*Anuranjani L, **Shah A, ***Chauhan AR..
(*Fourth Year Resident, ** Second Year Resident, *** Professor, Department of Obstetrics and Gynecology, Seth G.S. Medical College and K.E.M. Hospital, Mumbai, India.)
Hemophilia type A is an inherited bleeding condition which disrupts the hemostasis of pregnancy and has diverse clinical presentation, from hematoma to postpartum hemorrhage. Even though females are carriers of the disease, the severity of complications is inversely related to the level of Factor VIII. We report the management of pregnancy in a known case of hemophilia A carrier who had an uncomplicated pregnancy and vaginal delivery at term utilizing recombinant factor VIII concentrate. The focus of this case report is management of an obstetric case with bleeding disorder.
The hemostatic alterations during antenatal and postnatal phase result in a delicate state of hemostasis which if superimposed with coagulopathies can have cataclysmic outcome. Hemophilia A or classic hemophilia is an X- linked genetic disorder caused by deﬁciency of clotting Factor VIII (F VIII). Females are typically carriers due to X-linked inheritance and hence female neonates born to them have 50% chance of being carriers of the disease while male neonates have 50% chance of being affected. A 2014 survey by World Federation of Hemophilia states that India has 14,450 cases of Hemophilia A (among population of 1,236,344,631).
The normal level of F VIII required for hemostasis is > 50 IU/dL. It is estimated that 1 per 1,00,000 women are symptomatic hemophilia A carriers (F VIII < 30 IU/dL) while severe hemophilia A (F VIII < 1 IU/dL) is an extremely rare event. The information regarding the management and outcomes of hemophilia A in pregnancy is limited due to the rarity of the disease. Coagulopathies have an emotional and economic burden, and if inappropriately managed can have disastrous outcomes. We report our experience of a carrier where individualized obstetrical management along with multidisciplinary approach resulted in successful outcome of pregnancy.
A 24 year old primigravida, known case of hemophilia A presented at 9 weeks’ gestation to us.. She gave history of development of left labial hematoma due to fall one and half years ago for which she underwent surgical evacuation. Repetitive formation of hematoma at the same site during a span of 26 days was managed by re-evacuation, cauterization and re-suturing along with transfusion of 3 units of blood and 1 of fresh frozen plasma. This prompted further investigation after which she was diagnosed as a carrier of hemophilia A and was given Factor VIII. However no family member could be indexed. She was not on any treatment since then.
In the present pregnancy, at 9 weeks of gestation, when patient presented to us, she was explained fetal prognosis and advised prenatal detection for hemophilia A but she refused the same and was lost to follow up. She presented for ANC registration at 31 weeks by dates; growth corresponded with her ultrasonography scan. Her physical examination showed no evidence of ecchymosis, petechiae, purpura or vaginal bleeding. Hematology reference was done and no active management was advised. She attended regular ANC clinics and had an uneventful antenatal period.
She was admitted at 38 weeks of gestation for safe confinement. On admission patient had stable vital parameters and no pallor. On abdominal examination uterus was full term, relaxed, with cephalic presentation and regular fetal heart sounds. Local examination revealed a 3 x 2 cm left labial non-tender scar tissue with no discharge or redness in the region of the previous hematoma. On vaginal examination os was closed, firm, posterior in position and uneffaced.
All routine investigations were done along with ultrasonography, Doppler and biweekly non- stress test which were within normal limits. Coagulation profile was done where prothrombin time (PT) was 13.4, activated partial thromboplastin time (aPTT) was 30.1, von Willebrand factor was 117 % (normal: 50- 150 %) and factor VIII level was 26% (normal: 50 – 150 % normal pooled plasma) which was below the required values of 50% or 80% for vaginal and cesarean delivery respectively. Screening for Factor VIII inhibitors was negative.
Hematology reference for hemophilia A was done and plan of management charted out for vaginal delivery and cesarean section along with anesthesiologist and neonatologist. Based on prior events, availability of Factor VIII and this being a high risk pregnancy, planned induction of labor was undertaken at 39 weeks of gestation. 1000 IU of Factor VIII was given intravenously just prior to induction and dinoprostone gel was instilled after taking a valid, well informed consent. Due to an unfavorable Bishop’s score dinoprostone gel was re-instilled after 6 hours. Hematologist opinion was re-sought and Factor VIII 1000 IU was repeated during the end of 1st stage of labor. Additional Factor VIII and blood was kept in reserve during the intrapartum and postpartum period anticipating blood loss based on her prior history.
Approximately 14 hours after second instillation of dinoprostone gel, patient delivered a 2.91 kg female child with Apgar of 9/10. Episiotomy was given; 3rd stage was managed actively and there was no postpartum hemorrhage. There was no episiotomy extension or other perineal tears. Following delivery, 500 IU of Factor VIII was given intravenously twice daily for 3 days along with routine antibiotics. Patient complained of moderately increased bleeding on postpartum day 4. There was no evidence of PPH and patient was given 1000 IU of Factor VIII after which no similar complaints were noted. Patient and baby were discharged on post-delivery day 7 with a healthy episiotomy wound. Patient was advised to use LNG IUS at 6 weeks postpartum. The baby was not investigated at birth for Factor VIII levels; however follow up with the pediatrician and hematologist was advised especially as the neonate was a female child.
Hemophilia A disrupts the finely tuned hemostasis of pregnancy and can result in devastating consequences for both mother and neonate. The paucity of cases has made management of a pregnant woman with hemophilia challenging. There is progressive increase in the level of coagulation factors like Factor VIII during pregnancy, but these levels do not increase before second trimester and hence patients are at risk of hemorrhage. Levels of Factor VIII reach a peak during 29 to 35 weeks, normal level being > 50 IU/dL; hence the factor level should be tested at week 28 and again at 34 – 36 weeks. Females are carriers of the disease and can become symptomatic in cases when: (a) female is homozygous hemophilia carrier and male is affected hemophilic (b) hemizygous X chromosome in Turner syndrome or (c) lyonization of Factor VIII alleles.
Complications in pregnancy include first trimester bleeding, spontaneous miscarriage, antepartum hemorrhage, perineal hematomas and both primary and secondary postpartum hemorrhage and disseminated intravascular coagulopathy.
Successful management of hemophilia in pregnancy requires that the delivery be performed by the least traumatic method. Even though the mode of delivery is debatable, normal vaginal delivery is recommended. There is consensus that vacuum extraction should not be done; use of forceps, scalp electrodes and fetal blood sampling should also be avoided. Cesarean section (CS) is not indicated for mild to moderate cases; however some authors recommend CS in carriers with severe hemophilia with a potentially hemophiliac boy fetus. CS increases the risk of bleeding and need for transfusion and does not eliminate the risk of cranial hemorrhage. Active management of the third stage should be done to prevent postpartum hemorrhage. Mode of delivery should thus be determined on obstetrical grounds.
Among the 41 cases of hemophilia A carriers studied by Chi and Kadir, mean pregnancy and third-trimester FVIII levels in carriers was 46 IU/dL and 121 IU/dL respectively. Studies show that the incidence of primary and secondary PPH is 22% and 11% respectively in hemophilia carriers as compared with 5- 8% and 0.8% respectively in the general population.  The risk of PPH increases if FVIII level is < 50 IU/dL and this risk persists up to 3 - 5 weeks postpartum.
Chances of PPH can be reduced with the use of replacement therapy, altering mode of delivery, minimal trauma to the perineal region and measures to avoid uterine atony. The risk of PPH depends upon factor levels, thus hemostatic replacement is essential. Prophylactic therapy is given to raise FVIII levels to > 50IU/dL for vaginal delivery and ≥ 70 IU/dL for CS. Tranexamic acid and desmopressin can be used in carriers with borderline levels. Low molecular weight heparin is not recommended for thromboprophylaxis. Epidural analgesia can be given if factor levels are > 50 IU/dL. The factor levels should be monitored in the postpartum period for 3 - 4 days after normal delivery and for 7 days following cesarean section. Tranexamic acid, oral contraceptive pills or even Levonorgestrel IUS can be used for late postpartum bleeding.
Neonatal management includes careful observation for signs of bleeding, injection vitamin K and testing of cord blood; however prophylactic factor replacement should not be done due to risk of inhibitor development. Being carriers, female infants appear to be at low risk of bleeding during the neonatal period. Incidence of neonatal cranial hemorrhage is found to be maximum (64%) following vacuum delivery as compared to 3% with vaginal delivery and 15% with CS.
Another facet in management is prenatal diagnosis of haemophilia. The armamentarium includes techniques like chorionic villus sampling (11-14weeks), ultrasound examination, amniocentesis (> 15 weeks) or by non-invasive technique to detect free fetal DNA (ffDNA) in the maternal circulation (from the 5th week of gestation), or real- time duplex PCR identiﬁcation of Y-chromosome speciﬁc sequences, between 8 – 12 weeks of gestation.[9, 3] Cordocentesis (> 18 weeks) for factor VIII assay is an alternative in India where linkage analysis is not possible or molecular markers for linkage are uninformative or inversion mutation is absent or in sporadic hemophilia families.
As per the UK HCDO (Hemophilia Center Doctors’ Organization) guidelines, vaccination against Hepatitis B is recommended but should be administered subcutaneously to prevent hematoma formation at the injection site. Studies have shown that desmopressin which increases plasma levels of Factor VIII and vWF, can be given IV, subcutaneously or intranasally even in first and second trimester for treating mild and moderate cases. It has negligible or no oxytoxic effect, does not pass into breast milk in signiﬁcant amounts, and can be safely used in pregnancy, delivery and postpartum.
Women with a family history of a bleeding disorder, menorrhagia, postoperative bleeding, bleeding post dental extraction, PPH or prolonged aPTT should be screened for hemophilia prenatally or antenatally. Prompt pre-conceptional counselling and genetic testing should be advised; there are various centres and federations in India for hemophilia which act as support groups. Most pregnancies in hemophilia A carriers will be uneventful and without bleeding complications, provided there is prudence and preparedness to tackle the risks at various stages of pregnancy. Replacement therapy with Factor VIII remains the mainstay of treatment. Successful management of these cases requires collaboration with hematologist, anaesthesiologist, neonatologist and geneticist.
- Sharma V, Khalid A, Cohen AJ. Management of Pregnancy in a Patient with Severe Hemophilia Type A. Am J Perinatol Rep 2013;3(1):29–32.
- Kadir RA, Economides DL, Braithwaite J, Goldman E, Lee CA. The obstetric experience of carriers of hemophilia. Br J Obstet Gynaecol 1997;104(7):803–810.
- Kadir RA, Davies J, Winikoff R, Pollard D, Peyvandi F, Garagiola I et al. Pregnancy complications and obstetric care in women with inherited bleeding disorders. Hemophilia 2013;19(4):1–10.
- Chi C, Kadir RA. Management of women with inherited bleeding disorders in pregnancy. The Obstetrician and Gynaecologist 2007;9(1):27–33.
- Chi C, Lee CA, Shiltagh N, Khan A, Pollard D, Kadir RA. Pregnancy in carriers of hemophilia. Hemophilia 2008;14(1):56–64.
- Huq FY, Kadir RA. Management of pregnancy, labour and delivery in women with inherited bleeding disorders. Hemophilia 2011;17(1):20–30.
- Dunkley SM, Russell SJ, Rowell JA, Barnes CD, Baker RI, Sarson M et al. A consensus statement on the management of pregnancy and delivery in women who are carriers of or have bleeding disorders. Med J Aust 2009;191(8):460-463.
- Ljung R, Lindgren AC, Petrini P, Tengborn L. Normal vaginal delivery is to be recommended for hemophilia carrier gravidae. Acta Paediatr 1994;83(6):609–611.
- Zadeh NM, Namin SA. Evaluation of an improved noninvasive fetal sex determination in hemophilia A patients. J Clin Diagn Res. 2015;9(7): GC01-4.
- Panigrahi I, Ahmed RP, Kannan M, Kabra M, Deka D, Saxena R. Cord blood analysis for prenatal diagnosis of thalassemia major and hemophilia A. Indian Pediatr. 2005;42(6): 577-81.
- Keeling D, Tait C, Makris M. Guideline on the selection and use of therapeutic products to treat hemophilia and other hereditary bleeding disorders. A United Kingdom Hemophilia Center Doctors’ Organisation (UKHCDO) guideline approved by the British Committee for Standards in Haematology. Hemophilia. 2008;14(4):671–84.
- Mannucci PM. Use of desmopressin (DDAVP) during early pregnancy in factor VIII-deﬁcient women. Blood 2005;105(8):3382.
Anuranjani L, Shah A, Chauhan AR. Obstetric Care In A Case Of Hemophilia A. JPGO 2016. Volume 3 No. 7. Available from: http://www.jpgo.org/2016/07/obstetric-care-in-case-of-hemophilia-a.html