and women with other congenital bleeding disorders Dr.

Paul Giangrande BSc MD FRCP FRCPath FRCPCH Oxford Haemophilia & Thrombosis Centre, Oxford Radcliffe Hospitals and Nuffield Department of Clinical Medicine University of Oxford paul.giangrande@ndm.ox.ac.uk

Pregnancy in carriers of haemophilia

Books of interest:

Life expectancy and haemophilia:

Darby SC et al. Blood 110: 815-825 (2007)

Carriers of haemophilia:

Level of factor VIII (or IX) in a female carrier is typically half the normal level (50%) This is certainly enough to prevent bleeding after surgery etc. However, a few women may have lower level (in range of 20-50%): they might need treatment before operations and dental extractions, etc Severity of haemophilia remains constant in a family

General management issues:

Those with low levels may need treatment prior to surgery or other invasive procedures Factor level is not an accurate guide to carrier status Be conscious of psychological issues e.g.:
readiness of a young girl to deal with information about carrier status feelings of guilt in mothers of affected boys

Many carriers have normal factor levels

Tests are complex and can take weeks or months to do Pregnancy is not the best time to start discussions and testing Ensure males with haemophilia have genetic abnormality identified Information from national database may be available When should girls be tested? Male partners of carriers should not be overlooked when offering counselling
facilitates cascade testing in wider family

Testing for carrier status:

Would you test a 10-year old child whose parents wanted to know the genetic status for haemophilia?
Geneticists
(n=46)

YES 13

NO 33 74

Haematologists
(n=233)

159

UKHCDO register:

Now located in Manchester Royal Infirmary Registered under Data Protection Act Approximately 6000 live patients with haemophilia A or B registered Useful and unique research resource Available for enquiries about family Information about genetic defect may also be available

Tedgrd U et al: Br. J. Haematol. 106: 421-426 (1999)

Reproductive choice of haemophilia carriers:

Carriers who have experienced the complications of haemophilia or its treatment appear to be more in favour of prenatal diagnosis than women whose haemophilic children have received modern treatment without complications.

method of choice for antenatal diagnosis of haemophilia

Chorionic villus sampling (CVS):

Transabdominal approach Transvaginal approach

Chorion villus sampling:

Performed between 11-14 weeks of pregnancy Risk of fetal malformation if done too early Approach dictated by location of placenta: transvaginal or transabdominal May be need for haemostatic support if baseline factor VIII (or IX level) low Risk of miscarriage 1-2% Potential for Rhesus immunization: cover with anti-D in Rh D negative women

Changes in factor VIII and IX levels during pregnancy:

Chi C et al. Haemophilia 14: 56-64 (2008)

factor VIII factor IX

CVS applied to a twin pregnancy:

(CVS 1 is male, CVS 2 is female)

Finning KM & Chitty LS. Seminars in Fetal & Neonatal Medicine 13: 69-75 (2008)

Early determination of fetal sex:

Free fetal DNA present in maternal blood can be used to determine fetal sex in early pregnancy Technique involves identification of genes in Y chromosome (e.g. DYS14, SRY) Allows gender determination at 7-9 weeks 10-20 ml blood sample: result in 5 days. Cost UK 212 260 (www.ibgrl.blood.co.uk) Sensitivity and specificity approaching 100% Eliminates unnecessary CVS for female fetuses

Prenatal diagnosis by analysis of fetal cells in maternal circulation:

Cheung M-C et al. Nature Genetics 14: 264-268 (1996)

Prenatal diagnosis by analysis of fetal cells in maternal circulation:

Cheung M-C et al. Nature Genetics 14: 264-268 (1996)

Non-invasive method Fetal normoblasts present in maternal blood Fetal origin determined with anti-fetal ( or ) haemoglobin antibodies Isolated using anti-transferrin antibodies Fetal sex can be determined at 7 weeks Single gene defects (eg sickle cell disease) can be detected by PCR before 12 weeks

Uptake of prenatal diagnosis among carriers of haemophilia:

Chi C et al. Haemophilia 14: 56-64 (2008)

Retrospective study from London of 90 pregnancies 1995-2005 CVS in 17/65 (27%)

13 for haemophilia

rVIII or rIX given to cover 10/17 biopsies No complications after CVS CVS testing identified:
4 females 5 unaffected males 8 affected males

Termination in 5/8 21 affected males born

Fetal blood sampling:

Fetal blood sampling:

Fetal blood sampling:

Technically more difficult Only feasible at 18 weeks or beyond Ultrasound guidance Puncture umbilical vessels Exclude contamination with maternal blood at time of factor assay (MCV, Kleihauer) 1-2% risk of miscarriage

Fetal haematological values at 19-21 weeks gestation

Forestier et al Pediatric Research 20:342-6 (1986)

Factor VIII 40 iu/dl Factor IX 10 iu/dl VWFAg 60 iu/dl MCV 130 fl Fibrinogen 1 g/l Platelet count 240 x 109/l

Future prospects:

Sperm sorting: separation of X and Y bearing spermatozoa Pre-implantation diagnosis Sperm washing: for HIV positive patients Gene therapy

Ljung R. Acta Paediatrica 83: 609-611 (1994)

Swedish experience:

Retrospective survey of pregnancies involving 117 children with haemophilia born 1970-1990 45 born to women with known family history 72 babies: either new cases, or history of haemophilia discovered only after birth 104 vaginal deliveries and 13 Caesarean sections: 2 merely because of carrier status No concentrates needed (but 4 transfused)

Neonatal haemorrhagic complications:

Ljung R. Acta Paediatrica 83: 609-611 (1994)

Cephalhaematoma:12 Intracranial haemorrhage: 4 Umbilical bleeding: 4 Retro-orbital haematoma: 1 Haematuria: 1 Abnormal bleeding after procedures (venepuncture, surgery, injection): 28 NO PERINATAL DEATHS

Some bleeds are avoidable.:

Good liaison with obstetricians:

UKHCDO Guidelines Haemophilia 12: 301-336 (2006)

Management of delivery in pregnant carriers:

written delivery plan drawn up in advance delivery should be in unit with suitable expertise and facilities including stock of concentrates

Check factor level of mother at 34 weeks Determine fetal gender:

ultrasound blood test (fetal DNA in maternal circulation)

Fetal sex should be known to obstetrician at delivery

UKHCDO Guidelines Haemophilia 12: 301-336 (2006)

Management of delivery in pregnant carriers:

Epidural anaesthesia permitted if FVIII > 50 iu/dl Avoid fetal scalp electrodes Normal vaginal delivery should be routine option, but Delivery should be by least traumatic method and early recourse to Caesarean section should be considered Avoid vacuum (Ventouse) extraction

Fetal scalp electrode:

Ventouse (vacuum) extraction:

UKHCDO Guidelines Haemophilia 12: 301-336 (2006)

Management of delivery in pregnant carriers: (continued)

Check cord factor level after birth Withhold intramuscular vitamin K until result known Give recombinant factor VIII to baby if forceps applied (but not routinely otherwise) Be aware of risk of delayed post-partum haemorrhage in carriers: DDAVP may be useful Consider U/S or CT scan of brain after difficult delivery

Neonatal intracranial haemorrhage:

Affects 3.5-4% haemophilic boys in neonatal period even in countries with good standard of health care Much higher incidence than in normal population:
Towner D et al. New Eng J Med. 341: 1709-1714 (1999)

More frequent than previously thought

Ljung R. Brit. J. Haematology 140: 378-384 (2007)

1/1900 after normal vaginal delivery 1/2750 after Caesarean section anaemia, pallor lethargy, apnoea seizures, paresis

Clinical signs often vague:

Should we routinely give factor concentrate to all haemophilic neonates?

is it too late by then? difficulty with venepuncture is risk of inhibitors increased with early treatment?

Should clinical practice change?

Should we err on side of caution and perform Caesarean section more frequently?
Chi C et al. Haemophilia 14: 56-64 (2008)

Caesarean section rate high at 22/47 (47%) in recent series from Royal Free Hospital, up from 17% earlier

Should we perform imaging routinely?

ultrasound will not identify all bleeds sedation required for CT scan dose of ionizing radiation with CT scan is quite high

Risk and radiological examinations:

Picano E. BMJ 329: 849-851 (2004)

MASAC Advisory #311 (February 1998)

MASAC guidelines:

The majority of infants of hemophilia carriers can be safely delivered vaginally. Vacuum devices and instrumentation such as fetal scalp electrodes should not be used because of the risk of bleeding. A national registryshould be established for haemophilia and other bleeding disorders. All infants with unexplained subgaleal or intracranial haemorrhages should have an appropriate work-up for a bleeding disorder.

Haemostatic support during pregnancy and delivery:

Rarely required in carriers of haemophilia A in later stages of pregnancy Carriers of haemophilia B more likely to need replacement therapy If concentrate needed, use recombinant products only during pregnancy DDAVP may be used in pregnancy

DDAVP in pregnancy:

V2 agonist: little pressor or oxytocic effect Manufacturers still advise to use with caution in pregnancy No problem after delivery, with cord clamped Peptide does not pass into breast milk Growing experience of safe use in pregnancy:
Mannucci PM Blood 105: 3382 (2005)

32 cases, mainly to cover CVS or fetal blood sampling (11-18 weeks gestation) 54 cases: used throughout pregnancy
Snchez-Luceros A et al. Thrombosis Research 120: 387-390 (2007)

Dose used in both series was standard 0.3 g/kg

DDAVP in pregnancy: what dose?

Osmolality falls by 10 mosmol Threshold for AVP release gradually falls Increased intravascular volume Clearance of DDAVP unchanged Response to DDAVP may be greater in pregnant women My preference is to use lower dose of 0.1 or 0.2 g/kg and avoid repeated doses

Davison JM et al. Am. J. Physiology 264: F348-53 (1993) Lindheimer MD et al. Eur. J. Endocrinology 132: 133-43 (1995)

Von Willebrands disease (VWD):

Common but mild bleeding disorder Autosomal dominant inheritance (gene on chromosome 12p): females also affected Typical features include:
Easy bruising Prolonged bleeding from cuts and scratches Epistaxis Menorrhagia

Joint bleeding not a typical feature

von Willebrand factor is essential for platelet adhesion to collagen:

platelet
endothelial cells collagen

Inheritance of VWD:

A baby with von Willebrand disease:

Thromb. & Haemostasis 52: 176-182 (1984)

450 400 350 300 250 200 150 100 50 0 13 18 23 28 33 38 Post Basal Weeks gestation Factor level iu/dl

Haemostasis in pregnancy:

FVIII:C VWF Ag

Changes during pregnancy in VWD:

VWF levels start to rise by sixth week of gestation in VWD types 1 and 2 Level often well within normal range at term in type 1 VWD Progressive thrombocytopenia may develop in type 2B VWD VWF level does not rise in type 3 VWD

Ramsahoye RH et al. Haemophilia 1: 140-144 (1995)

Obstetric management in VWD:

24 pregnancies in 13 women with VWD (13 type 1, 11 type 2) 4 required Caesarean section Risk of bleeding higher than in haemophilia carriers: 3/19 vaginal deliveries (16%) 6/24 experienced postpartum haemorrhage (25%) 9 required cryoprecipitate or concentrate 1 received DDAVP after delivery

NHLBI Guidelines (USA). Haemophilia 14: 171-232 (2008) www. www.nhlbi.nih.gov/guidelines/vwd

Pregnancy in women with VWD:

Check factor levels at 34-36 weeks Vaginal delivery generally regarded as safe if VWF activity is 50 iu/dl Similar threshold for Caesarean section and epidural anaesthetic DDAVP may be used (beware fluid overload) Avoid aspirin-like analgesics Cord blood screening of baby is unlikely to yield reliable results in type 1 VWD Increased risk of post-partum haemorrhage (20%)

UKHCDO Guidelines. Haemophilia 10: 593-628 (2004)

Rare congenital bleeding disorders:

Afibrinogenaemia: regular treatment during pregnancy aiming for trough of 1 g/l Factor XI deficiency:
Level does not rise in pregnancy Plasma or concentrate to cover delivery only in women with severe deficiency (<15 iu/dl)

Monthly infusions of concentrate for factor XIII deficiency aiming for trough of 3%

Prenatal diagnosis of haemophilia readily available Levels of factor VIII and VWF rise in pregnancy Normal delivery should be routine option
haemostatic support rarely needed to cover delivery but with recourse to early Caesarean section if necessary to avoid instrumental delivery but only requested by minority of women

Conclusions:

Risk of intracranial haemorrhage greater than previously thought DDAVP may be used in pregnancy Significant risk of post-partum haemorrhage in women with VWD