours 75 g GTT. Hb A1c >10% is diagnostic of DM. However, it has a low sensitivity as a screening test. Indications for GTT include: abnormal result of a primary screening test (50g glucose challenge), previous birth weight >4500 g at term or >the 95th centile for gestational age, current macrosomia, maternal weight >100 kg and/or a BMI >30, previous unexplained perinatal death, previous glucose in-tolerance, DM in a first degree relative, polyhydramnios, previous congenital abnormality and 2+ glycos-uria (2 episodes in early pregn. or once in late pregnancy).

9. USA: 50g glucose challenge; if 1-h serum glucose 140mg/dl (7.8mmol/L) a 3-h 100g GTT is indicated. But it is costly & may not be justified in population with a low prevalence of DM or in developing countries.A screening system based on assaying RBS in the early 3rd trimester is less sensitive & specific but may be more convenient for the above-mentioned population. Alternatively, if glycosuria is detected, RBS is done. If >7 mmol/L, a 75 g GTT is performed. RBS >11mmol/L = abnormal glucose tolerance; a GTT is not needed. WHO&Europe 1-step screening procedure is a 2 h 75 g GTT.

10. Hb A1c >10% is diagnostic of DM. However, it has a low sensitivity as a screening test. Indications for GTT include: abnormal result of a 1ry screening test (50g glucose challenge), previous B Wt > 4500 g at term or >the 95th centile for gestational age, current macrosomia, maternal weight >100 kg &/or a BMI >30, previous unexplained perinatal death, previous glucose intolerance, DM in a 1st ° relative, polyhydramnios, previous congenital abnormality & 2+ glycosuria (2 episodes in early preg. or once in late pregnancy).

11. Interpretation of GTT: Fasting 105 mg/dl 6 mmol/L 1-h 190 mg/dl 11.5mmol/L 2-h 165 mg/dl 9.5mmol/L 3-h 145 mg/dl 7.5 mmol/L 2 of these values = GDM.

12. Effect of pregnancy: Pregnancy is diabetogenic. Diabetes may appear for the 1st time during pregnancy. Insulin antagonists (hPL & steroids) reduce the amount of glycogen deposited in liver & Ms. This poor glycogen reserve together with increased fat absorption & metabolism result in tendency to ketosis. Insulin is secreted in greater amounts during pregnancy. This is required postprandially to counter insulin resistance & anti-insulin factors. However, tissue sensitivity to insulin decreases as gestation advances by up to 80% as an effect mainly of hPL. This results in higher PPS &decrease in FBS. Therefore FBS is no more used in the definitions of IGT during pregnancy, and higher cut-offs are used. Insulin dose gradually increase after the 3rd month. However, early in pregnancy insulin dose may be reduced because N&V lead to maternal hypoglycaemia So, diabetes may be difficult to control. During labour there is liability to hypo-glycaemia because of uterine activity, & insulin requirem. decrease after delivery. Pregnancy  accelerated diabetic complications. Retinopathy progresses in 85% of patients and the deterioration in nephropathy persist postpartum. Either of these complic. is indication for termination Laser photocoagulation is safe Retinal hages may increase in initial stages of improved glucose control as bl flow increases to these terminal bl.v. clearing atherosclerotic plaques. Diabetic nephropathy: Bacteriuria, PE, edema & nephrotic syn

13. Effect on pregnancy: Maternal complications: Increased abortion rate. Pregnancy-specific complications are more frequent. There is a 14.4% prevalence of pre-eclampsia (directly related to the degree of control & the presence of renal & vascular complic.). There is increased incidence of polyhyd. There is increased liability to infections including candidiasis, UTI (triple the normal rate of asymptomatic bacteri-uria) & puerperal sepsis. GDM→a 50% chance of developing NIDDM within 10-15 years if dietary control was sufficient. 20% will develop IDDM within 5 years if insulin was required.

14. Fetal complications: 1- Major malformations = 8% (7-8-x ). The RR is 3-5:1. The risk is related to the degree of glucose control in early pregnancy. NTDs, gut atresia (duodenal, anorectal & small Lt colon syndr) & cardiomegaly, transposition of the great vessels, VSD, coarct The RR of caudal atresia(sacral agenesis,the caudal regression syndrome) & situs inversus is much more high. Renal vein thrombosis, hydronephrosis, renal agenesis & ureteral duplic. It is vital that control is achieved before pregnancy. If the initial Hb A1c value is <8, the % of major malformations would be about 3.3; values between 8 & 10 are associated with 8%; while >10 values are associated with 23%. 2- DM  low AFP levels  invalid screen for Down syndrome. 3- Although the fetus of diabetic mother is too much prone to macrosomia, the embryo may show early growth delay! There is increase in body fat, mass of muscle &organomegally except kidneys & brain. This predisposes to dystocia. However, excess of heavy weight infants can be prevented by ttt with insulin. 4- Fetal hyperglycaemia delays lung maturity because it blocks surfactant production by type 2 pulmonary cells. 5- NN hypoglycaemia (<40mg/dl in up to 40% of the neonates), polycythaemia (Ht V >65%), hypomagnesaemia & hypocalcem 6- Increased perinatal mortality rate: IUD occurs in 5% of cases especially after 36w due to maternal ketosis, hypoglycaemia, congenital malformation, preeclampsia or placental insuffici. NND (5%) occurs mainly due to prematurity, RDS, congenital anomalies & hypoglycaemia. 7- IDM has a 10-x increased risk of developing DM in later life. The lighter babies are most at risk.

15. Management: Multidisciplinary provided by an obstetrician, a diabetologist and a diet-atian. However, the most important member of the team is the woman herself. Members of the extended primary health care team who have an important role in managing the patient’s pregnancy are dietician, community midwife, health visitor, diabetic liaison nurse and GP. Extended primary health care team are those working in the practice and those who visit the practice and/or patients in the community. Preconception: Good control can be monitored by assaying glycosylated haemoglobin (Hb A1c) level. Dietetic control: No regimen is best. Shift from oral hypoglycaemics to insulin once planned for pregnancy.

16. During pregnancy: The aim should be to limit weight gain to 7 kg for obese patients by supplying 25-35 Cal/kg (1500-1800Cal/day to obese & 1800-2400 Cal/day to non-obese women) in 3 meals & 3 snacks; 50% from carbohydrate sources. Soluble fibre satiates hunger & reduces glycaemic swings. In addition it improves insulin receptor sensitivity. Increased exercise with a particular attention to abdominal muscles. Water intake is increased prior to & during exercise. Swimming is the safest exercise for massively obese patients to reduce joint trauma; walking or stationary biking are excellent alternatives.

17. Insulin is very rarely required for GDM. The goal of control is to achieve a bl sugar level as close to normal as possible (ie fasting & prepran. level <105mg/dl if this is possible without hypoglycemia (>70mg/dl) & a postprandial level <120 mg/dl. If fasting & pre-prandial levels are 7mmol/L insulin would not be beneficial. If preprandial level is>8mmol/l or remains>6mmol/l after dietetic control pre-prandial short-acting insulin is added. The desired dose is 0.5, 0.6 &0.7U/kg/d in the 1st, 2nd & 3rd trimesters, 2:1 morning:evening 2:1 1 : 1 NPH R NPH R R is injected a min of 30 min prior to meal. The evening NPH injection is transferred to bedtime. Noctural hypoglycaemia could be suggested with nightmares, sleep walking, tossing & turning in bed, & waking with headache The snack for hypoglycemia shouldbe milk or peanut Alternatively, the dose can be provided as 3 pre-prandial R insulin inj + a single NPH inj at bed time. Monitoring: Ideally, the dose of insulin is established by 'trial & error'. Glucose is assayed in 4 bl samples (Fasting, 2-h after breakfast, before dinner & 2-h after dinner) & the type & dose of insulin is adjusted accordingly. Alternatively, a glucose meter is needed to estimate bl glucose levels 6-x /day before each meal & snack. This can be reduced to 2-3 times weekly with good control. It is advised to avoid squeezing the area of lancet puncture; the sample becomes diluted with tissue fluid. The risk of tight control is nocturnal hypoglycemia which causes rebound hyperglycemia by the morning. Generally, pregnant diabetic women are more resistant to hypoglycemia than non-pregnant women especially in the 3rd trimester. In the event of severe hypoglycemia glucagon IM should be given. Dexamethazone inj to enhance fetal lung maturity = concurrent insulin.

18. 4- Treatment of diabetic ketoacidosis: R insulin 0.15 U/kg bolus then 0.15 U/kg/h (=5-10 U/ 100 ml saline). If after 2 h glucose did not come down to 200mg/dl, the dose is doubled 5- ANC visits/2 weeks until 28 w, then weekly. 6- Monthly glycosylated Hb. 7- Folate 5 mg daily due to the interaction of hyperglycaemia with folate receptors. 8-Funduscopy shouldbe performed at least 3-x 9- Thyroid function tests because of the potential multi-endocrine impact of DM. 10- ECG in patients ≥35y or with disease duration >5 years. 11- 24h creatinine clearance & total protein if protein is <200 mg, test urine for microalbminuria which is associated with increased vascular disease in the future.

19. 12- Antenatal fetal assessment: As usual. NST is performed twice/w after the 30th week + BPP weekly or twice weekly from 36 w. 13- Postdatism is not allowed. Pregn may even be terminated at 37-38 w if the fetus is considered to be excessively grown or if glucose values remain labile. In such cases lung maturity may be determined by PG or an L/S ratio of ≥3.5. Fetal hyperglycemia delays lung maturity

20. During labour • The IV infusion may be given separately as D5 Lactated Ringer’s solution. Women >160kg will require more glucose. If insulin is needed 25U/250mL saline ( 0.1U/mL) is given at a rate of 0.5-2U/h. Alternatively, ½ the insulin dose + 500ml 5%glucose is given /4 h. Ideally, bl. glucose should remain between 70-100mg/dl. Bl. glucose & potassium levels are checked/2 h. Urine should be checked for ketones/2h too If the pregnancy insulin dose is unknown, add 10U insulin to 500ml 10% glucose at a rate of 2 U/h. • Epidural anaesthesia is ideal. • CEFM. Give careful attention to decelerations as fetal tolerance to stress is limited. Scalp pH is indicated if worrisome patterns persist. • Induction: Morning insulin dose is omitted. 5 U/500 ml D5%w is infused.

21. After delivery: Postpartum insulin dose decreases to ½ or 1/3 the dose needed in late pregnancy; the pre-pregnancy dose is required again within 4-7 days of delivery. GTT is recommended 6 w to 3 months postpartum. A high 1-h value represents decreased insulin capacity and advocates limitation of simple sugars in the diet, whereas an elevated 3-h value reflects decreased insulin receptors. • Care of the newborn: The newborn should be managed as a preterm baby regardless of its weight. Exchange transfusion is indicated if Ht.V. is >65%.

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