Foetal alloimmune thrombocytopenia (FAIT)
Thrombocytopenia of the foetus caused by maternally transmitted diaplacental alloantibodies directed against paternally-inherited human platelet antigens (HPA). The pathogenesis is analogous to that of haemolytic disease of the newborn.
Incidence
1:1000 births. Cases of FAIT are unfortunately often overlooked and hence inadequately monitored and incorrectly treated. The consequences of this can be grave. Similar observations have been made in other countries such as Great Britain (Murphy et al. 1999, Turner et al. 2005, Tiller et al. 2009). The course of FAIT may be severe (see below) and the incidence is greater than for several other neonatal diseases for which screening programmes exist.
Antibody specificity
~75% anti-HPA 1a (Zwa or PlA1), ~15% anti-HPA 5b (Bra), ~4% anti-HPA 15b and other.
Clinical picture
About half of the intracranial haemorrhages detected on ultra-sound occur before birth (approx. 15%-20% of all cases). Cases of intra-cranial haemorrhaging have been documented which occurred as early as in the 16th week of pregnancy, but the majority occur after the 30th week. Possible consequences of this haemorrhaging: hydrocephalus, blindness, mental and physical disability.
Diagnosis
Clinical indication: The occurrence of FAIT or NAIT in a previous pregnancy or neonate. The chance of NAIT/FAIT recurring in subsequent pregnancies is between 50% and 100% depending on whether the paternal antigen is hetero- or homozygous. Often the severity is similar from pregnancy to pregnancy. Cerebral ultra-sound scan of the intra-uterine child: ventriculomegalia in the sense of a hydrocephalus aresorbtivus after intraventricular haemorrhaging, septal defect through rupture after intraventricular haemorrhaging, porencephalic cysts, usually only a moderate macrocephalia. The neuro-radiological findings can be an aid to diagnosis and can, in certain unexpected cases, be critical for the well-being of the child (Dale and Coleman 2002) Cordocentesis (NB: see below) is capable of detecting foetal thrombocytopenia even when the platelet count of the gravida is normal. Non-immunological origins for the foetal thrombocytopenia cannot be determined. See table for differential diagnosis!
Laboratory: If severe FAIT cannot be ruled out because of intra-cranial haemorrhaging in the foetus either in the medical history or during the present pregnancy, a sample of the foetal blood should be taken from the umbilical cord sometime during the 30th-32nd week of pregnancy. On the one hand the cordocentesis should be performed early enough to avoid cerebral haemorrhaging. On the other hand it should be late enough to ensure that a child is mature enough to be delivered in case unexpected, catastrophic umbilical cord haemorrhaging occurs. Such an invasive diagnostic procedure as cordocentesis, which carries substantial risks, is difficult to justify when not directly indicated by intra-cranial haemorrhaging either during this or in earlier pregnancies. The gravida types negative, the father positive for the antigen which corresponds to the alloantibody. The father is serologically tested and/or genotyped to check whether the antigen is homozygous or heterozygous. An attempt should be undertaken to detect the antibodies responsible for the FAIT, but even if such antibodies are not found, a FAIT diagnosis cannot be ruled out; even in severe cases of FAIT/NAIT, it is occasionally only possible to detect antibodies after several days (postpartum), and in approximately 10% (according to several authors, in as many as 30%) of the cases it is not possible to detect them at all. It is important to detect the presence of any human leukocyte antigen (HLA) antibodies of the gravida to ensure that transfusion with foreign platelets will be successful. Similarly the ABO blood groups of the mother, father and child have to be determined to ensure the significance of the interpretation of the various blood tests.
Examination material required
Mother: 30ml EDTA blood, 10ml clotted blood, 10ml heparinised blood;
Father: 10ml EDTA blood, 10ml heparinised blood;
Child: 3-5ml EDTA blood for blood count, including platelet count, and 50µl EDTA blood for the ABO typing.
Therapy
Prenatal therapy if a severe FAIT is suspected
This may be assumed if intracranial haemorrhaging has been observed in a previous foetus (especially in early pregnancy, Bussel and Sola-Visner, 2009) or during the present pregnancy. We suggest in these cases that 1g/kg intravenous immunoglobulin be administered weekly to the pregnant woman, beginning in the 14th week of pregnancy or from the time the haemorrhaging occurs. Platelet transfusions are generally administered on a weekly basis via the umbilical cord vein (see below) from the 30th week of pregnancy until birth when the foetal platelet concentration is below 50,000/µl. The substantial risk of such a transfusion has to be calculated when the indication is assessed. Intra-uterine foetal levels have to be over 100,000/µl, ideally around 300,000/µl following the transfusion.
Procedure for the initial, prophylactic transfusion and dosage: immediately before cordocentesis by an experienced hospital team 10-20ml (up to 20-40ml as of the 35th week of gestation) of washed, CMV antibody-negative, irradiated blood group O platelet concentrate should be ready for use. A foetal blood sample should be taken for a platelet count immediately after puncturing the umbilical cord vein. If for any reason the result of the platelet count is not immediately available, the platelet concentrate should be transfused prophylactically, for 6-10 minutes via the centesis needle which is still in place inserted in the umbilical cord vein. When the blood analysis results take too long, there is a high risk of fatal umbilical cord haemorrhaging due to the centesis needle dislocating when the foetus moves in the uterus.
The transfused platelets have to test negative for the platelet antigen corresponding to the antibody of the gravida. If this is unknown, then they have to be HPA 1a negative or donated by the gravida, and washed (centrifuged once, donor plasma should be substituted with AB plasma). Only if none of these are available may they be HPA-unselected (Kiefel et al. 2006, te Pas et al. 2007). If no platelets of the gravida are transfused, then her HLA antibodies should be taken into account when selecting platelet donors. HLA compatible siblings of the gravida can act as platelet donors if absolutely necessary. If the results of the foetal platelet count are available in a short time, the platelet concentrate should only be transfused if the result is lower than 150,000/µl.
Subsequent transfusions via the umbilical cord: transfusions with foreign platelets are recommended. These must test negative for the platelet antigen against which the original maternal platelet antibody is directed and also negative for an HLA antigen if there is a corresponding maternal antibody (aid: the transfusion material should not contain any paternal HLA antigens and should be HLA identical or at least similar to those of the mother). To reduce transfusion complications, the platelets have to be obtained from blood group O donors and have to be washed and irradiated. Due to the risk of fatal umbilical cord haemorrhaging due to the centesis needle dislocating when the foetus moves in the uterus in cases of severe thrombocytopenia, it is important in all subsequent transfusions that the centesis needle does not remain inserted for extensive periods. When the laboratory results of the foetal platelet count take too long, the platelet concentrate should be administered as described above for the initial prophylactic transfusion. Platelet transfusions are usually performed weekly. No observations have understandably been made as to whether the resultant high platelet count continues only for a number of hours or for a few days post-transfusion.
Physical activity of the gravida: She has to avoid all physical activities that could lead to jolting and contusion within the abdominal cavity, and such drugs as acetylsalicylic acid which are detrimental to the function of platelets.
Monitoring therapy effectiveness: in cordocentesis, blood samples are taken immediately before and after transfusion via the cannula still inserted in the umbilical cord vein (after flushing the system). Ultra-sound monitoring. Even after the foetal platelet level has stabilised, thrombocytopenia can still occur after several weeks in some rare cases. It is therefore crucial that the paediatrician performs necessary laboratory and ultra-sound examinations after the child has been discharged from hospital. These should continue until levels have normalised. It is not advisable tho treat the newborn with high-dose immunoglobulins i.v. Monitoring therapy effectiveness in the child after birth: as described under NAIT:
Therapy in cases of mild FAIT
These are cases where there is no sign of intra-cranial haemorrhaging in the foetus either in the medical history or during the present pregnancy. In these cases the gravida should be given high-dose immunoglobulins i.v. (1g/kg/week) from the 16th week onwards. See Neonatal Alloimmune Thrombocytopenia (NAIT) for diagnosis and therapy after the birth.
Premature caesarean section: the majority of working groups recommend a caesarean section in the 32nd to 35th week of pregnancy (or 36th-38th week according to Kjeldsen-Kragh et al. 2007) once the lungs are mature enough. This is to avoid the risk of administering further cordocenteses in the foetus since the platelets can be more safely administered in a neonate until platelet concentration has spontaneously reached normal levels.
Legal aspects
Standardised documentation of clinical, laboratory, functional and medical history data. Documentation of the exact time and week of pregnancy the diagnosis was established. The gravida should be informed about the risks involved in a diagnostic cordocentesis and in prenatal platelet transfusions. She should also be made aware of the possible occurrence of possible mental and physical disabilities. She should also be informed about the probability of recurrence in any subsequent pregnancy and about the importance of consulting a specialised medical centre at the beginning of any subsequent pregnancy. She should be made aware of the necessity to transfuse the thrombocytopenic child with HPA and HLA-compatible platelet concentrates until such a time as the thrombocytopenia has been overcome and that she has to be transfused with HPA and HLA-compatible platelet concentrates whenever in the future she needs treatment for thrombocytopenia. She should be informed about the necessity for her paediatrician to monitor the child's platelet levels and general state of health when the child has been discharged from hospital with an elevated platelet level which is not yet within the normal range. This information should be documented in a medical letter for her family doctor and for herself. The mother should carry a warning document specifying her HPA and, if present, her HLA antibody.
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Hamburg und Bad Bramstedt, Dr. med. J. Neppert, Dr. med. E. v. Witzleben-Schürholz
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