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Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management

Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management
Literature review current through: Jan 2024.
This topic last updated: Apr 04, 2023.

INTRODUCTION — Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a rare disorder (1 out of 1000 births) in which maternal-fetal platelet incompatibility leads to formation of maternal antibodies that result in fetal and neonatal thrombocytopenia. Platelet function remains relatively normal. The most serious potential consequence of FNAIT is intracranial hemorrhage.

This topic will provide an overview of FNAIT, with a focus on parental and fetal evaluation and management of affected pregnancies. Postnatal evaluation and care of the newborn are reviewed separately. (See "Neonatal immune-mediated thrombocytopenia", section on 'Neonatal alloimmune thrombocytopenia'.)

PATHOGENESIS — FNAIT occurs when fetal platelets contain a paternal antigen (most commonly human platelet antigen [HPA]-1a) that the mother lacks. Formation of maternal immunoglobulin G antibodies against this antigen, followed by transplacental passage and binding to fetal platelets, and then clearance of the antibody-bound platelets results in fetal/neonatal thrombocytopenia. Maternal anti-HPA-1a antibodies can also directly suppress fetal megakaryopoiesis, thereby exacerbating fetal/neonatal thrombocytopenia [1].

Two plausible mechanisms have been proposed to explain the occurrence of maternal alloimmunization in FNAIT. One mechanism involves maternal exposure to the antigen on fetal platelets due to fetomaternal bleeding or on adult platelets due to previous platelet transfusions, and the other involves maternal exposure to integrin beta-3 on placental syncytiotrophoblast cells during pregnancy [2].

DIAGNOSTIC CRITERIA — The Platelet Immunology Scientific Subcommittee (SSC) of the International Society on Thrombosis and Haemostasis recommended suspecting FNAIT when one or both of the following criteria are present without an alternative identifiable cause [3]:

Fetal intracranial hemorrhage, or

Neonatal nadir platelet count below 100,000/microL at birth or within seven days after birth

CLINICAL PRESENTATION — The mother is asymptomatic.

The spectrum of fetal/neonatal disease ranges from mild asymptomatic thrombocytopenia to severe thrombocytopenia leading to spontaneous intracranial hemorrhage (ICH), which is often fatal or associated with adverse neurodevelopmental outcome [4-6]. Mild cases typically present with thrombocytopenia in the newborn and are identified postnatally during work-up of these infants. Severe cases may present antenatally with fetal ICH. Extracranial fetal hemorrhage is extremely rare [7].

Most cases are first identified after the birth of an affected neonate. In some cases, parental platelet incompatibility with/without maternal alloantibodies is detected by prenatal or preconception screening, or testing performed because the mother's sister had an affected child. (See 'Screening' below and 'Patients with a sister whose child had or may have had FNAIT' below.)

In contrast to red cell alloimmunization caused by fetomaternal bleeding, FNAIT often affects the first pregnancy of an at-risk couple. In the largest worldwide registry of FNAIT cases, 70 percent of ICH were in first-born children [8].

COMMONLY INVOLVED PLATELET ANTIGENS — Human platelet antigen (HPA)-1a is the platelet antigen involved in 85 percent of FNAIT. In these cases, the father is HPA-1a positive (ie, 1a/1a or 1a/1b) and the mother is HPA-1a negative (ie, HPA-1b/1b) and has anti-HPA-1a antibodies. Only approximately 2 percent of the White population is HPA-1a negative; anti HPA-1a antibody (an immunoglobulin G antibody) has been detected in approximately 10 percent of HPA-1a negative pregnant people [9,10].

The HPA-5b antigen is the second most common platelet antigen causing FNAIT in the White population [11]. In the Asian population, the HPA-4 antigen system is the most frequent cause of FNAIT; the HPA-1ab polymorphism is not present in patients of Chinese or Japanese descent [12]. More than 30 other platelet antigens have been associated with FNAIT, but these other antigen systems account for ≤1 percent of cases [13,14].

FACTORS AFFECTING SEVERITY OF THROMBOCYTOPENIA — The severity of FNAIT can be affected by several factors, including [4,10,15]:

Pregnancy order – The body of evidence from retrospective studies suggests that the second pregnancy is almost always more severely affected than the first pregnancy; however, the only prospective study of human platelet antigen (HPA)-1a immunized pregnant individuals did not confirm these findings [16]. In this study, 45 pregnant people underwent platelet antibody screening, screened positive, and had two or more HPA-1a incompatible pregnancies. Neonatal platelet counts in the second incompatible pregnancy were as follows:

If the child in the index pregnancy had a normal platelet count (no FNAIT), neonatal platelet counts in the subsequent pregnancy were normal in 67 percent of cases.

If the child in the index pregnancy had thrombocytopenia (ie, FNAIT), neonatal platelet counts in the subsequent pregnancy were the same or higher in two-thirds of cases.

If the child in the index pregnancy had severe thrombocytopenia, neonatal platelet counts in the subsequent pregnancy were the same or higher in 29 percent of cases.

None of the mothers received antenatal intravenous immunoglobulin treatment, and not all index pregnancies were first pregnancies. Larger studies need to be performed to confirm or refute these findings.

Change in maternal HPA-1a antibody level – A low, stable level of maternal HPA-1a antibody appears to be associated with a low risk of FNAIT, while a rising and high level is predictive of neonatal thrombocytopenia. In the prospective study described above [16], a clear increase in maternal anti-HPA-1a antibody levels in subsequent pregnancies was associated with a lower fetal/neonatal platelet count compared with previous siblings. When the maternal antibody level was low and unchanged or fell, subsequent siblings had normal or higher platelet counts than index siblings. However, more data are needed to determine whether a change in maternal anti-HPA-1a antibody titers may be useful in clinical management.

By contrast, a single antibody level is not highly predictive of outcome [17].

Intracranial hemorrhage (ICH) in previous pregnancies – Fetal ICH related to FNAIT increases the probability of fetal ICH in subsequent pregnancies, and the hemorrhage is likely to occur earlier in gestation. When a previous sibling had an ICH, there is an 80 to 90 percent chance that the next affected sibling will also have an ICH, unless in utero treatment is administered [18,19]. In general, approximately half of ICHs occur before 28 weeks gestation [8], and the risk for recurrent hemorrhage in a subsequent pregnancy is higher the earlier the ICH occurred in the index pregnancy.

Type of platelet antigen – HPA-1a alloimmunization causes severe disease; HPA-5b alloimmunization is less severe.

Human leukocyte antigens (HLA) type – In homozygous HPA-1b females who are not pregnant or who are early in their first pregnancy, the absence of maternal HLA-DRB3*01:01 haplotype is highly predictive that alloimmunization will not develop (negative predictive value 99.6 percent), while its presence has a positive predictive value of 35 percent [10,20]. In a systematic review evaluating the impact of HLA-DRB3*01:01 on fetal/neonatal outcome (four prospective and eight retrospective studies), in prospective studies, all of the 64 severely thrombocytopenic newborns were born of mothers who were HLA-DRB3*01:01 positive; in the retrospective studies, 205 of the 214 (95.8 percent) severely thrombocytopenic newborns were HLA-DRB3*01:01 positive [20]. For the HLA-DRB3*01:01-negative pregnant patients, the odds ratio (OR) for alloimmunization was 0.05 (95% CI 0.00-0.60), and for severe neonatal thrombocytopenia, OR 0.08 (95% CI 0.02-0.37).

Antenatal intravenous immunoglobulin therapy may be more effective in HLA DRB3*01:01(+)/HLA DRB4*01:01P(+) patients than for HLA DRB3*01:01(+)/HLA DRB4*01:01P(–) patients [5]. (See 'Screening' below.)

Presence of anti-HPA-1a antibodies of alpha-v beta-3 subtype specificity in maternal sera – These antibodies induce endothelial cell apoptosis (cell death), which affects fetal vessel wall integrity, a critical factor in causing fetal ICH in FNAIT that is distinct from ICH related to other causes of thrombocytopenia [21]. Although measurement of these antibodies is not currently available for clinical use, elegant murine models of FNAIT have clearly demonstrated that the presence of specific anti-beta antibodies, and not the presence of thrombocytopenia, were responsible for fetal ICH. These antibodies led to ICH in the absence of thrombocytopenia by inhibiting angiogenic signaling, thereby inducing endothelial cell apoptosis and decreasing blood vessel density in the brain and retina [22]. These studies may explain why ICH does not occur in all cases of severe fetal thrombocytopenia and why ICH can occur in the occasional case where the fetal platelet count is normal.

SCREENING — We do not perform HPA-1a typing on all pregnant patients to identify those at risk for developing FNAIT, but population-based testing programs are evolving. Arguments against universal testing include the low prevalence of FNAIT (<1 out of 1000 births) in the overall population, the low risk of major clinically detectable bleeding among untreated HPA-1a-negative pregnant people (11 per 10,000 [95% CI 0-32 per 10,000] [23]), and unanswered questions regarding optimum management of alloimmunized pregnancies. Presently, no major medical organizations consider maternal HPA-1a typing an appropriate routine prenatal screening test.

However, other arguments may lead to eventual support for universal HPA-1a typing to identify pregnancies at risk for developing FNAIT, provided that testing and prophylaxis can be performed efficiently and safely [12]. Platelet antigen typing has a low error rate (<1 percent) and population-based studies have found that 75 percent of patients with pregnancies that developed FNAIT caused by HPA-1a became sensitized in their first pregnancy. Furthermore, we now know that HPA-1a-negative patients who do not carry HLA-DRB3*01:01 antigen are extremely unlikely to develop high titers of HPA-1a antibody and therefore very unlikely to have a fetus/neonate affected with severe thrombocytopenia.

A possible testing approach would consist of universal maternal HPA-1a1b platelet genotyping in the first trimester at approximately 10 weeks. Ninety-eight percent of the tested population would be identified as HPA-1a positive and require no further evaluation. The remaining 2 percent of HPA-1a-negative pregnant patients would then be tested for HLA-DRB3*01:01 antigen status and anti-HPA-1a antibody.

Approximately 1 percent of these remaining patients would be both HLA-DRB3*01:01 antigen positive and anti-HPA-1a antibody positive. They would be managed in the same way as patients with a history of FNAIT but no history of fetal or neonatal ICH (ie, standard risk pregnancies). (See 'Standard risk pregnancies (no ICH)' below.)

Approximately 72 percent of these patients would be HLA-DRB3*01:01 antigen negative and thus at low risk of developing FNAIT with an HPA-1a-positive fetus. They would receive routine prenatal care.

Approximately 27 percent of these patients would be HLA-DRB3*01:01 antigen positive and anti-HPA-1a antibody negative. These patients would undergo noninvasive cell-free DNA testing for fetal HPA-1a typing:

Approximately 15 percent of these fetuses will be HPA-1a negative and thus not at risk for developing FNAIT. These pregnancies could receive routine prenatal care.

The other 85 percent of these fetuses would be HPA-1a-positive fetuses and their mothers would be at high risk for developing anti-HPA-1a antibodies during pregnancy. These patients would be eligible for FNAIT prophylaxis if it existed. We would serially test maternal serum for development of anti-HPA antibodies at 12, 24, and 32 weeks of gestation and if positive, they would meet criteria for FNAIT. (See 'No personal history of fetal intracranial hemorrhage or neonatal thrombocytopenia, but HPA incompatibility' below.)

Alternatively, the partner could be genotyped as the next step with no further evaluation if both partners are HPA-1a negative; however, since 98 percent of partners will be HPA-1a positive, the author prefers to just check the pregnant patient for the HLA-DRB3*01:01 antigen since its absence is so predictive of not having a fetus affected with severe thrombocytopenia.

Ultimately, universal testing programs will depend upon widely available, efficient, and less costly high throughput maternal serum testing methods for maternal and fetal HPA-1a status [24].

EVALUATION OF COUPLES AT RISK FOR FNAIT

Patients with a personal pregnancy history suggestive of FNAIT — Couples who have had a child that meets the diagnostic criteria for suspected FNAIT (see 'Diagnostic criteria' above) can be evaluated before their subsequent pregnancy. Demonstration of maternal-paternal human platelet antigen (HPA) incompatibility plus maternal anti-HPA antibody to the incompatible antigen is diagnostic of FNAIT. In the absence of these findings, testing during pregnancy should be performed as described below and is illustrated in the algorithm (algorithm 1).

Step 1: Maternal platelet count – The maternal platelet count is checked to exclude maternal thrombocytopenia. Those with thrombocytopenia may have anti-platelet autoantibodies from an etiology such as systemic lupus erythematosus, or antiphospholipid syndrome, or immune thrombocytopenia. Although the fetus and/or neonate of these mothers may have thrombocytopenia, the pathophysiology, management, and outcome are different from that in FNAIT. (See "Thrombocytopenia in pregnancy".)

Step 2: Maternal-paternal platelet antigen typing (serological) – If the maternal platelet count is normal, maternal and paternal serological HPA typing is typically performed simultaneously, looking for a potential incompatibility for the HPA-1a/b antigen system, the most common cause of FNAIT in White individuals.

Reference laboratories vary in the number of platelet alloantigens screened. They typically test for HPA-1a and b, 3a and b, 4a and b, 5a and b, 6a and b, 9a and b, and 15a and b, but this may vary depending on the antigen frequency of the geographic region or the population served by the laboratory [3,25].

Laboratories cannot test for every platelet antigen, but incubating paternal platelets with maternal serum can detect low frequency platelet incompatibilities [26].

Step 3: Maternal HPA antibody testing – If parental platelet antigen incompatibility exists, then the maternal serum is tested for HPA antibodies to determine whether the mother has specific antibodies directed against the antigen missing from maternal platelets but present on the paternal platelets. Maternal antibodies in serum should be assessed by two different testing methods and by a crossmatch with paternal platelets. If the maternal antibody screen is negative, consider evaluating maternal serum for delayed or low-affinity alloantibodies two to eight weeks after the birth of a neonate with suspected FNAIT.

A commonly employed reference laboratory test is a crossmatch between maternal serum and platelet glycoprotein IIb/IIIa (GP IIb/IIIa), the site of most of the significant platelet antigens involved with FNAIT; however, this test will not detect antibodies directed at rare polymorphisms not located on paternal GP IIb/IIIa structures. Testing maternal serum against paternal platelets helps to detect these cases [27].

A common test is the modified antigen capture ELISA (enzyme-linked immunosorbent assay; MACE), which is a two-step procedure that tests for the presence of antibodies in maternal serum directed against platelet glycoprotein complexes [28]. Antibodies against human leukocyte antigens (HLA) or ABO antigens will often be identified. Anti-HLA antibodies are detected in up to 30 percent of multiparous patients, and rarely, FNAIT has been identified only in the presence of HLA class I antibodies (ie, absence of HPA incompatibility) [29-31]. Anti-HLA antibodies have not been proven to be a major cause of clinical FNAIT; thus, if these antibodies are detected, their results must be interpreted in the clinical context [3].

In contrast to RhD alloimmunization, the anti-platelet antibody titer has not been considered a key prognostic factor. In a systematic review examining whether the maternal HPA-1a antibody level could be used to identify severity of FNAIT (3 prospective and 10 retrospective studies), the positive predictive value was generally too low (54 to 97 percent) to be useful for clinical decision making; the negative predictive value was higher (88 to 95 percent) in prospective studies [17]. Interlaboratory variation in measurement of antibody level, use of different thresholds, and different patient populations limited interpretation of these data.

More prospective data are needed to determine whether maternal anti-HPA-1a antibody titers may be useful for risk assessment and selecting appropriate candidates for glucocorticoid and immunoglobulin therapy during pregnancy. (See 'Factors affecting severity of thrombocytopenia' above and 'Severity-based treatment approach' below.)

Step 4: Maternal-paternal platelet antigen typing (genotyping) – If maternal and paternal serological platelet antigen typing documents an incompatibility between maternal and paternal platelet antigens and the presence of a maternal anti-HPA antibody, then maternal and paternal platelet antigen genotyping is performed to determine offspring risk of developing FNAIT [32].

Platelet antigens are inherited as codominant genes. Approximately 98 percent of White individuals are HPA-1a positive. Thus, when the maternal genotype is homozygous HPA-1b/1b, approximately 25 percent of their partners will be heterozygous HPA-1a/1b and 50 percent of their progeny will also be HPA-1a/1b and at-risk of FNAIT. The other 75 percent of partners will be homozygous HPA-1a/1a and 100 percent of their progeny will be HPA-1a/1b and at-risk of FNAIT. Therefore, on average, over 85 percent of the couple's future fetuses will carry the problem platelet antigen and be at-risk for FNAIT and 15 percent will not be at risk.

Patients with a sister whose child had or may have had FNAIT — Patients with a sister who had a pregnancy with laboratory-confirmed FNAIT or a pregnancy history suggestive of FNAIT are at increased risk for FNAIT when they become pregnant. These patients are likely to carry the same uncommon platelet antigens as their sister and thus at high risk of maternal-paternal/fetal platelet incompatibility and alloantibody formation. We evaluate them using the same approach described above, except HPA antibody testing is omitted if they have not been pregnant, since exposure to the offending platelet antigen is required for eliciting an antibody response. (See 'Patients with a personal pregnancy history suggestive of FNAIT' above.)

SEVERITY-BASED TREATMENT APPROACH

Key principles — Pregnancies complicated by FNAIT should be managed by a specialist in maternal-fetal medicine. The key principles are:

The fetal platelet type should be determined as described below because the fetus will not be at risk of FNAIT if it does not carry the platelet antigen that caused maternal alloimmunization.

If the father is heterozygous for the incompatible platelet antigen, most commonly human platelet antigen (HPA)-1a/1b, fetal HPA status can be determined by typing fetal DNA for platelet antigens using polymerase chain reaction PCR. Fetal DNA is available from trophoblast cells obtained by chorionic villus sampling (CVS, performed at 10 to 14 weeks of gestation) or amniocytes obtained by amniocentesis (performed at ≥15 weeks of gestation); fetal blood is not necessary [33,34]. Of the two procedures, amniocentesis is preferred since theoretically CVS is more likely to be associated with exacerbation of maternal immune response in cases of affected fetuses since the placenta is disrupted.

A noninvasive test for fetal genotyping using cell-free DNA in maternal blood is an option but not widely available [24].

Intracranial hemorrhage (ICH) is responsible for most of the morbidity and mortality and occurs in 7 to 26 percent of FNAIT:

Up to 75 percent of cases occur prenatally between 20 weeks of gestation and term [4,18,35-37]. In the largest series, which is from an international multicenter registry, 54 percent of ICH occurred before 28 weeks of gestation.

Fetuses at highest risk are those with a previously affected sibling: The earlier the ICH occurred in the previous sibling, the greater the risk for ICH in the currently affected fetus.

Fetal platelet counts in affected fetuses are typically less than 20,000/microL and often less than 10,000/microL [38].

The high occurrence of ICH in thrombocytopenic fetuses is the basis for initiating treatment to raise the platelet count prenatally rather than postnatally. Treatment reduced the overall risk of ICH to 2.7 percent in a literature review [39].

Our approach — Our approach to management and delivery of pregnancies at risk for FNAIT is supported by a 2017 systematic review of randomized trials and nonrandomized studies that found that a noninvasive approach involving weekly maternal administration of intravenous immunoglobulin (IVIG), with or without the addition of glucocorticoids, was optimal [40]. The gestational age for initiation of treatment and dosing depends on the severity of FNAIT in the previous pregnancy, as described below and shown in the algorithm (algorithm 2). (See 'Standard risk pregnancies (no ICH)' below and 'High-risk pregnancies (late ICH)' below and 'Extremely high-risk pregnancies (early ICH)' below.)

In addition to medical therapy, we also perform ultrasound examinations to look for fetal ICH at four- to six-week intervals beginning at 16 to 20 weeks and continuing until delivery. If fetal ICH is detected despite medical therapy, which is rare, we reevaluate and individualize our approach. In pregnancies that have reached viability, early delivery may be indicated to adequately treat the fetal/neonatal thrombocytopenia, despite known risks of preterm birth.

Controversies — The optimum strategy for managing pregnancies at risk of FNAIT remains controversial due to the lack of randomized placebo controlled trials [41]. The greatest controversy is whether IVIG be omitted or the dose reduced in a patient whose prior child had FNAIT without ICH (ie, standard risk pregnancy). The following data address this issue:

A cohort study of such patients in which 46 received a reduced IVIG dose (0.5 g/kg per week) and 63 received the minimum standard IVIG dose (1 g/kg per week) starting at 28 and 32 weeks, respectively, reported no statistically significant differences between groups in birth platelet count or rate of severe thrombocytopenia, and neither group had a case of ICH [42]. These results suggest that a high dose of antenatal IVIG may not be necessary to reduce the risk of ICH if the mother has previously given birth to a child with FNAIT without ICH, but the small sample size does not enable a clear conclusion.

A subsequent retrospective study compared neonatal outcomes of 71 untreated HPA-1a-alloimmunized pregnancies during a 20-year period with 403 IVIG-treated pregnancies identified through a systematic review [43]. Patients with high HPA-1a antibody levels (>3 IU/mL) were delivered by cesarean one to two weeks before term with immediate access to HPA-1a negative platelets if the newborn platelet count was <35 x109/L or signs of bleeding. Patients were stratified into two groups: low risk (previous child with FNAIT without ICH) and high risk (previous child with FNAIT with ICH). Major findings were:

Low-risk group: No cases of ICH in the 64 low risk untreated pregnancies (0 percent, 95% CI 0.0-5.7 percent) and two cases of ICH in 313 low risk treated pregnancies (0.6 percent, 95% CI 0.2-2.3); the difference between groups was not statistically significant (p value 1.00).

High-risk group: The untreated high-risk group showed a trend toward more ICH (untreated: two ICH cases among seven newborns, 29 percent, 95% CI 8.2-64.1 versus treated: five ICH cases among 90 newborns, 5.6 percent, 95% CI 2.4-12.4 , p value 0.08), consistent with the North American experience.

These results suggest that antenatal IVIG may be unnecessary if the mother has previously given birth to a child with FNAIT without ICH. The strength of this study is that it is the only and largest study of its kind and it would likely be impossible to conduct an adequately powered randomized trial of IVIG versus no treatment using ICH as a primary outcome, given the rarity of ICH and the potential harm of not administering IVIG to patients who would have benefited from the therapy. Nevertheless, it may be possible to reduce overtreatment by identifying a group of patients who can be safely managed by withholding IVIG rather than attempting to identify patients who would benefit from IVIG [44].

We favor continuing to administer IVIG in the antenatal management of FNAIT and await more robust data that can identify at-risk pregnancies where IVIG can be withheld. We recognize the need to balance the use of IVIG to reduce ICH risk with risks of overtreating with IVIG.

Standard risk pregnancies (no ICH) — We define standard risk pregnancies as those in which a previous child had thrombocytopenia due to FNAIT but no history of fetal or neonatal ICH.

We use a two-step treatment approach, which is also used by other experts:

At 20 weeks of gestation, we suggest therapy with either (A) IVIG 2 g/kg/week or (B) IVIG 1 g/kg/week plus prednisone 0.5 mg/kg/day [45]. One treatment is not clearly better than the other in the standard risk group. We consider either option a reasonable approach because IVIG infusion is costly, time intensive (double dose usually means double the time commitment for the infusion), and both IVIG and steroids have risks.

At 32 weeks, we switch all patients to IVIG 2 g/kg/week plus prednisone 0.5 mg/kg/day [45,46].

Evidence — This approach is based upon a prospective, randomized trial including 99 patients with FNAIT whose prior affected child did not have an ICH [45]. Beginning at 20 to 30 weeks, patients were randomized to receive IVIG at 2 g/kg/week (Group A) or IVIG 1 g/kg/week plus prednisone 0.5 mg/kg per day (Group B). At 32 weeks, all patients received IVIG 2 g/kg/week plus prednisone 0.5 mg/kg/day. Major findings were:

The birth platelet counts of the neonates treated in utero were significantly higher than those of the prior affected but untreated siblings: For Group A: 169,000/microL versus 28,000/microL, and for Group B: 135,000/microL versus 39,000/microL.

The percentage of neonates with birth platelet counts under 50,000/microL were similar for both groups (6/55 [11.1 percent] for Group A and 7/49 [14.3 percent] for Group B).

Three out of 104 neonates had an ICH diagnosed on postnatal ultrasound; all three ICH were grade 1, and none were associated with neurologic sequelae. The birth platelet counts for these three cases were >100,000/microL. Two of the neonates were born preterm by cesarean: one because of HELLP (Hemolysis, Elevated Liver enzymes, Low Platelets) at 29 weeks and the other because of preeclampsia at 32 weeks. The third infant was born vaginally at 37 weeks.

The majority of patients (n = 80) underwent cordocentesis around 32 weeks, and none underwent an initial cordocentesis prior to therapy. Based upon a 12.5 percent complication rate associated with cordocentesis, this procedure would only be performed currently to determine if the fetal platelet count was adequate for patients desiring to deliver vaginally.

The rationale for an escalated therapy at 32 weeks was based upon data from a previous randomized trial demonstrating that both IVIG 2 g/kg/week and IVIG 1 g/kg/week plus prednisone 0.5 mg/kg/day were effective and had similar efficacy in preventing severe fetal thrombocytopenia in 73 standard risk pregnancies [46]. In this trial, the fetal platelet count was checked at 32 weeks and salvage therapy (IVIG 2 g/kg/week plus prednisone 0.5 mg/kg/day) was administered if the platelet count was <30,000/microL, which occurred in 27 percent of the higher-dose IVIG group and 17 percent of the lower-dose IVIG plus prednisone group. The salvage regimen maintained or raised the platelet count in all but one case; two grade 1 neonatal ICHs occurred but were not due to treatment failure (platelet counts at birth 133 and 197,000/microL, respectively). This trial established the efficacy of the salvage regimen for treatment of standard risk pregnancies and provided indirect evidence that cordocentesis, with its attendant risks, could be avoided if this regimen was used as primary therapy.

A lower dosing regimen (IVIG 0.5 g/kg/week or 1 g/kg/week beginning at 28 weeks and continuing until delivery without prednisone) may not be as effective, although desirable in terms of cost and side effects. Available data are limited [42,47,48], but at least one study suggests a greater percentage of newborns with low platelet counts [48]. The poorer response to lower dosing regimens may be related to factors beyond the dose, such as the brand of IVIG (Endobulin) and the types and frequencies of other interventions [39].

High-risk pregnancies (late ICH) — We define high-risk pregnancies as those in which a previous child had an ICH in the third trimester or neonatal period due to FNAIT.

Treatment in high-risk pregnancies is more intense than standard-risk pregnancies and has three steps:

At 12 weeks of gestation, begin IVIG at 1 g/kg/week.

At 20 weeks of gestation, add prednisone 0.5 mg/kg/day or increase IVIG to 2 g/kg/week.

At 28 weeks, administer IVIG 2 g/kg/week and prednisone 0.5 mg/kg/day to all patients [49].

Evidence — This approach is based on findings from a prospective trial that stratified 33 patients (37 pregnancies) with FNAIT and ICH in a previous child according to the timing of the previous child's ICH (second trimester, third trimester, perinatal) [19]. Major findings were:

Initiation of treatment at 12 weeks was associated with better outcomes than later initiation; the lowest birth platelet counts were in patients who started IVIG therapy at 20 to 24 weeks of gestation.

There were only 5 ICHs among the 37 treated fetuses, even though all 33 mothers had a previous baby with ICH. Two ICHs were attributed to treatment failure and in both cases the dose of IVIG had not been raised to 2 g/kg/week.

Although the number of patients in this study was small, it provides the best available data for guiding therapy. Another group of investigators also reported that lower dose IVIG does not work well in high-risk pregnancies, but other aspects of the treatment regimen were different in their study [48].

The recommendation for administering both IVIG 2 g/kg/week and prednisone 0.5 mg/kg/day is based on data that 10 to 20 percent of patients who received only IVIG 2 g/kg/week or IVIG 1 g/kg/week plus prednisone 0.5 mg/kg/day had fetal platelet counts <50,000/microL, suggesting that neither lower-dose regimen alone is optimal [49]. Although administration of prednisone 1 mg/kg/day appeared to improve fetal platelet counts in a group of four pregnancies, there were substantial bothersome maternal glucocorticoid side effects.

Extremely high-risk pregnancies (early ICH) — We define extremely high-risk pregnancies as those in which a previous child had an ICH in the second trimester due to FNAIT.

The treatment strategy for extremely high-risk pregnancies involves higher drug doses compared with high-risk pregnancies:

At 12 weeks of gestation, begin IVIG at 2 g/kg/week.

At 20 weeks of gestation, add prednisone 1 mg/kg/day to the IVIG regimen.

Evidence — There are sparse data supporting any treatment regimen for the extremely high-risk pregnancy. The regimen described above represents the most aggressive combination of drugs, doses, and timing of intervention reported effective in a trial with eight extremely high-risk pregnancies [19].

MEDICATION RISKS AND MONITORING — Long-term follow-up of surviving offspring after antenatal treatment of FNAIT with intravenous immunoglobulin (IVIG) has not revealed adverse effects on general health or neurodevelopmental outcome, but these data are limited [50,51]. One study showed improved neurodevelopment outcomes in the treated sibling, despite being born at an earlier gestational age and lower birth weight [51].

Glucocorticoids – Side effects of maternal glucocorticoid administration include osteoporosis, impaired glucose tolerance and gestational diabetes, depressed immunity, mood swings, gastrointestinal irritation, and suppression of the hypothalamic-pituitary-adrenal axis during times of stress. (See "Major adverse effects of systemic glucocorticoids".)

Although use of glucocorticoids in pregnant patients has been associated with an increased risk of preterm prelabor rupture of membranes, this has not been described in the literature of pregnancies complicated by FNAIT, but may not be evident due to small sample size. We usually screen patients for diabetes within a month of initiating glucocorticoid therapy. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention".)

IVIG – Side effects of IVIG include a local reaction at the administration site, fever, rash, altered immunity, aseptic meningitis, and potentially transmission of infectious agents [52].

Patients with non-O blood group (ie, A, B, AB) receiving high-dose IVIG (2 g/kg/week) but not low-dose IVIG (1 g/kg/week) are at increased risk for anemia, possibly from isohemagglutinin-mediated hemolysis. (See "Overview of intravenous immune globulin (IVIG) therapy".)

We monitor hemoglobin or hematocrit monthly in these patients and treat anemia with additional iron supplementation. In our experience, maternal transfusion with red cells because of IVIG related anemia has never been necessary. Administration of lots of IVIG with low titers of anti-A and anti-B might lessen severity of anemia, but such IVIG is not widely available [53].

TIMING OF CESAREAN BIRTH

For standard and high-risk pregnancies, we perform a cesarean birth at 37+0 to 38+0 weeks of gestation [54].

For extremely high-risk pregnancies, we generally perform a cesarean birth at 36+0 to 37+0 weeks of gestation. These pregnancies are delivered earlier due to the higher risk of intracranial hemorrhage (ICH).

The goal is to remove the fetus from the source of anti-platelet antibodies, minimize risks from preterm birth, and enable neonatal evaluation and treatment.

Management of patients who want a trial of labor — We recommend cesarean birth for all patients in the extremely high risk category. For patients in the standard and high risk categories who wish to undergo a trial of labor, we perform fetal blood sampling at ≥32 weeks of gestation to determine if the fetal platelet count is adequate (>100,000/microL) to minimize the risk of fetal bleeding related to labor and vaginal birth (see 'Use of cordocentesis and platelet transfusion' below). However, there is no consensus on criteria for selecting fetuses at low risk of complications from vaginal birth, and platelet count alone, especially at 32 weeks, may not adequately reflect all of the factors that modulate risk of ICH [55-57]. If the patient has not begun to labor by 38+0 weeks of gestation, we suggest induction or scheduled cesarean birth at that time.

One group of investigators who described their 23 year single-center experience employing a policy of routine fetal blood sampling, intravenous immunoglobulin, and steroids (alone or in combination) and performing cesarean birth for obstetric indications only reported no ICH and a 36.7 percent overall cesarean rate [58]. They suggested a more flexible approach to allowing vaginal birth, particularly in multiparous patients. More studies are needed to address route of delivery in FNAIT cases, particularly the safety of labor and vaginal birth.

Intrapartum and postpartum management of maternal steroids — Prolonged glucocorticoid therapy can suppress the hypothalamic-pituitary-adrenal axis and, during times of stress such as labor and delivery, the adrenal glands may not respond appropriately. The management of these patients is reviewed separately. (See "The management of the surgical patient taking glucocorticoids".)

MANAGEMENT OF OTHER CLINICAL SCENARIOS

Personal history of fetal intracranial hemorrhage/neonatal thrombocytopenia and HPA incompatibility but no antibodies — Patients with human platelet antigen (HPA) incompatibility and a pregnancy history of fetal intracranial hemorrhage (ICH)/neonatal thrombocytopenia but who have no anti-HPA antibodies before pregnancy do not meet criteria for FNAIT (table 1); however, these patients have the potential for developing anti-HPA antibodies over the course of pregnancy.

We suggest serially testing maternal serum for anti-HPA antibodies at 12, 24, and 32 weeks of gestation by both a panel of platelets expressing common HPA antigens and cross-matching against paternal platelets to detect alloimmunization to a rare antigen carried by the father.

If the mother is HPA-1a negative, testing for HLA-DRB3*01:01 early in pregnancy can be informative as the results can help predict the likelihood of developing an HPA-1a antibody response in the index pregnancy. (See 'Factors affecting severity of thrombocytopenia' above and 'Screening' above.)

In the absence of demonstrable maternal anti-HPA antibodies, no further intervention is necessary. If maternal anti-HPA antibodies are identified, then criteria for FNAIT are met, and the pregnancy is managed as described above. (See 'Severity-based treatment approach' above.)

Personal history of fetal intracranial hemorrhage/neonatal thrombocytopenia, but no HPA incompatibility and no antibodies — Patients with a pregnancy history of fetal ICH/neonatal thrombocytopenia but no HPA incompatibility and no anti-HPA antibodies do not meet criteria for FNAIT (table 1). Management of these patients depends on the cause of neonatal thrombocytopenia, which is reviewed separately. (See "Neonatal thrombocytopenia: Etiology".)

If no cause for fetal ICH/neonatal thrombocytopenia is identified, one expert group suggested testing maternal serum for anti-HPA antibodies at 30 weeks of gestation to check for development of previously undetected antibodies [49]. We agree with this approach.

No personal history of fetal intracranial hemorrhage or neonatal thrombocytopenia, but HPA incompatibility — Although we recommend not routinely screening for HPA incompatibility at present, if screening is performed and a platelet incompatibility is detected, we suggest serially testing maternal blood for the specific antibody associated with the platelet incompatibility. We would begin testing at 12 weeks of pregnancy and repeat at 24 and 32 weeks of gestation.

If the specific antibody associated with the platelet incompatibility is detected, then we would offer the management protocol for standard risk pregnancies because FNAIT frequently occurs in the first pregnancy. (See 'Our approach' above and 'Standard risk pregnancies (no ICH)' above.)

If screening was performed because the patient's sister had a child with suspected or confirmed FNAIT, we follow this same protocol if a platelet incompatibility is detected. In addition, screening the mother for HLA-DRB3*01:01 may be useful if their sister is HLA-DRB3*01:01 positive as the results can help predict the likelihood of developing an HPA-1a antibody response in the index pregnancy. (See 'Factors affecting severity of thrombocytopenia' above.)

Pregnancies at high risk for preterm birth — Pregnancies at high risk for preterm birth should receive antenatal betamethasone or dexamethasone according to standard obstetric indications. (See "Antenatal corticosteroid therapy for reduction of neonatal respiratory morbidity and mortality from preterm delivery".)

Use of cordocentesis and platelet transfusion — Serial cordocentesis had been used to monitor fetal platelet count and response to therapy in pregnancies complicated by FNAIT, but this approach has largely been abandoned in favor of empiric therapy (intravenous immunoglobulin and prednisone) due to the significant procedure-related risks [45,59] (see "Fetal blood sampling"). The major advantage of the information gained is that it may avoid undertreatment of fetuses with thrombocytopenia, which can result in fetal morbidity and mortality, and avoid overtreatment of fetuses with adequate platelet counts, which is costly and may cause serious maternal side effects and pregnancy complications. Empiric therapy has not been compared with fetal blood sampling-indicated treatment in a randomized trial, but a decision analysis supported use of empiric therapy for treatment of FNAIT when the risk of ICH was less than 28 percent [60].

Procedure — Fetal blood sampling and in utero platelet transfusion should only be performed by an experienced operator. The sampling needle should be small diameter, 22-gauge, and the procedure should be performed in an operating room in the event that emergency cesarean birth is needed. There should be immediate access to an automated hemocytometer to obtain a rapid fetal platelet count, and antigen negative platelets should be immediately available for in utero transfusion if the platelet count is <50,000/microL, in part to reduce the risk of excessive cord bleeding [49]. The platelets for transfusion may be obtained from the mother or from an appropriately typed donor.

Platelet infusions should have a concentration greater than 2000 x 106/microL to reduce the risk of fetal volume overload and should be leukoreduced and irradiated to prevent graft-versus-host disease. In cases of Rh(D) incompatibility with the pregnant patient, Rh(D) immune globulin should be given. If maternal platelets are used, donations should be planned 48 hours in advance of cordocentesis to allow adequate time for processing while still maintaining platelet viability. An additional step of washing is required to remove the alloimmune antibody. This is usually not undertaken until just before the cordocentesis since washing can result in activation of the platelets and reduce survival time.

The volume of platelet transfusion is determined using the following equation [61]:

Volume transfused (mL) = (volume of fetoplacental unit in mL) x (final – initial platelet count) x 2 divided by (platelet count of the transfused concentrate)

The fetoplacental volume is calculated by multiplying the ultrasound estimate of fetal weight (grams) by 0.14. The factor of "2" is used in the numerator of the equation to allow for possible platelet sequestration in the fetal spleen or liver. The clinician must be careful that the units of measurement for the platelet count of the transfused concentrate are the same units of measurement as those for the initial and final fetal platelet counts.

Since the half-life of platelets is only an approximate three days and the mean drop in platelet count is in the range of 40,000/microL per day, the target final fetal platelet count is 300,000 to 500,000/microL to achieve a nadir platelet count of 30,000 to 50,000/microL at the time of the next transfusion [61]. For in utero platelet transfusion for FNAIT, a typical volume of platelet concentrate transfused is 5 to 15 mL [37]. In one series, approximately 50 percent of nonresponders received ≥3 intrauterine platelet transfusions [58].

REPRODUCTIVE OPTIONS — For patients with high-risk and extremely high-risk prior pregnancies with FNAIT, options for avoiding conception of an affected fetus include intrauterine insemination with sperm from a human platelet antigen (HPA)-1b/1b donor or, if the partner is an HPA heterozygote (HPA-1a/1b), the patient can undergo in vitro fertilization with preimplantation genetic testing. Another potential option for these very severe cases is to use a gestational carrier who is platelet antigen compatible. (See "Preimplantation genetic testing" and "Gestational carrier pregnancy".)

SUMMARY AND RECOMMENDATIONS

Diagnostic criteria – Fetal and neonatal alloimmune thrombocytopenia (FNAIT) should be suspected when one or both of the following criteria are present without an alternative identifiable cause (See 'Diagnostic criteria' above.):

Fetal intracranial hemorrhage (ICH), or

Neonatal nadir platelet count below 100,000/microL at birth or within seven days after birth

Pathogenesis – FNAIT is a disorder in which fetal platelets contain an antigen inherited from the father that the mother lacks. The mother then develops antibodies against this paternal antigen, and these antibodies cross the placenta and bind to the fetal platelets. Clearance of the antibody-coated platelets results in fetal/neonatal thrombocytopenia. Antibodies to human platelet antigen (HPA)-1a are the most common cause of FNAIT. Inhibition of fetal megakaryopoiesis by maternal HPA-1a antibodies further exacerbates fetal/neonatal thrombocytopenia. (See 'Pathogenesis' above and 'Clinical presentation' above and 'Commonly involved platelet antigens' above.)

Clinical consequences – FNAIT often affects the first pregnancy of at-risk parents, and may be severe. ICH is responsible for most neonatal morbidity and mortality in FNAIT, occurs in 7 to 20 percent of cases, and up to 75 percent of these cases occur antenatally. It is associated with platelet counts primarily less than 20,000/microL, particularly less than 10,000/microL. Fetuses at highest risk are those in whom a fetal ICH occurred in a previous affected sibling: The earlier the ICH occurred in the previous sibling, the greater the risk for ICH in the currently affected fetus. (See 'Clinical presentation' above.)

Screening – Screening all pregnant patients to identify those who are at risk of FNAIT due to maternal-fetal HPA-1a discordancy is costly, and the optimal management of these patients is unknown. We suggest not routinely screening pregnant patients for HPA-1a (Grade 2C).

We perform maternal and paternal platelet antigen typing, as well as maternal human anti-platelet antibody evaluation when the patient or their sister has an obstetric history suggestive of this diagnosis (eg, fetal death due to intracranial hemorrhage [ICH], neonatal thrombocytopenia of undetermined etiology). We perform paternal platelet antigen genotyping if the fetus is at risk of FNAIT. (See 'Screening' above.)

If the mother is HPA-1a negative, testing the mother for HLA-DRB3*01:01 is useful as the results can help predict the likelihood of developing an HPA-1a antibody response in the index pregnancy. (See 'Factors affecting severity of thrombocytopenia' above and 'Screening' above.)

Prenatal management

Determine fetal genotype – The fetus is not at risk of FNAIT if it does not carry the platelet antigen that caused maternal alloimmunization; therefore, the fetal genotype should be determined if the father is heterozygous of HPA incompatibility. (See 'Key principles' above.)

Risk stratification and treatment – The high occurrence of in utero fetal bleeding is the basis for initiating treatment to raise the platelet count prenatally, rather than waiting until after birth. Treatment significantly reduces but does not eliminate the risk of ICH. The choice of prenatal prevention strategy is based upon the risk of ICH (see 'Severity-based treatment approach' above):

-Standard risk – For patients whose previous child had thrombocytopenia without ICH, we suggest a two-step approach: At 20 weeks of gestation, initiate therapy with intravenous immunoglobulin (IVIG) 2 g/kg/week or IVIG 1 g/kg/week with prednisone 0.5 mg/kg/day and, at 32 weeks, switch to IVIG at 2 g/kg/week with prednisone 0.5 mg/kg/day (Grade 2C).

We perform a cesarean birth at 37+0 to 38+0 weeks.

-High risk – For patients whose previous child had an ICH in the third trimester or neonatal period, we suggest beginning IVIG 1 g/kg/week at 12 weeks of gestation; at 20 weeks of gestation, either prednisone 0.5 mg/kg/day is added or the dose of IVIG is increased to 2 g/kg/week; at 28 weeks, all patients receive IVIG 2 g/kg/week and prednisone 0.5 mg/kg/day (Grade 2C).

We generally perform a cesarean birth at 37+0 to 38+0 weeks.

-Extremely high risk – For patients whose previous child had an ICH in the second trimester, we begin IVIG 2 g/kg/week at 12 weeks; prednisone 1 mg/kg/day is added to the IVIG regimen at 20 weeks of gestation (Grade 2C).

We generally perform a cesarean birth at 36+0 to 37+0 weeks.

Ultrasound monitoring – We perform ultrasound examinations to look for ICH at four- to six-week intervals beginning at 16 to 20 weeks and continuing until delivery since ICH can occur antenatally in pregnancies at risk of FNAIT. (See 'Our approach' above.)

Delivery – We suggest cesarean birth with consideration of vaginal birth only if the fetal platelet count is greater than 100,000/microL prior to delivery (Grade 2C). (See 'Severity-based treatment approach' above and 'Use of cordocentesis and platelet transfusion' above.)

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References

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