Antenatal Intravenous Immunoglobulin Research Articles

Identifying Pregnancies at Higher Risk for HPA-1a Alloimmunization and Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT): An International, Prospective, Natural History Study

Background and significance Fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from parental incompatibility of human platelet antigen (HPA) and subsequent maternal sensitization. When this occurs, fetal platelet production is impaired and platelet destruction accelerated. FNAIT is the platelet counterpart of Rhesus disease (RhD); however, FNAIT is rarer, more often occurs in first pregnancies, and alloimmunization may be detected as early as the 2nd trimester. Clinical presentation of FNAIT ranges from no/mild symptoms to severe thrombocytopenia and intracranial hemorrhage, which can take place in the second trimester and cause death or lifelong neurological impairment. Severe FNAIT outcomes impose substantial emotional and financial burden on affected families and healthcare systems. Among pregnant HPA-1a-negative women bearing an HPA-1a-positive fetus at risk of alloimmunization, ~27% carry the HLA-DRB3*01:01 gene variant, increasing sensitization risk ~25 fold and thus leading to much higher FNAIT risk. Screening for FNAIT in pregnancy is not routinely performed, unlike in RhD, resulting in failure to identify at-risk pregnancies prior to birth. To prevent severe FNAIT outcomes, we believe at-risk pregnancies must be identified very early in the second trimester, and prophylactic interventions started immediately. Current management of women with existing alloimmunization due to a prior FNAIT-affected pregnancy involves months of weekly antenatal intravenous immunoglobulin with or without steroid administration. Although fetal platelet counts often improve, this therapy is very burdensome to patients. Most data on FNAIT prevalence and risk are from Caucasian populations; studies in non-Caucasian populations have been too small to be informative. This is the first epidemiological study that seeks to identify HPA-1a-based FNAIT in a racially and ethnically diverse international population of pregnant women. Data to be tracked are: frequency of DRB3*0101 in HPA-1bb women; anti-HPA-1a alloimmunization; pregnancy outcomes; and neonatal thrombocytopenia. These data will provide a contemporary control population preceding future single-arm studies of a novel human anti-HPA-1a monoclonal antibody, RLYB212, in prophylaxis of maternal HPA-1a alloimmunization and FNAIT. The virtual elimination of RhD by screening of all pregnancies and administration of prophylaxis in at-risk cases remains one of the most significant medical advances ever achieved and provides a roadmap for FNAIT. Study design and methods Prospective, non-interventional, natural-history study assessing HPA-1a alloimmunization in pregnant women, conducted across multiple European centers in Norway, Netherlands, UK, and Germany, and in the USA. It will provide insights into anti-HPA-1a-mediated FNAIT risk and frequency among Caucasian and non-Caucasian pregnant women. Up to 30,000 women will be screened at gestational weeks 10-14 to enable early identification and follow-up of those women at higher alloimmunization risk, so that in the future, prophylaxis of the higher-risk women could be initiated. Informed consent will be requested for blood-sample collection at the 10-14 week visit for evaluation of FNAIT risk. Inclusion criteria Pregnant women aged ≥18 years Exclusion criteria Prior history of FNAIT or known HPA-1a alloimmunization Statistical methods Demographic, baseline characteristics and discrete variables will be summarized Primary objective To inform frequency of higher FNAIT risk among pregnant women of diverse racial and ethnic characteristics (all comers). (Figure) Secondary objectives Frequency of HPA-1a maternal alloimmunization at Weeks 10-14 postpartum in pregnant women at higher FNAIT risk and outcomes such as: - Spontaneous abortion: non-deliberate fetal death prior to 19 weeks of gestation - Elective abortion: deliberate termination of pregnancy at any time in gestation - Stillbirth: non-deliberate fetal death after 19 weeks of gestation - Premature birth: live birth prior to 37 completed weeks of gestation - Live births: ≥37 completed weeks of gestation Neonatal and severe neonatal thrombocytopenia: platelet count <150 × 10 9/L and <50 × 10 9/L, respectively, within 72 hours of birth Current status Enrolment for clinical-trial NCT05345561 is ongoing and expected to continue for ~3 years.

Pregnant Women at Low Risk of Having a Child with Fetal and Neonatal Alloimmune Thrombocytopenia Do Not Require Treatment with Intravenous Immunoglobulin.

Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare condition in which maternal alloantibodies to fetal platelets cause fetal thrombocytopenia that may lead to intracranial hemorrhage (ICH). Off-label intravenous immunoglobulin (IVIg) has for 30 years been the standard of care for pregnant women who previously have had a child with FNAIT. The efficacy of this treatment has never been tested in a placebo-controlled clinical trial. Although IVIg treatment may improve the neonatal outcome in women who previously have had a child with FNAIT-associated ICH, the question is whether IVIg is necessary for all immunized pregnant women at risk of having a child with FNAIT. The results from some recent publications suggest that antenatal IVIg treatment is not necessary for women who are (1) HPA-1a-immunized and HLA-DRB3*01:01-negative, (2) HPA-1a-immunized with a previous child with FNAIT but without ICH or (3) HPA-5b-immunized. If IVIg is not used for these categories of pregnant women, the amount of IVIg used in pregnant women with platelet antibodies would be reduced to less than ¼ of today's use. This is important because IVIg is a scarce resource, and the collection of plasma for the treatment of one pregnant woman is not only extremely expensive but also requires tremendous donor efforts.

Long-term neurodevelopmental outcome in children after antenatal intravenous immune globulin treatment in fetal and neonatal alloimmune thrombocytopenia

Children with fetal and neonatal alloimmune thrombocytopenia face increased risk of intracranial hemorrhage potentially leading to developmental impairment. To prevent intracranial hemorrhage, pregnant women with alloantibodies against fetal platelets are often treated with intravenous immunoglobulin. Intravenous immunoglobulin seems effective in vastly reducing the risk of fetal or neonatal bleeding complications. However, information on long-term neurodevelopment of these children is lacking. This study aimed to evaluate long-term neurodevelopmental outcome in children with fetal and neonatal alloimmune thrombocytopenia who were treated with intravenous immunoglobulin antenatally. An observational cohort study was performed, including children of mothers treated with intravenous immunoglobulin during pregnancy because a previous child was diagnosed with fetal and neonatal alloimmune thrombocytopenia. Children were invited for a follow-up assessment including standardized cognitive and neurologic tests. The parents were asked to complete a behavioral questionnaire and school performance reports. The primary outcome was severe neurodevelopmental impairment, defined as severe cognitive impairment (intelligence quotient <70), cerebral palsy with Gross Motor Function Classification System Level ≥3, bilateral blindness, and/or bilateral deafness (requiring amplification). The secondary outcome was mild to moderate neurodevelopmental impairment, defined as either mild to moderate cognitive impairment (intelligence quotient <85), cerebral palsy with Gross Motor Function Classification System Level ≤2, minor neurologic dysfunction, vision loss, and/or hearing loss. Between 2003 and 2017, 51 children were live-born after antenatal intravenous immunoglobulin treatment. One family moved abroad and was therefore not eligible for inclusion. In total, 82% (41/50) of the eligible cases were included for neurodevelopmental assessment at a median age of 9 years and 8 months. Severe neurodevelopmental impairment was not detected. The incidence of mild to moderate neurodevelopmental impairment was 14% (6/41; 95% confidence interval, 6%-29%). The children's mean cognitive score, behavioral scores, and academic achievement were not different from those observed in the Dutch norm groups. Neuroimaging was performed in 90% (37/41) of cases. Severe intracranial hemorrhage was diagnosed in 2 cases (5%), one antenatally before the start of intravenous immunoglobulin and the other case 1 day after birth. Both cases had a normal neurodevelopmental outcome. The risk of neurodevelopmental impairment in children whose mothers were treated for fetal and neonatal alloimmune thrombocytopenia with antenatal intravenous immunoglobulin is comparable to that reported in the general population.

Antenatal intravenous immunoglobulins in pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia: comparison of neonatal outcome in treated and nontreated pregnancies

Maternal alloantibodies to human platelet antigen-1a can cause severe intracranial hemorrhage in a fetus or newborn. Although never evaluated in placebo-controlled clinical trials, most Western countries use off-label weekly administration of high-dosage intravenous immunoglobulin in all pregnant women with an obstetrical history of fetal and neonatal alloimmune thrombocytopenia. In Norway, antenatal intravenous immunoglobulin is only recommended in pregnancies wherein a previous child had intracranial hemorrhage (high-risk) and is generally not given in other human platelet antigen-1a alloimmunized pregnancies (low-risk). To compare the frequency of anti-human platelet antigen-1a-induced intracranial hemorrhage in pregnancies at risk treated with intravenous immunoglobulin vs pregnancies not receiving this treatment as a part of a different management program. This was a retrospective comparative study wherethe neonatal outcomes of 71 untreated human platelet antigen-1a-alloimmunized pregnancies in Norway during a 20-year period was compared with 403 intravenous-immunoglobulin-treated pregnancies identified through a recent systematic review. We stratified analyses on the basis of whether the mothers belonged to high- or low-riskpregnancies. Therefore, only women who previously had a childwith fetal and neonatal alloimmune thrombocytopenia were included. Two neonates with brain bleeds were identified from 313 treated low-risk pregnancies (0.6%; 95% confidence interval, 0.2-2.3). There were no neonates born with intracranial hemorrhage of 64 nontreated, low-risk mothers (0.0%; 95% confidence interval, 0.0-5.7). Thus, no significant difference was observed in the neonatal outcome between immunoglobulin-treated and untreated low-risk pregnancies. Among high-risk mothers, 5 of 90 neonates from treated pregnancies were diagnosed with intracranial hemorrhage (5.6%; 95% confidence interval, 2.4-12.4) compared with 2 of 7 neonates from nontreated pregnancies (29%; 95% confidence interval, 8.2-64.1; P=.08). The most reliable data hitherto for the evaluation of intravenous immunoglobulins treatment in low-risk pregnancies is shown herein. We did not find evidence that omitting antenatal intravenous immunoglobulin treatment in low-risk pregnancies increases the risk of neonatal intracranial hemorrhage.

Platelet alloimmunization is associated with low grade chronic histiocytic intervillositis - A new link to a rare placental lesion?

IntroductionMaternal alloimmunization against human platelet antigen (HPA)-1a has been implied to mediate both reduced birth weight and chronic placental inflammation. Fetal growth restriction is associated with different types of chronic inflammation in the placenta, mainly chronic histiocytic intervillositis and chronic villitis. The aim of this prospective study was to do a systematic examination of placentas from HPA-1a alloimmunized pregnancies, with focus on the histopathological and immunohistochemical diagnosis of variants of chronic inflammation. Material and methodsIn a Polish-Norwegian study, 48 placentas were examined. The histopathology of placentas from 27 HPA-1a immunized women was compared with 21 placentas from non-immunized HPA-1a negative women (controls). In the group of alloimmunized women, ten received antenatal intravenous immunoglobulin G (IVIg). Tissue sections from formalin fixed paraffin embedded placental tissue were stained with hematoxylin and eosin and microscopically examined with focus on various types of chronic placental inflammations. ResultsChronic histiocytic intervillositis was observed in 40.7% of placentas from HPA-1a alloimmunized pregnancies, compared to none in the control group (p ​= ​0.001). Chronic villitis of unknown etiology was more frequently found in the alloimmunized group, however this difference was not statistically significant. Maternal administration of IVIg did not seem to protect against chronic inflammatory lesions. DiscussionPlacentas with detectable maternal anti-HPA-1a antibodies are associated with highly increased risk of low-grade chronic histiocytic intervillositis.

Maternal intravenous immunoglobulin: A non-invasive treatment option for Rhesus D-sensitised women with previous adverse pregnancy outcomes

Background. Maternal intravenous immunoglobulin (IVIG) may delay the onset and severity of fetal anaemia in Rhesus D (RhD)- sensitised pregnancies, thereby minimising the need for intrauterine transfusion and its associated complications. Objective. To compare the pregnancy outcomes of RhD-sensitised women who received antenatal IVIG with those who did not receive antenatal IVIG. Methods. This was a retrospective cross-sectional analysis of RhD-sensitised women who attended the Wits Fetal Medicine Centre (Johannesburg) from 1 January 2008 to 31 May 2018. Criteria for maternal IVIG administration were: (i) previous adverse pregnancy outcome (early neonatal death, intrauterine fetal death or miscarriage related to RhD sensitisation), ( ii ) women with high antibody titre levels (≥1:64) in the absence of fetal anaemia; and ( iii ) rising antibody titre levels. Maternal antibody titre levels, pregnancy and neonatal outcomes were compared in women who received IVIG v. those who did not receive IVIG. Results. Of the 42 RhD-sensitised women, 14 received IVIG. A greater proportion of women experienced a decrease in antibody titres in the IVIG v. no-IVIG group (43% v. 11%, respectively; p =0.04). Nine of the 10 women in the IVIG group with a previous adverse pregnancy outcome had a successful pregnancy outcome following IVIG treatment. Conclusion. Maternal IVIG may provide a successful pregnancy outcome in RhD-sensitised women with previous adverse pregnancy outcomes related to Rh disease, or women with raised or increasing maternal antibody titre levels who present in the first or early second trimester.

Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT): Guidance to Reduce the Risk of Intracranial Bleeding

IntroductionFNAIT is associated with severe bleeding, especially intracranial hemorrhage (ICH), in the fetus and/or newborn. More than 75% of ICHs occur in utero and up to 50% before 32 weeks gestation. The consequences of ICH include death (35%) or serious neurological sequelae in survivors (83%). FNAIT requires prompt identification and treatment antepartum, postpartum and in subsequent pregnancies. An international panel was convened by the International Collaboration for Transfusion Medicine Guidelines (ICTMG) to develop evidence based recommendations for diagnosis and management of FNAIT.MethodsThe international panel consisted of specialists in adult and pediatric hematology, maternal fetal medicine (MFM), neonatology, methodology, transfusion medicine, and a patient representative. Clinical questions were developed for diagnostic testing, antenatal screening and management, and postnatal interventions. A systematic search for articles published between 1946 and June 2017 in MEDLINE, EMBASE and Cochrane was conducted. Recommendations were formulated based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method which incorporates the quality of the evidence, benefits and risks, and resource utilization. Web conferences and electronic correspondence were used to discuss the results of the systematic reviews and formulate recommendations. Considerations for clinical practice such as dosing of intravenous immunoglobulin (IVIG) and corticosteroids were detailed. Electronic surveys were sent to all members to assess agreement with recommendations. The final guidance document was sent to maternal fetal, hematology and pediatric societies for comments.ResultsThree systematic reviews (antenatal management, postnatal management and use of laboratory investigations to identify pregnancies at risk) were developed. Antenatal recommendations: Women with FNAIT in a previous pregnancy or sisters of women with FNAIT should be referred to MFM centers. Fetal HPA typing (e.g. HPA-1a/1b) should be performed in HPA-immunized pregnant women when the paternity is unknown or the partner is heterozygous or unavailable for testing. Prenatal HPA-1 typing should preferentially be performed by a non-invasive method e.g. cell-free fetal DNA (cffDNA) in maternal plasma if adequately quality assured. Antenatal IVIG administration to the mother commencing at 12-16 weeks gestation should be offered to all women in a subsequent pregnancy with maternal fetal incompatibility who have had a previous fetus or neonate with FNAIT related ICH. For all other pregnancies with a previous neonate with FNAIT (without ICH), administering antenatal IVIG to the mother should be discussed prior to a subsequent pregnancy or when pregnancy with maternal fetal incompatibility is confirmed. If corticosteroids are used with IVIG, dexamethasone should not be used because of the associated risk of oligohydramnios. Postnatal recommendations: HPA-selected platelets should be made available at delivery for potentially affected infants to increase the neonatal platelet count. If HPA-selected platelets are not immediately available, unselected platelets should be used. In the presence of life-threatening neonatal hemorrhage such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain platelet counts above 50 to 100x109/L for at least 7 days. In the absence of life-threatening bleeding in a neonate such as intracranial or gastrointestinal bleeding, platelets should be transfused to maintain a platelet count above 30x109/L.ConclusionsThe intent of this guidance document developed from systematic reviews is to promote best practices in the management of FNAIT. The guideline development group developed algorithms for treatment, podcasts for physicians and patients, pamphlets for patients and a slide set to assist with the implementation of recommendations into practice. This expert panel identified key areas for future research. One is the optimal approach to antenatal management of the next affected pregnancy. Developing biomarkers of fetal severity would be critical to this endeavor. In addition, creating comprehensive screening to identify HPA-1b1b women at risk of FNAIT would advance successful prevention of this disease. DisclosuresBakchoul:German Research Society (DFG): Research Funding; Aspen Germany gGmbH, CLS Behring, Stago gGmbH: Honoraria; Robert Bosch gGmbH: Research Funding. Kjaer:Prophylix Pharma: Equity Ownership. Kjeldsen-Kragh:Prophylix Pharma: Equity Ownership. Oepkes:Towards routine HPA screening in pregnancy: Research Funding. Bussel:Uptodate: Honoraria; Rigel: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Protalex: Consultancy; Amgen Inc.: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Momenta: Consultancy. Arnold:Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding; UCB: Consultancy; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; UCB: Consultancy; Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Savoia:Neonatal Alloimmune Thrombocytopenia Registry of the Transfusion Outcomes Research Collaborative (TORC) Australia: Membership on an entity's Board of Directors or advisory committees.

Antenatal Treatment with Intravenous Immunoglobulin to Prevent Gestational Alloimmune Liver Disease: Comparative Effectiveness of 14-Week versus 18-Week Initiation

Background: Antenatal therapy with high-dose intravenous immunoglobulin (IVIG) may prevent gestational alloimmune liver disease (GALD). Objective: The objective of this study was to determine the effectiveness of this approach in a large cohort of women at risk for poor pregnancy outcome due to GALD. Methods: Women with a history of affected offspring were provided antenatal IVIG treatment and data were acquired prospectively from 1997 to 2015. The outcomes of treated pregnancies were compared to those of untreated pregnancies, and the effectiveness of starting at 14 weeks was compared to that of starting at 18 weeks. Results: A total of 188 treated pregnancies in 151 women were analyzed. Only 30% (n = 105) of untreated gestations resulted in healthy offspring as compared to 94% (n = 177) of treated pregnancies (p < 0.0001). Treated gestations of both the 14-week (n = 108) and the 18-week (n = 80) start cohort showed a decreased rate of fetal loss relative to untreated gestations (p < 0.0001). Equivalent outcomes were recorded in the 18-week versus the 14-week start cohort (p > 0.05). Few adverse events or complications of antenatal therapy were recorded. Conclusion: Antenatal therapy with high-dose IVIG initiated at either 18 or 14 gestational weeks effectively prevents poor outcome of pregnancies at risk for GALD.

Blood group A mothers are more likely to develop anemia during antenatal intravenous immunoglobulin treatment of fetal and neonatal alloimmune thrombocytopenia.

Incompatibility between parental platelet (PLT) antigens may lead to sensitization of mother and development of fetal and neonatal alloimmune thrombocytopenia (FNAIT) resulting in fetal thrombocytopenia. Intravenous immunoglobulin (IVIG) with or without prednisone is the most effective, evidence-based antenatal treatment for subsequent FNAIT-affected pregnancies. IVIG infusion causes hemolysis in other settings, the degree depending upon patient blood groups (BGs). In ClinicalTrials.gov NCT00194987, 102 pregnant women received randomized antenatal treatment: Arm A received 2g/kg/week IVIG; Arm B received 1 g/kg/week IVIG + 0.5 mg/kg/day prednisone. This post hoc analysis explored BG and anemia in 69 FNAIT mothers treated with Arm A or Arm B without salvage treatment to explore the effects of IVIG and steroid treatment on development of anemia in these women. Mothers whose treatment changed, for example, those with insufficient or unknown fetal PLT response who received salvage therapy, were excluded. For Arm A, 17 of 21 (hemoglobin [Hb]<10 g/dL) mothers with anemia but only three of 15 mothers without anemia had BG-A and/or BG-B (p=0.0005). BG was unrelated to anemia in Arm B; only nine of 33 Arm B mothers became anemic during treatment. The mean decrease in Hb level in women with BG-non-O was 1.9g/dL and in women with BG-O was 1.1 g/dL (p=0.004). Anemia was not caused by iron deficiency; the lowest mean corpuscular volume was 79. FNAIT women with BG-non-O more frequently develop anemia secondary to high-dose IVIG infusion (2g/kg/week), quite possibly from isohemagglutinin-mediated hemolysis; maternal Hb requires monitoring. IVIG at 1g/kg/week did not cause anemia in women with BG-non-O; concomitant prednisone likely alleviated the IVIG effect. Maternal BG could influence selection of antenatal treatment for FNAIT.

Fetal and neonatal alloimmune thrombocytopenia: predictive factors of intracranial hemorrhage.

In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most frequently caused by maternal alloimmunization against the human platelet antigen HPA-1a. The most serious complication of severe FNAIT is intracranial hemorrhage (ICH). ICH mainly occurs in utero; therefore, there is a need to identify noninvasive predictive factors of ICH to facilitate early identification of this condition and to determine response to maternal therapy. We studied gynecologic and immunogenetic variables of severe cases of anti-HPA-1a FNAIT within three groups: Group I, FNAIT without ICH; Group II, FNAIT with ICH; and Group III, suspected FNAIT cases without detectable maternal anti-HPA-1a alloantibodies. ICH was associated with a poor outcome because it led to death in 59% of cases. Multigravida (two or more pregnancies) was overrepresented in Group II, consistent with the high concentrations of maternal HPA-1a alloantibody and the frequent detection of a strong newborn-specific HLA class I antibody response at delivery. The proportion of HLA-DRB4*01:01P (*01:01 or *01:03) women was similar in Groups I and II, but this allele was overrepresented in Group III, in which FNAIT was less severe than in the other two groups. Finally, antenatal intravenous immunoglobulin therapy tended to be more effective in HLA-DRB3*01:01(+)/HLA-DRB4*01:01P(+) women than for HLA-DRB3*01:01(+)/HLA-DRB4*01:01P(-) women. The number of gestations is a predictive factor of ICH in anti-HPA-1a-alloimmunized women. Maternal immunogenetic variables should be investigated in the context of maternal immunization and may predict response to maternal therapy in subsequent pregnancies.

Suppression of in vitro megakaryopoiesis by maternal sera containing anti-HPA-1a antibodies

AbstractIncompatibility of the human platelet antigen-1 (HPA-1) system is the most common cause of fetal/neonatal alloimmune thrombocytopenia (F/NAIT) and is thought to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We evaluated the effect of maternal sera containing anti-HPA-1a antibodies (F/NAIT sera) on in vitro megakaryopoiesis. Compared with control maternal sera, 14 out of 17 F/NAIT sera significantly reduced megakaryocyte (MK) number. This finding was associated with increased apoptosis and cell death of early MKs/MK progenitors, but normal maturation and differentiation of surviving MKs. An analysis of platelet counts in infants born to mothers following antenatal intravenous immunoglobulin (IVIG) ± prednisone therapy demonstrated a significant and moderately strong correlation between the MK growth in cultures and the infants' platelet counts at birth. These findings suggest that maternal anti-HPA-1a antibodies can suppress fetal megakaryopoiesis by inducing early cell death and that this influences the neonatal platelet count. Thus, the ability of maternal antibodies to suppress MK growth is a potential predictive factor for the fetal response to maternal IVIG therapy.

True risk of fetal/neonatal alloimmune thrombocytopenia in subsequent pregnancies: a prospective observational follow‐up study

To assess neonatal platelet counts by comparing alloimmunised pregnancies from a Norwegian screening and intervention study with subsequent pregnancies from the same women. Prospective observational follow-up study. A university hospital. HPA-1a immunised women from a large Norwegian screening study that gave birth to one or more children after the screening study ended (2004-2012). Follow-up of maternal anti-HPA-1a antibody levels and neonatal platelet counts from the screening pregnancies were compared with subsequent pregnancies. None of the women received antenatal intravenous immunoglobulin (IVIG) treatment and neonatal platelet counts were therefore comparable. Change in neonatal platelet counts from one HPA-1a incompatible pregnancy to the next. Maternal anti-HPA-a1 antibody levels from one HPA-1a incompatible pregnancy to the next. Forty-five incompatible subsequent pregnancies were identified. Overall, the neonatal platelet count in the subsequent pregnancy was improved (18%), unchanged (52%), or worse (30%), compared with the corresponding screening pregnancy. There was one case of fetal intracranial haemorrhage (ICH) identified in the screening (intrauterine fetal death detected at 30weeks of gestation) and no ICH cases recorded for the subsequent pregnancies. In cases where the platelet count was lower in the subsequent pregnancy, the maternal anti-HPA-1a antibody level was higher compared with the screening pregnancy. In comparison, the maternal antibody level was lower in subsequent pregnancies where the platelet count improved. In contrast to what is often stated, we found that the neonatal platelet count was increased or unchanged in the majority of subsequent pregnancies of HPA-1a-immunised women.

Neonatal liver failure: A refractory case to medical treatment

Neonatal liver failure (NLF) is rare and carries a high mortality. Common aetiologies include neonatal haemochromatosis (NH), haematological malignancies, viral infections and liver-based metabolic defects. Early diagnosis and referral to a paediatric liver centre is recommended as liver transplantation is the only definitive treatment when supportive or a disease-specific treatment fails. A baby girl was born by Emergency LSCS for pathological cardiotocography at 33+2 weeks of gestation. Her mother had been previously well and had normal pregnancy. She was birth in poor condition requiring cardiopulmonary resuscitation. She was transferred to a level 2 neonatal unit for ventilator management. At birth she had coagulopathy which remained refractory to medical treatment. She required multiple ionotropes, multiple blood products and high dextrose load. She was transferred to a tertiary neonatal unit for the management of acute renal failure. With persistent evidence of only marginally raised liver enzymes and significantly reduced synthetic and excretory function of liver it was unlikely to be explained by solely bacterial or viral illness. Extensive infection screen were negative. Metabolic screening tests were done. She was referred to liver unit. Lip biopsy confirmed the diagnosis of NH. She had a liver transplant on day 36 of life. Histology showed nodular cirrhosis secondary to neonatal haemochromatosis. At age 4 months, she is continuing to thrive well with normal liver function tests. NH is the single most common cause of NLF (40%) and usually presents with severe neonatal liver disease associated with hepatic and extrahepatic iron deposition but sparing the reticulo-endothelial system. NH is hypothesised to be an alloimmune process where maternal antibodies are directed towards fetal liver antigen. Rate of recurrence in subsequent pregnancy is up to 80% and could be effectively prevented by antenatal intravenous immunoglobulin. Early and aggressive medical treatment is essential for improving the outcome. Treatment conundrum of NH continues with some case series showing a success rate of 10 to 20% following a ‘cocktail’ of antioxidants and chelating agents which have not been evaluated systematically and liver transplantation remains the only definitive treatment.