Follow up of children after antenatal treatment for alloimmune thrombocytopenia

Early Human Development 80 (2004) 65 – 76 www.elsevier.com/locate/earlhumdev

Follow up of children after antenatal treatment for alloimmune thrombocytopenia Celine M. Raddera,*, Monique J.J. de Haana, Anneke Brandb, Gerlinde M.S.J. Stoelhorstc, Sylvia Veenc, Humphrey H.H. Kanhaia a

Department of Obstetrics, Leiden University Medical Center, H4-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands b Department of Immunohematology, Leiden University Medical Center, Leiden, The Netherlands c Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands Accepted 21 May 2004

Abstract Objective: To evaluate the long-term follow-up of surviving offspring after antenatal treatment for fetal or neonatal alloimmune thrombocytopenia (FNAIT). Patients: Fifty children at risk of FNAIT were antenatally treated with maternal intravenous immunoglobulins (IVIG) (n=11), IVIG with intrauterine platelet transfusions (IUPT) (n=26) or IUPT alone (n=9). In four cases (n=4), only fetal blood sampling (FBS) was performed. One child died in the neonatal period and one was lost to follow up. Methods: The remaining 48 children, aged 1.3–11.6 years (median 5.1 years), were given both general and neurological examinations and assessed on their development and susceptibility for infections or atopic constitution. In addition, immunoglobulin levels were measured in 17 infants, aged 5 years and older. Results: Intracranial hemorrhage (ICH) was not observed. The general health and neurodevelopmental outcome in the children was comparable to a normal Dutch population. Children not exposed to maternal IVIG treatment had significantly more infections and hearing problems than children

Abbreviations: C.I., 95% confidence interval; ENT, ear, nose and throat; FBS, fetal blood sampling; FNAIT, fetal or neonatal alloimmune thrombocytopenia; HPA, human platelet antigen; ICH, intracranial hemorrhage; IgGSc, immunoglobulin G subclasses; IUPT, intrauterine platelet transfusion; IVIG, intravenous immunoglobulins; LUMC, Leiden University Medical Center; PVL, periventricular leucomalacia. * Corresponding author. Tel.: +31 71 5262896; fax: +31 71 5266741. E-mail address: [email protected] (C.M. Radder). 0378-3782/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.earlhumdev.2004.05.007

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exposed to IVIG treatment or the normal population. Immunoglobulin G, A and M levels were within the normal range, independent of treatment and severity of FNAIT. A high IgE level was more frequently seen in children exposed to IVIG, but did not result in clinical consequences such as allergy or atopy. Conclusions: Antenatal treatment of children for FNAIT did not affect general health or neurodevelopmental outcome. In particular, exposure to IVIG in utero showed no adverse effect on the clinical outcome of these children. D 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Fetal or neonatal alloimmune thrombocytopenia; Follow-up; Intrauterine platelet transfusions; IVIG; Immunoglobulin

1. Introduction Fetal or neonatal alloimmune thrombocytopenia (FNAIT), due to maternal immunization against a paternal human platelet antigen (HPA) on fetal platelets, affects less than 0.1% of live births [1]. In Caucasians, HPA-1a is the most frequently involved antigen, with an estimated incidence of HPA-1a antibodies in HPA-1a negative women of about 12% [1,2]. The main complication of FNAIT is the risk of intracranial hemorrhage (ICH) in 7–26% of the children, 80% of which occurs antenatally [3–6]. ICH is associated with a high mortality in 10% of the cases and neurological sequelae in 20% of cases [4–6]. Antenatal treatment aims to prevent ICH, but the optimal treatment strategy for FNAIT is still controversial. Various management strategies include fetal blood sampling (FBS), followed by weekly fetal intrauterine platelet transfusions (IUPT) in case of thrombocytopenia, and/or weekly maternal high dose intravenous infusion of immunoglobulins (IVIG, 1g/kg) and/or maternal corticosteroids. Maternal IVIG administration increases the fetal platelet count in approximately 60% of cases. Moreover, observational studies have reported a decrease of the ICH risk, even in cases without an obvious response of fetal platelet counts to IVIG [7–9]. The development of the fetal immune system occurs in an almost sterile and alloantigen-free environment, apart from feto-maternal interactions. Placental transmission of maternal IgG antibodies occurs from about 12 weeks of gestation onwards, resulting in passive immunity for the first months of life. Antenatal treatment exposes the maturing fetal immune system to foreign alloantigens, which are present in IVIG and platelet transfusions. In addition, IVIG has been shown to downregulate proinflammatory cytokines suppressing T-helper 1 type of response, which may skew the immune response towards a T-helper 2 type reaction [10–12]. Although the significance of these effects on the maturing fetal immune functions and the effect of fetal treatment have not been extensively studied before, IVIG is used in a number of approved and non-approved obstetrical and neonatal indications [13,14]. To our knowledge, there are no data on the susceptibility for infections or for allergic or atopic expressions or data on the long-term neurodevelopmental outcome of children after antenatal treatment.

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The aim of this study was to determine the neurodevelopmental outcome and health status, focusing on infections and atopic constitution, of children antenatally treated for FNAIT over a period of 10 years in the Leiden University Medical Center (LUMC).

2. Patients and methods 2.1. Patients Women at risk for FNAIT with a history of severe thrombocytopenia (platelet count V50
109/l) or an ICH in the previous child are referred to the LUMC, a national reference center for severe red cell and platelet alloimmunization, for advice and treatment in their next pregnancy. From June 1988 to August 1999, 42 women (50 pregnancies) with confirmed HPA immunization were treated. The clinical characteristics are described in Table 1. Of the 50 fetuses with FNAIT, 9 were treated with IUPT alone, 26 with IUPT in combination with IVIG and 11 with IVIG alone. In 4 children, a FBS revealed a normal fetal platelet count and no further treatment was performed. Treatment with IVIG and IUPT was performed as described previously [9]. Briefly, in the last decade, the treatment strategy at the LUMC has been based on the obstetric history, severe thrombocytopenia with or without an ICH, and the prevention of ICH. The lower risk of ICH in the group of patients without a history of ICH and the reported beneficial effect of IVIG on ICH, Table 1 Clinical characteristics of 50 pregnancies at risk of platelet alloimmunization n (%)

Median (range)

Obstetric history Mother’s age (years) HPA-1a alloimmunization Other alloimmunization* Obstetric history with ICH in previous child Platelet count at birth of previous pregnancyy

42/42 37/42 5/42 8/42 37/42

(100) (88) (12) (19) (88)

30 (20–38)

Perinatal characteristics index pregnancy Gestational age (weeks) Preterm deliveryb Birth weight (g) Apgar score 5 min Platelet count at birthy§ count b50y Vaginal delivery Elective caesarean sectionO

50/50 15/50 50/50 48/50 50/50 24/50 32/50 18/50

(100) (30) (100) (96) (100) (48) (64) (36)

38 (32–40)

29 (2–82)z

2845 (1324–4100) 10 (2–10) 61 (1–252)

n=number; HPA=human platelet antigen; ICH=intracranial haemorrhage; *=alloimmunisation other than HPA-1a, such as HPA-3a, -5a, -5b and dprivateT antigen; y=
109/l; z=3/37 platelet count N50
109/l; b =gestational age at delivery less than 37 weeks: on account of nonresponse of fetal platelet count (b20
109/l) after several platelet transfusions (IUPT) (n=7), on account of high-risk pregnancies with an ICH in the obstetric history (n=5), and one emergency caesarean section due to a complication of IUPT; §=defined as either the platelet count before delivery, at the last FBS but before a possible IUPT, or if no FBS had been performed, by the count in the umbilical cord blood; O=elective in 18/18 caesarean sections and preterm in 9/18 (50%).

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gradually changed the key point of treatment from initial FBS towards dblindlyT administered IVIG, without preceding FBS [9]. The median gestational age at the start of weekly maternal IVIG administration (1 g/kg/week) was 32 weeks (range 17–36 weeks); only in severe cases with a history of ICH, IVIG was started very early in pregnancy. The median period of IVIG administration was 5 weeks (range 2–15 weeks) and the median number of FBS or IUPT was 1 (range 1–9). One mother received additional high dose prednisolon treatment (60 mg/day) over a 3-week period, due to participation in a randomized trial [7,15]. Nine mothers received corticosteroids (betamethason) to stimulate fetal lung maturation. Ultrasonographic cerebral examination was antenatally performed once every 2 weeks to detect ICH. 2.2. Methods Clinical information about the perinatal period (gestational age, mode of delivery, Apgar score, birth weight, arterial pH and platelet count at birth) and the neonatal period (clinical course, cerebral ultrasonography, medication, platelet transfusions and neonatal platelet counts) was obtained from the medical records by using a standard form. The platelet count at birth was defined as either the platelet count before delivery, at the last FBS but before a possible IUPT, or if no FBS had been performed, by the count in the umbilical cord blood. Perinatal asphyxia was defined as having an Apgar score less than 7 at 5 min, pH less than 7.10, neurological sequelae, or showing evidence of multiorgan dysfunction. The parents were contacted (by mail and telephone) and invited for a physical and neurological examination of the children by a pediatrician, according to Touwen’s method [16], and a cognitive assessment by a developmental psychologist. The neurological examination aimed at the detection of central motor deficit and minor neurological dysfunction. The neurological condition was defined as normal, minor neurological dysfunction (neurological abnormalities without influence on normal posture or movement) and cerebral palsy (neurological abnormalities with abnormal posture and movement). The children’s cognitive ability was assessed with various developmental tests, depending on the child’s age [17–20]. An intelligence quotient (IQ) between 90 and 110 was classified as normal, between 80 and 89 as mild delay, between 70 and 79 as moderate delay and below 70 as severe delay. Questionnaires were used to get additional information about respiratory infections and CARA, using a Dutch selection from WHO questionnaire [21]. Everyday functioning and well-being of children older than 4 years was assessed by the Dutch version of the Child Health Questionnaire (CHQ) [22] and the Child Behavior Checklists 2–3 and 4–18 [23–25] were used to assess behavior. The follow-up staff was not involved in the antenatal or perinatal management of the children. Heparinized blood samples were obtained from 68% (17/25) of the children born between 1989 and 1995, aged z5 years at the time of sampling. Plasmas were kept at 80 8C until assayed for IgM, IgA, IgG and IgG subclassification (IgG Sc 1–4) concentrations (g/l) by nephelometry. The samples were compared to normal human IgG (total and Sc 1– 4), IgA and IgM (Behring Diagnostics, Ubridge, Middlesex) by a standardized Heidelberger–Kendall curve on a Behring Nephalometer 100 (BN 100) analyzer, the lower limit of detection being 0.04 g/l. Total IgE levels (IE/ml) were determined by

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standard fluoroenzyme immunoassay (FEIA) and compared to normal human IgE, the lower limit of detection being 2.00 IE/l (Pharmacia CAP system, Pharmacia Diagnostics, Uppsala, Sweden). All Ig levels were adjusted for age and compared to those of healthy infants in the general population [26,27]. 2.3. Statistical analysis Statistical analysis was performed with SPSS 11.0 for Windows (SPSS, Chicago, IL, USA). The results were analyzed with the chi-square test, the Mann–Whitney test, Fisher’s exact test, the Student’s t-test, or ANOVA. Correction for confounding was done with logistic regression for discrete variables. Results were considered significant if pb0.05.

3. Results The perinatal characteristics of the 50 children included in the follow-up are depicted in Table 1. ICH was not observed in any of the children at antenatal cerebral ultrasonography. Postnatal cerebral ultrasound was performed in 75% of cases of severe thrombocytopenia and confirmed neonatal absence of ICH. Five children had petechiae at birth. In the neonatal period, 11 children needed platelet transfusion(s), four received platelet transfusion(s) and IVIG (0.4 g/kg, 5 consecutive days) and one received IVIG treatment alone. Two children had serious problems in the neonatal period, associated with complications of FBS and/or IUPT, causing massive bleeding from the puncture site of the umbilical cord in one case [9] and fetal bradycardia after distraction and unsuccessful reentry of the needle in the other [15]. Both infants were severely thrombocytopenic at the start of the procedure. They were delivered by emergency cesarean section with subsequent asphyxia and prematurity in the first case [9] and severe asphyxia and neonatal death in the second case [15]. A third child, prematurely and healthy delivered by cesarean section with a normal birth weight after four uncomplicated IUPT and IVIG treatment over a 5-week period, suffered from convulsions. A neonatal cerebral ultrasonography showed flaring at both sides and an additional CT scan of the brain showed thrombosis of the sagittal sinus [15]. The mother used benzodiazepines (oxazepam) and a tricyclic antidepressant (dosulepin) during the pregnancy. In a fourth child, who had been treated with uncomplicated IUPT twice, both within 3 weeks before birth, postnatal cerebral ultrasonography at 2 weeks revealed periventricular leucomalacia (PVL). This child was born at term by spontaneous vaginal delivery, with a normal birth weight and without signs of perinatal asphyxia. Except for one neonatal death (2%) and one child lost to follow-up (2%), the total follow-up rate was 96% (48/50). Thirty-six children were seen at our center and another pediatrician examined two children at a center in their neighborhood. A developmental psychologist assessed 39 children (81%). For 10 children, the requested information was obtained from the parents by telephone [28]. The characteristics of this group were comparable to those of the 38 children presented for examination. The median age of the children at follow-up was 5.1 years (range 1.3–11.6 years).

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General health, assessed by physical examination and questionnaires on physical wellness, everyday functioning and well being and behavior, was comparable to that of the Dutch population [17–25]. Physical examinations did not reveal any major problems, except the presence of vitiligo in two (4.2%) children (C.I. 0–9.9%). The most frequently reported health problems in the study population were ear, nose and throat (ENT) problems. Forty-six percent (C.I. 31.7–59.9%) of the children had (recurrent) ear infections, adenoid or throat problems during infancy. In addition, the main reasons for admittance to the hospital were ENT problems, and the majority of the operations performed were due to ear and adenoid problems. Fourteen percent (C.I. 4.5–24.4%) of the children 4 years and older had had productive coughing for more than three weeks in the last 12 months. Abnormalities of the eyes, mostly strabismus, were present in 10.4% (C.I. 1.8–19.0%) of the children. The CHQ [22] physical and psychosocial summary measures of our study population were all in the normal range. Behavior as measured by the CBCL [23,24] only revealed a significantly higher somatic problems scale score in the 2–3 year old FNAIT infants (n=11) when compared to the Dutch control population (mean 5.1 versus 0.3 (C.I. 2.9–6.9%)) [25]. However, the total problem score for this group was in the normal range. Even so, the total problem score of the FNAIT infants in the group of 4– 18 years (n=22) was in the normal range. Table 2 shows the abnormalities of the study group compared to the normal population of Dutch children. The neurological examination performed in 38 of the 48 children showed normal results in 36 of them (95%) (Table 2). One child had serious neurological problems, i.e. cerebral palsy due to PVL, as described before. Another child had minor neurological dysfunction, but postnatal cerebral examination by ultrasound had not been performed. Cognitive ability was assessed in 39 children, and the median IQ was 104 (range 63–150), Table 2 Results of the general health status, neurodevelopmental outcome and susceptibility for infections or atopic constitution in 48 children antenatally treated for alloimmune thrombocytopenia at the LUMC compared with a normal population of Dutch children Study group n Outcome variable General health vitiligo abnormalities of eyes (strabismus) well-being (somatic problem score; 2–3 years) Neurodevelopmental abnormality neurological problems impaired cognition (IQb90) Infections productive coughingy recurrent ear, nose and throat problems hearing problemsz

%

C.I. (%)

Dutch population (%)*

2/48 5/48

4.2 10 5.1

(0.0–9.9) (1.8–19.0) (2.9–6.9)

0.5 3–4 0.3

2/48 4/39

4.2 10.3

(0.0–9.9) (0.8–19.8)

6.0 14–16

7/48 22/48 6/48

14 46 13

(4.5–24.4) (31.7–59.9) (3.5–22.5)

1.7 46 3

n=number; C.I.=95% confidence interval; *=population of normal (healthy) Dutch children, comparable in age to the study group; neurological problems=minor neurological dysfunction, without influence on normal posture or movement, or cerebral palsy, with abnormal posture and movement; impaired cognition=intelligence quotient (IQ)b90; y=for more than 3 weeks in the last 12 months; z=abnormal result at audiometry.

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which is normal. Four children had mild developmental delay (4/39=10.3%), with a median IQ of 82 (range 80–83) (Table 2). Perinatal data revealed no particular abnormalities in these children. Only the child with thrombosis of the sagittal sinus had a severe delay (IQ 63) and lives in an institution. Information about this child was obtained from the parents by telephone. To explore the effect of antenatal treatment more specifically, we distinguished infants treated with IVIG (dIVIGT, defined as IVIG with or without FBS or IUPT; n=37) and without (dNo IVIGT, defined as FBS or IUPT without IVIG; n=13) (Table 3). Comparison between both groups revealed no correlation between antenatal treatment with or without IVIG and perinatal features, general health or neurodevelopmental outcome. In the group of children that received antenatal IVIG, fewer ENT and hearing problems were found, especially in those that received IVIG treatment alone and after correction for the confounding variables prematurity, low birth weight, neonatal morbidity and smoking of Table 3 Associations between antenatal treatment with or without IVIG and outcome of the children IVIG, n=37

No IVIG, n=13

p

Perinatal features GA in weeks—median (range) Birth weight (g)—median (range) Plat. count (
109/l)—median (range) Plat. count b50
109/l—n=(%) Perinatal asphyxia—n=(%) Preterm delivery—n=(%)

37 (32–39) 2815 (1324–4100) 67 (1–252) 17 (46%) 0/36 14/37 (38%)

38 (34–40) 2920 (2150–3850) 32 (3–240) 7 (54%) 2/12 (17%) 2/13 (15%)

NS NS NS NS NS NS

Follow-up

n=36

n=12

p

Outcome—abnormalities Impaired general health—n=(%) Neurological abnormalities—n=(%) Cognitive delay—n=(%)

0/30 1/30 (3%) 4/30 (13%)

0/8 1/8 (13%) 1/8 (13%)

NS NS NS

Susceptibility to: Ear, nose and throat problems—n=(%) Hearing problems—n=(%) Pulmonal problems—n=(%) Allergies—n=(%) Eczema—n=(%)

7/36 1/36 4/36 3/35 6/36

7/12 5/12 4/12 1/12 2/12

0.02* 0.002y NS NS NS

(19%) (3%) (11%) (9%) (17%)

(58%) (42%) (33%) (8%) (17%)

IVIG=antenatal treatment with maternal administration of Intravenous Immunoglobulin; No IVIG=antenatal treatment with fetal blood sampling (FBS) or intrauterine platelet transfusion (IUPT), without IVIG; n=number; p=significant when b0.05; NS=not significant; GA=gestational age; Plat. count=platelet count at birth, defined as either the platelet count before delivery, at the last FBS but before an eventual IUPT, or by the count in the umbilical cord blood, when no FBS had been performed; Perinatal asphyxia=Apgar score b7 at 5 min and/ or umbilical cord pH b7.10 and/or neurological sequelae and/ or evidence of multiorgan dysfunction; Preterm delivery = b37 weeks GA; Neurological abnormalities=minor neurological dysfunction, without influence on normal posture or movement, or cerebral palsy, with abnormal posture and movement; Cognitive delay = intelligence quotient (IQ)b90; Pulmonal problems=Wheezing, productive coughing and pulmonary medication; *=after correction for cases treated with FBS and/or IUPT, gestational age, birth weight and smoking of the parents, p=0.009; y=after correction for cases treated with FBS and/or IUPT, gestational age, birth weight and smoking of the parents, p=0.03.

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Table 4 Associations between antenatal treatment and immunoglobulin levels of the children aged N5 years Immunoglobulin levels

IVIG, n=10

No IVIG, n=7

Median (range)

Median (range)

IgG IgG1 IgG2 IgG3 IgG4 IgA IgM IgE

9.7 6.3 1.6 0.3 0.4 0.7 0.8 86.8

9.7 6.0 1.8 0.2 0.3 0.7 0.8 28.5

(7.9–11.1) (5.5–7.5) (0.9–1.9)* (0.2–0.5) (0.1–0.5) (0.3–2.2) (0.5–1.8) (6.7–1264)b

(7.3–11.6) (4.3–7.1) (1.2–2.6) (0.2–0.4) (0.1–2.2)y (0.5–1.9) (0.7–1.3)z (2.0–624)§

p NS NS NS NS NS NS NS NS (0.05)w

IVIG=antenatal treatment with maternal administration of Intravenous Immunoglobulin; No IVIG=antenatal treatment with fetal blood sampling (FBS) or intrauterine platelet transfusion (IUPT), without IVIG; p=significant when b0.05; NS=not significant; IgG1–4=IgG, subclass 1 to 4; *=1/10 (10%) lower IgG2 level than the normal range of healthy infants of the general population; y=1/7 (14%) higher IgG4 level than the normal range of healthy infants of the general population; z=1/7 (14%) lower IgM level than the normal range of healthy infants of the general population; b =7/10 (70%) higher IgE level than the normal range of healthy infants of the general population; §=1/7 lower and 1/7 higher (29%) IgE level than the normal range of healthy infants of the general population; w=after exclusion of cases in the IVIG group treated with fetal blood sampling and/ or intrauterine platelet transfusion, only one case remained treated with IVIG alone.

the parents. Alternatively, in the group treated without antenatal IVIG, the higher occurrence of ENT and hearing problems was on account of IUPT treatment only. Additionally, increase of IVIG exposure (z5 weeks) decreased the occurrence of ENT problems ( p=0.007). Neonatal treatment with IVIG, platelet transfusions or a combination of both revealed no difference in any of the follow-up parameters (data not shown). In 17 children, aged 5 years or older, plasma IgM, IgA, IgG and IgG subclass (Sc) levels were measured. The concentrations were within the normal range for age [26,27], and similar in children exposed to IVIG or not exposed to IVIG (Table 4). IgE levels were higher ( p=0.05) in children who had been treated with antenatal IVIG (n=10) when compared to children that had not (n=7) or to a normal population of children adjusted for age. These higher levels, however, did not result in clinical expressions of increased allergic or atopic reactions (data not shown). Because most of the older children had not been treated with IVIG, there was an age-related normalization of high IgE levels in this group. The median age of infants with increased IgE levels was 7.3 (range 6–9 years) versus a median age of 9.1 (range 5.1–11.6 years) for those with normal or low IgE levels ( p=0.04) (data not shown). IgE levels were independent of the severity of FNAIT and not associated with a positive family history for allergic diseases or atopy or passive smoking.

4. Discussion The main purpose of this study was to evaluate clinical signs or symptoms as sequelae of antenatal treatment of FNAIT and possible immunosuppressive or immunostimulative effects of IVIG on the immune system of the fetus.

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In general, perinatal features revealed favorable outcome of pregnancies. In 24 neonates (48%), the platelet count was b50
109/l, but none of these children had suffered from ICH. Of the 48 children that could be included in the follow-up study, general health was comparable to that of the Dutch population and general examinations revealed no major problems. Everyday functioning, wellbeing and behavior of the children were in the normal range, except for the higher somatic problem score in the 2–3 year old group, which can be explained by the general high frequency of recurrent ear infections at this age. The presence of vitiligo, an immune-mediated disease, in two patients (4.2%) was remarkable, since the prevalence is 0.5% in the general population [29]. One of them also had eczema and the other had recurrent glue ears and persistent abnormal hearing tests, treated by insertion of tympanostomy tubes. Both had been delivered by elective cesarean section and had not been exposed to antenatal IVIG. The neurodevelopmental outcome and cognitive ability was normal in more than 80% of the children examined. Two children had serious neurodevelopmental abnormalities, but the incidence of 4.2% is comparable to the 6% disability and handicap rate among 2 year olds in the normal Dutch population [30]. Thrombosis of the sagittal sinus [31] and PVL are both associated with major neurodevelopmental sequelae and the causal relation to FNAIT is ambiguous. Four children (10.3%) had an IQ just above 80, without any elucidating clues in the perinatal period, compared to an IQ of 80–89 in 14–16% of children in the normal population [32,33]. Special attention was paid to the occurrence of upper respiratory infections and asthma, using a recommended selection of questions about symptoms of asthma and recurrent respiratory tract infections from the WHO questionnaire [21]. Productive coughing occurred more frequently in the study group than in a normal population of Dutch school children (14% compared to 1.7%), but there was no difference in the prevalence of wheezing or shortness of breath [34]. Forty-six percent of the study group had (recurrent) ear infections, adenoid or throat problems during infancy, which agrees with an observational study reporting more than three episodes of acute otitis media in 46% of children by the age of three [35]. In general, acute otitis media and otitis media with effusion are among the most frequent health problems in infancy. In a Dutch population, otitis media with effusion was observed in 20% of children aged one to six years, and hearing problems in 3% of children aged 4–18 years [36]. Antenatal treatment was divided into treatment with or without IVIG and treatment with or without interventions (FBS or IUPT). Interventions in alloimmunized pregnancies are known to be associated with at least 1.6% fetal loss per procedure [37,38], compared to a 0.8% perinatal death rate in the Netherlands (1999). In addition, emergency cesarean section is reported as a result of invasive procedures in 5% of cases [9,39]. In the study group two children were born severely asphyxiated due to procedure related complications of FBS and/or IUPT: one of them died shortly after birth (2%), while the other recovered and is developing well. Finally, 96% (23/24) of children with severe thrombocytopenia and all preterm deliveries were in the dinterventionT group [9]. An unexpected observation was the influence of IVIG on the prevalence of ENT problems in the infants. In the group of children treated with IVIG, 19% (C.I. 6.2–32%) had ENT problems and 3% (C.I. 0–8.6%) hearing problems, which is comparable to rates in the normal Dutch population (20% and 3%, respectively) [36]. In contrast, in the group of

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children treated without IVIG, 58% (C.I. 30–86%) ENT problems and 42% (C.I. 14–70%) hearing problems were reported. Differentiation in the dIVIGT group, including those children treated with IVIG alone without FBS and/or IUPT (n=9), even strengthened these associations. These results suggest that IVIG does not have an adverse effect and might even have a favorable influence on susceptibility for ENT and hearing problems compared to antenatal treatment without IVIG, although the small study groups may bias these results. IgG, IgGSc, IgA and IgM levels revealed concentrations within the normal range adjusted for age and independent of antenatal treatment and the severity of FNAIT. Only IgE levels revealed higher plasma concentration levels in children treated with antenatal IVIG compared to children not treated with IVIG or the normal population. There was an age-related decrease in IgE levels, likely due to the fact that the older children had not been treated with IVIG. Increased IgG4 levels, which have been described in atopic individuals, were not found. In the two cases with vitiligo, Ig levels were not measured, because information was obtained by telephone in one case and the child’s age was less than five years in the other. Although an almost significant association between a high IgE level and antenatal IVIG treatment was seen, there was no association between IgE level and ENT or hearing problems or other clinical expressions. Presumed mechanisms of immunomodulation by IVIG have been extensively described [11,14]. No specified data on the effect of IVIG treatment on the long-term developmental outcome of children treated for FNAIT were found in the literature. One study mentioned normal growth and development of children (up to 12 years old) which had been treated for FNAIT during fetal life [40]. A second study described normal IgG levels in a neonate after maternal IVIG treatment for ITP during fetal life [41]. We found a possible increase of IgE in children after maternal IVIG administration compared to the normal population. However, since a variety of different antenatal and postnatal factors may affect IgE levels in childhood, and considering the small number of our study population, confounding cannot be excluded. Therefore, an explanation for this interesting finding is not unequivocal. Individuals with atopy and allergy (asthma, rhinitis and dermatitis) generally have increased IgE and antigen-specific IgE levels associated with an imbalance of Th function towards an increased Th2 reaction [42]. It could be speculated that IVIG, by downregulating Th1 cytokines, enhances IgE antibody production through an imbalance of Th1/Th2 ratio. However, no associated clinical consequences were observed in any of the children. Perhaps the reversibility of the immunomodulating effects of IVIG described by Kawada and Terasaki [10] could offer an explanation for this observation. In conclusion, the general health status and neurodevelopmental outcome of children treated for FNAIT is comparable to that of the normal population and exposure to IVIG in utero does not seem to have clinically apparent adverse effects in early childhood. In order to draw more definitive conclusions, further immunological research and long-term follow-up studies, preferably in a larger group of patients, are required.

Acknowledgements The authors thank J. Verdoes, research nurse, for her logistical support and assistance; J. Feenstra and E. Kooyman for their assessment of the infants’ cognition; C.D. Wesseling

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