Unlike in hemolytic disease of the fetus and newborn (HDFN) caused by maternal sensitization to fetal Rhesus D (RhD) inherited from the father (the red cell equivalent of FNAIT), FNAIT often occurs in the first pregnancy. However, there is currently no consensus regarding the utility of screening in previously unaffected women for antiplatelet antibodies and thus identifying women whose babies could be affected by FNAIT early in gestation (discussed in Sect. 16.11). Active antenatal management of this disease is confined to those women who have had a previously affected fetus [7]. There are important differences between RhD isoimmunization and FNAIT (Table 16.2).

The diagnosis of FNAIT is based on clinical and serological findings. The typical picture is of a neonate presenting with purpura within minutes to hours after birth, born to a healthy mother with no history of a bleeding disorder, after an uneventful pregnancy with a normal maternal platelet count [37–40]. The first step in the diagnosis of FNAIT is confirmation of neonatal thrombocytopenia, followed by exclusion of the most frequent causes of neonatal thrombocytopenia such as infection, disseminated intravascular coagulation, and maternal immune thrombocytopenia (ITP) [11, 39]. The platelet count is low at birth and tends to fall further during the first 24–48 h of life. Laboratory diagnosis involves the detection of maternal circulating alloantibodies against a HPA type shared by neonatal and paternal platelets. This is accomplished using the monoclonal antibody-specific immobilization of platelet antigen (MAIPA) test [41], the platelet immunofluorescence test, or a novel antigen-specific particle assay [11, 26, 42–46]. The diagnosis of FNAIT is unequivocal when a parental incompatibility with corresponding maternal alloantibody is present [4, 10, 39, 47].

Recognition of FNAIT and appropriate therapy are important both for the affected neonate and for the management of subsequent pregnancies [48]. Indications for testing for FNAIT prenatally include any fetus with ICH, selected cases of ventriculomegaly (e.g., moderate to severe unilateral), neonates with thrombocytopenia of unclear etiology, neonatal ICH with significant thrombocytopenia, and familial transient neonatal thrombocytopenia [49–52]. A number of FNAIT cases (10 %) have been reported in which no HPA antibody could be detected [53–56]. The diagnosis is then based on maternal-fetal or maternal-paternal HPA incompatibility and exclusion of other causes of thrombocytopenia [54, 57, 58]. In some cases, antibodies may become detectable in the weeks or months after delivery or during/after a subsequent pregnancy [39, 40, 59, 60]. In unconfirmed FNAIT cases, antibodies detected before 20 weeks in a subsequent pregnancy require confirmation by a later specimen, because early transient antibodies may exist and do not seem to be of clinical significance [60]. Some studies have demonstrated significant correlation between high anti-HPA-1a antibody titers (>1:32) and a fetal platelet count below 50 × 10⁹/L [21, 59, 60], whereas others have not [17, 36, 61]. This discrepancy may be due to differences in the size of the series, parity of the women, timing of blood sampling, or the method of antibody titration [61].

HPA typing of mother, father and fetus/neonate is important, not only for the diagnosis of FNAIT but also for provision of HPA-matched blood components to neonates with FNAIT, for genetic counseling and for estimation of the recurrence risk [62]. Conventional serological immuno-phenotyping for HPA is limited by the lack of certain rare but well-characterized typing antisera, such as anti-HPA-1b and anti-HPA-4b [62]. Even when non-paternity has been ruled out, it is not always possible to demonstrate parental incompatibility of platelet-specific alloantigens in the presence of corresponding maternal alloantibodies, especially if the mother is sensitized to a rare paternal antigen, making the diagnosis more difficult [63]. If there is a strong suspicion of FNAIT, testing the maternal serum against the paternal platelets (using a blood sample from the father or the fetus/neonate) may confirm incompatibility.

FNAIT may affect the fetus as early as the beginning of the second trimester and usually remits spontaneously within 1–3 weeks after delivery, depending on the rate of removal of maternal platelet antibodies from the neonatal circulation. Thrombocytopenia can be severe and can cause antenatal ICH in around 10–30 % of severe cases. ICH is associated with death in 10 % and neurological sequelae in a further 10–20 % [6, 11, 39, 50]. Chaoying et al. [64] found that FNAIT is the most important cause of ICH and poor outcome in neonates.

Around 25–50 % of cases of FNAIT-related ICH occur in utero. The majority occur between 30 and 35 weeks of gestation [7, 50], but ICH have also been reported at earlier gestations. The international No IntraCranial Haemorrhage (NOICH) registry, an observational cohort study, characterised pregnancies between 2001 and 2010 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. Of 592 FNAIT cases in the registry, 43 confirmed cases of ICH due to FNAIT were included in the study. The majority of bleeding episodes (23/43; 54 %) occurred before 28 weeks of gestation and often affected the first born child (27/43; 63 %). One-third (35 %) of the children died within 4 days after delivery. Twenty-three (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. The authors concluded that 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 [65]. Without treatment, there is a risk of ICH as long as severe thrombocytopenia persists [23]. Thrombocytopenia is most severe in the presence of HPA-1a incompatibility, which accounts for most cases of in utero ICH.

Although high levels of maternal anti-HPA-1a may correlate with the severity of thrombocytopenia [21, 66], in up to 30 % of cases no antibody is found [67]. In some cases, antibody detection can be improved by varying assay conditions [68, 69]. Severe thrombocytopenia or ICH in HPA-1a-alloimmunized pregnancies cannot be predicted with sufficient sensitivity and specificity for clinical application from maternal anti-HPA-1a potency, bioactivity or isotype [32, 70, 71]. The maternal antibody level therefore has limited use in prediction of the severity of fetal/neonatal thrombocytopenia.

Neonatal thrombocytopenia due to FNAIT usually becomes progressively more severe and occurs earlier in subsequent pregnancies [10, 38, 44]. Following severe neonatal thrombocytopenia (<50 × 10⁹/L), a cerebral ultrasound or nuclear magnetic resonance (MRI) scan is advised to detect clinically silent ICH [7, 11]. A few cases of ICH resulting from incompatibility for HPA-3a, HPA-4b, HPA-5b, or HPA-9b alloantigens have been reported [72, 73].

The goal of antenatal management is to prevent severe thrombocytopenia and thus ICH which may result in death, either in utero or after birth, or long-lasting disability. A balance must be found between the inherent risks of the condition itself and the risks of diagnostic testing and therapy. The antenatal treatment of FNAIT has evolved over the past 25 years, largely based on published case series, detailing outcomes with differing regimens. They include: (a) fetal blood sampling (FBS) and serial intrauterine platelet transfusions (IUT) [54, 74]; (b) weekly intravenous immunoglobulin (IVIg) infusions; and (c) immunosuppression with corticosteroids [5, 57, 75]. Over the last 15 years, there has been a gradual change from invasive management to a less invasive management protocol to a completely non-invasive approach. However, controversy still exists over the optimal antenatal management strategy.

Following the affected pregnancy, the father should be tested for the presence of the relevant HPA. The risk of recurrence in subsequent pregnancies is virtually 100 % if the father is homozygous for the responsible HPA and 50 % if he is heterozygous. In the latter case, it is possible to determine the fetal platelet type by 16 weeks of gestation via PCR amplification of DNA obtained from amniocytes (obtained at amniocentesis). If the fetus is found to be negative for the HPA allele, no further testing is indicated [12, 96, 97]. Pre-implantation diagnosis (PGD) can be considered [98]. Non-invasive prenatal diagnosis (NIPD) using cell-free fetal DNA obtained from maternal plasma and serum is now a clinical reality, particularly in the management of RhD hemolytic disease, and many investigators are evaluating NIPD in FNAIT that may in the future form part of national antenatal screening programs.

The severity of FNAIT usually increases with each pregnancy. Attempts have been made to predict a fetus at risk from severe thrombocytopenia by the use of serial antibody titers in order to determine which fetus needs treatment. As stated above (Sect. 16.5), the antibody titer measurements are not a reliable predictor of the severity of FNAIT and are thus of limited use in the clinical management of FNAIT. The clinical history of an affected sibling is currently the best indicator of risk in a current pregnancy [37, 38, 99]. The recurrence rate of ICH in the subsequent pregnancies of women with FNAIT was 72 % (when the previous pregnancy was without fetal death) and 79 % (when the previous pregnancy included a fetal death). Conversely, the risk of ICH in those with a history of FNAIT but without ICH was estimated at 7 % [99].

It is presumed that, in fetuses with early severe fetal thrombocytopenia, ICH will be seen in a second pregnancy even though this did not occur in the first sibling. In a study by Bussel and Kaplan [47], 50 % of 98 affected fetuses already had a platelet count of <20 × 10⁹/L by 25 weeks’ gestation, indicating early severity. Forty percent had a lower fetal platelet count at that time than their previously affected siblings had at birth, indicating increasing severity in subsequent pregnancies. These authors concluded that when FNAIT occurs at an early gestation, it is severe; and it is more severe in fetuses with an older affected sibling that had an antenatal ICH. This suggests that fetuses may require different management strategies depending on the history of their previous sibling. There has been a trend and a strong recommendation to utilize non-invasive strategies (IVIg) in the management of FNAIT at high risk of in utero or postnatal ICH [100, 101].