Rainer Bald

Maternal intravenous immunoglobulin treatment does not prevent intracranial haemorrhage in fetal alloimmune thrombocytopenia

SUMMARY. In fetal alloimmune thrombocytopenia (FAIT) the fetus is threatened by intracranial haemorrhage (ICH); therefore early diagnostic and therapeutic intervention is required. We followed the clinical course of a 30‐year‐old woman during her fifth pregnancy after she had given birth to a child with alloimmune thrombocytopenia due to anti‐Zwa. The fetus was monitored by 13 fetal blood samplings (FBS) always followed by transfusion of either maternal or compatible donor platelets. Intravenous immunoglobulin (ivIg) treatment of the mother was begun at 20 weeks of gestation when the fetal platelet count was 36 times 109/1. The fetal platelets were typed Zwa positive by DNA analysis. Despite 11 weeks of maternal ivIg treatment fetal platelet counts progressively declined to 6 times 10/1 and ICH occurred. Subsequently, the fetus was successfully managed by intrauterine platelet transfusions at shorter intervals (3–5 days) and elective Cesarean section was carried out at 35 weeks of gestation. We conclude that maternal ivIg treatment does not prevent ICH in FAIT. The treatment of choice for severely affected cases is serial FBS combined with transfusion of compatible platelets.

Intrauterine therapy of fetal tachyarrhythmias: Intraperitoneal administration of antiarrhythmic drugs to the fetus in fetal tachyarrhythmias with severe hydrops fetalis

In cases of fetal tachyarrhythmia with congestive heart failure accompanied by signs of non-immune hydrops fetalis, the transplacental treatment of the fetus with antiarrhythmic agents by administration of drugs to the mother is only rarely successful. In the two cases reported, the cardioversion of a supraventricular tachycardia to a sinus rhythm or a constant 2:1 AV conduction block to a 1:1 AV conduction with atrial flutter could only be achieved after additional antiarrhythmic treatment directly administered to the fetus using ultrasound guidance. Drugs used include: beta-methyldigoxin, verapamil, propafenon, and they were administered according to the dosing amounts for intravascular injections. This was carried out 12 times in case 1 by the intraperitoneal route into the fetal ascites and twice in case 2. This led in both cases to varying durations of a sustained sinus rhythm after 5-15 minutes. This technically relatively simple procedure affords the option of rapidly achieving high concentrations, even when antiarrhythmic agents are administered which do not adequately cross the placenta. This direct treatment is indicated in cases of tachyarrhythmia with advanced signs of non-immune hydrops fetalis as a supplement to the high-dose transplacental therapy using antiarrhythmic agents.

New Therapeutic Aspects in Nonimmune Hydrops fetalis Based on Four Hundred and Two Prenatally Diagnosed Cases

In 402 cases with prenatally diagnosed nonimmune hydrops fetalis, cardiovascular diseases were present in 18%, chromosomal disorders in 11%, and hematologic disorders of the fetus in 10%. In the last 3 years, fetal blood sampling has become a very important part of the differential diagnosis of nonimmune hydrops (chromosomal, hematologic and metabolic disorders, intrauterine infection). Also, transabdominal placental biopsy has been used for rapid karyotyping. A detailed fetal echocardiogram is absolutely necessary in all cases of nonimmune hydrops, in particular spectral and color Doppler flow mapping. Thus, congenital heart diseases can be accurately diagnosed. Further, in other causes of hydrops regurgitation of atrioventricular valves may be present in advanced stage. New important methods of intrauterine therapy are in particular: intravascular blood substitution in anemia, and the intravascular application of antiarrhythmic drugs in tachyarrhythmia. The overall survival rate was 19.4% (78 of 402); 4.0% (6 of 149) before 24 weeks of gestation, and 28.5% (72 of 253) after this age of gestation. The majority of survivors were in the tachyarrhythmia, hematologic disorder, isolated ascites and hydro-/chylothorax groups (53 of 78 survivors, 68%). In the other groups, the survival rate was generally low.

Prenatal management of alloimmune thrombocytopenia of the fetus

Alloimmune thrombocytopenia of the fetus is a serious disease, which may cause intracranial haemorrhage leading to death or permanent neurological disability. The prenatal management of fetuses at risk is therefore very important. Ten years ago we published an International Forum on this subject. At that time there was no consensus of opinion among the experts on this important issue. It therefore seemed of interest to obtain information on current opinions. To achieve this, the following questions were sent to experts in the field: Question 1. If a fetus is at risk of alloimmune thrombocytopenia, do you routinely measure the fetal platelet count by fetal blood sampling (FBS)? If so, at what time and do you administer compatible platelets during the procedure? Question 2. If the fetus is found to be thrombocytopenic, what is your form of treatment: (a) Transfusions of compatible platelets and, if so, what is the transfusion trigger, the dose and the frequency? (b) Intravenous immunoglobulin (IVIG), with or without corticosteroids, to the mother? (c) Both (a) and (b)? (d) Other treatment? How do you evaluate the efficacy of the treatment? Question 3. If you do not routinely determine the platelet count of the fetus, how do you manage the case? Question 4. What are the requirements for transfusion of platelets to the fetus: ABO/RhD compatibility; cytomegalovirus (CMV) status of the donor; irradiation; if maternal platelets are used, how are they washed; must maternal platelets be compatible for human leucocyte antigen (HLA) class I antibodies detectable in the mother against an antigen for which the fetus is negative; recommended dose, volume and frequency? It is clear from the answers that the management of fetuses at risk of alloimmune thrombocytopenia is by no means standardized. Most experts are reluctant to perform FBS because of the danger of this procedure. However, in three centres it is still performed routinely in all cases in which HPA (human platelet antigen) antibodies are detected in the mother and the father is positive for the corresponding antigen. For the other experts, the decision to perform FBS depends on further, additional factors, such as a previously affected child, homozygozity of the father, strength of the HPA antibodies, etc. In one centre, regular fetal platelet counting is strongly recommended when the mother has anti-HPA-1a or -3a and there was a previously affected child (Kroll et al .). One expert even restricts FBS to cases in which a previous child had intracranial haemorrhage and the umbilical cord insertion is anterior (Kanhai). For details, see the responses, below, of the individual authors. Transfusions of compatible platelets are given at each FBS by some of the experts, but others find the danger (such as prolonged bradycardia) of such transfusions to be too great. If the platelet count has been determined, therapy – either IVIG or corticosteroids alone, or both – depends on this count. Platelet transfusions are given by some if the above therapy is inadequate, but the transfusion trigger varies considerably, i.e. from < 30 × 10 9 /l to < 100 × 10 9 /l, or when bleeding is suspected or ‘seen’ on ultrasound. In the experience of Kroll et al ., the response of the mother to treatment with IVIG was found to often be poor and sometimes intracranial haemorrhage occurred during this treatment. Therefore, this group prefer to administer repeated platelet transfusions to the fetus. The effect of therapy is usually checked by FBS at monthly intervals. If the platelet count is not determined routinely, the mother is treated with IVIG from ± 20 weeks of gestation and the effect is checked at monthly intervals or only once, at 30 weeks, by FBS or ultrasound. FBS is usually carried out at the end of pregnancy to decide on the mode of delivery and further treatment. In order to fully appreciate the various policies of management, it is essential to read the answers from the individual groups, as stated below. The requirements for transfusion of platelets to the fetus are fairly standardized. However, only some experts take into account maternal HLA antibodies against an antigen that is absent in the fetus. The CMV status of the donor is not always considered if leucocyte-reduced platelet concentrates are used. In conclusion, the management of this serious condition of the fetus is by no means standardized. In fact, there seems to be less consensus of opinion concerning this management than 10 years ago when we published the first International Forum on this subject.

Prenatal diagnosis of atrioventricular canal malformations with up-to-date echocardiographic technology: report of 14 cases

Fourteen fetuses with atrioventricular canal malformations were examined by two-dimensional echocardiography, pulsed-wave Doppler echocardiography, and color Doppler flow mapping. Eleven fetuses had complete and three fetuses had partial atrioventricular canal malformations. Nonimmune hydrops fetalis was associated with six cases, and fetal arrhythmia was seen in three cases. With two-dimensional echocardiography, the atrioventricular canal malformations could be diagnosed accurately. The inclusion of color Doppler flow mapping, however, provided additional hemodynamic information that was important from the prognostic point of view. Incompetence of atrioventricular valves could be demonstrated in 10 of 14 cases by Doppler echocardiography. In nine cases, detailed Doppler echocardiographic evaluation of the regurgitation jet was possible. The proportion of systolic time during which atrioventricular valve insufficiency was demonstrated was related to the occurrence of nonimmune hydrops fetalis. When insufficiency of atrioventricular valves was associated with hydrops (four cases), a pansystolic insufficiency was always present. In cases without hydrops (five), regurgitation was confined to early systole. Thus a reliable method for semiquantitative evaluation of the degree of insufficiency seems to have been found. Moreover, an association appeared to exist between the occurrence of hydrops fetalis and the proportion of atrial area that was taken up by regurgitant jet area, as determined by planimetry in the four-chamber view. Prenatal diagnosis was confirmed by autopsy or neonatal cardiac evaluation. Only one neonate survived in our series. Two were stillborn, four died during the neonatal period, two died during infancy, and pregnancy was electively terminated prematurely in five cases. Eight fetuses were found to have a karyotypic abnormality.

Prenatal diagnosis and management in fetuses with cystic hygromata colli

We report on 45 fetuses with prenatally diagnosed bilateral cystic hygromata colli by ultrasound. Two of the 45 cases involved a twin pregnancy with only one fetus showing hygromata colli. In 2 cases there was only isolated hygromata colli. The other 43 cases showed the signs of non-immune hydrops fetalis. The cytogenetic findings were: 9 fetuses with Turner syndrome, 1 fetus with Turner mosaicism, 1 fetus with trisomy 18, 6 fetuses with trisomy 21, 12 fetuses with normal karyotype, and 16 fetuses with a failed chromosome culture. In fetuses with Turner syndrome and normal karyotype the sonographic findings were similar: massive bilateral hygromata colli, substantial fluid accumulations in skin and body cavities, oligohydramnios and intra-uterine growth retardation. In the cases with trisomy 21, the relative size of the hygromata colli was smaller. Intra-uterine growth retardation and oligohydramnios were not observed. The sole survivor of our group (elective pregnancy interruption: 30 cases; intra-uterine death: 14 cases) (karyotype: 46,XY) presented sonographically with massive ascites, a moderate cystic hygroma, and appropriate fetal development, and a normal amniotic fluid quantity. These findings are analysed in order to provide recommendations for prenatal diagnosis, prenatal management and genetic counselling of the couples concerned.

Chromosomal findings in fetuses with prenatally diagnosed cysts of the choroid plexus

SummaryChoroid plexus cysts were diagnosed in 25 out of 823 fetuses with prenatally diagnosed abnormalities (growth retardation/malformations). Among these, 5 revealed a chromosomal disorder (4 cases with trisomy 18 and one case with a translocation trisomy 21). Additional abnormalities, such as growth retardation, holoprosencephaly, hydrocephalus and club foot, were found in 6 out of the 20 fetuses with no chromosomal abnormality. All fetuses with a chromosomal disorder revealed further typical prenatally recognizable abnormalities. Our observation indicates that prenatally diagnosed choroid plexus cysts should be considered as an indication for prenatal chromosomal diagnosis, although the risk of there being an underlying chromosomal disorder is low in cases with no additional abnormalities.

Direct Intrauterine Fetal Treatment of Fetal Tachyarrhythmia with Severe Hydrops fetalis by Antiarrhythmic Drugs

In cases of non-immune hydrops fetalis caused by tachyarrhythmias, the transplacental passage of antiarrhythmic drugs may be hampered. When this is proven by fetal blood sampling in cases of tachyarrhythmia refractory to transplacental treatment, additional administration of antiarrhythmic drugs into the fetus is necessary and seems to improve the results. Although injections of antiarrhythmic agents in fetal ascites are also highly effective, intravascular administration by sonographic guidance is to be preferred. Then, simultaneous measurements of fetal and maternal drug levels are possible for the evaluation of pharmacokinetics and for monitoring the antiarrhythmic therapy.

Protein Analysis in Amniotic Fluid and Fetal Urine for the Assessment of Fetal Renal Function and Dysfunction

Micromolecular proteins (molecular weight less than 68 kD) in amniotic fluid are assumed to be derived largely from fetal urinary excretion and therefore may reflect fetal kidney function and maturation. Microprotein concentrations in amniotic fluid, neonatal urine and urine of fetuses with bilateral urinary tract dilation were analyzed using microgradient gel electrophoresis to separate proteins according to their molecular size. Alpha-1-microglobulin and beta 2-microglobulin were assayed as singular micromolecular marker proteins. Microproteins in amniotic fluid decreased progressively with advancing gestation during the 3rd trimester. Micromolecular protein concentrations in the first postnatal urine of healthy infants born prematurely or at term were similar to those in amniotic fluid of corresponding fetal age and yielded an identical developmental pattern. A strong correlation existed between the microprotein concentrations in amniotic fluid and fetal urine. It is concluded that fetal urinary production is the main determinant for the microprotein content of amniotic fluid and that a major fetal pathway exists for the intrauterine metabolism of these proteins. The 3rd trimester decrease in amniotic fluid seems to be dependent on the increasing reabsorption capacity of proximal tubular cells representing morphological and functional kidney maturation. The exact diagnostic value of microprotein analysis for the assessment of disturbed fetal kidney function has still to be defined by further investigation.

Color doppler flow mapping of fetal heart

Color Doppler flow mapping of fetal heart was performed in 582 fetuses between 16 and 38 weeks of gestation. Congenital heart diseases were excluded in 522 fetuses correctly. In 59 fetuses structural and/or functional cardiac abnormalities were diagnosed. In one fetus small multiple ventricular septal defects were missed. The most important additional information obtained by color Doppler flow mapping was: (1) Diagnosis of insufficiencies of atrioventricular valves; (2) Demonstration of turbulent high velocity jet in stenosis of semilunar valve; (3) Reverse flow in ascending aorta in atresia of aortic valves and on ductus arteriosus and main pulmonary artery in atresia of pulmonary valves; (4) Reverse perfusion of ductus arteriosus and main pulmonary artery as well as an antegrade turbulent high velocity jet in severe pulmonary stenosis as part of tetralogy of Fallot; (5) Bidirectional interventricular shunting of blood in ventricular septal defect. Color Doppler flow mapping allows rapid screening for flow abnormalities of the fetal heart. Exact localisation of sample volume by pulsed wave Doppler in area of abnormal flow pattern is possible, thus significantly reducing the Doppler examination time. The accuracy of prenatal diagnosis of congenital heart diseases is improved by application of color Doppler flow mapping, in particular in presence of complex cardiac defects.