Von Willebrand Disease, Hemophilia, and Other Inherited Bleeding Disorders in Pregnancy

Abstract

Inherited bleeding disorders, which comprise von Willebrand disease (VWD), hemophilia, other congenital clotting factor deficiencies, inherited platelet disorders, defects of fibrinolysis, and connective tissue disorders, have both maternal and fetal implications. Although mild platelet defects may actually be more prevalent, the most common diagnosed bleeding disorder among women is VWD. Other bleeding disorders, including hemophilia carriership, are much less common, but hemophilia carriers are unique in that they are at risk of giving birth to a severely affected male neonate. General guidance for maternal management of inherited bleeding disorders includes obtaining clotting factor levels in the third trimester, planning for delivery at a center with hemostasis expertise if factor levels do not meet the minimum threshold (eg, less than 0.50 international units/1 mL [50%] for von Willebrand factor, factor VIII, or factor IX), and using hemostatic agents such as factor concentrates, desmopressin, or tranexamic acid. General guidance for fetal management includes prepregnancy counseling, the option of preimplantation genetic testing for hemophilia, and consideration of delivery of potentially affected male neonates with hemophilia by cesarean delivery to reduce the risk of neonatal intracranial hemorrhage. In addition, delivery of possibly affected neonates should occur in a facility where there is newborn intensive care and pediatric hemostasis expertise. For patients with other inherited bleeding disorders, unless a severely affected neonate is anticipated, mode of delivery should be dictated by obstetric indications. Nonetheless, invasive procedures such as fetal scalp clip or operative vaginal delivery should be avoided, if possible, in any fetus potentially affected with a bleeding disorder.

Reproductive Carrier Screening Results With Maternal Health Implications During Pregnancy

“…Three of the genes ( ABCB11 , COL4A3 , and COL4A4 ) have been reported in association with both autosomal recessive and autosomal dominant inheritance (Table 2). 14–60…”

“…Pregnancy manifestations reported in the literature for carriers of these genes include cholestasis of pregnancy ( ABCB11 ); gestational hypertensive disorders ( COL4A3 , COL4A4 , COL4A5 , and GLA ); maternal cardiomyopathy ( DMD ); acute fatty liver of pregnancy or hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome ( CPT1A , and HADHA ); maternal virilization ( CYP19A1 ), hyperammonemic crisis ( OTC ); and maternal hemorrhage ( F9 and F11 ) (Tables 1 and 2). 14–60 Tables 1 and 2 summarize the genes, their potential manifestations in pregnancy, and published guidance for follow-up testing or management in pregnancy that could be considered. The reported incidence of pregnancy complications in carriers ranged from 10% to 62% depending on the gene involved, but information was limited for most of the conditions.…”

“…The reported incidence of pregnancy complications in carriers ranged from 10% to 62% depending on the gene involved, but information was limited for most of the conditions. 14–60 Recommendations for management of carriers were identified for 11 of the 12 genes (Tables 1 and 2).…”

“…Twelve genes in the 274-gene panel were considered to have potential implications for maternal carrier [20][21][22][23] Cardiology referral 20 Baseline EKG and echocardiogram (cardiac MRI) [25][26][27] Postpartum hemorrhage in 11-80% 28,29 Refer to detailed guideline documents [30][31][32][33][34] GLA, Fabry disease Proteinuria and possibly hypertension or preeclampsia 35,36 Uncertain in pregnancy; report of 37.2% proteinuria and 10.8% hypertensive disorders in pregnancy [35][36][37] Most females have some manifestations; can benefit from enzyme replacement 35,38 Referral to a specialist physician and genetic counselor for further evaluation and management recommendation 37 OTC, ornithine transcarbamylase deficiency Hyperammonemic crisis, particularly in peripartum or postpartum periods; can be life-threatening 39,40 Hyperammonemia in affected male neonates Variable At least 15% and probably more will have some manifestations in their lifetime Fasting, physical or emotional stress, and systemic corticosteroids can prompt a crisis [39][40][41] Management by a metabolic physician or biochemical geneticist and specialist metabolic dietitian 39 Adjustment of diet; monitor ammonia levels; dextrose infusion peripartum and more depending on the specific clinical situation 39,40,42 Autosomal conditions ABCB11, progressive familial intrahepatic cholestasis type 2…”

“…Hypertensive disorders of pregnancy, renal disease, nephrotic syndrome 14 Uncertain in pregnancy Estimated 15% lifetime risk of renal failure by age 53 y for COL4A3 and COL4A4 17,48 Nephrologist involvement in pregnancy care 17 See specific guideline documents 18 and on renal disease in pregnancy 19 F11, hemophilia C Hemorrhage, including postpartum 49 Neuraxial anesthesia [30][31][32][33] Variable, 30,49 but in pregnancy approximately 20% chance of postpartum hemorrhage if Factor XI deficiency 49 Refer to detailed guideline documents [30][31][32][33][34] EKG, electrocardiogram; MRI, magnetic resonance imaging; AD/AR, autosomal dominant/autosomal recessive.…”