Marije M. Kamphuis

Fetal intracranial haemorrhages caused by fetal and neonatal alloimmune thrombocytopenia: an observational cohort study of 43 cases from an international multicentre registry

Objective To characterise pregnancies where the fetus or neonate was diagnosed with fetal and neonatal alloimmune thrombocytopenia (FNAIT) and suffered from intracranial haemorrhage (ICH), with special focus on time of bleeding onset. Design Observational cohort study of all recorded cases of ICH caused by FNAIT from the international No IntraCranial Haemorrhage (NOICH) registry during the period 2001–2010. Setting 13 tertiary referral centres from nine countries across the world. Participants 37 mothers and 43 children of FNAIT pregnancies complicated by fetal or neonatal ICH identified from the NOICH registry was included if FNAIT diagnosis and ICH was confirmed. Primary and secondary outcome measures Gestational age at onset of ICH, type of ICH and clinical outcome of ICH were the primary outcome measures. General maternal and neonatal characteristics of pregnancies complicated by fetal/neonatal ICH were secondary outcome measures. Results From a total of 592 FNAIT cases in the registry, 43 confirmed cases of ICH due to FNAIT were included in the study. The majority of bleedings (23/43, 54%) occurred before 28 gestational weeks and often affected the first born child (27/43, 63%). One-third (35%) of the children died within 4 days after delivery. 23 (53%) children survived with severe neurological disabilities and only 5 (12%) were alive and well at time of discharge. Antenatal treatment was not given in most (91%) cases of fetal/neonatal ICH. Conclusions ICH caused by FNAIT often occurs during second trimester and the clinical outcome is poor. In order to prevent ICH caused by FNAIT, at-risk pregnancies must be identified and prevention and/or interventions should start early in the second trimester.

Incidence and Consequences of Neonatal Alloimmune Thrombocytopenia: A Systematic Review

BACKGROUND: Neonatal alloimmune thrombocytopenia (NAIT) is a potentially devastating disease that may lead to intracranial hemorrhage in the fetus or neonate, often with death or major neurologic damage. There are no routine screening programs for NAIT, preventive measures are taken only in a subsequent pregnancy. To estimate the population incidence of NAIT and its consequences, we conducted a review of the literature. Our results may aid in the design of a screening program. METHODS: An electronic literature search included Medline, Embase, Cochrane database and references of retrieved articles. Eligible for inclusion were all prospective studies aimed at diagnosing NAIT in a general, nonselected newborn population, with sufficient information on platelet count at birth, bleeding complications, and treatment. Titles and abstracts were reviewed, followed by review of full text publications. Studies were independently assessed by 2 reviewers for methodologic quality. Disagreements were resolved by consensus, including a third reviewer. RESULTS: From the initial 768 studies, 21 remained for full text analysis, 6 of which met the inclusion criteria. In total, 59 425 newborns were screened, with severe thrombocytopenia in 89 cases (0.15%). NAIT was diagnosed in 24 of these 89 newborns (27%). In 6 (25%) of these cases, an intracranial hemorrhage was found, all likely of antenatal origin. CONCLUSIONS: NAIT is among the most important causes of neonatal thrombocytopenia. Intracranial hemorrhage due to NAIT occurs in 10 per 100 000 neonates, commonly before birth. Screening for NAIT might be effective but should be done antenatally.

Implementation of routine screening for Kell antibodies: does it improve perinatal survival?

BACKGROUND: In 1998 a national program for first‐trimester screening for red cell (RBC) antibodies in all pregnant women was implemented. The aim of our study was to assess the impact on perinatal mortality caused by Kell alloimmunization

Low-Dose versus Standard-Dose Intravenous Immunoglobulin to Prevent Fetal Intracranial Hemorrhage in Fetal and Neonatal Alloimmune Thrombocytopenia: A Randomized Trial

Objective: Pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia (FNAIT) are commonly treated using weekly intravenous immunoglobulin (IVIG) at 1 g/kg maternal weight. IVIG is an expensive multidonor human blood product with dose-related side effects. Our aim was to evaluate the effectiveness of IVIG at a lower dose, i.e. 0.5 g/kg. Methods: This was a randomized controlled multicenter trial conducted in Sweden, the Netherlands and Australia. Pregnant women with human platelet antigen alloantibodies and an affected previous child without intracranial hemorrhage (ICH) were enrolled. The participants were randomized to IVIG at 0.5 or 1 g/kg per week. The analyses were per intention to treat. The primary outcome was fetal or neonatal ICH. Secondary outcomes were platelet count at birth, maternal and neonatal IgG levels, neonatal treatment and bleeding other than ICH. Results: A total of 23 women were randomized into two groups (low dose: n = 12; standard dose: n = 11). The trial was stopped early due to poor recruitment. No ICH occurred. The median newborn platelet count was 81 × 109/l (range 8-269) in the 0.5 g/kg group versus 110 × 109/l (range 11-279) in the 1 g/kg group (p = 0.644). Conclusion: The risk of adverse outcomes in FNAIT pregnancies treated with IVIG at 0.5 g/kg is very low, similar to that using 1 g/kg, although our uncompleted trial lacked the power to conclusively prove the noninferiority of using the low dose.

Severe bleeding complications other than intracranial hemorrhage in neonatal alloimmune thrombocytopenia: a case series and review of the literature

The most feared bleeding complication in fetal and neonatal alloimmune thrombocytopenia (FNAIT) is an intracranial hemorrhage (ICH). However, FNAIT may also lead to other severe bleeding problems. The aim was to analyze this spectrum and evaluate the occurrence of severe hemorrhages other than ICH in fetuses or neonates with FNAIT.

Lower-dose intravenous immunoglobulins for the treatment of fetal and neonatal alloimmune thrombocytopenia: a cohort study.

Intravenous immunoglobulins (IVIGs) are the cornerstone in the treatment of pregnancies at risk for fetal and neonatal alloimmune thrombocytopenia (FNAIT). The most commonly used dose is 1.0 g/kg/week, not based on any dose‐finding study. IVIG is an expensive multidonor human blood product with dose‐related side effects. Our aim was to describe the amount of severe thrombocytopenia according to two different doses of IVIG.

Fetal and Neonatal Alloimmune Thrombocytopenia: Management and Outcome of a Large International Retrospective Cohort.

Objective: To evaluate the management and outcome of a large international cohort of cases of pregnancies complicated by fetal and neonatal alloimmune thrombocytopenia (FNAIT). Methods: This was an observational prospective and retrospective cohort study of all cases of FNAIT entered into the international multicentre No IntraCranial Haemorrhage (NOICH) registry during the period of 2001-2010. We evaluated human platelet antigen (HPA) specificity, the antenatal and postnatal interventions performed, and clinical outcome. Results: A total of 615 pregnancies complicated by FNAIT from 10 countries were included. Anti-HPA-1a was the most commonly implicated antibody. Antenatal treatment was administered in 273 pregnancies (44%), varying from intrauterine platelet transfusion to maternal administration of immunoglobulins, steroids, or a combination of those. Intracranial haemorrhage was diagnosed in 23 fetuses or neonates (3.7%). Overall perinatal mortality was 1.14% (n = 7). Conclusion: This study presents the largest cohort of cases of FNAIT published. Our data show that antenatal treatment for FNAIT results in favourable perinatal outcome. Over time, in most centres, treatment for FNAIT changed from an invasive to a complete non-invasive procedure.

Perinatal Outcome and Long-Term Neurodevelopment after Intracranial Haemorrhage due to Fetal and Neonatal Alloimmune Thrombocytopenia

Objectives: To evaluate the perinatal and long-term neurodevelopmental outcome in a cohort of children with intracranial haemorrhage (ICH) due to fetal and neonatal alloimmune thrombocytopenia (FNAIT) and to clearly outline the burden of this disease. Subjects and Methods: We performed an observational cohort study and included all consecutive cases of ICH caused by FNAIT from 1993 to 2015 at Leiden University Medical Centre. Neurological, motor, and cognitive development were assessed at a minimum age of 1 year. The primary outcome was adverse outcome, defined as perinatal death or severe neurodevelopmental impairment (NDI). Severe NDI was defined as any of the following: cerebral palsy (Gross Motor Function Classification System [GMFCS] level ≥II), bilateral deafness, blindness, or severe motor and/or cognitive developmental delay (<–2 SD). Results: In total, 21 cases of ICH due to FNAIT were included in the study. The perinatal mortality rate was 10/21 (48%). Long-term outcome was assessed in 10 children (n = 1 lost to follow-up). Severe and moderate NDI were diagnosed in 6/10 (60%) and 1/10 (10%) of the surviving children. The overall adverse outcome, including perinatal mortality or severe NDI, was 16/20 (80%). Conclusions: The risk of perinatal death or severe NDI in children with ICH due to FNAIT is high. Only screening and effective preventive treatment can avoid this burden.

Contents Vol. 41, 2017

R. Achiron, Tel Hashomer N.S. Adzick, Philadelphia, PA L. Allan, London A.A. Baschat, Baltimore, MD K.J. Blakemore, Baltimore, MD T.-H. Bui, Stockholm F.A. Chervenak, New York, NY T. Chiba, Tokyo R. Chmait, Los Angeles, CA F. Crispi, Barcelona J.E. De Lia, Milwaukee, WI J.A. Deprest, Leuven G.C. Di Renzo, Perugia J.W. Dudenhausen, Berlin N.M. Fisk, Brisbane, QLD A.W. Flake, Philadelphia, PA U. Gembruch, Bonn M.R. Harrison, San Francisco, CA J.C. Hobbins, Denver, CO L.K. Hornberger, Edmonton, AB E.R.M. Jauniaux, London M.P. Johnson, Philadelphia, PA J.-M. Jouannic, Paris P.M. Kyle, London O. Lapaire, Basel S. Lipitz, Tel Hashomer E. Llurba, Barcelona G. Malinger, Tel Aviv G. Mari, Detroit, MI M. Martinez-Ferro, Buenos Aires A. McLennan, Sydney, NSW K.J. Moise, Houston, TX F. Molina, Granada K.H. Nicolaides, London L. Otaño, Buenos Aires Z. Papp, Budapest R.A. Quintero, Miami, FL G. Ryan, Toronto, ON J. Rychik, Philadelphia, PA H. Sago, Tokyo W. Sepulveda, Santiago P. Stone, Auckland D.V. Surbek, Bern B.J. Trudinger, Westmead, NSW Y. Ville, Paris J.M.G. van Vugt, Nijmegen Clinical Advances and Basic Research