Endocrine disorders in pregnancy

By By

Dr. Khattab OmarDr. Khattab Omar

Prof. & Head of Obstetrics and Prof. & Head of Obstetrics and Gynaecology DepartmentGynaecology Department

Faculty of Medicine, Al-Azhar Faculty of Medicine, Al-Azhar University, University, DamiettaDamietta

Diabetes mellitus (DM)

Physiology:Physiology:

In the nonpregnant state the ingested glucose is:In the nonpregnant state the ingested glucose is:

1- through the general circulation: 1- through the general circulation:

A- a proportion is metabolised directly by the tissues;A- a proportion is metabolised directly by the tissues;

B- some is converted to depot fat; B- some is converted to depot fat;

C- a proportion is stored as muscle glycogen (with the aid C- a proportion is stored as muscle glycogen (with the aid of insulin). of insulin).

2- through the enterohepatic circulation, and with the aid 2- through the enterohepatic circulation, and with the aid of insulin, is deposited in the liver as glycogen. of insulin, is deposited in the liver as glycogen.

Blood glucose is Blood glucose is maintained maintained between 4.5 and between 4.5 and 5.5 mmol/L5.5 mmol/L

Cerebral and Cerebral and placental glucose placental glucose uptake is uptake is independent of independent of insulin. insulin.

This is the commonest cause of This is the commonest cause of glycosuria during pregnancy.glycosuria during pregnancy.

It occurs in 15% of healthy pregnant It occurs in 15% of healthy pregnant women due to higher postprandial women due to higher postprandial glucose levels and due to glucose levels and due to increased glomerular filtration increased glomerular filtration rate. rate.

False glycosuria i.e. more than usual False glycosuria i.e. more than usual glycosuria without hyperglycemia glycosuria without hyperglycemia may have sustained renal damage may have sustained renal damage from earlier untreated UTI.from earlier untreated UTI.

Physiological glycosuria of pregnancyPhysiological glycosuria of pregnancy

Gestational Impaired Glucose Tolerance & Gestational Impaired Glucose Tolerance & Gestational DMGestational DM: :

They are defined as carbohydrate intolerance They are defined as carbohydrate intolerance with onset or first recognition during pregnancy with onset or first recognition during pregnancy

GDM & GIGT occur as a consequence of the in-GDM & GIGT occur as a consequence of the in-creased insulin resistance that develops during creased insulin resistance that develops during pregnancy due to the secretion of placental pregnancy due to the secretion of placental hormones, particularly progesterone & hPL.hormones, particularly progesterone & hPL.

GDM in the first half of pregnancy may suggest GDM in the first half of pregnancy may suggest glucose intolerance before pregnancy. glucose intolerance before pregnancy.

There may be There may be markedmarked weight gain weight gain, particularly in , particularly in the abdominal region. There may be the abdominal region. There may be oedemaoedema earlyearly in pregnancy. in pregnancy.

Screening:Screening:

Screening may be not recommended Screening may be not recommended in women under 25 years, with in women under 25 years, with normal weight, no personal or normal weight, no personal or family history of DM, no history of family history of DM, no history of poor obstetric outcome & does not poor obstetric outcome & does not belong to an ethnic group predis-belong to an ethnic group predis-posed to DM (posed to DM (selective screening – selective screening – American schoolAmerican school). ).

The Canadian and the British The Canadian and the British authorities opted for 'authorities opted for 'routine routine screeningscreening'.'.

Screening timing:Screening timing:Low riskLow risk = No screening. < = No screening. <25 yo, <25 BMI, 25 yo, <25 BMI,

no personal or family history of DM, no no personal or family history of DM, no history of poor obstetric outcome & does history of poor obstetric outcome & does not belong to an ethnic group not belong to an ethnic group predisposed to DM. predisposed to DM.

High riskHigh risk = screening = screening at booking & again at booking & again at 24-28 w. at 24-28 w. >35 yo, BMI >30, multiple >35 yo, BMI >30, multiple pregnancy, gestational glycosuria in ≥2 pregnancy, gestational glycosuria in ≥2 separate occasions, previous GDM, separate occasions, previous GDM, family history of DM, poor obstetric family history of DM, poor obstetric history or ethnicity, PCOS, smokers).history or ethnicity, PCOS, smokers).

Intermediate riskIntermediate risk = screening = screening at 28 w. at 28 w.

Age: 25-35, BMI: 25-30,...Age: 25-35, BMI: 25-30,...

Screening procedure

75 g oral GTT at booking and at 24-28 75 g oral GTT at booking and at 24-28 w for all pregnant women.w for all pregnant women.

Fasting as well as 1-h & 2-h post-Fasting as well as 1-h & 2-h post-prandial samples are collected. prandial samples are collected.

The test is deemed abnormal if:The test is deemed abnormal if:- FBS ≥5.1 mmol/L (92mg/dl); FBS ≥5.1 mmol/L (92mg/dl); - 1-h PPS ≥10 mmol/L (180mg/dl) 1-h PPS ≥10 mmol/L (180mg/dl) - 2-h PPS ≥8.5mmol/L (153mg/dl)2-h PPS ≥8.5mmol/L (153mg/dl)

Overt or clinical DM:Overt or clinical DM: Abnormal 2 values of a 3-h Abnormal 2 values of a 3-h GTT with polyphagia, polyuria, poly dipsia,…….GTT with polyphagia, polyuria, poly dipsia,…….

Indications for GTT include: abnormal 1ry Indications for GTT include: abnormal 1ry screening test, previous birthweight >4.5 kg at screening test, previous birthweight >4.5 kg at term or >the 95th centile for age, current term or >the 95th centile for age, current macrosomia, maternal weight >100 kg &/or a macrosomia, maternal weight >100 kg &/or a BMI >30 previous un-explained perinatal death, BMI >30 previous un-explained perinatal death, previous gluc. intolerance, DM in a 1st degree previous gluc. intolerance, DM in a 1st degree relative, unexplained polyhydramnios, previous relative, unexplained polyhydramnios, previous

congenital abnormality and 2+ glycosuriacongenital abnormality and 2+ glycosuria

Diagnosis

Interpretation of GTT:Interpretation of GTT:

Fasting Fasting 95 mg/dl 95 mg/dl 6 mmol/L 6 mmol/L

1-h 1-h 180 mg/dl 180 mg/dl 11.5mmol/L 11.5mmol/L

2-h 2-h 155 mg/dl 155 mg/dl 9.5mmol/L 9.5mmol/L

3-h 3-h 140 mg/dl 140 mg/dl 7.5 mmol/L 7.5 mmol/L

2 of these values = GDM. 2 of these values = GDM.

Hb A1c >10% is diagnostic Hb A1c >10% is diagnostic of DM. of DM.

However, it has a low However, it has a low sensitivity as a screening sensitivity as a screening test. test.

Sacral agenesisSacral agenesis

Aetiology

Type I DM usually results from a cell-Type I DM usually results from a cell-mediated autoimmune destruction of mediated autoimmune destruction of

the the cells marked by the presence cells marked by the presence of auto-antibodies to insulin & to islet of auto-antibodies to insulin & to islet

cells in 85-90% of cases.cells in 85-90% of cases.

In type II DM, insulin receptors are In type II DM, insulin receptors are deficient. deficient.

Effect of pregnancy:Effect of pregnancy: Pregnancy is Pregnancy is diabetogenicdiabetogenic. Poor glycogen . Poor glycogen

reserve together with increased fat ab-reserve together with increased fat ab-sorption & metabolism result in tendency sorption & metabolism result in tendency to to ketosisketosis. .

InsulinInsulin is secreted in greater amounts. is secreted in greater amounts. However, tissue sensitivity to insulin de-However, tissue sensitivity to insulin de-creases as gestation advances by up to creases as gestation advances by up to 80% as an effect mainly of hPL. This 80% as an effect mainly of hPL. This results in higher postprandial results in higher postprandial glucoseglucose & & decrease in FBS.decrease in FBS.

Insulin Insulin dosedose gradually increases after the gradually increases after the 3rd month. However, early in pregnancy 3rd month. However, early in pregnancy insulin dose may be reduced because insulin dose may be reduced because N&V lead to maternal hypoglycemia. So, N&V lead to maternal hypoglycemia. So, DM may be difficult to control. During DM may be difficult to control. During labour there is liability to hypoglycaemia labour there is liability to hypoglycaemia because of uterine activity, & insulin because of uterine activity, & insulin requirements decrease after delivery. requirements decrease after delivery.

Effect of pregnancy:Effect of pregnancy: Pregnancy Pregnancy accelerated diabetic accelerated diabetic

complicationscomplications. Retinopathy progresses in . Retinopathy progresses in 85% of patients. Retinal hages may 85% of patients. Retinal hages may increase in initial stages of improved increase in initial stages of improved glucose control as bl. flow increases to glucose control as bl. flow increases to these terminal vessels clearing athero-these terminal vessels clearing athero-sclerotic plaques. sclerotic plaques.

Diabetic nephropathy: Bacteriuria, pre-Diabetic nephropathy: Bacteriuria, pre-eclampsia, edema & nephropathy. eclampsia, edema & nephropathy.

GDM GDM → → a 50% chance of developing NIDDM a 50% chance of developing NIDDM within 10-15 years if dietary control was within 10-15 years if dietary control was sufficient. 20% will develop IDDM within sufficient. 20% will develop IDDM within 5 years if insulin was required.5 years if insulin was required.

Effect on pregnancy:Effect on pregnancy:Maternal complications:Maternal complications:Increased Increased abortionabortion rate. rate. There is about 15% prevalence of There is about 15% prevalence of pre-pre-

eclampsiaeclampsia (directly related to the (directly related to the degree of control & the presence of degree of control & the presence of renal & vascular complications). renal & vascular complications).

There is increased incidence of There is increased incidence of poly-poly-hydramnioshydramnios..

There is increased liability to There is increased liability to infectionsinfections including candidiasis, UTI including candidiasis, UTI (triple the normal rate of AB) & (triple the normal rate of AB) & puerperal sepsis. puerperal sepsis.

Fetal complications:Fetal complications:1- Major malformations = 8% (8-x 1- Major malformations = 8% (8-x ). The risk is ). The risk is

related to the degree of glucose control in early related to the degree of glucose control in early pregnancy. pregnancy. NTDsNTDs, , gutgut atresia (duodenal, ano- atresia (duodenal, ano-rectal & small Lt colon) & cardiomegaly, trans-rectal & small Lt colon) & cardiomegaly, trans-position of the great vessels, VSD, coarctation of position of the great vessels, VSD, coarctation of the aorta. the aorta. Caudal atresiaCaudal atresia & situs inversus. & situs inversus. RenalRenal vein thrombosis, hydronephrosis, renal agenesis vein thrombosis, hydronephrosis, renal agenesis & ureteral duplication. It is vital that control is & ureteral duplication. It is vital that control is achieved before pregn. If the initial Hb A1c value achieved before pregn. If the initial Hb A1c value is <8, the % of major malformations would be 3.3is <8, the % of major malformations would be 3.3

2- DM 2- DM low AFP levels low AFP levels invalid screen for Down. invalid screen for Down. 3-Although the fetus of diabetic mother is too 3-Although the fetus of diabetic mother is too

much prone to macrosomia, the embryo may much prone to macrosomia, the embryo may show early growth delay! There is increase in show early growth delay! There is increase in body fat, mass of muscle & organomegaly except body fat, mass of muscle & organomegaly except kidneys & brain This predisposes to dystocia. kidneys & brain This predisposes to dystocia. Excess of heavy weight infants can be prevented Excess of heavy weight infants can be prevented by insulin ttt. by insulin ttt.

4- Fetal hyperglycemia delays lung maturity be-4- Fetal hyperglycemia delays lung maturity be-cause it blocks surfactant production by type 2 cause it blocks surfactant production by type 2 pulmonary cells. pulmonary cells.

Neonatal & adult-life complications:Neonatal & adult-life complications:5- NN hypoglycemia (<40mg/dl in up 5- NN hypoglycemia (<40mg/dl in up

to 40% of the NN), polycythaemia to 40% of the NN), polycythaemia (Hct >65%), hypomagnesaemia & (Hct >65%), hypomagnesaemia & hypocalcemia. hypocalcemia.

6- Increased perinatal mortality rate: 6- Increased perinatal mortality rate: IUD 5% especially after 36w due to IUD 5% especially after 36w due to maternal ketosis, hypoglycaemia, maternal ketosis, hypoglycaemia, congenital malformation, preeclamp. congenital malformation, preeclamp. or placental insufficiency. NND (5%) or placental insufficiency. NND (5%) occurs mainly due to prematurity, occurs mainly due to prematurity, RDS, congenital anomalies & hypo-RDS, congenital anomalies & hypo-glycemia. glycemia.

7- IDM has a 10-x increased risk of 7- IDM has a 10-x increased risk of developing DM in later life. developing DM in later life.

Management:Management: Multidisciplinary provided by an obstetrician, a Multidisciplinary provided by an obstetrician, a

diabetologist and a dietatian. The most im-diabetologist and a dietatian. The most im-portant member of the team is the woman her-portant member of the team is the woman her-self. Members of the extended team are comm-self. Members of the extended team are comm-unity midwife, health visitor, diabetic liaison unity midwife, health visitor, diabetic liaison nurse and GP. nurse and GP.

Preconception:Preconception:Good control can be monitored by assaying Good control can be monitored by assaying

glycosylated haemoglobin (Hb A1c) level. glycosylated haemoglobin (Hb A1c) level. Dietetic control: No regimen is best. Dietetic control: No regimen is best. Shift from oral hypoglycaemics to insulin once Shift from oral hypoglycaemics to insulin once

planned for pregnancy.planned for pregnancy.

During pregnancy:During pregnancy:

1- The aim should be to limit 1- The aim should be to limit weightweight gain to 7 kg for gain to 7 kg for obese patients by supplying 1500-1800 obese patients by supplying 1500-1800 CalCal/day /day (1800-2400 Cal/day to non-obese) in 3 meals & 3 (1800-2400 Cal/day to non-obese) in 3 meals & 3 snacks; 50% from snacks; 50% from carbohydratecarbohydrate sources. Soluble sources. Soluble fibrefibre satiates hunger & red-uces glycaemic satiates hunger & red-uces glycaemic swings. In addition, it impro-ves insulin receptor swings. In addition, it impro-ves insulin receptor sensitivity.sensitivity.

2- Increased 2- Increased exerciseexercise with a particular attention to with a particular attention to abdominal muscles. Water intake is in-creased abdominal muscles. Water intake is in-creased prior to & during exercise. Swimming is the safest prior to & during exercise. Swimming is the safest exercise for massively obese patients to reduce exercise for massively obese patients to reduce joint trauma; walking or stationary biking are joint trauma; walking or stationary biking are excellent alternatives. excellent alternatives.

3- 3- InsulinInsulin is very rarely required for GDM. The goal of control is to achieve a bl sugar 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 & preprandial level <105mg/dl & a level as close to normal as possible (ie fasting & preprandial level <105mg/dl & a postprandial level <120mg/dl postprandial level <120mg/dl

If fasting & pre-prandial levels are If fasting & pre-prandial levels are 7mmol/L insulin would not be beneficial7mmol/L insulin would not be beneficial. . If preprandial level is>8 mmol/l or remains >6 mmol/l after dietetic control insulin is If preprandial level is>8 mmol/l or remains >6 mmol/l after dietetic control insulin is

addedadded. The desired dose is 0.5, 0.6 & 0.7U/kg/ day in the 1st, 2nd & 3rd trimesters, . The desired dose is 0.5, 0.6 & 0.7U/kg/ day in the 1st, 2nd & 3rd trimesters, 2:1 morning : evening2:1 morning : evening

2 : 1 1 : 1 2 : 1 1 : 1

NPH R NPH R NPH R NPH R is injected a min of 30 min is injected a min of 30 min prior to meal. The evening NPH injection is transferred to bedtime. prior to meal. The evening NPH injection is transferred to bedtime.

The risk of tight control is nocturnal hypoglycemia which causes re-bound hyperglycemia The risk of tight control is nocturnal hypoglycemia which causes re-bound hyperglycemia by the morning. Noctural hypoglycaemia could be suggested with nightmares, sleep by the morning. Noctural hypoglycaemia could be suggested with nightmares, sleep walking, tossing & turn-ing in bed, & waking with headache. The snack for hypogly. walking, tossing & turn-ing in bed, & waking with headache. The snack for hypogly. should be milk or peanut. Glucagon IM should be given for severe hypogly should be milk or peanut. Glucagon IM should be given for severe hypogly

Alternatively, provide 3 preprandial R insulin inj + single NPH inj noct Alternatively, provide 3 preprandial R insulin inj + single NPH inj noct Monitoring: trial & error. Glucose is assayed in 4 bl. samples (Fasting, 2 h after breakf., Monitoring: trial & error. Glucose is assayed in 4 bl. samples (Fasting, 2 h after breakf.,

before dinner & 2 h after dinner) & the type & dose of insulin is adjusted accordingly.before dinner & 2 h after dinner) & the type & dose of insulin is adjusted accordingly.Alternatively, glucose levels are estimated by a glucosemeter 6-x/ day before each meal Alternatively, glucose levels are estimated by a glucosemeter 6-x/ day before each meal

& snack. This can be reduced to 2-3 times weekly with good control. Avoid squeezing & snack. This can be reduced to 2-3 times weekly with good control. Avoid squeezing the area of puncture. the area of puncture.

4- 4- Insulin analogues:Insulin analogues:

Rapid-acting insulin analogues (RAIA): Humalog and Rapid-acting insulin analogues (RAIA): Humalog and Novolog achieve more rapid insulin peak and better Novolog achieve more rapid insulin peak and better postprandial gluc. control. postprandial gluc. control.

Long-acting insulin analogues do not yet have sufficient Long-acting insulin analogues do not yet have sufficient safety evaluation. safety evaluation.

5- 5- GlyburideGlyburide does not cross the placenta. A 10-25% failure does not cross the placenta. A 10-25% failure rate is more likely to occur in women with a BMI >41 rate is more likely to occur in women with a BMI >41 kg/mkg/m22. .

Metformin alone or with supplemental in-sulin is not Metformin alone or with supplemental in-sulin is not associated with increased per-inatal complications as associated with increased per-inatal complications as compared with inscompared with ins

6- Treatment of 6- Treatment of diabetic ketoacidosis: diabetic ketoacidosis: Reg insulin Reg insulin 0.15 U/kg bolus then 0.15 U/kg/h (=5-10 U/ 100 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 ml saline). If after 2 h, glucose did not come down to 200 mg/dl, the dose is doubled. down to 200 mg/dl, the dose is doubled.

7- ANC visits/2 weeks until 28 w, then weekly. 7- ANC visits/2 weeks until 28 w, then weekly. 8- Monthly glycosylated Hb. 8- Monthly glycosylated Hb. 9- Folate 5 mg daily due to the interaction of 9- Folate 5 mg daily due to the interaction of

hyperglycaemia with folate receptors. hyperglycaemia with folate receptors. 10- Funduscopy should be performed at least 3-x 10- Funduscopy should be performed at least 3-x 11- TFTs. 11- TFTs. 12- ECG in patients ≥35y or with >5 year disease 12- ECG in patients ≥35y or with >5 year disease

duration. duration. 13- 24 h creatinine clearance & total protein; if 13- 24 h creatinine clearance & total protein; if

protein is <200 mg, test urine for microalbmin-protein is <200 mg, test urine for microalbmin-uria which is associated with increased vascular uria which is associated with increased vascular disease in the future. disease in the future.

14- Antenatal fetal assessment as 14- Antenatal fetal assessment as usual. NST is performed twice/w usual. NST is performed twice/w after the 30th week + BPP weekly after the 30th week + BPP weekly or twice weekly from 36 w. or twice weekly from 36 w.

15- Postdatism is not allowed. Preg 15- Postdatism is not allowed. Preg may even be terminated at 37-38 may even be terminated at 37-38 ww if the fetus is considered to be if the fetus is considered to be excessively grown or if glucose excessively grown or if glucose values remain labile. In such cases values remain labile. In such cases lung maturity may be determined lung maturity may be determined by PG or an L/S ratio of ≥3.5. by PG or an L/S ratio of ≥3.5.

During labourDuring labour Check bl. glucose & potassium levels and for Check bl. glucose & potassium levels and for ketonuria every 2 h.ketonuria every 2 h.IV infusion of D5 Lactated RingerIV infusion of D5 Lactated Ringer’’s solution. s solution. Women >160 kg will require more glucose. If Women >160 kg will require more glucose. If insulin is needed, insulin is needed, 2525 U/ U/250250ml saline is given at a ml saline is given at a rate of rate of 22 U/h. Alternatively, half ( U/h. Alternatively, half (0.5)0.5) the insulin the insulin dose + dose + 500500 ml ml 55% glucose is given /% glucose is given /55 h. If the h. If the pregnancy insulin dose is unknown, add pregnancy insulin dose is unknown, add 1010 U U insulin to insulin to 500500ml ml 1010% glucose at a rate of % glucose at a rate of 22U/ h U/ h Ideally, bl glucose should remain between 70 & Ideally, bl glucose should remain between 70 & 100 mg/dl.100 mg/dl.Epidural anaesthesia is ideal. Epidural anaesthesia is ideal. CEFM. Give careful attention to decelerations as CEFM. Give careful attention to decelerations as fetal tolerance to stress is limited. Scalp pH is fetal tolerance to stress is limited. Scalp pH is indicated if worrisome patterns persist. indicated if worrisome patterns persist. Induction: Morning insulin dose is omitted. Induction: Morning insulin dose is omitted. 55 U/ U/ 500500 ml D ml D55%w is infused. %w is infused.

After delivery:After delivery: Decrease to Decrease to ½½ or 1/3 the dose or 1/3 the dose needed in late pregnancy; the pre-pregnancy needed in late pregnancy; the pre-pregnancy dose is required again within 4-7 days. GTT is dose is required again within 4-7 days. GTT is recommended 6 w to 3 months postpartum. A recommended 6 w to 3 months postpartum. A high 1-h value represents decreased insulin high 1-h value represents decreased insulin capacity and advocates limitation of simple capacity and advocates limitation of simple sugars in the diet, whereas an elevated 3-h sugars in the diet, whereas an elevated 3-h value reflects decreased insulin receptors.value reflects decreased insulin receptors.

Care of the newborn:Care of the newborn: The newborn should be The newborn should be managed as a preterm baby regardless of its managed as a preterm baby regardless of its weight. Exchange transfusion is indicated if Hct weight. Exchange transfusion is indicated if Hct is >65%. is >65%.

ThankThank you you