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Medical Disorders Complicating Pregnancy Jeffrey C. Faig, M.D., FACOG, FACP Clinical Professor Division of Obstetrics and Gynecology Medical Disorders Complicating Pregnancy Hypertensive Disease/Preeclampsia Diabetes Mellitus Thyroid Disease Obesity OBJECTIVES Define and classify hypertension in pregnancy and describe the pathophysiology of preeclampsia/eclampsia syndrome Describe the pathophysiology of diabetes mellitus and thyroid disease in pregnancy and obstetric complications of obesity Medical Disorders and Pregnancy Some medical problems unique to the pregnant state, others may antedate or arise de novo during gestation Gestation alters anatomy and physiology of most organ systems, and may profoundly influence natural history of medical disorders Disease may jeopardize mother and/or fetus – increased perinatal mortality and morbidity Perinatal Mortality Fetal Demise + Neonatal death in the first 28 days after birth Hypertensive Disorders (ACOG, 2013) Chronic Hypertension Gestational Hypertension Preeclampsia/Eclampsia Preeclampsia superimposed on CHTN ◦ complicate 10-20% of pregnancies Chronic Hypertension Systolic bp >140 mm Hg ◦ or Diastolic bp > 90 mm Hg ◦ Antedates pregnancy, present before 20 wk ega, or persists longer than 12 wks postpartum ◦ Essential HTN, or due to medical disorders ◦ Risk of adverse pregnancy outcome w/mild CHTN: Superimposed preeclampsia: 10-25% Abruptio placentae: 1% Preterm birth: 12-34% Fetal growth restriction: 8-16% Gestational Hypertension Sbp > 140 mm Hg ◦ or Dbp > 90 mm Hg ◦ and No proteinuria or systemic findings ◦ Developing after 20 wks ◦ If develops before 20 wks - CHTN Gestational Hypertension Development of preeclampsia in 15-25% High recurrence rate, associated with subsequent CHTN If mild, outcomes favorable if severe, increased perinatal and maternal morbidity similar to superimposed preeclampsia Pre-eclampsia New onset of hypertension and proteinuria after 20 wks gestation in previously normotensive woman. In absence of proteinuria, preeclampsia with severe features diagnosed as HTN in association with: ◦ ◦ ◦ ◦ ◦ Thrombocytopenia (< 100K_ Impaired liver function (LFT’s 2x normal) New renal insufficiency (creat > 1.1 mg/dl) Pulmonary edema New-onset visual or cerebral disturbances End –organ manifestations from mild-to severe microangiopathy of target organs Brain Liver Kidney placenta Pathogenesis: abnormal development of placental vasculature early in pregnancy ◦ ◦ relative placental underperfusion/hypoxia release of factors which alter maternal endothelial cell function. Clinical features of generalized endothelial cell dysfunction Disturbed endothelial control of vascular tone ◦ hypertension Increased vascular permeability ◦ Proteinuria/edema Abnormal endothelial expression of procoagulants ◦ coagulopathy Endothelial dysfunction in vasculature of target organs ◦ ◦ ◦ ◦ Brain – headache, seizures Liver – transaminitis, liver capsule distention/rupture Kidney – oliguria, renal failure Placenta – Intrauterine growth restriction, fetal hypoxia/distress, IUFD Pathogenesis Normal placental development: Invasive cytotrophoblasts of fetal origin invade the maternal spiral arteries transforming them from small-caliber resistance vessels to high caliber capacitance vessels capable of providing placental perfusion adequate to sustain fetal growth Preeclampsia: Cytotrophoblasts fail to adopt invasive endothelial phenotype invasion of spiral arteries is shallow and they remain small caliber resistance vessels may result in placental ischemia Preeclampsia Critical role of placenta ◦ Placental tissue in necessary for development of the disease, fetus is not ◦ Preeclampsia always cured after delivery of the placenta Preeclampsia Defective cytotrophoblast cell differentiation of the developing placenta Defective cytotrophoblast invasion of the spiral arteries, decidual not myometrial Abnormal remodeling of spiral arteries Placental hypoperfusion ◦ Critical component for elaboration of factors which alter maternal endothelial cell function Pathogenesis of Preeclampsia Preeclampsia ◦ Systolic bp > 140mm Hg or ◦ Diastolic bp > 90 mm Hg ◦ Proteinuria > 300 mg/24 hr ◦ Or, in the absence of proteinuria, new-onset HTN with plts < 100K, creat > 1.1 mg/dl, LFTs 2x nl, pulmonary edema, cerebral or visual symptoms Preeclampsia with severe features Sbp > 160 mm Hg Dbp >110 mm Hg CNS dysfunction ◦ Severe headache, scotomata, altered mental status, CVA Hepatocellular Injury ◦ Transaminase elevation Liver capsule distention ◦ RUQ/epigastric pain, nausea, vomiting Thrombocytopenia < 100K Oliguria/creatinine > 1.1 mg/dl Pulmonary edema Complications Maternal ◦ ◦ ◦ ◦ ◦ ◦ ◦ Seizures CVA Pulmonary edema Liver hemorrhage Renal failure Thrombocytopenia Placental abruption/Hemorrhage Fetal ◦ Growth restriction ◦ Stillbirth Management Surveillance ◦ Maternal ◦ Fetal Delivery ◦ Always beneficial for the mother ◦ Fetus at risk for complications of prematurity, esp. RDS Deferred delivery ◦ Seizure prophylaxis ◦ Acute HTN control ◦ Steroids to promote fetal lung maturity Diabetes Gestational Diabetes ◦ A1 GDM (diet-controlled) ◦ A2 GDM (insulin- or OHA- requiring) Type II Diabetes Type I Diabetes Diabetes Affects up to 20%% of the more than 4 million pregnancies in the U.S. yearly Almost 75% of cases occur in women with GDM or undiagnosed DM II Type I diabetes accounts for 1-2% of the pregnancies complicated by diabetes (6000 in U.S. annually) Etiological Classification of Diabetes Type I Type II ◦ Weak ethnic/familial concordance ◦ autoimmune activation (anti-glutamic acid decarboxylase (anti-GAD) and anti-islet cell (anti-ICA) antibodies) ◦ relatively rapid progression of beta cell destruction ◦ failure of endogenous insulin production ◦ minimal insulin resistance ◦ ◦ ◦ ◦ ◦ manifestation of peripheral insulin resistance strong ethnic/familial concordance absence of autoimmune activation slowly progressing failure of endogenous beta cell function and insulin production positive correlation with obesity and sedentary lifestyle Insulin Resistance Human placental lactogen Progesterone Prolactin Placental growth hormone Cortisol Diabetes Coexistence of DM and pregnancy rare before the discovery of insulin in 1921: maternal mortality of 20%, perinatal mortality of 60% Since the 1940’s, perinatal mortality rates in DM decreased from 30% to 3% In the 1980’s fetal perinatal mortality in context of type I diabetes was still 25% Congenital malformations instead of IUFD now the major cause of perinatal death and morbidity among infants of diabetic mothers Dx - Pregestational Diabetes FBS >125 mg/dl Postprandial or random BS >200 mg/dl Impaired glucose tolerance: FBS 95-125, RBS 140-200 Additional important history, distinguish type I, II: BMI duration of disease Rx hx DKA hypoglycemia unawareness retinopathy nephropathy autonomic neuropathy HTN, cardiac/vascular disease recent gHb Dx- Gestational Diabetes ACOG ◦ 50 gm glucose load: < 135 mg/dl ◦ 100 gm GTT: 95/180/155/140 – 2 abnl values ◦ Early screening: History prior GDM Known impaired glucose tolerance BMI > 30 Dx – Gestational Diabetes Use of risk factors alone (fmhx DM, obesity, glycosuria, etc.) will miss half of GDM pts Need outcomes-based system to screen large population, prevent adverse outcomes ◦ macrosomia/shoulder dystocia ◦ neonatal hypoglycemia ◦ risk of obesity/diabetes in offspring Hyperglycemia and Adverse Pregnancy Outcome Frequency of Primary Outcomes across the Glucose Categories The HAPO Study Cooperative Research Group. N Engl J Med 2008;358:1991-2002 Dx – Gestational Diabetes Gestational Diabetes ◦ HgbA1c at initial visit ≤ 5.6%: normal 5.7% - 6.4%: prediabetes ≥ 6.5%: pregestational DM, type 1 or 2 Dx – Gestational Diabetes ◦ 75 gm 2 hr GTT at 28 weeks (92/180/153) 1 abnormal value dx GDM ◦ 2 hr GTT at initial visit if risk factors: hx prior GDM BMI > 30 known impaired glucose tolerance (PCOS, prediabetes) prior hx fetal macrosomia Risks of Diabetes in Pregnancy Fetal ◦ Pregestational Diabetes Congenital anomalies Miscarriage Inadequate amniotic fluid Fetal growth restriction or excess Fetal Demise ◦ Gestational or Pregestational Diabetes Fetal growth excess Excessive amniotic fluid Risks of Diabetes in Pregnancy Neonatal ◦ Respiratory Distress Syndrome ◦ Hypoglycemia ◦ Hyperbilirubinemia Childhood ◦ Insulin resistance/Impaired Glucose Tolerance ◦ Obesity ◦ DM I and II Risks of Diabetes in Pregnancy Maternal ◦ Pregestational Diabetes Severe hypoglycemia DKA/hyperosmolar coma Accelerated retinopathy/nephropathy Pyelonephritis ◦ Pregestational or Gestational Diabetes Gestational hypertension Preeclampsia Eclampsia Risk Reduction Preconception care ◦ 50% of pregnancies in U.S. are unplanned Assessment for maternal complications Strict glycemic control Antepartum fetal surveillance Fetal Complications – Congenital Malformations Fetal Complications – Fetal Demise Poorly controlled DMI or II esp. with vascular disease Prior to 1950, ½ of stillbirths occurred after 38 wks; early delivery advocated No risk in well-controlled DC-GDM, with antenatal surveillance Management - Nutritional Goals ◦ ◦ ◦ ◦ achieve normoglycemia prevent ketonemia foster adequate weight gain avg 30 kcal/kg/day, BMI 22-27 Management - Insulin Indications: ◦ Pregestational DM I or II ◦ Gestational DM or Undiagnosed pregestational DM II Fbs > 95 mg/dl Postprandial > 200 mg/dl Fbs > 95 mg/dl (>20% of values) or pp > 135 mg/dl (> 20% of values) while adhering to diet guidelines Insulin Pharmacokinetics Type Onset Lispro/Aspart5-15 min Regular 30 min NPH 2 hr Glargine 2 hr Detemir 2 hr Peak 45-75 2-4 hr 6-10 hr no peak 6-8 hr Duration 2-4 hr 5-8 hr 18-28 hr 20-24 hr 20-24 hr Continuous Subcutaneous Insulin Infusion Advantages ◦ flexibility in physical activity and meal planning ◦ Adjustment of basal rate to avoid nocturnal hypoglycemia and fasting hyperglycemia from Dawn phenomenon ◦ Insulin bolus injection may be rapid or extended ◦ Multiple injections are avoided ◦ Subcutaneous injection only every 2-3 day CSII Disadvantages ◦ Patient should be motivated, compliant, and technically sophisticated ◦ Pump failure may result in ketoacidosis ◦ Pump and supplies more expensive and less readily available ◦ Insertion site infections may result in abnormal glycemic control ◦ Poor compliance more likely to result in patient complications Thyroid Disease Hypothyroidism Hyperthyroidism Thyroid Nodules/Cancer Postpartum Thyroid Dysfunction Thyroid Thyroid disorders are second only to diabetes as the most common endocrinopathy of childbearing women Worldwide most common cause is: Iodine deficiency over 1 billion people at risk 500 million living in areas of overt iodine deficiency In the developed world most common cause is: autoimmune thyroid disease Thyroid Disorders Prevalence in pregnant women Subclinical hypothyroidism: 2% Overt hypothyroidism: 0.5% Hyperthyroidism: 0.2% Thyroid Complex interplay of factors in pregnancy: ◦ Iodine deficiency profoundly impairs maternal and fetal thyroid function resultant increased risk of pregnancy loss major implications for fetal neuronal multiplication and organization during the 2nd trimester irreversible neurologic deficit Thyroid ◦ Maternal autoimmune thyroid disease may affect the fetus as well as the mother Transplacental passage of abnormal maternal hormone concentrations TSH-receptor antibodies – (stimulatory or blocking) antithyroid medications Sab Intrauterine growth restriction Preterm labor Neonatal thyrotoxicosis Cognitive dysfunction Thyroid ◦ Thyroid function tests altered by the physiology of pregnancy ranges of normal, particularly TSH should be adjusted ◦ Hypermetabolic symptoms of normal pregnancy may mimic the clinical picture of some thyroid disorders Hypothalamic-Pituitary-Thyroid Axis in Pregnancy Twofold elevation of TBG ◦ Reduced peripheral TBG degradation and clearance rates ◦ Result is increased total T4 and T3 Rise in TBG ◦ begins as early as the 20th postovulatory day ◦ maximum at week 20-24 ◦ remains at this level until a few weeks postpartum H-P-T Axis in Pregnancy hCG has mild TSH activity ◦ structural homology between the beta subunits and the extracellular receptor binding domains of hCG and TSH hCG levels peak at 50-100,000 IU ◦ plateau at 10-20,000 IU at 20 wks. ◦ 10,000 IU/L increment of hCG is associated with reduction of basal TSH by 0.1 mU/L During the first trimester 9% of pregnant women had subnormal (>0.05,<0.4), and additional 9% had suppressed TSH Hypothyroidism and Pregnancy – Differential Diagnosis ◦ Iodine deficiency most common cause worldwide fetal thyroid requires iodine substrate after first trimester for thyroxine synthesis endemic cretinism is result of severe iodine deficiency <25 mcg/day Hypothyroidism Ddx Post RAI Rx or thyroidectomy for Graves disease Subacute viral thyroiditis/Suppurative thyroiditis Hypothalamic/pituitary disease ◦ Sheehan’s syndrome ◦ lymphocytic hypophysitis Inadequate replacement ◦ FeSo4, sucralfate interfere with absorption of T4; ◦ carbamazepine, phenytoin and rifampin increase renal clearance of T4 Hypothyroidism Clinical Implications - Untreated ◦ Maternal PTD < 32 wks PTL < 37 wks Abruption Gestational HTN LBW Sab Odds ratio 3.1 (< 34 wks 1.8) 1.8 3.0 3.1 3.1 2.8 Hyperthyroidism and Pregnancy 2/1000 pregnancies Clinical presentation difficult to distinguish from hypermetabolic state of pregnancy ◦ heat intolerance, fatigue, tachycardia ETIOLOGY OF HYPERTHYROIDISM Graves Disease (85% of cases) Toxic adenoma Toxic multinodular goiter Hyperemesis gravidarum Gestational trophoblastic disease THS-producing pituitary tumor Metastatic follicular cell carcinoma Exogenous T4 and T3 De Quervain (subacute) thyroiditis Painless lymphocytic thyroiditis Struma ovarii Postpartum Thyroid Disease Ddx ◦ Postpartum Thyroiditis transient hyperthyroidism transient hypothyroidism permanent hypothyroidism ◦ Graves disease (60% of cases present postpartum) exacerbation of hyperthyroidism ◦ Hypothalamic-pituitary disease Sheehan’s syndrome Lymphocytic hypophysitis Postpartum Thyroiditis New onset autoimmune thyroid disease in up to 10% of all postpartum women Postpartum thyroiditis: ◦ Abnl TSH during postpartum year 1, in absence of TSI or toxic nodule ◦ Strong association with antithyroid antibodies: 76% of pts with positive Ab titers at 2-4 months postpartum had PPT Obstetric Complications of Obesity Prevalence: U.S. women of reproductive age: Overweight: 56.7% Obesity: 30.2% African-American: 48.8% Mexican-American: 38.9% Caucasian: 31.3% Prevalence of obesity in children as young as 2 y.o. and adolescents has increased by > 11% between 1994 and 2000 Obesity WHO and NIH definitions BMI (kg/m2) 18.5-24.9 25-29.9 30-34.9 35-39.9 > 40 normal overweight obese class 1 obese class 2 obese class 3 Obstetric Complications in Obese Pregnant Women Early Pregnancy Late Pregnancy ◦ Neural tube defect ◦ Gestational hypertension/Preeclampsia ◦ Gestational diabetes ◦ Preterm delivery (related to maternal medical and obstetric conditions) ◦ IUFD Obstetric Complications in Obese Pregnant Women Peripartum ◦ C/S, failed VBAC ◦ Operative Morbidities Anesthesia complications Postpartum endometritis Wound breakdown Postpartum thrombophlebitis Fetus/Neonate ◦ Macrosomia ◦ Childhood Obesity Odds Ratio for NTD-Affected Pregnancy Overweight: Obese: Severely obese 1.22 1.70 3.11 Complications Moderate obesity 0R ◦ ◦ ◦ ◦ ◦ 2.18 1.93 1.86 1.58 1.60 PIH Antepartum thromboembolism IOL C/S Wound infection Complications Severe obesity ◦ ◦ ◦ ◦ ◦ ◦ 0R PIH 2.51 Antepartum thromboembolism 4.32 IOL 2.52 C/S 2.31 Anesthesia complication 2.40 Wound infection 4.45 Gestational Hypertension/Preeclampsia ◦ Prospective multicenter study of over 16,000 pts Gestational HTN Preeclampsia Obese RR 2.5 Morbidly obese 3.2 1.6 3.3 Risk of preeclampsia doubles with every 5-7 kg/m2 increase in prepregnancy BMI Gestational Diabetes FASTER Trial Am.J.Ob.Gyn 2004;190:1091 OR ◦ Obese 2.6 ◦ Morbidly obese 4.0 ◦ Screen in first trimester IUFD Danish National Birth Cohort ◦ 54,000 births, 1998-2001 ◦ Compared with normal weight women, fetal death rate among obese women was increased Hazard Ratio ◦ 28-36 wks 2.1 ◦ 37-39 wks 3.5 ◦ 40 wks 4.6 IUFD – Metaanalysis of 9 controlled studies published in 2007 IUFD IUFD ◦ Risk of stillbirth Overweight: OR 1.47 Obese: OR 2.07 Operative Morbidity Cesarean delivery ◦ ◦ ◦ ◦ ◦ ◦ prolonged incision to delivery intervals blood loss > 1000 ml longer operative times wound breakdown and infection Endometritis thromboembolism. Anesthesia management ◦ difficult epidural and spinal placement ◦ intraoperative respiratory events from failed or difficult intubation Macrosomia Amer. J. Ob Gyn 2004; 191: 964 Retrospective study of > 12,000 deliveries ◦ Odds ratio of LGA infant Obesity Diabetes 1.6 4.4 However since relative prevalence of overweight is 47%, and diabetes is 5%, there is a four-fold greater number of LGA infants born of obese women than women with diabetes Macrosomia Population risk of LGA delivery ◦ disproportionate prevalence of obesity The population-attributable risks of LGA caused by ◦ obesity 1.3% ◦ overweight 0.5% ◦ pregestational diabetes 0.4% Macrosomia Of every 100 LGA deliveries: 15 attributable to obesity or overweight 4 attributable to pregestational diabetes Pregravid maternal obesity is a strong independent risk factor for delivering a LGA infant Growing number of obese women responsible for growing number of LGA infants, who in turn become obese adults and perhaps produce similarly large offspring themselves Increasing Birth Weight Macrosomia Maternal weight gain during pregnancy is positively correlated with birth weight Implication: mean increase of 116 gm in term singleton birth weight over the past 30 years more related to maternal obesity than diabetes Childhood Obesity Children born to obese mothers (BMI > 30 in first trimester) ◦ Prevalence of childhood obesity (BMI > 95%ile) at ages 2, 3, and 4 yrs was 15, 20, 24% respectively ◦ Approx 2.5 times prevalence of obesity observed in children of mothers with normal BMI Both maternal pregravid obesity and presence of maternal diabetes may independently affect risk of adolescent obesity in the offspring Complications ◦ Gestational hypertension/Preeclampsia ◦ Gestational diabetes ◦ Increased preterm delivery as associated with maternal medical and obstetric conditions ◦ IUFD ◦ Neural tube defects ◦ Cesarean delivery Complications ◦ ◦ ◦ ◦ ◦ ◦ Fetal macrosomia Macrosomic infants at risk for childhood obesity Anesthesia complications Failed Trial of Labor after C/S Thromboembolism Endomyometritis and wound breakdown Take-Home Points Pregnancy may complicate or exacerbate preexisting medical conditions, to the detriment of mother, baby or both Most common associated conditions are hypertensive disorders, diabetes, thyroid disorders, and obesity Good contraception and preconception planning is particularly important in this setting Take-Home Points Healthy outcome for mother and baby requires planning, thorough evaluation, good longitudinal care with interdisciplinary coordination Caring for these patients integrates the intellectual challenges of internal medicine with the interventional and compelling nature of obstetrics and gynecology practice
