A 31-year-old gravida 1 para 1-0-0-1 woman presented for preconception consultation with Maternal-Fetal Medicine. She had 1 prior vaginal delivery that was complicated by atony and hemorrhage requiring transfusion. However, just after birth, the well-appearing infant was evaluated in the neonatal intensive care unit (NICU) for petechiae with platelets less than 10 K/uL. The infant was presumptively diagnosed with neonatal alloimmune thrombocytopenia (NAIT) and was treated with both a platelet transfusion and intravenous immunoglobulin (IVIG). A head ultrasonography was performed, and no intracranial hemorrhage (ICH) was noted. The couple later met with Hematology, and parental testing revealed paternal homozygosity for human platelet antigen (HPA)-1a, lack of maternal HPA-1a, and maternal HPA-1a antibody positivity. The patient was counseled about the mechanism of disease, the likelihood of disease in future pregnancies, and the recommendation for prophylactic treatment with maternal steroids and IVIG in subsequent pregnancies.Shortly afterwards, the patient presented at 10 weeks and 3 days of gestation for an initial obstetric visit. At 20 weeks’ gestation, she was started on IVIG at a dose of 2 g/kg weekly. At 32 weeks’ gestation, prednisone was added at 0.5 mg/kg daily. In the third trimester, she started weekly fetal assessments including fetal brain ultrasonography to assess for an ICH. The patient had a consultation with Neonatology regarding postnatal care and had an otherwise uncomplicated prenatal course.Balancing the risk of early-term delivery with the risks of continued transfer of maternal platelet antibodies to the fetus, a planned delivery was scheduled at 37 weeks’ gestation. In preparation, the blood bank reserved HPA-1a–negative platelets in case a neonatal transfusion was needed. Given the risk of neonatal thrombocytopenia and ICH associated with vaginal delivery, the patient had a scheduled primary cesarean section. The infant was delivered without complications. The umbilical cord was clamped after 30 seconds, and the neonate was placed on the warmer to the awaiting Neonatology team for evaluation.The delivery was complicated by maternal hemorrhage secondary to large venous sinuses and atony. Surgical bleeding from vascular sinuses responded well to surgical interventions. Atony was treated with methylergonovine, carboprost, and tranexamic acid. The patient required pressors intraoperatively but weaned off these medications before leaving the operating room. The estimated blood loss was 2000 mL. The postoperative complete blood count revealed a hemoglobin of 9.2 g/dL and hematocrit of 26.0% from a starting hemoglobin of 11.2 g/dL and hematocrit of 33.0%. One unit of packed red blood cells was administered. On postoperative day 1, the hematocrit improved to 29.0%. Given chronic antepartum steroid exposure, she received a weeklong steroid taper. The patient progressed well and had no further complications.A female infant was born weighing 3345 g with an Apgar score of 8 and 8 at 1 and 5 minutes, respectively. At approximately 5 minutes after birth, the infant was noted to have increased work of breathing with cyanosis and an oxygen saturation of 75%. She was started on continuous positive airway pressure and was then admitted to the NICU for further care. Her initial physical examination did not reveal petechiae, and her initial platelet count was 280 K/uL. Her platelet trend throughout admission ranged between 211 K/uL and 271 K/uL. By hospital day 3, she no longer required respiratory support. The infant was discharged in good condition at 10 days of age.Incidentally, at the time of delivery, the maternal serology returned positive for treponema antibody with a negative rapid plasma reagin (RPR). The treponema antibody had been equivocal earlier in the pregnancy despite being negative in the first trimester. The Neonatology team opted not to treat the newborn because of the suspicion that the laboratory value was a false-positive result in the setting of maternal IVIG treatment. Repeat maternal treponema testing was negative 1 month after delivery.NAIT, also known as fetal and neonatal alloimmune thrombocytopenia, occurs in approximately 1 in 1000 live births.1 It is the most common cause of severe thrombocytopenia and ICH in fetuses and neonates.1 The condition results from maternal-fetal incompatibility for a platelet-specific antigen. When fetal platelets are incompatible with maternal platelets, maternal sensitization can occur.2 In this type II hypersensitivity reaction, maternal immunoglobulin G antibodies form against the fetal platelet antigen and cross the placenta, binding to and causing destruction of fetal platelets.2Figure 1 represents the likely pathologic mechanism for NAIT. In contrast to Rh disease, sensitization may occur in the index pregnancy. In NAIT, the fetus typically inherits the paternal HPA that is lacking in the maternal circulation. HPA-1a is the most commonly involved antigen, followed by HPA-5b, HPA-1b, and HPA-15.2HPA inheritance follows an autosomal dominant pattern.3 When the father is heterozygote for the incompatible HPA, there is a 50% chance that the fetus will inherit the allele.3 If there is paternal homozygosity for the incompatible HPA and maternal sensitization has occurred, fetuses in subsequent pregnancies have a 100% chance of developing NAIT.3 For the patient described in this case, the partner was homozygous for HPA-1a; therefore, all offspring would inherit the incompatible platelet antigen, placing future offspring at risk for thrombocytopenia, ICH, and related complications.Given the rare incidence, genetic testing for HPAs is not routinely performed.3 As a result, in at-risk couples, NAIT is often first diagnosed postnatally at the time of birth. Affected neonates typically present with severe thrombocytopenia, petechiae, purpura, cephalohematoma, or significant bruising.4 Screening with head ultrasonography is recommended as ICH is the most serious complication of NAIT. ICH is estimated to occur in 10%–20% of affected neonates, with approximately 75% of these hemorrhages occurring in utero.4 In suspected cases of NAIT, the infant’s platelet count is low, the maternal platelet count is normal, and maternal anti-HPA antibodies are present.3If an infant is suspected to have NAIT, both parents should undergo platelet antigen testing to assess the risk of NAIT in future pregnancies. If maternal-paternal antigen incompatibility is confirmed, management in subsequent pregnancies follows a risk-stratified approach. In cases of paternal heterozygosity, fetal HPA genotyping may be performed using noninvasive prenatal testing with cell-free fetal DNA at select laboratories,5 although this is not widely available or well-validated. Amniocentesis is preferred over chorionic villus sampling for obtaining fetal HPA status, as chorionic villus sampling could exacerbate the maternal immune response.3 For pregnancies with confirmed HPA incompatibility or presumed positivity based on prior sensitization and paternal homozygosity, management involves maternal treatment with a combination of IVIG and steroids,4 as was implemented in the patient in this vignette. Treatment is stratified based on the presence of fetal thrombocytopenia and whether the prior fetus was impacted by ICH and at what gestational age.4,6 An example of a risk-stratified management algorithm is presented in the Table 1. Based on risk, treatment with IVIG can begin between 12 and 20 weeks’ gestation, ranging from 1–2 g/kg/week,4 and the addition of prednisone can begin at 20–32 weeks’ gestation, ranging from 0.5 to 1.0 mg/kg/day.4 Known adult side effects of IVIG include headache, flushing, myalgias, hypotension, and wheezing.4 Headache is the most common side effect, which can be mitigated with methylprednisolone, intravenous hydration, slower infusion rate, and premedication with acetaminophen and diphenhydramine.4 Adverse effects of prednisone include gestational diabetes, hypertension, immunosuppression, mood swings, acne, and osteoporosis.3 Those treated with chronic prednisone should be screened for gestational diabetes.3 Supplementation with calcium and vitamin D is recommended to prevent osteoporosis.4 During the pregnancy, patients are monitored with fetal ultrasonography to assess for ICH. Although the patient in this vignette did not have any findings of ICH on fetal ultrasonography, Figure 2 demonstrates an abnormal fetal ultrasonography with ICH.The patient in this vignette had a new treponema antibody detected with an inconclusive particle agglutination test around the time of delivery with a nonreactive RPR and no symptoms. Given this constellation of findings, the patient was suspected to have had antibody transfer from the IVIG she received. However, close follow-up was planned with repeat antibody testing. Unlike RPR, treponema antibody, if consistent with a syphilis diagnosis, remains positive for life. Repeat testing in this patient was negative 1 month after delivery and stopping IVIG infusions. False-positive infectious serology is a known complication of IVIG infusions7–9 because IVIG contains antibodies from donors, including those directed against viruses, red blood cells, and proteins. False-positive results have been reported for syphilis, hepatitis B, and HIV10–17; blood group antibodies such as anti-A; and autoantibodies such as antithyroglobulin and M-spikes mimicking multiple myeloma.18 In rare instances, such immunoglobulin G antibodies can be transferred across the placenta to the fetus. Positive antibody testing should be interpreted with care in patients with known IVIG exposure. Care should be taken to avoid unnecessary interventions in neonates with positive serologies. Antibodies are often no longer detectable after 2 to 4 weeks.For cases of known NAIT, delivery via cesarean section between 37 and 38 weeks’ gestation is typically recommended to minimize birth trauma and the risk of ICH.4 For patients who desire a vaginal delivery and accept the risks, fetal blood sampling may be considered after 32 weeks’ gestation.4 Fetuses with a platelet count greater than 100 K/uL may be considered candidates for vaginal birth.4 However, the procedure carries up to an 8% risk of serious complication because of the inherent risk of bleeding.4Given the complex coordination required to take care of patients with NAIT, a multidisciplinary approach with Maternal-Fetal Medicine, Hematology, and Neonatology is recommended.3 For consideration of future pregnancies, assisted reproductive technologies can be considered to avoid possible high-risk scenarios. For those with paternal heterozygosity, patients can undergo in vitro fertilization using preimplantation genetic testing to select embryos that are HPA compatible.3 For those with prior sensitization and paternal homozygosity, donor sperm, gestational carriers that are compatible are potential options,3 or adoption are potential approaches.American Board of Pediatrics Neonatal-Perinatal Content SpecificationRecognize neonatal platelet disorders.Know treatments relating to neonatal anemias.
Cox et al. (Mon,) studied this question.