Heart Disease in Pregnancy

• In the developed world: congenital heart disease (CHD) is the most common etiology
• In the developing world: rheumatic heart disease predominates
• Other causes include connective tissue disorders, cardiomyopathies, and ischemic disease

Hemodynamic Changes of Normal Pregnancy

Diagnosis: Normal vs. Pathological Findings

• Dyspnea (very common)
• Orthopnea
• Easy fatigability, dizziness, occasional syncope
• Dependent edema, basal lung rales
• Systolic murmurs (>95% of pregnant women)
• S3 gallop, small pericardial effusion
• Venous hums and mammary flow murmurs

• Severe dyspnea or dyspnea at rest
• Syncope with exertion
• Hemoptysis
• Paroxysmal nocturnal dyspnea
• Exertional chest pain
• Diastolic murmurs
• S4 gallop, cyanosis, clubbing
• Sustained cardiac arrhythmias
• Loud, harsh systolic murmurs

• ECG: non-specific ST/T changes and axis shifts are normal in pregnancy; interpret cautiously
• Echocardiography: safe and useful - chambers appear enlarged, EF and stroke volume are higher than non-pregnant norms
• Chest X-ray and radionuclide imaging: avoid unless essential for maternal safety
• A small pericardial effusion is a normal finding in pregnancy

Preconception Counseling

1. Complete workup: history and exam (including O2 saturation), ECG, echocardiogram, CT/MR angiography where aortic evaluation is needed, and consideration of cardiopulmonary stress testing
2. Medication review: adjust or discontinue teratogenic/contraindicated drugs
3. Functional capacity: exercise capacity >80% of predicted is associated with more favorable outcomes (European guidelines)
4. Fetal echocardiogram at 20-22 weeks if a parent has CHD (risk of CHD in offspring increases from 0.8% to 2-6%)
5. Genetic counseling for heritable conditions (Marfan syndrome, HCM, long-QT syndrome)

• Large intracardiac shunt with significant chamber enlargement, mild pulmonary hypertension, or arrhythmia
• Severe coarctation of the aorta
• Severe mitral or aortic stenosis/regurgitation
• Residual or uncorrected congenital heart disease

Conditions Where Pregnancy is Contraindicated (WHO Class IV)

Risk Stratification Models

Modified WHO Classification

• Class I: No detectable risk (e.g., small VSD, repaired simple lesions)
• Class II: Small increased risk (e.g., repaired TOF, most arrhythmias)
• Class III: Significantly increased risk - requires expert care (e.g., mechanical valve, Fontan, systemic RV)
• Class IV: Extremely high risk - pregnancy contraindicated (listed above)

CARPREG II Score

• 0-1 points: 5% cardiac event rate

• 4 points: 41% cardiac event rate

• Events predominantly: heart failure and arrhythmias

Specific Heart Diseases in Pregnancy

Valvular Heart Disease

• The rise in cardiac output + heart rate shortens diastolic filling time, dramatically raising left atrial pressure
• Risk: pulmonary edema, atrial fibrillation, systemic embolism
• Management: heart rate control (beta-blockers), diuretics for congestion; percutaneous balloon commissurotomy if severe and refractory; anticoagulation if AF develops

• Moderate-to-severe symptomatic AS poorly tolerated (fixed obstruction in the face of increased demands)
• Pregnancy contraindicated if severe and symptomatic; consider balloon valvuloplasty pre-pregnancy

• Bioprosthetic: no anticoagulation issues, but accelerated structural valve deterioration during pregnancy
• Mechanical: require anticoagulation throughout - this is a major management challenge (see below)

Anticoagulation with Mechanical Valves

• Warfarin throughout: lowest maternal thrombosis risk but warfarin embryopathy (6-10 weeks), fetal hemorrhage, miscarriage
• LMWH in 1st trimester, warfarin in 2nd/3rd: reduces embryopathy; anti-Xa monitoring essential
• UFH throughout: no fetal risk but high maternal thrombosis rates with mechanical valves

Congenital Heart Disease

Cardiomyopathies

• LV dysfunction developing in the last month of pregnancy or within 5 months postpartum, without another identifiable cause
• Incidence 1:3000-1:4000 in the US (higher in Africa, Haiti)
• Risk factors: multiparity, advanced maternal age, multiple gestation, preeclampsia, African descent
• Presentation: heart failure symptoms
• Treatment: standard heart failure therapy adapted for pregnancy/lactation; bromocriptine may accelerate LV recovery
• Recovery: ~50% recover LV function; future pregnancy carries high recurrence risk if LV function has not normalized

• Generally tolerated, though volume depletion and tachycardia are poorly tolerated (worsen obstruction)
• Beta-blockers continued throughout pregnancy

Hypertensive Disorders of Pregnancy

• Complicates ~10% of pregnancies
• Gestational hypertension: BP ≥140/90 mmHg after 20 weeks, no proteinuria
• Preeclampsia: hypertension + proteinuria/end-organ damage - systemic syndrome with placental origin; can progress to seizures (eclampsia)
• Severe if BP ≥160/110 mmHg - requires urgent treatment
• First-line antihypertensives: labetalol, nifedipine, alpha-methyldopa
• Preeclampsia/eclampsia history increases future risk of cardiovascular disease

Cardiac Arrhythmias

Ischemic Heart Disease and Spontaneous Coronary Artery Dissection (SCAD)

• Acute MI in pregnancy is rare but increasing (older mothers, more risk factors)
• SCAD is the most common cause of ACS in young pregnant/postpartum women - treat conservatively when possible (PCI preferred over thrombolytics if intervention needed)
• Thrombolytics are relatively contraindicated during pregnancy

Pulmonary Arterial Hypertension

• Maternal mortality 25-50%; pregnancy is contraindicated
• If pregnancy occurs, manage in expert center; advanced PAH therapies; planned early delivery

Infective Endocarditis in Pregnancy

• Rare but associated with high maternal and fetal mortality
• Management follows standard principles; surgery can be performed in 2nd trimester if necessary

Cardiovascular Medications: Safety in Pregnancy

Delivery Planning

• Mode of delivery should be guided primarily by obstetric indications - most women with CVD can deliver vaginally
• Continuous hemodynamic monitoring during labor is recommended for high-risk patients
• Epidural analgesia reduces hemodynamic fluctuations from pain - beneficial in most cardiac conditions (use cautiously with severe AS or obstructive physiology)
• The second stage (Valsalva) is the highest-risk phase - assisted delivery (forceps/vacuum) considered selectively; passive laboring down reduces Valsalva requirement
• Postpartum period: highest risk window due to autotransfusion - close monitoring for at least 24-48 hours; pulmonary edema and decompensation most common here

Cardiopulmonary Resuscitation in Pregnancy

• Follow standard ACLS protocols - life-saving medications must not be withheld
• Critical modification: displace the uterus 15 degrees to the left (left lateral tilt ~1.5 cm) to relieve aortocaval compression and improve venous return
• Perimortem cesarean section (within 4-5 minutes of arrest) may improve maternal resuscitation by relieving caval compression

Multidisciplinary Care

• Cardiologist (with expertise in pregnancy)
• Maternal-fetal medicine specialist
• Obstetric anesthesiologist
• Neonatologist (for high-risk deliveries)
• Cardiac surgery availability when needed

Mediators of Preeclampsia

Stage 1: Defective Trophoblast Invasion and Placental Ischemia

• Abnormal expression of implantation-related adhesion molecules and receptors on trophoblasts
• Failure of trophoblasts to undergo "pseudovasculogenesis" (acquiring endothelial cell surface markers)
• Abnormal HLA-G expression by invasive cytotrophoblasts - HLA-G normally induces immune tolerance at the maternal-fetal interface; its loss may provoke rejection-like immunologic damage
• Complement deposition within decidual vessels (resembling transplant rejection)
• Elevated hypoxia-inducible factor 1α (HIF-1α) - a marker of placental cellular oxygen deprivation

Stage 2: Systemic Mediators Released into the Maternal Circulation

A. Angiogenic Imbalance (Central Pathway)

1. sFlt-1 (Soluble Fms-like Tyrosine Kinase-1) - the key villain

• sFlt-1 is a splice variant of the full-length VEGF receptor FLT-1, lacking the transmembrane and cytoplasmic domains
• It acts as a soluble decoy receptor - circulating freely in plasma and binding VEGF and PlGF with high affinity, preventing them from reaching endothelial cell-surface receptors
• The ischemic placenta massively upregulates sFlt-1 production weeks before clinical preeclampsia manifests
• Elevated sFlt-1 → decreased free VEGF and free PlGF → endothelial dysfunction
• In the kidney: loss of VEGF signaling causes glomerular endotheliosis (swelling of fenestrated endothelial cells, obliterating capillary lumens) - the pathognomonic renal lesion of preeclampsia - leading to proteinuria

2. PlGF (Placental Growth Factor) - depleted

• PlGF is a proangiogenic VEGF family member secreted by the placenta
• Normally promotes endothelial survival, vasodilation, and normal placental angiogenesis
• In preeclampsia: PlGF is decreased both due to reduced placental production and increased scavenging by sFlt-1
• The sFlt-1:PlGF ratio ≥40 is associated with a high risk of developing preeclampsia with severe features within 2 weeks - used clinically for risk prediction

3. VEGF (Vascular Endothelial Growth Factor) - depleted

• Required for endothelial cell homeostasis and survival
• Free VEGF is scavenged by excess sFlt-1
• Loss of VEGF signaling → decreased prostacyclin and NO production → endothelial dysfunction, vasoconstriction, proteinuria

4. Soluble Endoglin (sEng) - the co-conspirator

• sEng is the soluble form of endoglin, a TGF-β co-receptor expressed on syncytiotrophoblasts and endothelial cells
• In preeclampsia, placental sEng is elevated and released into the circulation
• sEng blocks TGF-β1 signaling on endothelial cells - TGF-β1 normally promotes vasodilation via eNOS activation
• Acts synergistically with sFlt-1 to worsen endothelial dysfunction; in animal models, combined sFlt-1 + sEng infusion produces a severe HELLP-like syndrome

B. Prostacyclin-Thromboxane Imbalance

• Prostacyclin (PGI₂) is decreased - less endothelial production
• Thromboxane A2 (TXA₂) is increased - a potent vasoconstrictor and platelet activator, produced by platelets and trophoblasts
• The TXA₂/PGI₂ ratio is shifted toward vasoconstriction and platelet aggregation
• This imbalance also increases sensitivity to angiotensin II (normally pregnant women are relatively resistant to Ang II; preeclamptic women become highly sensitive)
• Aspirin (low-dose) acts by inhibiting TXA₂ production from platelets >> PGI₂ inhibition → restores the balance → this is the basis for aspirin prophylaxis in high-risk women

C. Nitric Oxide (NO) Deficiency

• Endothelial nitric oxide synthase (eNOS) is the major source of vascular NO - a critical vasodilator and inhibitor of platelet aggregation
• In normal pregnancy, NO is a major mediator of the fall in systemic vascular resistance
• In preeclampsia: NO production is reduced due to endothelial injury/dysfunction
• Additionally, NOS becomes uncoupled (producing superoxide instead of NO), contributing to oxidative stress
• Evidence: elevated tissue nitrotyrosine (a product of NO reacting with superoxide) in placenta and vasculature of preeclamptic women
• The loss of NO → impaired vasodilation → hypertension + platelet activation

D. Endothelin-1 (ET-1) - the Final Common Vasoconstrictor Pathway

• ET-1 is a potent endothelium-derived vasoconstrictor
• In preeclampsia: ET-1 levels are markedly elevated in placental tissue and plasma
• Multiple experimental models (placental ischemia, sFlt-1 infusion, TNF-α infusion, AT1-AA infusion) all produce elevated tissue ET-1
• Hypertension in these models can be attenuated by ET receptor antagonism - strongly suggesting ET-1 is a final common pathway linking placental ischemia to elevated BP
• ET-1 also promotes sodium retention in the kidney, contributing to volume expansion

E. Angiotensin II Hypersensitivity and AT1-AA (Autoantibodies)

• Preeclamptic women have markedly increased vascular sensitivity to angiotensin II compared to normal pregnant women
• A key mechanism: AT1-receptor agonistic autoantibodies (AT1-AA) - IgG autoantibodies identified in preeclamptic women that bind and activate the AT1 receptor
• AT1-AA can:
  • Stimulate production of sFlt-1 from trophoblasts and vascular smooth muscle cells
  • Activate NADPH oxidase → reactive oxygen species
  • Promote ET-1 production
  • Stimulate plasminogen activator inhibitor-1 (PAI-1) → impaired fibrinolysis, thrombosis
• Heterodimerization of AT1 receptors with bradykinin B2 receptors has also been proposed as a mechanism of Ang II hypersensitivity
• This autoimmune component links the immunologic tolerance failure with the vasoconstrictor phenotype

F. Oxidative Stress and Reactive Oxygen Species (ROS)

• The ischemic placenta generates excess reactive oxygen species (ROS) through xanthine oxidase, NADPH oxidase, and uncoupled eNOS
• Superoxide quenches NO (forming peroxynitrite/nitrotyrosine) → reduces bioavailable NO
• Oxidative stress activates NF-κB → proinflammatory cytokine production
• Activates lipid peroxidation → oxidized LDL, lipid peroxides detected in preeclampsia
• Excess ROS causes syncytiotrophoblast necrosis/apoptosis → release of trophoblastic fragments (microparticles) into the maternal circulation → endothelial activation

G. Inflammatory Cytokines and Immune Dysregulation

• Placental ischemia and oxidative stress trigger release of TNF-α, IL-6, IL-1β into the maternal circulation
• TNF-α: directly promotes endothelial dysfunction, stimulates sFlt-1 production, activates AT1-AA effects
• Impaired Treg-mediated immune tolerance: normal pregnancy requires regulatory T cells (Tregs) to establish tolerance to paternal antigens; in preeclampsia this tolerance is reduced
• NK cell dysregulation: decidual NK cells normally guide trophoblast invasion; aberrant NK activity contributes to poor spiral artery remodeling
• Dendritic cells and macrophages: abnormal polarization promotes a proinflammatory M1 phenotype in the decidua
• Abnormal HLA-C/KIR interactions between trophoblasts and decidual NK cells are genetically linked to preeclampsia risk
• Complement activation (C3d, C4d deposition in spiral arteries) resembling allograft rejection

H. Coagulation Activation

• Decreased prostacyclin and NO → platelet activation and aggregation
• Release of von Willebrand factor (vWF) from activated endothelium → enhanced platelet adhesion
• Elevated fibronectin (marker of endothelial damage)
• Elevated PAI-1 (promoted by AT1-AA, sFlt-1, and TNF-α) → impaired fibrinolysis
• Microthrombi formation → end-organ ischemia (liver, kidney, brain)
• Severe form: HELLP syndrome (hemolysis, elevated liver enzymes, low platelets)

Integrated Pathophysiologic Model

Genetic predisposition + Paternal factors + Immunologic intolerance
        ↓
Defective trophoblast invasion of spiral arteries
        ↓
Uteroplacental ischemia → hypoxia, oxidative stress, NF-κB activation
        ↓
Placenta releases into maternal circulation:
  • ↑ sFlt-1 (scavenges VEGF, PlGF)           → endothelial dysfunction
  • ↑ sEng (blocks TGF-β1)                    → endothelial dysfunction
  • ↑ TNF-α, IL-6, trophoblast microparticles  → inflammation
  • ↑ AT1-AA (activates AT1 receptor)          → Ang II hypersensitivity
        ↓
Maternal systemic endothelial dysfunction
  • ↓ Prostacyclin, ↓ NO → vasoconstriction, platelet activation
  • ↑ Thromboxane A2, ↑ ET-1 → vasoconstriction
  • ↑ Oxidative stress, ↑ coagulation activation
        ↓
Clinical syndrome:
  Hypertension | Proteinuria (glomerular endotheliosis)
  Thrombocytopenia | Liver dysfunction (HELLP)
  Cerebral edema/seizures (eclampsia) | Pulmonary edema

Clinical Significance of Mediators

Mediators of Preeclampsia - Summary

Stage 1: Failed Spiral Artery Remodeling

• Shallow trophoblast invasion leaves spiral arteries narrow and vasoactive
• Results in uteroplacental ischemia, oxidative stress, and NF-κB activation
• Complement deposition and HLA-G loss reflect the immunologic tolerance failure

Stage 2: Circulating Mediators

The Central Diagram

Clinical Correlates

• sFlt-1:PlGF ratio ≥40 → predicts severe preeclampsia within 2 weeks (used clinically)
• Low-dose aspirin → shifts TXA₂/PGI₂ balance back toward vasodilation (prophylaxis)
• Anti-VEGF cancer drugs (bevacizumab) → mimic preeclampsia, validating the VEGF pathway
• Magnesium sulfate → prevents eclamptic seizures (also attenuates ET-1 effects)

Anemia in Pregnancy

Physiologic (Dilutional) Anemia of Pregnancy

• Blood volume increases by 40-45% by 34 weeks, driven disproportionately by plasma volume expansion (+47%) versus red cell mass expansion (+17%)
• This "hemodilution" lowers Hb, hematocrit, and RBC count - but does not change MCV or MCHC (key distinguishing feature from iron deficiency)
• Physiologic anemia peaks at 28-34 weeks

• Normocytic anemia with Hb >11 g/dL (1st trimester) or >10 g/dL (2nd/3rd) → physiologic anemia, no further workup needed
• Lower values, or microcytic or macrocytic morphology → must investigate

Iron Deficiency Anemia (IDA) - Most Common Pathologic Cause

Iron Demands of Pregnancy

Iron Transfer to the Fetus

• The fetal compartment preferentially extracts iron from the mother via transferrin receptors on placental syncytiotrophoblast
• If maternal iron is low, placental transferrin receptor expression upregulates to maintain fetal supply
• Iron deficiency detectable in ~11% of pregnant women in the third trimester (Harrison's 22e)

Stages of Iron Deficiency

1. Prelatent - depleted marrow stores; ↓ serum ferritin only; Hb normal
2. Latent - ↓ serum iron, ↑ TIBC, ↓ transferrin saturation; Hb still normal
3. Overt IDA - ↓ Hb, eventually ↓ MCV (microcytic hypochromic anemia)

Diagnosis

Note: Ferritin is an acute phase reactant - it may be falsely elevated in chronic inflammatory disease, masking iron deficiency. In such cases, sTfR is more reliable.

Effects on Mother and Fetus

• Preterm delivery
• Low birth weight (LBW)
• Perinatal death
• Impaired maternal immune function and fatigue
• Maternal anemia → neonatal anemia (Cochrane 2024 meta-analysis confirms the association)
• Postpartum hemorrhage risk is magnified

Treatment

• Recommended daily dose: 60 mg of elemental iron during 2nd and 3rd trimesters
• Standard preparations: ferrous sulfate (325 mg tablet = ~65 mg elemental iron), ferrous gluconate, ferrous fumarate
• Take on empty stomach with vitamin C (ascorbic acid) to enhance absorption; avoid with calcium, antacids, tea
• Side effects: nausea, constipation - dose can be split or given on alternate days to improve tolerance
• Iron supplementation reduces incidence of anemia by up to 73%
• The Cochrane review (2024, PMID 39145520) confirms daily oral iron improves maternal hemoglobin and reduces IDA rates

• Indications: failure or intolerance of oral iron, severe anemia in late pregnancy, malabsorption, inflammatory bowel disease
• Options: iron sucrose, ferric carboxymaltose, low molecular weight iron dextran
• More rapid repletion; ferric carboxymaltose allows a single large-dose infusion
• Safe in 2nd and 3rd trimester; avoid in 1st trimester

• Reserved for severe, symptomatic anemia (Hb <7 g/dL) or hemodynamic instability
• Each unit of packed RBCs raises Hb by ~1 g/dL

• 1st trimester and again at 24-28 weeks (Harrison's)
• Measure ferritin alongside Hb to detect pre-anemic iron depletion

Megaloblastic Anemia - Second Most Common Nutritional Anemia

Folate Deficiency

• Non-pregnant: 400 μg/day
• Pregnant: 600 μg/day (a ~50% increase)
• Increase is driven by: enhanced fetal demand, increased erythropoiesis, and hemodilution

• Dietary polyglutamate folates require intestinal conjugase for absorption - activity reduced by anticonvulsants, oral contraceptives, alcohol, sulfa drugs
• Multiple gestation multiplies the demand further
• Hemolytic anemias also increase folate requirements

• Megaloblastic anemia
• Neural tube defects (NTDs) - spina bifida, anencephaly (risk reduced by 50-70% with periconceptional folic acid supplementation)
• Increased risk of placental abruption, preterm delivery

• Prophylaxis: 0.4-0.8 mg (400-800 μg) folic acid daily starting at least 1 month before conception and through the first 12 weeks
• Women with previous NTD-affected pregnancy: 4-5 mg/day (high-dose)
• Treatment of established deficiency: 1-5 mg/day
• In countries with food fortification (e.g., US), 0.8 mg/day is sufficient to prevent deficiency in most women

Vitamin B12 Deficiency

• Less common than folate deficiency in pregnancy but important
• Risk groups: strict vegetarians/vegans, women with pernicious anemia (anti-intrinsic factor antibodies), prior gastric surgery, Crohn's disease
• Presents with macrocytic anemia + neurologic symptoms (subacute combined degeneration - peripheral neuropathy, posterior column signs)
• Important distinction: treating B12 deficiency with folate alone corrects anemia but does not prevent neurological damage - B12 must be replaced
• Diagnosis: serum B12 <118-130 pg/mL (range varies by trimester); positive anti-intrinsic factor antibody in pernicious anemia
• Treatment: parenteral cyanocobalamin or hydroxocobalamin; oral high-dose B12 may be used if parenteral is not available

Laboratory Reference Ranges in Pregnancy (Creasy & Resnik)

Hemolytic Anemias in Pregnancy

Hemoglobinopathies

• Particularly high-risk in pregnancy
• Maternal complications: increased vaso-occlusive crises (pain), acute chest syndrome, stroke, infection, pulmonary hypertension, preeclampsia, peripartum cardiomyopathy
• Fetal complications: growth restriction, preterm birth, fetal death
• Management: multidisciplinary team; prophylactic blood transfusions in severe cases; hydroxyurea is teratogenic - must be discontinued before conception; folic acid supplementation; aggressive pain management (avoid NSAIDs in 3rd trimester); Pneumococcal/meningococcal vaccination
• Hemoglobinopathy screening (MCV, MCH, Hb electrophoresis) is recommended for all pregnant women

• Generally uncomplicated; no increased hemolysis, but slight increased risk of UTI and hematuria

• Alpha-thalassemia trait/beta-thalassemia trait: usually tolerated, microcytic hypochromic picture
• Beta-thalassemia major: severe anemia requiring transfusion
• Hemoglobin H disease (α-thalassemia): moderate hemolytic anemia; may worsen in pregnancy

Hereditary Spherocytosis (HS)

• Autosomal dominant structural defect in RBC membrane
• Can cause hemolytic crises in pregnancy (precipitated by infection, trauma, increased splenic blood flow)
• Diagnosis: EMA flow cytometry (most sensitive/specific) - more reliable than older osmotic fragility test
• Pre-pregnancy splenectomy reduces morbidity; folic acid supplementation essential

Autoimmune Hemolytic Anemia (AIHA)

• Warm-reactive IgG antibodies (Rh system) - associated with lupus, lymphoproliferative disorders, drugs (penicillin, α-methyldopa), viral infections
• Cold-reactive IgM antibodies (anti-I/i) - mycoplasma, infectious mononucleosis
• Diagnosis: positive direct Coombs (direct antiglobulin) test, macrocytic/hyperproliferative smear with spherocytes
• Treatment: corticosteroids, blood transfusion, IV immunoglobulin; rarely splenectomy
• Pregnancy-induced AIHA (rare): resolves spontaneously after delivery

Aplastic Anemia

• Rare; pancytopenia from bone marrow failure
• Management: transfusion support; immunosuppression (cyclosporine); stem cell transplantation deferred if possible; folic acid supplementation
• Pregnancy itself can trigger or worsen aplastic anemia

Approach to Anemia in Pregnancy

Hb < 11 g/dL (1st trimester) or < 10 g/dL (2nd/3rd trimester)
                    ↓
         Check MCV, blood smear, ferritin
                    ↓
    ┌──────────────┬──────────────┬──────────────┐
  Microcytic        Normocytic       Macrocytic
  (↓ MCV)          (normal MCV)     (↑ MCV)
     ↓                  ↓                ↓
Iron deficiency    Dilutional      Folate deficiency
(↓ ferritin,       anemia          Vit B12 deficiency
 ↑ TIBC)          Hemolysis        Hypothyroidism
Thalassemia        (↑ retics,       Drug effect
Sideroblastic      Coombs test,    (anticonvulsants,
 anemia            ↑ LDH, ↓Hb)    methotrexate)
                   Blood loss
                   Anemia of
                   chronic disease

• Hb electrophoresis: all women (screen for hemoglobinopathy)
• Peripheral blood smear: always useful for morphology
• Reticulocyte count: distinguishes hypo- vs. hyperproliferative anemia
• Direct Coombs: if hemolysis suspected

Maternal and Fetal Consequences of Anemia

Anemia in Pregnancy — Summary

Definition (WHO)

• Hb <11 g/dL at any point in pregnancy
• Severe: Hb <7–8 g/dL

1. Physiologic (Dilutional) Anemia

• Plasma volume ↑ 47% vs. RBC mass ↑ only 17% → hemodilution
• Nadir at 28–34 weeks
• MCV and MCHC remain normal (key distinguishing feature from IDA)
• Hb >11 g/dL (1st trimester) or >10 g/dL (2nd/3rd) = physiologic; no treatment needed

2. Iron Deficiency Anemia (IDA) — Most Common

1. Prelatent - ↓ ferritin only; Hb normal
2. Latent - ↓ serum iron, ↑ TIBC, ↓ transferrin saturation; Hb normal
3. Overt IDA - ↓ Hb, eventually ↓ MCV

• Oral iron: 60 mg elemental iron/day (2nd and 3rd trimester) - reduces anemia incidence by up to 73% (Cochrane 2024, PMID 39145520)
• IV iron (iron sucrose, ferric carboxymaltose): for oral failure/intolerance, severe anemia, malabsorption
• Blood transfusion: Hb <7 g/dL or hemodynamic instability

3. Megaloblastic Anemia — Second Most Common

Folate Deficiency

• Requirements increase from 400 → 600 μg/day in pregnancy
• Risk factors: anticonvulsants, alcohol, sulfa drugs, multiple gestation, hemolytic anemia
• Consequences: megaloblastic anemia + neural tube defects (NTDs)
• Prophylaxis: 400–800 μg/day folic acid starting ≥1 month before conception
• High-risk women (prior NTD): 4–5 mg/day

Vitamin B12 Deficiency

• Risk groups: vegans, pernicious anemia, prior gastric surgery, Crohn's disease
• Presents: macrocytic anemia + neurologic symptoms (subacute combined degeneration)
• Treating with folate alone corrects anemia but will not prevent neurologic damage - B12 must be replaced
• Diagnosis: ↓ serum B12, positive anti-intrinsic factor antibody (pernicious anemia)
• Treatment: parenteral cyanocobalamin/hydroxocobalamin

4. Hemolytic Anemias

5. Diagnostic Approach

Hb low → Check MCV + ferritin + smear
     ↓
Microcytic → IDA, thalassemia
Normocytic → Physiologic dilution, hemolysis, blood loss, chronic disease
Macrocytic → Folate/B12 deficiency, hypothyroidism, drug effect

Screening Schedule

• 1st trimester + again at 24–28 weeks (Harrison's 22e)
• Measure ferritin alongside Hb to detect pre-anemic iron depletion

Extragenital (Medical & Surgical) Disorders Complicating Pregnancy

I. CARDIOVASCULAR DISORDERS

• Complicates 1-4% of pregnancies; leading cause of indirect maternal mortality (37% of non-obstetric deaths, UK)
• Plasma volume ↑40-50%, cardiac output ↑30-50%, HR ↑15-20 bpm → exacerbates any underlying disease
• Hypertension: complicates ~10% of pregnancies; first-line drugs: labetalol, nifedipine, methyldopa; ACE inhibitors and ARBs are contraindicated
• Peripartum cardiomyopathy (PPCM): LV dysfunction in last month or within 5 months postpartum; treated with standard HF therapy (adapted for pregnancy/lactation); bromocriptine may accelerate recovery
• Congenital heart disease: most common etiology in the developed world; management depends on lesion type; WHO Class IV conditions (PAH, EF <30%, severe AS, Fontan complications) contraindicate pregnancy
• Valvular disease: mitral stenosis most dangerous; regurgitant lesions generally better tolerated

II. DIABETES MELLITUS

Types in Pregnancy

• Type 1 DM (T1DM) - pre-existing
• Type 2 DM (T2DM) - pre-existing (increasingly common with obesity epidemic)
• Gestational Diabetes Mellitus (GDM) - glucose intolerance first recognized in pregnancy

Physiologic Basis

• Human placental lactogen (hPL), progesterone, cortisol, and prolactin are counter-regulatory hormones that cause progressive insulin resistance (peaks 3rd trimester: 50-60% reduction in insulin sensitivity)
• Normal beta cells compensate with increased insulin secretion
• GDM occurs when beta cell reserve is insufficient to overcome insulin resistance (shifted down on the DI curve)
• Insulin requirements increase from 0.7-0.8 units/kg (1st trimester) → 0.9-1.2 units/kg (3rd trimester) in T1DM

Screening and Diagnosis (GDM - 8% of pregnancies)

1. 50-g glucose challenge test (GCT) → glucose at 60 min; threshold: >7.2 mmol/L (130 mg/dL)
2. If positive → 100-g oral GTT (fasting + 1h, 2h, 3h); 2 elevated values = GDM

Maternal Complications of Pregestational Diabetes

• Hypertension (OR 14.2), preeclampsia (OR 3.4)
• Cesarean delivery (OR 11.3), preterm birth (OR 4.4)
• Retinopathy worsening (especially with duration >10 years, poor pre-pregnancy HbA1c; rapid normalization can transiently worsen retinopathy)
• Nephropathy progression
• Hypoglycemia unawareness
• Ketoacidosis (especially T1DM)
• Maternal mortality 60/100,000 pregnancies (vs 7-12/100,000 general population)

Fetal Complications

• Macrosomia (large for gestational age) → shoulder dystocia, birth trauma
• Congenital malformations (cardiac, neural tube, skeletal - risk proportional to 1st trimester HbA1c)
• Intrauterine growth restriction (with vasculopathy)
• Polyhydramnios
• Neonatal hypoglycemia (fetal hyperinsulinism)
• Neonatal respiratory distress syndrome
• Stillbirth (3-4x increased risk with poor control)
• Offspring at lifelong increased risk of obesity, T2DM

Management

• Target HbA1c <6% before conception to minimize congenital malformation risk
• Ophthalmologic, renal, cardiac evaluation
• Stop teratogenic drugs (ACE-I, statins, metformin - safety debated)
• Insulin is the preferred drug in pregnancy - best safety profile, lowest treatment failure

• HbA1c is unreliable in pregnancy (accelerated RBC turnover gives falsely low values) - use daily glucose monitoring and continuous glucose monitoring (CGM) instead
• Insulin dose: basal-bolus regimen or insulin pump (CSII); CSII significantly reduces retinopathy progression
• GDM: start with dietary/nutritional therapy; if targets not met → insulin (first-line) or metformin (acceptable per some guidelines)

• Fetal surveillance: growth ultrasounds, biophysical profile, Doppler
• Induction of labor: 37-39 weeks (early term)
• Cesarean: reserved for estimated fetal weight ≥4500 g (macrosomia) or obstetric indications

III. THYROID DISORDERS

Physiologic Changes in Pregnancy

• hCG (structurally similar to TSH) stimulates thyroid → transient ↑ free T4, ↓ TSH in 1st trimester (especially weeks 8-14)
• Thyroxine-binding globulin (TBG) increases (↑ estrogen) → total T4/T3 increased, but free levels change less
• Iodine requirement increases; renal iodine clearance increases

Hypothyroidism in Pregnancy

• Prevalence: 2-3% (overt); 2-5% (subclinical)
• Most common cause: Hashimoto's thyroiditis (autoimmune)
• Risks of untreated hypothyroidism: miscarriage, preterm birth, preeclampsia, placental abruption, LBW, impaired fetal neurodevelopment (fetus depends on maternal T4 in 1st trimester)
• TSH target in pregnancy: 0.1-2.5 mIU/L (1st trimester); 0.2-3.0 mIU/L (2nd/3rd trimester)
• Treatment: levothyroxine - dose usually increases by 25-50% in pregnancy; check TSH every 4 weeks in 1st half, then every 4-6 weeks thereafter
• Screen: TSH at booking in high-risk women (history of thyroid disease, family history, symptoms, goiter, type 1 DM, prior radiation)

Hyperthyroidism in Pregnancy

• Prevalence: ~0.1-0.4%; most common cause: Graves' disease
• Distinguish from physiologic hCG-mediated TSH suppression (gestational transient thyrotoxicosis)
• Risks: miscarriage, preterm birth, FGR, stillbirth, neonatal hyperthyroidism (from maternal TSH receptor antibodies crossing placenta), thyroid storm (life-threatening)
• Treatment:
  • Propylthiouracil (PTU): preferred in 1st trimester (crosses placenta less; methimazole associated with aplasia cutis/choanal atresia in 1st trimester)
  • Methimazole/carbimazole: preferred in 2nd and 3rd trimesters (PTU associated with hepatotoxicity)
  • Target: maintain maternal free T4 at upper normal range (minimizes fetal hypothyroidism)
  • Radioiodine: absolutely contraindicated in pregnancy
  • Beta-blockers (propranolol): short-term for symptomatic control
  • Thyroidectomy: 2nd trimester if drug failure

Postpartum Thyroiditis

• Autoimmune; occurs in 5-10% of women postpartum
• Triphasic: thyrotoxicosis (1-4 months) → hypothyroidism (4-8 months) → resolution (most cases)
• May be permanent hypothyroidism in 25%

IV. RENAL AND URINARY DISORDERS

Physiologic Changes

• GFR increases by 50% by end of 1st trimester (due to ↑ cardiac output, ↑ renal plasma flow)
• Serum creatinine normally falls to 0.4-0.8 mg/dL (normal non-pregnant levels of 0.9-1.0 mg/dL may indicate significant renal impairment in pregnancy)
• Glucosuria can occur with normal glucose (tubular reabsorption cannot keep up with filtered load)
• Physiologic hydronephrosis (right > left) from uterine compression

Urinary Tract Infections (UTI)

• Most common bacterial complication of pregnancy
• Asymptomatic bacteriuria (ASB): 2-7% of pregnant women; higher risk of progression to pyelonephritis (20-30% if untreated vs <1% in non-pregnant)
• Universal screening for ASB by urine culture at first prenatal visit is recommended
• Treatment of ASB: 7-14 days nitrofurantoin, cephalexin, or amoxicillin (avoid nitrofurantoin at term - neonatal hemolysis; avoid trimethoprim in 1st trimester - folate antagonist; avoid fluoroquinolones)
• Pyelonephritis: most common cause of non-obstetric hospitalization in pregnancy; IV ceftriaxone or ampicillin + gentamicin; risk of preterm labor, septic shock, ARDS

Chronic Kidney Disease (CKD) in Pregnancy

• Outcomes depend on degree of renal impairment and hypertension
• Creatinine <125 μmol/L: pregnancy generally tolerated
• Creatinine >180 μmol/L: significant risk of accelerated renal decline, preeclampsia (50%), FGR, preterm birth
• Proteinuria worsens in pregnancy (increased GFR + altered tubular function)
• Monitor BP closely; target <140/90 mmHg
• ACE inhibitors/ARBs must be stopped - switch to labetalol, methyldopa, nifedipine
• Dialysis patients: conception is rare; if pregnant, increase dialysis to >36 hours/week

Nephrolithiasis

• Occurs in 1:200-1:1500 pregnancies; most common in 2nd/3rd trimester
• Increased urinary calcium excretion (↑ intestinal absorption, ↑ GFR)
• Presents: renal/ureteric colic, hematuria
• 70-80% pass spontaneously
• Diagnosis: renal ultrasound first; MRI if needed (avoid CT radiation if possible)
• Management: IV fluids, analgesia (opioids safe; NSAIDs avoid after 20 weeks); urological intervention if obstruction/sepsis

V. RESPIRATORY DISORDERS

Asthma

• Most common obstructive lung disease in pregnancy (~8%)
• Rule of thirds: 1/3 improve, 1/3 unchanged, 1/3 worsen during pregnancy
• Risks of uncontrolled asthma: preeclampsia, preterm birth, FGR, low birth weight, neonatal mortality
• Risks of asthma medications in pregnancy are less than the risk of uncontrolled asthma to mother and fetus
• Treatment:
  • Inhaled beta-2 agonists (salbutamol/albuterol): safe; continue
  • Inhaled corticosteroids (budesonide preferred): safe; continue
  • Oral corticosteroids: use if needed; associated with cleft palate (1st trimester) and preeclampsia at high doses but benefits outweigh risks in severe exacerbations
  • Leukotriene receptor antagonists (montelukast): acceptable to continue if already on it
  • Systemic steroids for acute severe exacerbation: do not withhold
  • Avoid aspirin and NSAIDs in aspirin-sensitive asthmatic patients
• Monitor with peak flow/spirometry; avoid known triggers

Pneumonia

• Most common cause: Streptococcus pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae
• Influenza (H1N1) disproportionately severe in pregnancy (higher mortality, especially with underlying asthma, diabetes, hypertension, renal disease); vaccinate all pregnant women
• Varicella pneumonia: rare but severe (mortality 40% if untreated); treat with IV acyclovir
• Management: hospitalize readily; empirical beta-lactam + macrolide; adjust for gestation

Pulmonary Embolism (PE) and DVT

• Pregnancy is a hypercoagulable state: ↑ factors II, VII, VIII, IX, X, XII, fibrinogen, vWF; ↓ protein S, antithrombin III; venous stasis; endothelial injury
• DVT/PE complicates ~1 in 500 pregnancies; highest risk postpartum
• Diagnosis: compression ultrasound for DVT; V/Q scan or CTPA for PE (both acceptable in pregnancy)
• Treatment: LMWH throughout pregnancy (does not cross placenta; preferred over UFH); warfarin contraindicated (teratogenic in 1st trimester; fetal hemorrhage); NOACs contraindicated
• Inherited thrombophilias (Factor V Leiden, prothrombin gene mutation) and antiphospholipid syndrome increase risk significantly

VI. GASTROINTESTINAL AND LIVER DISORDERS

Nausea and Vomiting / Hyperemesis Gravidarum

• Nausea in 70-80% of pregnancies; vomiting in 50%
• Hyperemesis gravidarum (HG): persistent vomiting with weight loss >5%, dehydration, ketonuria; requires hospitalization
• Pathogenesis: hCG stimulates CTZ; elevated in multiple pregnancy, molar pregnancy, Down syndrome
• Management: IV fluid replacement, antiemetics (ondansetron, metoclopramide, prochlorperazine), thiamine (B1) supplementation (prevent Wernicke encephalopathy), pyridoxine (B6) + doxylamine (first-line combination), nasogastric/parenteral nutrition if severe

Gastroesophageal Reflux Disease (GERD)

• Very common (40-80%); due to ↑ progesterone → lower esophageal sphincter relaxation + mechanical upward displacement of stomach
• Management: antacids, H2 blockers (safe), PPIs (safe if needed); lifestyle modification

Appendicitis

• Most common non-obstetric surgical emergency in pregnancy (1:500-1:1500)
• The appendix migrates upward and laterally as the uterus enlarges - pain is NOT in the classic RIF in later pregnancy (may be RUQ or right flank)
• Diagnosis is more difficult - nausea/vomiting are physiologic; white cell count rises normally in pregnancy; imaging: ultrasound first, then MRI (preferred over CT to avoid radiation)
• Perforation risk is higher if diagnosis delayed (perforation → peritonitis → preterm labor, fetal loss)
• Treatment: prompt appendectomy regardless of gestational age; laparoscopic approach safe in 1st/2nd trimester; avoid delays

Acute Cholecystitis and Cholelithiasis

• Pregnancy increases cholesterol secretion and gallbladder stasis → increased gallstone formation
• Second most common non-obstetric surgical emergency in pregnancy
• Management: initial conservative (IV fluids, antibiotics, analgesia); cholecystectomy in 2nd trimester if conservative management fails or for recurrence; ERCP safe for choledocholithiasis

Inflammatory Bowel Disease (IBD)

• Crohn's disease and ulcerative colitis: flares in pregnancy affect outcomes (preterm birth, FGR)
• Active disease at conception has worse outcomes than quiescent disease
• Medications:
  • 5-aminosalicylates (mesalazine): safe
  • Corticosteroids: safe for acute flares
  • Azathioprine/6-mercaptopurine: generally continued (risks of flare > teratogenicity)
  • Anti-TNF agents (infliximab, adalimumab): generally safe through 2nd trimester; discontinue in 3rd trimester to avoid neonatal immunosuppression (but case-by-case)
  • Methotrexate: contraindicated - folate antagonist, teratogenic
  • Thalidomide: absolutely contraindicated

Liver Diseases Specific to Pregnancy

VII. NEUROLOGICAL DISORDERS

Epilepsy and Seizure Disorders

• Affects ~0.5% of pregnancies
• Pregnancy effects on epilepsy: altered antiepileptic drug (AED) pharmacokinetics (increased volume of distribution, altered protein binding, increased renal clearance) → drug levels may fall → breakthrough seizures
• Uncontrolled seizures are more dangerous to mother and fetus than most AEDs

• Folic acid 5 mg/day (high dose) for all women with epilepsy on AEDs from pre-conception
• Monitor AED levels through pregnancy; adjust doses accordingly
• Vitamin K 10 mg/day to mother from 36 weeks (AEDs induce enzyme degradation of clotting factors)
• Neonatal: IV vitamin K at birth

Migraine

• Usually improves in pregnancy (especially those with menstrual migraine - due to stable estrogen)
• Acute treatment: paracetamol (acetaminophen) (safe); codeine (short-term); aspirin/NSAIDs (avoid 3rd trimester); triptans (limited data - use with caution if needed)
• Avoid ergotamine (causes uterine vasoconstriction - contraindicated)
• Prophylaxis: beta-blockers (propranolol); amitriptyline; avoid valproate, topiramate (teratogenic)

Stroke in Pregnancy

• Risk is increased: hypercoagulable state, venous stasis, cerebral vein thrombosis
• Ischemic stroke: IV tPA can be given in pregnancy if clinically indicated (though data limited); thrombus may be considered
• Cerebral vein thrombosis: anticoagulate with LMWH
• Subarachnoid hemorrhage (SAH): aneurysmal rupture risk increases; treat definitively (coiling preferred to clipping in pregnancy)

VIII. AUTOIMMUNE AND RHEUMATOLOGIC DISORDERS

Systemic Lupus Erythematosus (SLE)

• Predominantly affects women of childbearing age
• Pregnancy can trigger lupus flares (immunologic and hormonal changes)
• Clinically significant kidney disease in ~30% of women with SLE
• Poor pregnancy outcomes: miscarriage, preterm birth, FGR, stillbirth, neonatal lupus (anti-Ro/La antibodies)
• Antiphospholipid syndrome (APS): thrombosis, recurrent pregnancy loss; treat with LMWH + low-dose aspirin in pregnancy
• Predictors of poor pregnancy outcomes: active nephritis, hypertension, antiphospholipid antibodies, thrombocytopenia, anti-Ro/SS-A antibodies (neonatal complete heart block risk)
• Safe drugs in pregnancy: hydroxychloroquine (continue - protective against flares), azathioprine, low-dose prednisolone, LMWH, low-dose aspirin
• Avoid: cyclophosphamide (teratogenic), mycophenolate (teratogenic), methotrexate

Rheumatoid Arthritis (RA)

• Often improves dramatically during pregnancy (due to immune tolerance mechanisms)
• Postpartum flares are common (within 3 months)
• Safe drugs: hydroxychloroquine, sulfasalazine, low-dose prednisolone; some anti-TNF agents (stop in 3rd trimester)
• Avoid: methotrexate, leflunomide (teratogenic)

IX. HEMATOLOGIC DISORDERS

Thrombocytopenia in Pregnancy

• Occurs in 5-10% of pregnancies
• Gestational thrombocytopenia (most common, benign): mild, no treatment, resolves postpartum; platelets typically >80-100 × 10⁹/L
• ITP (Immune thrombocytopenic purpura): IgG antiplatelet antibodies cross placenta → neonatal thrombocytopenia; treat mother with steroids/IVIG if platelets <30 × 10⁹/L or bleeding; splenectomy (2nd trimester if refractory)
• Preeclampsia/HELLP: platelet consumption; delivery is treatment
• TTP (Thrombotic thrombocytopenic purpura): ADAMTS13 deficiency; microangiopathic hemolysis; plasma exchange is treatment
• Platelets <100 × 10⁹/L → unlikely to be gestational thrombocytopenia; investigate further

VTE and Thrombophilias (see Pulmonary section above)

Sickle Cell Disease and Thalassemia (see Anemia section)

X. INFECTIOUS DISEASES COMPLICATING PREGNANCY

TORCH Infections

Other Key Infections

• Listeria monocytogenes: foodborne (deli meats, soft cheese); flu-like illness → bacteremia, stillbirth, neonatal meningitis; treat with ampicillin + gentamicin
• Group B Streptococcus (GBS): universal screening at 35-37 weeks; intrapartum IV penicillin prophylaxis if positive
• HIV: antiretroviral therapy (ART) throughout pregnancy; target undetectable viral load; HAART reduces MTCT to <1%; elective cesarean if VL >400 copies/mL; avoid breastfeeding (in resource-rich settings)
• Syphilis: universal screening at booking; benzathine penicillin G (crosses placenta); prevents congenital syphilis
• Malaria: P. falciparum causes severe disease in pregnancy (cerebral malaria, hypoglycemia, severe anemia, placental infection → FGR, preterm birth); chloroquine (safe); artemisinin-based combinations (2nd/3rd trimester); avoid primaquine (hemolysis)
• COVID-19: pregnant women at higher risk of ICU admission, preterm birth; vaccinate; monitor closely

XI. SURGICAL CONDITIONS IN PREGNANCY

General Principles for Surgery in Pregnancy

• 2nd trimester is the optimal time for elective/semi-elective surgery
• 1st trimester: organogenesis risk; avoid if possible
• 3rd trimester: technically difficult; high risk of preterm labor
• General anesthesia is generally safe; maintain left lateral tilt to avoid aortocaval compression
• Fetal monitoring before and after surgery; tocolysis may be needed for preterm contractions
• Continue thromboprophylaxis (LMWH) perioperatively

Appendicitis in Pregnancy

• Most common non-obstetric surgical emergency
• Appendix displaced superolaterally as pregnancy progresses - pain in right flank/RUQ, not RIF
• Delay in diagnosis and perforation rate is higher (10-43%)
• Perforated appendicitis → peritonitis → preterm labor, fetal mortality ~20%
• Prompt surgical intervention is mandatory - risk of delay far exceeds operative risk
• Laparoscopy is safe in 1st and 2nd trimesters; open approach preferred in 3rd trimester
• Antibiotics: metronidazole + cephalosporin

Cholecystitis and Biliary Disease

• Conservative management initially; cholecystectomy in 2nd trimester if needed
• Symptomatic cholelithiasis recurs in 40-70% without definitive treatment

Ovarian Torsion

• Most common gynaecologic emergency in pregnancy
• Ovarian cysts (especially corpus luteum, dermoid, stimulated ovaries from IVF) predispose
• Presents: acute severe unilateral pelvic pain, N/V
• Diagnosis: Doppler ultrasound (absent/reduced blood flow)
• Treatment: laparoscopic detorsion (even if appears necrotic - the ovary often recovers)

Trauma in Pregnancy

• Leading cause of non-obstetric maternal death
• Physical examination unreliable (displaced organs); maintain high suspicion
• Kleihauer-Betke test for feto-maternal hemorrhage in Rh-negative mothers → anti-D immunoglobulin
• Fetal monitoring 4-6 hours after significant trauma (risk of placental abruption)
• DPL, FAST, and CT can be performed when clinically indicated
• Left lateral tilt for all unconscious or supine patients

Summary Table: Key Drug Safety Principles