Haemophilia (2014), 20, 854–858

DOI: 10.1111/hae.12516

ORIGINAL ARTICLE Women with bleeding disorders

Prenatal diagnosis of haemophilia in Sweden now more commonly used for psychological preparation than termination of pregnancy A. M AR T E N S S O N , * † U . T E D G  AR D * † and R . L J U N G * † *Department of Clinical Sciences Malm€ o, Lund University, Sweden; and †Department of Paediatrics and Malm€ o Centre for Thrombosis and Haemostasis, Sk ane University Hospital, Lund University, Malm€ o, Sweden

Summary. The aims of the study were to define the frequency, outcome and reasons for prenatal diagnosis (PND) in Sweden during a 30-year period in order to study trends and changes. The study population, from the Swedish nationwide registry of PND of haemophilia, consisted of 54 women, compromising >95% of all, who underwent PND (n = 90) of haemophilia during 1977–2013. PND was performed by amniocentesis (n = 10), chorionic villus sampling (n = 64) or by analysis of foetal blood (n = 16). A total of 27/90 foetuses were found to have haemophilia. Sixteen went to termination and the remaining 11 were born during the end of the study period (2000–2013). Three of 90 pregnancies were terminated due to findings other than haemophilia and 3/90 PNDs led to miscarriage. In the 30 families

with known haemophilia, PNDs (n = 55) were used in 27/55 cases for ‘psychological preparation’ and in 23/55 cases with the aim to terminate the pregnancy. A subgroup of women (n = 17) who consecutively underwent PND in the years 1997–2010 were further interviewed. For 11/17, being a carrier had a negative effect on the decision to become pregnant, and in 11 cases PND had influenced their decision to conceive. Our study show that PND of haemophilia is stable over time but increasingly used during the last decade as a psychological preparation for having a child with haemophilia as compared to earlier where more terminations of pregnancies were conducted.

Introduction

life [1–5]. However, in the 1980s serious side effects occurred due to the transmission of HIV and other viral infections [6]. Despite the advances made in the management for haemophilia about one-third of patients develop neutralizing inhibitors against the factor concentrate which is a major complication [7]. Prenatal diagnosis (PND) of haemophilia was introduced in the late 1970s by analysis of foetal blood obtained in the 18th–20th gestational week. Since the mid-1980s when the F8/F9 genes were characterized, DNA analysis can be performed on foetal cells obtained by chorionic villus sampling (CVS) in gestational weeks 11–13 or by amniocentesis in the second trimester. Until the beginning of the 1970s many female carriers of severe haemophilia were advised to avoid having children. When prenatal sex determination became available, some carriers interrupted pregnancies with male foetuses, although 50% were not affected by haemophilia. Today the standard method of PND in Sweden is by CVS in the first trimester but in the near future Y–PCR testing and preimplantation genetic diagnosis may become safer and more

Haemophilia A and B are X-linked recessive inherited bleeding disorders caused by lack or deficiency of coagulation factor VIII (FVIII; haemophilia A) or factor IX (FIX; haemophilia B). The tendency to bleed is related to the FVIII/IX concentration in blood and the disease is clinically classified as mild, moderate or severe according to the residual plasma activities of factor VIII or IX: severe (5–40%). In about half of all new cases of haemophilia there is no previous known family history, i.e. sporadic cases. The introduction of plasma-derived factor VIII/IX concentrates in the 1960s/70s dramatically improved morbidity, mortality and quality of Correspondence: Annika M artensson, Department of Paediatrics and Malm€ o Centre for Thrombosis and Haemostasis, Sk ane University Hospital, Lund University, SE–205 02 Malm€ o, Sweden. Tel.: +46 40 33 19 64; fax: +46 40 33 62 26; e-mail: [email protected] Accepted after revision 4 July 2014 854

Keywords: carrier, factor IX, factor VIII, haemophilia A, haemophilia B, prenatal diagnosis

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PRENATAL DIAGNOSIS OF HAEMOPHILIA IN SWEDEN

generally available as an option for PND. A carrier of haemophilia and her partner face difficult choices regarding reproduction (with half of the sons being at risk of having haemophilia) and the different options of PND. The choices can be influenced by psychological, ethical, cultural and family-related factors [8–18]. The main reasons for PND may be to prevent the birth of a haemophilia-affected boy by termination of the pregnancy, to prepare for the obstetrical procedures or, for the parents-to-be, to be psychologically prepared for having a child with haemophilia. The aims of this study were to define the frequency, outcome and reasons for PND in Sweden during a 30-year period to study trends and changes.

Materials and methods Study population The study population consisted of 54 women, who consecutively underwent PND (n = 90) of haemophilia during the years 1977–2013 (February). The laboratory work-up of all PNDs of haemophilia in Sweden (except a few cases) have been done at the haemophilia centre in Malm€ o and have been carefully registered, i.e. the material thus represents almost 100% of all PNDs in Sweden during the study period. The PND procedure was either by amniocentesis in the 15th–16th week of gestation (n = 10), CVS in the first trimester (n = 64) or by analysis of foetal blood (n = 16). The foetal blood was collected by puncture of a placental vessel or the umbilical cord at foetoscopy or by ultrasound-guided heart puncture in the 18th–20th gestational week, mainly used in 1977– 1983. A total of 13/54 women who underwent 16/90 PNDs between 1977 and 1983 with foetal blood were only analysed for outcome of PND as well as another two women with 4/90 PNDs, two amniotic fluid in the 1980s and two CVS in the early 1990s, due to missing data.

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The remaining study group of women (n = 39) who underwent 70 PNDs during 1980–2013 using modern techniques was further analysed. To study the psychological aspects of the current practice of PND, a subgroup (n = 17) compromising all who consecutively underwent PND during 1997– 2010, were subjected to a Quality of Life (QoL) questionnaire. See Fig. 1 for the study population.

Data collection Data were collected from the PND-registry, by semistructured personal interviews and, for a subgroup (n = 17), a QoL questionnaire. All interviews in the study group (n = 39) were made through telephone calls and of the 17 interviews in the QoL study group, 10 were performed in the woman0 s home and 7 through telephone calls. Each interview took 30– 60 min. The semi-structured questionnaire used consisted of questions regarding the total number of children the woman had given birth to, whether haemophilia was known beforehand in the family, and when, how many, what kind, the results of and the reasons for the PNDs that the woman had undertaken. The QoL questionnaire in the subgroup of the 17/39 women consisted of 88 questions on the following areas: genetic information, the perception of being a carrier of haemophilia and how the women perceived the PND procedure before, during and after it. The answers were written down as the interview went on and the answers were afterwards translated into a numerical system where each digit represented a specific answer. The study was approved by the Regional Ethical Review Board in Lund and all participants gave written informed consent.

Data analysis Descriptive statistical methods were used.

Fig. 1. Flow charts of the study population.

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Haemophilia (2014), 20, 854--858

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A. M  ARTENSSON et al. Table 2. Number and outcome of prenatal diagnosis (PND) procedures and pregnancies (n = 90).

Results Number of PND The characteristics of the study population are described in Table 1. One PND was performed by 46% (18/39). All but one of these carriers chose CVS, and the remaining carrier chose amniocentesis. A total of 54% (21/39) underwent PND in more than one pregnancy; 13/21 in two pregnancies, of whom 10 had the same prenatal method each time: CVS (n = 9) and amniocentesis (n = 1). Three or four PNDs were made by, respectively, 6/21 and 2/21 carriers of whom the first six chose CVS on each occasion.

A total of 27 foetuses, carried by 23 women, were found to be affected by haemophilia and 16/27 underwent termination of pregnancy. The majority of the terminated pregnancies were in the 1990s (7/11) and 4/11 during 2001–2009. The outcomes of the remaining 74/90 PNDs were: 11/90 showing haemophilia continued the pregnancy and all children were born (during 2000–2013), 57/90 of the PNDs showed healthy foetuses and went to term. Three of 90 were terminated because of findings other than haemophilia and 3/90 PNDs led to miscarriage. Of these three PNDs one was made from foetal blood 1980 and two from CVS, one in the 1990s and one in early 2000. See Table 2.

Reasons for PND Haemophilia in the family was known beforehand in 55 of the PNDs undertaken by 30 of the women where half (16/30) did not have boys of their own with haemophilia. PNDs were performed in 27/55 cases for ‘psychological preparation’ and in 23/55 cases with the aim of terminating the pregnancy if the PND showed haemophilia. In 5/55 cases in known

Table 1. Study population characteristics; carriers (n = 39; haemophilia A 31/haemophilia B 8) who underwent prenatal diagnosis (PND) (n = 70) 1980–2013. Categorized according to the status at first PND. Total

Haemophilia (2014), 20, 854--858

PND procedures (n) Haemophilia: Termination/Born No haemophilia: Termination/Born Haemophilia status not known: Miscarriage/ termination of other causes

1990– 1999

2000– 2009

2010– 2013

4 3 16 23 5/0

2 21 0 23 7/0

3 27 0 30 4/7

1 13 0 14 0/4

0/16

0/14

0/17

0/10

1/1

1/1

1/1

0/0

Total 10 AF 64 CVS 16 FB* 90 27 16/11 57 0/57 6 3/3

*During 1977–1983. AF, amniotic fluid; CVS, chorionic villus sampling; FB, foetal blood; PND, prenatal diagnosis.

Prevalence and outcome of PND

Family history of haemophilia (n) No family history (n) Severity of haemophilia in the family: severe/moderate/mild Age at time of data collection (years, range) Age at time of first pregnancy with PND (years/range) Living with spouse/without spouse (n) Having children at the time of the first PND (n/sons with haemophilia) Number of children (in total) (n, range) Women who opted for PND one/two/three/four times (n)

Subgroups of PND procedures

1977– 1989

30 9 24/12/3 36.5 (24–55) 30 (20–37) 38/1 18/14 1–5 (mean: 2.15) 18/13/6/2

haemophilia families, PND were primarily performed for reasons other than haemophilia. In families with sporadic cases, i.e. the woman had a boy with haemophilia as the first known in the family and then performed PND in the coming pregnancies, 15 PNDs were undertaken by nine women; 5/15 PNDs were performed for psychological reasons and 10/15 to decide on termination of pregnancy. See Table 3.

Family size It was found that 25/39 families had children with at least one boy with haemophilia and 14 families had children without haemophilia. The most common family pattern in the 25 families found was that of two children (14/25) and the most common finding among these was that the eldest had haemophilia (11/14).

Outcome of QoL In this subgroup who underwent PND during 1997– 2010 (n = 17), 35 PNDs were performed on 17 women and in 14/35 the foetuses had haemophilia. Of these, 8/14 pregnancies were terminated in five of the 17 women and 6/14 pregnancies led to birth of a boy with haemophilia. Three of five women terminating their pregnancy due to haemophilia felt that the following months were difficult and one regretted the

Table 3. Reasons for prenatal diagnosis (PND) among carriers (n = 39; haemophilia A 31/haemophilia B 8) who underwent PND (n = 70) 1980– 2013.

Psychological preparation Termination of pregnancy Other reason

Family history of haemophilia

Sporadic case

27/55 (49%) 23/55 (42%) 5/55 (9%) 30 women; 55 PND

5/15 (33%) 10/15 (67%) 0 9 women; 15 PND

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PRENATAL DIAGNOSIS OF HAEMOPHILIA IN SWEDEN

decision. Two of five women later gave birth to a boy with haemophilia. For 11/17, being a carrier had a negative effect on the decision to become pregnant, and in 11 cases PND had influenced their decision to conceive. Six of the 17 chose PND to terminate the pregnancy if the foetus had haemophilia, 7/17 to prepare them psychologically for having a boy with haemophilia and 3/17 changed the reason between different PNDs between preparation and termination of pregnancy. One of 17 chose PND mainly to find chromosomal abnormalities. The PND procedure was unexpectedly distressing for 11/17. Eight of 17 described it as physically very painful. Table 4 shows background characteristics of this subgroup.

Discussion During the long study period, advances in PNDs as well as improved treatment have affected the reasons, methods and possibilities of performing PND. Our results show that 54 women in total underwent 90 PNDs. Analyses decade for decade show that CVS has by far become the most commonly used procedure: 13/14 PNDs were by this method during 2001– 2013. In total 27/90 PNDs (23 women) showed a haemophilia-affected foetus and 16/27 of foetuses (23 women) underwent termination of pregnancy; the majority in the 1990s. All of the pregnancies leading to the birth of a haemophilia-affected boy were seen in 2000–2013, which seems to reflect a changing view of having a child with haemophilia. Our results show that the investigated carriers had an average of 2.15 (mean) children. This can be compared to the average woman in Sweden who during the study period gave birth to between 1.50 and 1.92 children [19]. This differs slightly from what has been found earlier in Sweden and the Netherlands [12,20] where carriers were found to have the same number of children compared to the populations in each country, respectively.

Table 4. Background data on subgroup (n = 17; haemophilia A 12/haemophilia B 5) who underwent prenatal diagnosis (PND) (n = 35) during 1997–2010 and participated in the Quality of Life (QoL) survey. Total Family history of haemophilia (n) No family history (n) Severity of haemophilia in the family: severe/moderate/mild Age at time of data collection (years, range) Age at time of first pregnancy with PND (years, range) Living with spouse/without spouse (n) Children at the time of the first PND (n/sons with haemophilia) Number of children (in total) (n, range) Women who opted for PND one/two/three/four times (n)

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14 3 13/3/1 40 (28–50) 28.5 (20–37) 14/3 7/5 1–4 (mean: 2.29) 5/8/2/2

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The majority of our study group, 30/39 women, came from a family with a known history of haemophilia making it possible that the results found were not applicable to sporadic carriers. A weakness of this study is that the subgroups were small, due to the small size of the population in our country and the rarity of the disease. The strength of this study is that the results cover >95% of all women in our country undergoing PND due to haemophilia. Balak et al. [20] found in a nationwide survey 112 carrier in the Netherlands that during 1992–2004 underwent PND. In 26 pregnancies (23%) a haemophilia-affected male foetus was found and 18 of these pregnancies were terminated. In a Dutch survey in 1987 of 218 obligate and potential carriers who had ever been pregnant, 11% had opted for invasive PND [21]. In Sweden in 1994, 14% of 376 estimated carriers underwent PND by foetal blood sampling or by CVS and gene analysis [12]. However, we do not know the number of carriers who have been pregnant without having PND during the study period. In 1996, a survey conducted in London of 197 obligate and potential carriers found that 36 of 160 (23%) women who had been pregnant had opted for invasive PND [13]. PND of haemophilia is still requested, but we found that the number of pregnancies terminated due to an affected foetus has diminished. The results suggest that the decline in incidence of haemophilia due to PND observed in the 1990s [22] no longer exists since in our study almost half of the women today use PND to prepare themselves for having a child with haemophilia and not to terminate the pregnancy. A decrease in invasive testing has been shown in two studies among English carriers, in whom the percentage of invasive PND for haemophilia decreased from 35% during 1985– 1995 to 20% in 1995–2005 [23,24]. Our results show that most carriers today choose PND as a mode of preparation and not with the intention to terminate if foetus is affected. In families with known haemophilia, PNDs were used in 27/55 (49%) cases for ‘psychological preparation’ and in 23/55 (51%) cases with the aim to terminate the pregnancy if the finding was a foetus affected with haemophilia. In families with sporadic cases, 5/15 (33%) PNDs were used to prepare themselves psychologically and 10/15 (66%) was used to decide termination of pregnancy. Although the figures are small, it may reflect that women in sporadic families who already have a son with haemophilia may be reluctant to have a second child with haemophilia. During 2009–2013 all chose PND to prepare themselves psychologically. The same trend was found in a qualitative and descriptive study carried out in Australia, where Thomas et al. showed that most members in the haemophilia community interviewed thought that testing was necessary for adolescent girls to determine Haemophilia (2014), 20, 854--858

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carrier status to help prepare families for a child with haemophilia, rather than leading them to choose to terminate a pregnancy or not to have children [25]. During the first decade of the study period, we believe there was an accumulated need for PND that ceased with time since treatment has improved substantially in combination with a lowered perceived severity of haemophilia. The frequency of invasive PND may cease further when foetal gender determination such as Y–PCR testing in the maternal blood becomes more common. Furthermore, there seem to be more women becoming mothers since the improvement of care, thus giving birth to even more children (2.15) than the average Swedish woman (1.50–1.92), both boys and girls, the latter being possible carriers. Our QoL results showed for 11/17 that being a carrier had a negative effect on the decision to become pregnant, and in 11 cases PND had influenced their decision to conceive. To gain more knowledge, the next step would be to interview known and obligate carriers of haemophilia to understand the reasons, and for carriers choosing or not choosing PND.

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Haemophilia (2014), 20, 854--858

Conclusion Our study show that PND of haemophilia is stable over time but increasingly used during the last decade as a psychological preparation for having a child with haemophilia as compared to earlier where more terminations of pregnancies were conducted.

Acknowledgements Annika M artensson, Rolf Ljung and Ulf Tedg ard participated in the design of the study. Annika M artensson sampled all data, made the interviews and the primary calculations of the results. Annika M artensson, Rolf Ljung and Ulf Tedg ard discussed the results. Annika M artensson wrote the manuscript and all authors discussed and revised the manuscript to its final version. This study was supported by grants from Lund University and Region Sk ane (ALF, Regionalt forskningsst€ od) and the Swedish Research Council (Ljung).

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

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© 2014 John Wiley & Sons Ltd

Prenatal diagnosis of haemophilia in Sweden now more commonly used for psychological preparation than termination of pregnancy.

The aims of the study were to define the frequency, outcome and reasons for prenatal diagnosis (PND) in Sweden during a 30-year period in order to stu...
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