Thrombocytopenia is defined as a platelet count below 150 × 103/µL (150 × 109/L) and is subcategorized as mild (100–149 × 103/µL or 100–149 × 109/L), moderate ( 50– 99 × 103/µL or 50–99 × 109/L) and severe (<50 × 103/µL or <50 × 109/L). The incidence of neonatal thrombocytopenia is estimated to be 1% to 5%,1 and newborns are at higher risk of thrombocytopenia compared to adults.2,3,4
Neonates admitted to the NICU have an increased risk of severe thrombocytopenia5,6 and this risk increases with decreasing gestational age.3
Neonatal thrombocytopenia has many etiological factors, which can be summarized by the underlying mechanism: decreased production or increased destruction/consumption of platelets.
Alloimmune neonatal thrombocytopenia (NAIT) and autoimmune thrombocytopenia are immune-mediated processes that result in increased platelet destruction. Although caused by similar mechanisms, these 2 diseases are associated with different clinical presentations of affected newborns and require separate prenatal and postnatal management. In this review, we summarize these distinctions using case illustrations.
| Alloimmune neonatal thrombocytopenia |
> Presentation of the case
Male and female dichorionic diamniotic twins are born via cesarean section at 35 1/7 weeks of gestation in a setting of preterm labor. The parents had a previous child affected by TNAI diagnosed as part of the hydrops fetalis evaluation. During that evaluation, prenatal fetal MRI showed bilateral intraventricular hemorrhage and periventricular hemorrhages with subsequent cerebellar encephalomalacia, pleural effusion, and skin edema at 23 5/7 weeks of gestation.
The father was found to be homozygous for human platelet antigen (HPA) 1a and the mother was negative. The child was born by emergency cesarean section at 25 4/7 weeks of gestation due to intrauterine growth restriction (IUGR), elevated middle cerebral artery pressure on Doppler ultrasound, and hydrops fetalis, but unfortunately, he died from complications of hydrops fetalis and severe IUGR. the day after birth.
To prevent severe manifestations of TNAI, the woman received intravenous immunoglobulin (IVIG) weekly beginning at 12 weeks’ gestation during her subsequent twin pregnancy. Her platelet count was normal throughout the pregnancy. She received betamethasone in anticipation of delivery at 35 weeks of gestation and both neonates initially did well with Apgar scores of 8/8 and 8/9 at one minute and 5 minutes of life, respectively. The infants were placed on continuous positive pressure due to respiratory distress due to fetal lung fluid retention and were then transferred to the NICU.
On the day of birth, the girl had moderate thrombocytopenia with a platelet count of 61 × 103/µL (61 × 109/L), while the boy had severe thrombocytopenia, with a platelet count of 29 × 103/µL (29 × 109/L). She consulted the pediatric hematology service. On that day, both infants received donor pool platelets at 15 ml/kg.
The hematology team recommended checking the post-transfusion platelet count before considering IVIG. No clinically significant findings were seen on brain ultrasound in any of the babies on the day of birth or 3 days later. Both infants’ platelet counts increased after platelet transfusion to more than 150 × 103/µL (150 × 109/L) and continued to improve. Subsequently, both infants had stable platelet counts of more than 300 × 103/µL (300 × 109/L) at 3 weeks of age and were discharged with weekly platelet monitoring and hematology follow-up.
> Definition and background
TNAI is caused by the transplacental transfer of maternal immunoglobulin G-type antibodies directed toward inherited antigens on fetal platelets. These antibody-bound platelets are then destroyed by the spleen, resulting in thrombocytopenia. This disease most commonly results from a fetus inheriting the HPA-1a antigen that is missing from maternal platelets.7
Inheritance of the HPA-5b antigen can also cause clinically significant effects, although less severe disease. The incidence of TNAI varies from 1 in 1,000 to 10,000 live births8,9,10 and fetal/neonatal thrombocytopenia and clinical symptoms are usually severe. The incidence of severe thrombocytopenia in the general population of newborns is less than 1%11; However, 25% of these cases are diagnosed as TNAI.12
> Prenatal management
Prenatal management is determined by the level of suspicion of fetal NAI (TNAIF). Unlike Rh isoimmunization, which does not result in significant hemolytic disease of the fetus or newborn during the first pregnancy, TNAI can be clinically significant in the first pregnancy. This may be due to the fact that the platelet glycoprotein that carries the HPA-1a/5b antigen is present in the placental villi from the first trimester, providing the necessary exposure to mount an immune response in the pregnant woman.13
Unfortunately, screening for parental platelet antigens is not routinely performed due to cost and the relative low incidence of the disease, so diagnosis in a first pregnancy affected by TNAI may be delayed until after the baby is born.
Pregnant women are typically asymptomatic, with normal platelet counts; Therefore, TNAIF is often not suspected unless the fetus unexpectedly develops an intracranial hemorrhage (ICH), a previous sibling is affected, or the pregnant woman’s sister has an affected child.14,15
If TNAIF is suspected in the prenatal period, parental blood work is used to guide management. The tests consist of typing of maternal and paternal platelet antigens and evaluation of maternal anti-HPA antibodies. If the results demonstrate parental incompatibility, then the paternal genotype can help determine whether the father is heterozygous or homozygous for the specific antigen gene. If the father is homozygous, the diagnosis of TNAIF is made. If the father is heterozygous, fetal HPA genotyping can be performed by amniocentesis.16,17 Non-invasive cell-free fetal DNA has been developed but has not yet been validated for this purpose.17
The specific goal of prenatal management of a fetus known to be at risk for TNAI is to prevent the fetus/newborn from developing ICH, the most common cause of morbidity and mortality. Cordocentesis to monitor fetal platelet counts and intrauterine platelet transfusions are less common today given the risks of such invasive procedures.17 Empirical treatment options, including a combination of weekly maternal IVIG infusions with or without steroids, are available for pregnancies at risk of TNAI.18
IVIG has been shown to result in higher neonatal platelet counts alone or in combination with steroids compared with no treatment.19 Empiric treatment is based on the degree of risk, which is determined primarily by the severity of TNAIF in pregnancies. previous. A history of fetal ICH, particularly before 28 weeks’ gestation, confers an increased risk of worse disease in future pregnancies.
Early recognition and initiation of prenatal treatment, and subsequent escalation of the IVIG dose with the addition of steroids as the pregnancy progresses beyond 32 weeks of gestation, improves neonatal outcomes.20,21 Overall, There is no consensus on the mode and timing of delivery of a fetus with TNAIF. Some obstetricians recommend cesarean section, and allow a trial of labor only if the fetal platelet count, determined by cordocentesis, is greater than 100 × 103/µL (100 × 109/L).22
> Presentation of the newborn and risk factors
TNAI should be suspected in any neonate with thrombocytopenia of unknown cause (<50 × 103/µL [50 × 109/L]),23 including asymptomatic infants and small-for-gestational-age neonates with thrombocytopenia that persists beyond 7 to 10 days. .2 It is important to remember that TNAI caused by anti-HPA-5b antibodies is typically milder than by anti-HPA-1a, with less severe thrombocytopenia.
Asymptomatic thrombocytopenia occurs in 34% of cases of TNAI.24 Affected newborns may show petechiae, bruising or bleeding, with the most worrying complication being ICH. The overall risk of ICH is estimated to be 10% to 25%, with 25% to 80% occurring in utero.7
Multiple risk factors predict the severity of TNAI thrombocytopenia. A small study showed that high or increasing level of maternal anti-HPA-1a antibodies predicts more severe neonatal thrombocytopenia, while a low or stable level of maternal antibodies is predictive of less severe thrombocytopenia.25 However, this remains controversial. and further studies are needed to determine the prognostic value of maternal platelet antibody titers.
A history of a previous sibling with ICH as a consequence of TNAI increases the risk of ICH occurring at an early gestational age in subsequent pregnancies if no intervention is provided.21,26
> Postnatal management
Close monitoring of neonatal platelet counts and platelet transfusions, as noted, are hallmarks of postnatal management of TNAI. Typically, the platelet counts of affected neonates decrease during the first few days after birth and then increase over the next 4 weeks as maternal antibodies are cleared from the newborn’s circulation.
Platelet counts should be monitored at least daily in affected neonates, or more often in cases of severe thrombocytopenia or active bleeding. If the platelet count is less than 50 × 103/µL (50 × 109/L), a brain ultrasound should be performed to evaluate the possibility of ICH as soon as possible.2,27
There is no evidence-based approach detailing specific transfusion guidelines for TNAI, and current practice is driven by expert clinical experience. Reasonable indications for platelet transfusions are provided in Table 1. Because most ICH occurs with platelet counts of less than 30 × 103/µL (30 × 109/L), platelet counts should be maintained above of this level regardless of whether the newborn shows clinical symptoms of thrombocytopenia.28
Clinical signs of bleeding may indicate the need for platelet transfusion from a random donor.29
If time and resources permit, it is best to provide a transfusion of maternal platelets or HPA-1a antigen-negative platelets to prevent further destruction; However, this may not be feasible in the first week after birth when platelets are at their lowest. If maternal platelets are used, they should be washed and irradiated to remove antibodies and prevent graft versus host disease. (30) Maintaining an adequate platelet count in the first 72 to 96 hours is important because the risk of ICH is highest during this period.
Current evidence does not support the use of IVIG alone for TNAI because IVIG does not raise platelet counts rapidly; however, it can be used to help increase the count more quickly when given with a platelet transfusion.31 A reasonable approach is to provide high doses of IVIG (either 400 mg/kg per day for 3–4 days or 1 g /kg per day for 1 to 3 days) if the platelet count does not respond to the initial platelet transfusion.
Intravenous methylprednisolone has been used in life-threatening situations when patients do not respond to administration of platelets and IVIG32; however, data on the usefulness of methylprednisolone for TNAI are lacking and it is not routinely recommended. An infant may be discharged if the platelet count is stable and increasing; however, the exact platelet count at which discharge is safe is unknown. Close hematologic follow-up is necessary for repeated evaluation of platelet counts because of the long half-life of maternal antibodies in the infant’s circulation and the possibility of late-onset thrombocytopenia.
| Autoimmune neonatal thrombocytopenia |
> Presentation of the case
A girl was born by cesarean section at 39 4/7 weeks of gestation after induction of labor for oligohydramnios and lack of progress. The pregnancy was complicated by maternal immune thrombocytopenic purpura (ITP) and an adequately treated syphilis infection. During
During pregnancy, the nadir of maternal platelet count was 35 × 103/µL (35 × 109/L). The pregnant woman did not receive steroids but was closely followed on an outpatient basis by the hematology service. Her platelet count was 75 × 103/µL (75 × 109/L) on the day of delivery. The newborn was in good general condition at birth and she was initially admitted to the maternity unit.
Her initial platelet count was 65 × 103/µL (65 × 109/L) and she was asymptomatic at that time. Based on the mother’s history and the newborn’s presentation, the girl was diagnosed with autoimmune thrombocytopenia. The baby’s platelet count was followed daily and when it decreased to 50 × 103/µL (50 × 109/L) the day after her birth, a brain ultrasound was performed, which showed normal findings.
The pediatric hematology service was consulted when the platelet count decreased to 45 × 103/µL (45 × 109/L) the next day and continuous monitoring with contingent plans based on platelet trend was recommended. Three days after birth, when the platelet count further decreased to 35 × 103/µL (35 × 109/L), the hematology team recommended admission to the NICU and administration of IVIG 1 g/kg.
The infant received 2 doses of IVIG, which led to a subsequent increase in her platelet count to 57 × 103/µL (57 × 109/L) within 10 hours of the second dose of IVIG. Her count remained stable, at more than 70 × 103/µL (70 × 109/L) for 2 days after IVIG, and she was discharged from the hospital on the fifth day after birth with close hematology follow-up. . Her platelet count was 212 × 103/µL (212 × 109/L) 9 days after her birth.
> Definition and background
In contrast to TNAI, autoimmune neonatal thrombocytopenia is caused by maternal autoantibodies that attack maternal and fetal platelets. This condition is associated with maternal autoimmune disorders, most notably ITP and systemic lupus erythematosus. Most affected babies are healthy, with normal or slightly low platelet counts. However, in cases of maternal ITP, the risk of severe neonatal thrombocytopenia is 10% to 30%.33,34
> Prenatal management
Prenatal management is determined by the type of autoimmune disorder affecting the pregnant woman. The management of ITP seems to be the most relevant because the incidence of ITP in pregnancy is 1 to 3 in 10,000,35 10 times higher than the incidence in the general population.36 The general objective of the management of ITP in the pregnancy is to reduce the risk of bleeding in the pregnant woman and the fetus, rather than normalizing the platelet count.
Observation alone is indicated for maternal platelet counts greater than 100 × 103/µL (100 × 109/L), while treatment is indicated in pregnant women with moderate to severe bleeding, regardless of platelet count.37 Treatment is recommended before of delivery if the maternal platelet count is less than 30 × 103/µL (30 × 109/L) or if it is less than 50 × 103/µL (50 × 109/L) and a cesarean section is planned.35
Treatment strategies to increase maternal platelet count in the setting of severe illness in pregnant women include IVIG and systemic steroids. If steroids are indicated for maternal reasons only, prednisone is often used because it does not cross the placenta, avoiding unnecessary exposure of the fetus to steroids.
If preterm labor is a concern, betamethasone may be used instead. Although it usually takes 2 to 14 days to see a first response in platelet count after administration of steroids, the effects of IVIG are much faster, with an initial response within 1 to 3 days.38, 39 For this reason, IVIG is provided when there is an urgent need to increase maternal platelet count. These treatments have not been shown to improve neonatal outcomes.40
> Presentation of the newborn and risk factors
The diagnosis of autoimmune neonatal thrombocytopenia is usually evident in a newborn with thrombocytopenia who is born to a mother with thrombocytopenia or an autoimmune disorder. Of note, the maternal platelet count may be normal if there is a history of splenectomy or if there is sufficient compensatory thrombopoiesis. Although the majority of affected neonates are asymptomatic,33 some affected by autoimmune thrombocytopenia may show petechiae or mild bleeding.
Platelet counts can decrease dramatically during the first few days after birth due to persistent maternal antibodies, with a nadir observed around 2 to 5 days of life. Persistent thrombocytopenia at 4 months of age due to transmission of maternal IgA has been reported in breastfed infants.41 In general, the risk of severe thrombocytopenia and ICH is significantly lower than in TNAI.
Risk factors for severe disease in the newborn include a history of maternal splenectomy, maternal platelet count less than 50 × 103/µL (50 × 109/L) at any time during pregnancy,42,43 and having an affected sibling. .33
> Postnatal management
There are no specific guidelines for the management of neonatal autoimmune thrombocytopenia. Close monitoring of platelets is important, especially during the first few days after birth when a dramatic decrease in platelet count is expected. The main difference in the postnatal management of alloimmune and autoimmune thrombocytopenia is the effectiveness of platelet transfusions.
Since the antigens contributing to autoimmune thrombocytopenia are more ubiquitous than those involved in alloimmune thrombocytopenia, donor platelets are usually destroyed by circulating antibodies in the newborn, leading to less effective platelet transfusion.
If there is acute bleeding or the platelet count is less than 20 to 30 × 103/µL (20–30 × 109/L), a transfusion of platelets from a random donor may be provided as a temporary measure. However, IVIG (typically 1 g/kg) is the therapy of choice and induces a rapid increase in platelet count.44
Repeated doses of IVIG may be necessary over weeks or months, especially in cases of maternal ITP. Steroids have not been shown to be beneficial in neonates with autoimmune thrombocytopenia, but may be administered in life-threatening situations when the platelet count has not recovered despite IVIG and platelet transfusions.
In this scenario, methylprednisolone 1 mg/kg twice daily for 5 days is a possible treatment approach.45 Discharge criteria are similar to those for TNAI with close hematology follow-up.
| Summary |
Alloimmune and autoimmune thrombocytopenia in neonates are distinct entities, both caused by the transplacental passage of maternally derived antiplatelet antibodies. The differences between these 2 diseases and their prenatal and postnatal management recommendations are summarized in Table 2.
Alloimmune thrombocytopenia is generally more severe and affected fetuses/neonates are at risk for ICH. There are no specific guidelines for the prenatal management of either disease; However, treatment of pregnant women with IVIG can be useful in both diseases, with steroids being a second-line treatment if no improvement is observed.
In the newborn, platelet transfusion is the first-line treatment for alloimmune thrombocytopenia, while IVIG is the first-line treatment for autoimmune thrombocytopenia. More severe symptoms occur in TNAI, so close attention should be paid to the platelet count.
In neonates with autoimmune thrombocytopenia, the platelet count should be monitored until normalization, but treatment is usually not necessary unless the child is symptomatic or the thrombocytopenia is severe. Current evidence does not support the routine use of steroids for postnatal management of either disease, and both require outpatient hematology follow-up.
Table 1. Indications for platelet transfusion for a neonate with TNAI.
|
Table 2. Neonatal Alloimmune Thrombocytopenia vs. Autoimmune
| Alloimmune neonatal thrombocytopenia | Autoimmune neonatal thrombocytopenia | |
| Etiology | HPA incompatibility between pregnant and fetus. Maternally derived antibodies that attack the platelets of the fetus and neonate (no impact on maternal platelets during pregnancy). | Maternal autoimmune disorder. Maternally derived antibodies that attack maternal, fetal and neonatal platelets. |
| Clinical suspicion | Unexpected moderate/severe neonatal thrombocytopenia. Prenatal or postnatal ICH of unknown etiology. Previous child with suspected TNAI (including close maternal relatives). | Neonatal thrombocytopenia in the context of maternal thrombocytopenia and/or autoimmune disease. |
| Neonatal presentation | It may be asymptomatic but with a high risk of severe symptomatic thrombocytopenia. | Generally asymptomatic. Normal or slightly low platelet count. |
| Diagnosis | Genotyping of parental and fetal HPA demonstrating incompatibility | Diagnosis of exclusion in the context of maternal and neonatal thrombocytopenia. |
| Prenatal management | If known prenatally, increase the dose of IVIG and steroids to the pregnant woman as the pregnancy progresses. Cesarean section if the fetus remains severely thrombocytopenic. | Follow treatment guidelines for maternal autoimmune disease. |
| Postnatal management | Obtain a STAT brain ultrasound. First line: Platelet transfusion (random donor if acute need, HPA negative or maternal donor platelets if persistent). Second line: IVIG (with platelet transfusion). There is no data to support the routine use of steroids. Testing of the baby’s maternal aunt(s) is recommended. | First line: IVIG. Second line: Platelet transfusion (pool) for symptomatic bleeding. There is no data to support the routine use of steroids. |
HPA=human platelet antigen, HIC=intracranial hemorrhage, IVIG=intravenous immunoglobulin; NAIT = neonatal alloimmune thrombocytopenia
| Comment |
Neonatal thrombocytopenia has many etiological factors, and is manifested by decreased production or increased destruction/consumption of platelets. Alloimmune neonatal thrombocytopenia and autoimmune thrombocytopenia are immune-mediated processes that result in increased platelet destruction.
Although they are caused by similar mechanisms, these 2 diseases are associated with different clinical presentations in affected newborns and require separate prenatal and postnatal management.
If maternal thrombocytopenia is suspected, it is important to know the state of health during pregnancy, platelet counts, as well as personal and family history and history of previous births, in order to take the necessary measures to protect the health of the fetus, the neonate. and the mother.
