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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
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