Bernard Soulier syndrome in pregnancy: a ... - Wiley Online Library

Haemophilia (2010), 16, 584–591

DOI: 10.1111/j.1365-2516.2009.02137.x

REVIEW ARTICLE

Bernard Soulier syndrome in pregnancy: a systematic review P. PEITSIDIS,* T. DATTA,* I. PAFILIS,* O. OTOMEWO, E. G. D. TUDDENHAMà and R. A. KADIR*à *Royal Free Hospital, Obstetrics and Gynaecology; Brighton and Sussex Medical School; and àRoyal Free Hospital, Haemophilia Centre and Thrombosis Unit, London, UK

Summary. Bernard Soulier syndrome (BSS) is a rare disorder of platelets, inherited mainly as an autosomal recessive trait. It is characterised by qualitative and quantitative defects of the platelet membrane glycoprotein (GP) Ib-IX-V complex. The main clinical characteristics are thrombocytopenia, prolonged bleeding time and the presence of giant platelets. Data on the clinical course and outcome of pregnancy in women with Bernard Soulier syndrome is scattered in individual case reports. In this paper, we performed a systematic review of literature and identified 16 relevant articles; all case reports that included 30 pregnancies among 18 women. Primary postpartum haemorrhage was reported in 10 (33%) and secondary in 12 (40%)

Introduction Bernard Soulier syndrome (BSS) is a rare disorder of platelets. It was first described in 1948 by Bernard and Soulier [1] in a young patient with severe haemorrhagic symptoms, prolonged bleeding time, and thrombocytopenia with presence of extremely large platelets. The syndrome is transmitted in an autosomal recessive manner and often occurs in individuals whose parents are close relatives. It is characterized by the absence of ristocetin-induced platelet aggregation caused by quantitative or qualitative defects within the membrane glycoprotein (GP) Ib-IX-V complex, a primary adhesion receptor of platelets [2,3]. The GP Ib-IX-V complex has two important roles in platelet function that explain the often severe Correspondence: Rezan A. Kadir, Royal Free Hospital, Obstetrics and Gynaecology, London, UK. Tel.: +44 207 794 0500; extn 35317; fax: +44 207 472 6759; e-mail: [email protected] Accepted after revision 27 September 2009

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of pregnancies, requiring blood transfusion in 15 pregnancies. Two women had an emergency obstetric hysterectomy. Alloimmune thrombocytopenia was reported in 6 neonates, with one intrauterine death and one neonatal death. Bernard Soulier syndrome in pregnancy is associated with a high risk of serious bleeding for the mother and the neonate. A multidisciplinary team approach and individualised management plan for such women are required to minimise these risks. An international registry is recommended to obtain further knowledge in managing women with this rare disorder. Keywords: Bernard Soulier syndrome, pregnancy, labour and delivery, postpartum haemorrhage

bleeding symptoms that occur with its defect. It mediates platelet adhesion to the blood vessel walls at sites of injury by binding von Willebrand factor and enhances the capacity of thrombin at low concentrations to activate the platelets [4]. The GP Ib-IX-V complex is composed of four distinct transmembrane polypeptide subunits GP Iba, GP Ibb, GP IX and GP V, with a stoichiometry based on monoclonal antibody binding of 2:2:2:1 respectively [5]. More than 30 mutations in the GP Ib-IX-V complex have been identified as causes of BSS [6]. Bernard–Soulier syndrome (BSS) occurs extremely rarely in the populations of Europe, North America and Japan, which have been studied most intensively; a prevalence of less than 1/1 000 000 has been estimated from the cases reported in the international literature. Clinical manifestations commonly include frequent episodes of epistaxis, gingival and cutaneous bleedings and trauma-related bleedings. The severity of bleeding can vary depending on the underlying mutation. In women, menorrhagia is a very common and severe bleeding symptom and can be challenging to manage [7].

Ó 2010 Blackwell Publishing Ltd

BERNARD SOULIER IN PREGNANCY

In this systematic review, we analyse the existing literature on the clinical course and management of BSS during pregnancy.

Materials and methods Search strategy and inclusion criteria We performed an electronic search on PUBMED, EMBASE, COCHRANE, Google Scholar databases using the following keyword combination: ‘Bernard Soulier’ AND ‘Pregnancy OR Gestation’ without language and time restrictions. Two reviewers (P.P. and T.D.) independently performed the search and examined the identified relevant articles for further evaluation. Clinical studies were considered eligible only if they were related to pregnant women with BSS. Studies related to the clinical course of BSS in non-pregnant women were excluded. Articles reporting the clinical course of BSS in women prior to or after their pregnancies were also excluded. The bibliographic references of all retrieved studies were hand-searched and assessed for additional reports and clinical studies. Any disagreement between the authors was resolved after common consensus of all authors. Study selection We identified 57 potentially relevant articles. After assessment of the abstracts, 24 articles were excluded on grounds of duplication. The remaining 33 articles were examined in full-text. Seventeen articles were excluded on grounds of irrelevance to pregnancy and the remaining 16 articles [8–23] were included in this systematic review. All the studies were cases reports, 13 from PUBMED, one from EMBASE and two from SCOPUS electronic database. Case studies dated from 1984 to 2008. Articles were written in English, French and Polish. Data extraction After study selection, the following data were extracted and placed in a table: Author and year of publication; age at diagnosis; the ethnic group and the country of origin; gravidity and parity; data regarding previous history of bleeding episodes; the causative genetic mutation if available; platelet count; data on bleeding or other complications reported antenatally in each pregnancy; data on prophylactic treatment prior to delivery; mode of delivery; blood loss at delivery and maternal and neonatal outcome.


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Results The main clinical characteristics and outcome of the pregnancies are outlined in Table 1. A total of 30 pregnancies (including one twin pregnancy) among 18 women were identified from all the articles. Diagnosis of BSS in the reported cases was based upon laboratory findings: prolonged bleeding time (>20 min), platelet count and morphology (existence of large platelets >3.5 mm), lack of platelet aggregation in presence of ristocetin. Mean age of the women during pregnancy was 26 years (median 27, range 19–38). Age at diagnosis was reported in nine women (mean and median 19 years, range 12–24). All women had bleeding symptoms prior to pregnancy except for two [11,17]. Menorrhagia [8,13,15,18–22] and epistaxis [13,16,20–23] were the most common bleeding symptoms, reported in eight women. The genetic defect associated with BSS was defined in seven women [9, 14, 16, 19, 21, and 23]. Consanguinity was reported in six cases [10,14,15,18,20,21]. Platelet count in the reported pregnancies before delivery ranged from 10 000 to 150 000 per mm3 with a mean of 58 300 mm3 [8–11,15,17–19,21–23]. There was one early pregnancy bleeding at 5 weeks of gestation [9]. Bleeding during pregnancy was reported in four pregnancies at 5, 36, 38 and 40 weeks of gestation respectively [9,11,14,21]. Antiplatelet antibody was reported to be positive in 10 pregnancies among six women including; anti GP1B IX antibody in seven [10,12,16,17,23] and anti-HLA antibody in three pregnancies [23]. Among these, administration of intravenous immunoglobulin (IVIG) was performed in eight pregnancies [10,12,23], corticosteroids in two [16,17] and plasmapheresis in one pregnancy [10] to reduce platelet consumption and to reduce the risk of neonatal alloimmune thrombocytopenia. Platelet transfusion was the most common prophylactic measure used to cover labour and delivery in 12 pregnancies [10,17– 19,21,23]. Tranexamic acid [21] and desmopressin/ 1-deamino 8 d-arginine vasopressin (DDAVP) [14] were also used prophylactically to cover labour and delivery. The mode of delivery was reported in 27 pregnancies and included a caesarean section in 16 pregnancies [9–11,13,14,16–19,22,23] and vaginal delivery in 11 [8,11,12,15,20,21] including two assisted deliveries with forceps [15] and ventouse [21]. Data about estimated blood loss during delivery was provided in nine pregnancies, the mean blood loss was 1200 mL with a range of 200–1700 mL [10,14,18,20,21]. Primary (intraoperative during

Haemophilia (2010), 16, 584–591

Greece Caucasian

New Zealand Caucasian

USA White American

Lebanon Arab

Heslop et al. 1986 [9]

Peaceman et al. 1989 [10]

Saade et al. 1991 [11]

Country E.G.

Michalas et al. 1984 [8]

Author (year)

Haemophilia (2010), 16, 584–591

37/NS

27/teenager

25–6/23

30/NS

Maternal age (years) /age at Dx

G4P3 Singleton

G2P0 Singleton

Primi Twins

Primi Singleton

Gravidity arity/ F.N Consanguinity

NS

Yes 2nd cousins

NS

NS

NA

Bleeding after minor trauma

Bruisingexcessive bleeding after trauma

Menorrha gia, dental bleeding

Bleeding history prior to pregnancy

NA

2nd; Plasmapheresis + RBC + SDP + PLT + CC + Cryoprecipitate + IVIG

28 000/GP 1b/IX Abs

50 000/NS

NA

NA

Prophylactic treatment for delivery

57 000/NS

80 000/NS

PLT count mm)3/detected antiplatelet Abs

Table 1. Main characteristics of the reported pregnancies with Bernard Soulier syndrome.

1st and 2nd uneventful. 3rd; PP bleeding from Haemorrhoids. 4th; at 38 weeks, APH +2° PPH

1° PPH (episiotomy haemorrhage) 2° PPH; at 8th and 14th PP 5 and 7 weeks; APH settled spontaneously. 35 weeks; membrane rupture + prolapsed cord. Superficial CS wound haematoma, wound dehiscence and ooze, 2° PPH 1st; NS. 2nd; gum bleeding, suprapubic ecchymotic amniocentesis site, 2° PPH

Pregnancy complications

CS

1200

3rd Vaginal 4th CS

CS

NA

Mode of Delivery Vaginal

NS

NS

Blood loss (mL)

3rd; Blood + FFP 4th; blood

2nd; Plasma pheresis + Blood + PLT + DDAVP

Superficial haematoma evacuated + PLT + Blood + DDAVP + Tranexa mic acid

PLT + blood + Vaginal Tampon ade + EOH

Treatment and maternal outcome

Second; ascites and pericardial effusion because of Rh isoimmunization/nor mal PLT Third and 4th healthy/ PLT NS

Both; Healthy/ normal PLT

Healthy/ normal PLT

Neonatal outcome/ PLT status

586 P. PEITSIDIS et al.



Osmana gaoglu et al 2005 [17] Kriplani et al. 2005 [18]

19/19

31/15

India Asian

26/24

Turkey Mediterranean

Japan Asian

19/14

Lebanon Arab

Fujimori et al. 1999 [16]

28/NS

Germany Caucasian

Greinacher et al. 1993 [14] Khalil et al. 1998 [15]

27/NS

35/NS

Brazil Latin American

USA White American

Peng et al. 1991 [12]


Avila et al. 1993 [13]

Country E.G.

Author (year)

Table 1. (Continued).

Primi Singleton

Primi Singleton

G1P0 Singleton

Primi Singleton

NS

G2P1

G4P3 Singleton

Gravidity arity/ F.N Consanguinity

Yes 1st cousins

NS

NS

Yes G.G parents siblings Yes 1st cousins

NS

NS

Menorrhagia, spontaneous bruising

NA

Bleeding from corpus luteum, epistaxis

Menorrhagia, Epistaxis, gingival and GI bleeding Lifelong mild bleeding tendency Menorrhagia, petechiaes

NS


150 000/ Not detected

80 000/GP 1b/IX Abs

132 000/GP 1b/IX Abs

40 000/NS

35 000/NS

16 000/NS

NS/GP 1b/IX Abs


SDP (2 hrs pre surgery)

PLT + CC

IVIG + CC

NA

DDAVP

2nd; PLT

4th; IVIG


Maternal throm bocytopenia, Intraoperative bleeding (1° PPH) Intraoperative uterine Haemorrhage (1° PPH), CS wound oozing, 2° PPH

36 weeks; APH (retroplacental haemorrhage) 1° and 2° PPH left vaginal wall laceration and episiotomy wound 32 weeks: Gum Bleeding

1st; Uneventful 2nd; 2° PPH

1st; 1° PPH 2nd; 2° PPH 3rd; NS 4th; 2° PPH (28hrs later)


1500

1600

CS

CS

RBC + Tranexa mic acid + PLT rich plasma

PLT + RBC

Tranexamic acid + EOH

CS )36 weeks NS

Crystalloids

Vaginal forceps

NA

DDAVP

NA

1st; blood 2nd; blood + EACA 4th; EACA + Blood

CS

1st Vaginal 2nd CS

All Vaginal

Mode of Delivery


6 h after delivery because of intracranial haemorrhage, alloimmune thrombocytopenia Healthy/normal PLT

Healthy/normal PLT

Healthy/normal PLT

1st; healthy/PLT NS 2nd; 38 weeksIUFD because of severe GI bleeding/ (alloimmune thrombocytopenia) 3rd; no complications/ low PLT (alloimmune thrombocytopenia) four; healthy/ normal PLT Second healthy/ PLT NS


BERNARD SOULIER IN PREGNANCY 587

Haemophilia (2010), 16, 584–591

1st 23/23

2nd 17/12

UK Asian

UK Asian

Prabu et al. 2006 [21]

Haemophilia (2010), 16, 584–591 G3P3 Singleton

2nd NS/21

Finland Caucasian

Consanguinity

NS

NS

NS

Yes

Yes

NS

NS

Epistaxis, excessive bleeding Epistaxisecchymoses

Epistaxis, bruising, iron deficient anaemia, menorrhagia Epistaxis, Menorrhagia, shock, Intraperito neal bleeding

Epistaxis, bruising

Epistaxis, Menorrhagia

Menorrhagia


1000– 10 000/ HLA Abs

19 000–109 000/ GP 1b/IX Abs

40 000/Not detected

NS/NS

37 000/NS

25 000/NS

21 000/NS


All 3 pregnan cies; PLT + IVIG All 3 pregnan cies; HLA mat ched PLT + IVIG

NA

1st and 2nd; PLT + Tranexamic acid

PLT

NA

PLT + RBC


1st and 2nd; intraoperative haemorrhage during CS (1° PPH). All 3 pregnancies; remarkable wound bleedings, HLA Abs

13 weeks: mild gum bleeding 25 weeks: pregnancy induced hypertension 37 weeks: pre-eclampsia Epistaxis

1st; APH 2nd; 2° PPH

1° PPH 2° PPH + hypervolaemic shock

34 weeks; Epistaxis, thrombocytope nia, anaemia, 2° PPH 1° PPH


NS

NS

500

1st 1500 2nd 1700

1000

200

NS

Blood loss (mL)

CS (all pregnancies)

CS ( all pregnancies)

CS

Vaginal (all pregnancies)

Vaginal (Ventouse)

Vaginal

CS

Mode of Delivery

PLT

NA

Tranexamic acid + DDAVP + SDP RBC + PLT + DDAVP + Tranexa mic acid 1st and 2nd; PLT + RBC + Tranexa mic acid SDP + blood

PLT + RBC


All born with alloimmune thrombocytopenia, ecchymoses, petechiae. Treatment; IVIG + PLT + CC + ranitidine/ 6–10 weeks all had normal PLT

All healthy/normal PLT

Ventricular septal and patent ductus arteriosus/ normal PLT

Both neonates healthy/ normal PLT

Healthy/ normal PLT

Healthy/ normal PLT

Healthy/ normal PLT


NF, number of foetus(es); SDP, single donor platelet; PP, postpartum; IPH, intrapartum haemorrhage; APH, antepartum haemorrhage; CS, caesarean section; FFP, fresh frozen plasma; DDAVP, desmopressin, EACA-, aminocaproic acid; NS, not stated, NA, not applied; EOH, emergency obstetric hysterectomy; E.G., Ethnic group; CC, corticosteroids; SDP, single donor platelets; RBC, red blood cells; IVIG, intravenous immunoglobulin (aka gammaglobulin) Antepartum haemorrhage (APH) at 40 weeks treated with 2 units of PLT and oral Tranexamic acid. Postpartum the patient received 4 units of RBC and 2 units of PLT because of low haemoglobin (6.3 g dL)1), blood loss1500 mL. *The current article is describing the clinical course of three pregnancies in a single patient, which were all uneventful, PLT count ranged from 19 000 to 109 000 – mild platelet associated autoantibodies detected. CS was performed in all pregnancies. In this patient, the third pregnancy, the patient received PLT transfusions with HLA-matched donors combined with i.v. gamma globulin, there was no PPH.

G3P3 Singleton

1st* NS/19

Finland Caucasian

Primi Singleton

Uotila et al. 2008 [23]

26/child hood

Pakistan Asian

G2P1 Singleton

Primi Singleton

Primi Singleton

G1PO Singleton

Gravidity arity/ F.N

Zafar et al. 2007 [22]

24/NS

Poland Caucasian

Kopec et al. 2005 [20]

22/NS

Germany Caucasian

Country E.G.


Rahimi et al. 2005 [19]

Author (year)

Table 1. (Continued).

588 P. PEITSIDIS et al.



caesarean section and within 24 h of delivery) postpartum haemorrhage (PPH) was reported in 10 (33%) and secondary (reported from 28 h to 6 weeks postpartum) PPH in 12 (40%) pregnancies. Both primary and secondary PPH were reported in four pregnancies [8,15,18,21]; two of whom had instrumental deliveries [15,21]. PPH was the first bleeding manifestation in one case [17]. Blood transfusion for PPH was required in 15 [8–12,17– 22]. Platelet transfusion was used to control PPH in 14 [8–10,17–23], tranexamic acid in seven [9,11,18,20,21] and DDAVP in four [9,10,14,21] pregnancies. All women survived; however, two underwent emergency obstetric hysterectomy [8,16]. Caesarean hysterectomy was carried out as a prophylactic measure against PPH, in a woman who had developed antiplatelet antibodies subsequent to multiple platelet transfusions [16]. The second one was in a woman with uncontrollable PPH [8]. Eighteen neonates (including a twin) were reported to have normal platelet count after delivery [8–12,14,15,17–23]. In four neonates platelet count was not stated but they were reported to be healthy. No information was provided for three neonates. Alloimmune neonatal thrombocytopenia was reported in six neonates [12,16,23]. Antiplatelet antibody was reported to be positive in maternal blood during pregnancy in all these six cases. Among the six affected neonates, there was one intra-uterine death caused by severe fetal gastrointestinal bleeding [12] and one neonatal death 6 h postdelivery with intracranial haemorrhage [16]. One neonate had low platelet count but no bleeding complications [12]. In the remaining three neonates, alloimmune neonatal thrombocytopenia presented with ecchymosis, petechiae and bruising after birth [23].

Discussion In this study, we review all cases of BSS reported during pregnancy in the international literature. The review highlights that pregnant women with BSS have a significant risk of PPH and can be subjected to emergency obstetric hysterectomy. The foetus/neonate is also at risk of serious bleeding such as intracranial haemorrhage attributable to fetal alloimmune thrombocytopenia. In women, as highlighted in this review, the diagnosis of BSS is usually confirmed prior to pregnancy, mostly during childhood or adolescence with manifestation of several haemorrhagic symptoms. Prior diagnosis is essential for appropriate management of pregnancy and delivery. Pregnancy is


589

associated with maternal bleeding complications; the most common manifestation is PPH (primary and secondary). There is also a risk of wound haemorrhage [8,9,22]. Bleeding may be provoked by caesarean section wound, perineotomy or perineal trauma during delivery. In 30 pregnancies covered by this review, 11 (34%) and 12 (40%) had primary and secondary PPH respectively, two of whom required emergency obstetric hysterectomy [8,16]. Thorough haemostatic assessment of the mother and arrangement for appropriate haemostatic cover during delivery are essential to reduce the risk of PPH. The options for haemostatic agents include tranexamic acid, DDAVP, recombinant FVIIa (rFVIIa) and platelet transfusion [24]. It is preferable to avoid platelet transfusion if at all possible because of its associated risk of alloantibody formation. The use of rFVIIa combined with tranexamic acid is recommended for uncomplicated vaginal delivery [24]. However, HLA-matched platelet infusion with tranexamic acid is recommended as a first line treatment for caesarean sections or if bleeding occurs during vaginal delivery. Women with BSS often experience significant bleeding episodes requiring platelet transfusions. Thus, they are often sensitized to platelet alloantigens, making it difficult to find compatible platelets. Although, in an acute emergency, random platelets could be used, it is advisable to administer HLA-matched platelets [24,25]. In women, the alloantibodies may have serious consequences during pregnancy. Alloantibodies can cross the placenta and cause fetal or neonatal alloimmune thrombocytopenia [26]. Gammaglobulin, plasmapheresis and corticosteroids have also been used to enhance response to platelet transfusion [12,16] and to prevent alloimmune neonatal thrombocytopenia [10,12,17]. Aggressive use of uterotonics for the management of third stage of labour to avoid uterine atony is recommended to minimize risk of PPH. Avoidance of traumatic delivery, especially difficult instrumental deliveries, is also essential to reduce the risk bleeding and for prevention of perineal haematomas. Regional analgesia/anaesthesia is contraindicated because of the risk of spinal/epidural haematoma. Similarly, pudendal anaesthesia can result in noncompresssible pelvic haematomas and should be avoided [24]. If episiotomy is necessary or if perineal lacerations occur, local anaesthetic can be used in the perineum. For caesarean sections, general anaesthesia is more appropriate and safe for these women, dibucaine as anaesthetic agent should be avoided because of platelet compromise [20]. Management of pregnancy in these women requires a multidisciplinary team approach, including obstetricians, haema-

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P. PEITSIDIS et al.

Table 2. Guideline for management of pregnancy in women with Bernard Soulier syndrome. 1. Women with BSS should be informed of the risks of pregnancy before becoming pregnant 2. Pregnant women with BSS should be managed by a multidisciplinary team including obstetricians, haematologists and anaesthetists in a tertiary unit with experience in managing such patients and readily available access to platelet and other blood products 3. In communities with high consanguinity, the father should be screened to help identify at risk fetuses 4. Prenatal diagnosis should be offered if both parents are carriers or for parents of an affected child 5. Women should be monitored for the development of anti-HLA and GPIb antibodies to identify fetuses at risk of alloimmune thrombocytopenia. Pregnancies with at risk fetuses should be managed in a tertiary fetal medicine unit in close collaboration with the haemophilia centre 6. Appropriate haemostatic cover and active management of third stage of labour are essential to minimize risk of PPH 7. rFVIIa 90 lg kg)1 (early pregnancy weight) combined with tranexamic acid is recommended for a vaginal delivery. HLA-matched platelet infusion is needed for operative deliveries and in case of bleeding 8. There is also a high risk of secondary PPH; therefore a close observation of up to 6 weeks postpartum is recommended. Tranexamic acid to cover this period may be used to reduce this risk 9. Regional analgesia/anaesthesia is contraindicated 10. The safest mode of delivery for fetuses at risk of fetuses alloimmune thrombocytopenia is unknown. Each case should be assessed individually taking into consideration obstetric maternal and fetal risks and fully discussed with the parents. Instrumental deliveries should be avoided

tologists and anaesthetists. These women should be managed in a tertiary unit with experience in managing such patients and readily available access to platelet and other blood products. On site interventional radiology services for uterine embolization could prevent the need for caesarean hysterectomy. A close observation of up to 6 weeks postpartum is strongly recommended as these women are at a high risk of secondary PPH. Tranexamic acid to cover this period may be used to reduce this risk. As BSS is transmitted as autosomal recessive trait, the risk of neonate inheriting BSS is rare. However, it should be considered in communities with high consanguinity. Several mutations responsible for BSS have been identified. Most of them are missense mutations or frame shifts resulting in premature stop codons. Thus, prenatal diagnosis is theoretically feasible when the genetic defect has been identified in particular kindred. The need for prenatal diagnosis in affected women is extremely infrequent. However, parents of an affected child should be offered prenatal diagnosis for future pregnancies. Maternal alloantibodies can cross the placenta and cause fetal or neonatal alloimmune thrombocytopenia [26]. Alloantibodies can be attributable to previous platelet transfusion or maternal sensitization to fetal platelet antigens. Fetal platelets are carriers of specific paternal Ib/IX antigens that are not present on the maternal BSS platelets. The fetal platelets may traverse the placenta and alloimmunize the mother. The maternal antiplatelet immunoglobulin G antibodies then pass into the fetal circulation, causing fetal-maternal alloimmune thrombocytopenia [27]. The risk of fetal alloimmune thrombocytopenia in pregnant women with BSS should be evaluated by testing parental platelet antigen incom-

Haemophilia (2010), 16, 584–591

patibility and specific antiplatelet antibodies in a specialized laboratory to identify at-risk fetuses. If the antibodies are present, management of the pregnancy can be challenging and involve cordocentesis for checking fetal platelet counts and treatment with maternal steroids and/or IVIG, fetal platelet transfusions or fetal IVIG [28]. Management of such pregnancies requires a close collaboration between a specialized fetal medicine unit and a haemophilia centre. Serial intrauterine platelet transfusion as a therapy for alloimmune thrombocytopenia is controversial because the risk of haemorrhage after fetal blood sampling is substantially increased in fetuses with poor platelet function. In addition, it may ensure reasonable platelet levels for only 1 week. Therefore, it should be restricted to the most severe cases with a history of fetal loss or significant fetal haemorrhage [27]. The safest mode of delivery for the foetus and the mother is controversial. In most of the reported cases, caesarean section was the preferred mode of delivery. PPH was reported in patients delivered vaginally and by caesarean section. Based on current information, no firm recommendation can be made. However, the risk of bleeding to the foetus is only in association with alloimmune thrombocytopenia. If this diagnosis is excluded, caesarean section should be reserved for obstetric indications. In the presence of alloimmune thrombocytopenia, caesarean delivery does not seem to eliminate the risk of haemorrhage. Spontaneous haemorrhage can happen in utero. Severe intrauterine gastrointestinal bleeding leading to intrauterine death at 38 weeks has been reported [12]. However, parents and obstetricians may prefer a caesarean delivery to avoid any further risks during labour. When vaginal delivery is contemplated,



prolonged labour especially during the second stage and instrumental deliveries should be avoided. In conclusion, pregnancy in women with BSS may be associated with a life-threatening PPH. The foetus/neonate is also at risk of serious bleeding such as intracranial haemorrhage because of alloimmune thrombocytopenia. Multidisciplinary approach to management can reduce the maternal and neonatal risks. Because of the limited data in the literature, it is not possible to provide firm management recommendations for all women. General guidance is provided in Table 2. However, each case should be managed individually. Report of further cases and individual experience in managing these pregnancies will be helpful to obtain better knowledge. This can only be obtained by an international registry for BSS in pregnancy.

12

13

14

15

16

17

Disclosures

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The authors stated that they had no interests which might be perceived as posing a conflict or bias.

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References

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