PB 78 Hemoglobinopathies in Pregnancy

TLDR

• Screen African descent pts with CBC + Hb electrophoresis; Southeast Asian/Mediterranean with CBC first, then electrophoresis if MCV <80 fL after excluding iron deficiency - solubility tests (Sickledex) alone are INADEQUATE

• SCD in pregnancy: 4 mg/day folate, hydroxyurea is contraindicated, prophylactic transfusion NOT standard of care (only 1 RCT - reduced crisis/anemia but no difference in pregnancy outcome)

• Prenatal diagnosis via CVS (10-12w) or amniocentesis (>15w) using DNA analysis - not electrophoresis alone

Sickle Cell Trait (Hb AS)

Heterozygous Hb S; asymptomatic, no hemolytic anemia. 1 in 12 African Americans affected. Hb electrophoresis: predominant Hb A with smaller Hb S fraction. Clinically benign in the carrier, but reproductive pairing risk is the central concern.

• Offer partner testing; if both AS, genetic counseling + prenatal diagnosis options (CVS vs amnio)

• Complications & f/u: No maternal complications, usual counseling.

Sickle Cell Anemia (Hb SS)

Autosomal recessive; Glu->Val substitution at beta-globin position 6 (thymine for adenine). Functional asplenia by adolescence (autosplenectomy). 1 in 300 African-American newborns has SCD; 1 in 600 has Hb SS specifically. Diagnosis by electrophoresis: nearly all Hb S, small amounts Hb A2 and Hb F.

Maternal risks vs Hb AA: PTL, PPROM, antepartum hospitalization, postpartum infection. Fetal risks: IUGR, LBW, preterm delivery. Most common cause of recurrent morbidity: painful vasoocclusive crisis.

• 4 mg/day folic acid (standard prenatal 1 mg inadequate given RBC turnover)

• Painful crisis: rapid pain assessment, opioids (PO/IV/IM/SQ), O2 if SpO2 <95%, assess for ACS (fever + tachypnea + chest pain + hypoxia), infection, dehydration, severe anemia, cholecystitis - multidisciplinary (OB + hematology + anesthesia)

• Transfusion (clinically indicated, NOT prophylactic): target Hb S <40% and total Hb ~10 g/dL; monitor Hb levels + % Hb S serially

• Hydroxyurea: CONTRAINDICATED in pregnancy (teratogenic) - effective in nonpregnant pts

• Delivery: cesarean for obstetric indications only; epidural OK if hypotension/hypoxemia avoided

• Fetal surveillance: serial U/S + antepartum testing reasonable given IUGR/stillbirth risk; NST/BPP may be transiently abnormal during crisis but revert with resolution

• Complications & f/u: ACS is most significant threat (pulmonary infiltrate + fever -> hypoxemia + acidosis, vasoocclusive NOT infectious etiology); alloimmunization + iron overload + viral transmission risk with transfusion

Hb SC Disease

Compound heterozygote: Hb S + Hb C (Lys replaces Glu at beta-6, adenine for guanine substitution). Vasoocclusive phenomena and hemolytic anemia similar to but less severe than Hb SS in pregnancy.

• Same management principles as Hb SS but lower overall risk magnitude

• Complications & f/u: Vasoocclusive crises, ACS - same spectrum as SS, attenuated

Hb S/beta-Thalassemia

Compound heterozygote; severity determined by beta-thal mutation type. Hb S/beta0-thal: no Hb A produced - clinically equivalent to Hb SS. Hb S/beta+-thal: some Hb A produced - less severe phenotype. Both carry vasoocclusive and hemolytic risk.

• Manage per SCD protocol; severity stratification guides intensity of monitoring

• Complications & f/u: Parallel to Hb SS (beta0) or intermediate phenotype (beta+)

Alpha-Thalassemia Trait (2-gene deletion)

MCV <80 fL, mild asymptomatic microcytic anemia. Two configurations: cis (--/αα, Southeast Asian - HIGH RISK for affected offspring) vs trans (α-/α-, African descent - LOW RISK for Hb Bart's). Neither Hb electrophoresis nor solubility testing identifies alpha-thal trait - requires DNA/molecular testing.

• If MCV low, iron deficiency excluded, electrophoresis normal (no elevated Hb A2 or Hb F): send alpha-globin gene deletion analysis (DNA-based)

• Partner testing if carrier confirmed; Southeast Asian cis genotype warrants urgent partner testing given Hb Bart's risk

• Complications & f/u: No significant maternal/fetal complications with 2-gene deletion; obstetric course essentially normal

Hb H Disease (3-gene alpha deletion, α-/-- )

Mild to moderate chronic hemolytic anemia. Pregnancy outcomes generally favorable but case series small - firm conclusions limited (Level III evidence only). More common in Southeast Asian descent.

• Serial Hb monitoring; transfusion if symptomatic severe anemia

• Complications & f/u: Chronic hemolytic anemia; limited data on pregnancy-specific outcomes

Hb Bart's / Alpha-Thalassemia Major (4-gene deletion, --/--)

Complete absence of alpha-globin. Results in hydrops fetalis, intrauterine death, and preeclampsia. Seen almost exclusively with homozygous cis deletions (Southeast Asian genotype - NOT African genotype).

• Prenatal diagnosis via CVS or amnio with DNA analysis if both parents are cis carriers

• Genetic counseling re: termination vs continuation; hydrops fetalis uniformly fatal without intrauterine intervention

• Complications & f/u: Maternal mirror syndrome / severe preeclampsia; referral to MFM mandatory

Beta-Thalassemia Minor (heterozygous beta-thal)

MCV low, MCH low, Hb A2 >3.5% (up to 7%), Hb F elevated. Mild asymptomatic microcytic anemia. Common in Mediterranean, Asian, Middle Eastern, Hispanic, West Indian descent. Study of 261 pts: higher rate of IUGR and oligohydramnios vs nonthalassemic, but no difference in low Apgar scores, congenital malformations, or perinatal mortality (Level II-2).

• Iron supplementation only if documented deficiency - do not supplement empirically

• Complications & f/u: IUGR, oligohydramnios risk; serial growth U/S reasonable

Beta-Thalassemia Major (Cooley's anemia, homozygous beta-thal)

Severe anemia, extramedullary erythropoiesis, delayed sexual development, death by age 10 without transfusion. With hypertransfusion + deferoxamine (since late 1970s), fertility restored. Hb F elevated (partially compensates). Pregnancy indicated ONLY in pts with: (1) normal cardiac function, (2) prolonged hypertransfusion maintaining Hb >=10 g/dL, (3) prior iron chelation.

• Maintain Hb >=10 g/dL with transfusions throughout pregnancy

• Deferoxamine: DISCONTINUE in pregnancy (safety not established)

• Serial growth U/S; fetal surveillance if growth suboptimal

• Delivery: individualized; cesarean for obstetric indications only

• Complications & f/u: Cardiac failure (hemosiderin deposition), hypothalamic dysfunction, infertility; iron overload worsened if deferoxamine held during pregnancy

Practice Questions

1. A 26-year-old G2P1 woman at 10 weeks with Hb SS presents for prenatal care. Her CBC shows Hb 8.1 g/dL. She is taking a standard prenatal vitamin with 1 mg folic acid daily and reports no pain episodes so far. Which of the following is the most appropriate adjustment to her supplementation regimen?

A. Continue current regimen; 1 mg folate is sufficient in pregnancy

B. Add iron supplementation 325 mg TID

C. Increase folic acid to 4 mg/day

D. Add vitamin B12 1000 mcg/day

E. Initiate hydroxyurea to reduce RBC turnover

ANSWER C - SCD patients have continuous RBC turnover requiring 4 mg/day folic acid; standard prenatal 1 mg is insufficient. Hydroxyurea (E) is teratogenic and contraindicated in pregnancy. Iron (B) is not indicated without documented deficiency.

2. A 32-year-old G1P0 woman of Southeast Asian descent presents at 9 weeks. Her CBC shows MCV 71 fL. Serum ferritin is 42 ng/mL. Hb electrophoresis is normal with Hb A2 2.1% and no elevated Hb F. Which of the following is the most appropriate next step?

A. Diagnose beta-thalassemia minor and counsel patient

B. Start iron supplementation and repeat CBC in 4 weeks

C. Send DNA-based alpha-globin gene deletion analysis

D. Perform isoelectric focusing for confirmatory hemoglobin identification

E. Reassure patient that no further workup is necessary

ANSWER C - Low MCV with normal iron stores, normal electrophoresis (no elevated Hb A2 or Hb F), Southeast Asian descent = alpha-thalassemia until proven otherwise. Electrophoresis cannot detect alpha-thal trait; only molecular/DNA testing identifies alpha-globin gene deletions. Southeast Asian patients carry high risk of cis deletions, making partner testing critical.

3. A 28-year-old woman with Hb SS is admitted at 32 weeks with severe diffuse bone pain, fever to 38.9°C, tachypnea, and SpO2 88% on room air. Chest X-ray shows a new right lower lobe infiltrate. Which of the following best describes the underlying mechanism of her pulmonary complication?

A. Community-acquired bacterial pneumonia secondary to functional asplenia

B. Pulmonary embolism from DVT during vasoocclusive stasis

C. Vasoocclusion from sickling or marrow fat embolism - not infectious in origin

D. Transfusion-related acute lung injury from prior alloimmunization

E. Amniotic fluid embolism

ANSWER C - This is ACS: new pulmonary infiltrate + fever + hypoxia. The mechanism is vasoocclusion from sickling within pulmonary vasculature or fat/marrow embolism from long bones affected by sickling - NOT infectious pneumonia. ACS is the most significant threat to life in SCD.

4. A couple presents for preconception counseling. The woman is of Mediterranean descent with beta-thalassemia minor (Hb A2 5.2%). Her partner's CBC shows MCV 68 fL, normal iron studies, normal Hb electrophoresis. He is of Southeast Asian descent. Which of the following is the most accurate statement regarding their reproductive risk?

A. Partner has iron deficiency anemia; no hemoglobinopathy risk to offspring

B. Partner likely has beta-thalassemia minor; 25% risk of beta-thalassemia major offspring

C. Partner likely has alpha-thalassemia; DNA-based testing is needed to determine specific genotype and fetal risk

D. Normal electrophoresis excludes all heritable hemoglobinopathies in partner

E. Only maternal carrier status affects offspring outcome; paternal alpha-thal trait is benign

ANSWER C - Normal Hb electrophoresis does NOT exclude alpha-thalassemia. Southeast Asian descent + low MCV + normal iron + normal electrophoresis = likely alpha-thal trait requiring DNA testing. If he carries a cis (--/αα) genotype and she has beta-thal minor, offspring could potentially inherit compound heterozygous disease; accurate genotyping is required for precise risk counseling.

5. A 30-year-old G1P0 with Hb SS is at 34 weeks. Her Hb is 6.8 g/dL and Hb S fraction is 78% on routine monitoring. She is asymptomatic with no crisis, normal fetal surveillance. Her MFM recommends transfusion. Which of the following correctly describes the transfusion goal?

A. Raise Hb to 12 g/dL regardless of Hb S fraction

B. Lower Hb S to <40% and raise total Hb to ~10 g/dL

C. Simple transfusion to achieve Hb >11 g/dL; Hb S fraction is not a target

D. Exchange transfusion to achieve Hb S <20% for maximal sickling prevention

E. Transfuse only if Hb falls below 6 g/dL or pt becomes symptomatic

ANSWER B - The transfusion target in clinically indicated SCD is: Hb S <40% AND total Hb ~10 g/dL. This minimizes sickling risk while avoiding hyperviscosity from overshooting Hb. Prophylactic exchange transfusion is not standard of care; the only RCT showed reduced crisis/severe anemia but no improvement in pregnancy outcome.