Hydrops Fetalis due to Rh iso-immunization in a Chinese Patient
A Chinese infant with immune hydrops fetalis due to Rh isoimmunization is presented. Rh isoimmunization is extremely rare in the Chinese population. This is the first patient we encountered in Hong Kong requiring treatment by in-utero blood transfusion. Following in-utero transfusion, fetal hydropic state as well as maternal pre-eclamptic state improved. Clinicians should be aware of the importance of antenatal blood group screening and instituting immunoglobulin prophylaxis for the at-risk women. Early diagnosis and timely prenatal intervention significantly improve the postnatal outcome. Subsequent postnatal anaemia can be protracted but long term neurodevelopment appears to be unimpaired.
Keyword : Chinese; Hydrops fetalis; In-utero blood transfusion; Rh isoimmunization
Madam HML, a 29 year-old Rh(D) -ye mother, gravida 3 para 1, was referred at 29 weeks gestation with pre-eclampsia and hydrops fetalis. The couple were Chinese (Cantonese) from the southern province of China. In 1984 the mother gave birth to a normal baby boy vaginally. In 1991 she had a medical termination of pregnancy because of anencephaly at 20 weeks gestation. She had no previous history of blood transfusion. In both pregnancies, her Rh blood group was not known.
She first attended antenatal clinic at 16 weeks gestation. Physical examination was normal. Blood pressure was 120/70 mmHg. There was no oedema or proteinuria and the uterine size corresponded to her period of amenorrhoea. Ultrasound examination showed normal fetal parameters and no obvious fetal abnormality. She was found to be Rh D -ye and her Rh-anti D antibody was at a titre of 1:2048.
Her pregnancy progressed normally until she developed hypertension, oedema and proteinuria at 29 weeks gestation. Her blood pressure was 150/90 mmHg. She developed severe oedema which was up to the abdominal wall and severe proteinuria of 2.02 g/24 hours. Ultrasound examination showed fetal hydrops. Fetal biparietal diameter and femur length corresponded to 28 weeks gestation. The fetal abdominal circumference was 32.1 cm, which was equivalent to 37 weeks gestation. The cardiothoracic ratio was raised to 0.7. The fetus was found to have pericardial effusion, gross ascites, scalp and subcutaneous oedema. The placenta was bulky with maximum thickness of 7.5 cm. Non-stress test was suboptimal with reduced variability.
Her haemoglobin was 10 g/dl, mean corpuscular volume (MCV) was 94 fl., blood group was A, Rh-we (ccdee). Red cell phenotyping showed NNss, Le(a-b+), P1+, Fy(a+b-), JK(a+b-), kk. Indirect Coomb's test was positive and anti-D warm alto-antibody (IgG type) titre was 1:512.
Her husband's blood group was O Rh+ve (CcDEe). Other cell typings were MNss, Le(a-b+), P1-, Fy(a+b-), JK(a+b+), kk. Antibody investigation of wife showed presence of potent anti-D, weakly reactive anti-E, and anti JKb.
Spectrophotometric analysis of the amniotic fluid showed a high absorbance of 0.759 at 450 nm which corresponded to zone 3 of Liley's graph. Fetal haemoglobin (Hb) was 2.4 g/dl. Haematocrit (Hct) was 8%. Haemoglobin study did not show Hb Bart's or Portland. Direct Coomb's test was positive. The fetus was Rh positive.
Intravascular fetal blood transfusion by cordocentesis was performed at 29 4/7, 29 6/7 and 32 2/7 weeks gestation. Irradiated group O, D-, E-, Jk(b-) blood compatible with maternal serum was transfused through white cell filter. Frusemide 1 mg was administered intravenously after each transfusion.
Following the first transfusion of 100 ml packed cells (Hb 17.7 g/dl and Hct 52%) the fetal Hb and Hct were raised from 2.4 g/dl and 8% to 7.1 g/dl and 20.9% respectively. Following the second transfusion of 200 ml packed cells (Hb 16.8 g/dl and Hct 52%) fetal Hb and Hct were raised from 7.7 g/dl and 21.1% to 14.6 g/dl and 43.85. At 32 2/7 weeks gestation after the third transfusion of 130 ml of packed cells (Hb 16.8 g/dl, Hct 51.5%) the fetal Hb and Hct were further raised from 8.3 g/dl and 24.5% to 19.5 g/dl and 52% respectively. Repeat ultrasound examination at 33 2/7 weeks gestation showed normal fetal growth, reduction in scalp edema and pericardial effusion and abdominal circumference. Liquor volume appeared normal. Cardiothoracic ratio remained high at 0.65. Fetal heart rate tracing became reactive with normal variability. Maternal weight decreased from 80.7 kg to 69.9 kg from 30 to 34 weeks gestation. Oedema improved. Blood pressure became normal at 120/80 mm Hg. Proteinuria decreased from 2.02 g/24 hr to 0.6 g/24 hr. Creatinine clearance increased from 78.9 ml/min to 127.5 ml/min.
A female baby weighing 2215g was delivered by elective Caesarean section at 34 2/7 weeks gestation with Apgar score of 6 at 1 minute and 9 at 5 minutes. The placenta weighted 750g. On examination the infant had moderate ascites, cardiomegaly and hepatosplenomegaly but no generalized oedema. She had mild respiratory distress and required oxygen supplement for the first week but did not develop respiratory distress syndrome. Her serum bilirubin level was 59 umol/l on day one, which peaked at day 4 with maximum bilirubin of 158 umol/l. Jaundice persisted for 2 weeks and she was treated with phototherapy. Her haemoglobin level on day one was 14 g/dl and reticulocyte count was <0.5%. Direct Coomb's test was positive and serum was positive for anti-D and anti-JKb antibodies, with a very high anti-D titre of 2048 against Rlr cells. She had persistent haemolysis with progressive decrease in haemoglobin level. She required top up transfusion for three times. Her reticulocyte count remained below 0.5% and the lowest haemoglobin was 4.9 g/dl on D54 when she received her third transfusion. Her subsequent progress was good. Her haemoglobin level was maintained at 11.6 gm/dl without further transfusion. Neurological examination was normal and her development was appropriate after correction for prematurity. Full developmental assessment was done at the age of 2 1/2 years which showed normal development with intelligent quotient of 104.
One of the commonest cause of fetal immune hydrops is Rh (D) isoimmunization. This condition is predominant in Caucasian population. The incidence of Rh- mother in the local Chinese population is 0.27% and consequently the prevalence of immune hydrops fetalis due to Rh incompatibility is expected to be low.1 However, hydrops fetalis due to Rh (D) isoimmunization has not been reported in the local Chinese population. To our knowledge, this is the first case diagnosed and treated successfully by intravascular fetal blood transfusions. The rare occurrence of hydrops fetalis due to Rh incompatibility in the local population cannot be explained on the basis of low incidence of Rh- mothers alone and other immunological factors may be responsible for this apparently low incidence. About 30% of the D negative Chinese tested posses weak expression of D antigen, they belong to the D-elution phenotype. This may further reduce the likelihood of Rh(D) isoimmunization.1 The severity of isoimmunization in this fetus may be related to coexistence of anti-E, and JKb isoimmunization. The lack of information about Rh and antibody status in both pregnancies has probably contributed to the development of marked isoimmunization in the third pregnancy. Until late 1980's it was not a routine practise for all obstetric units to check Rh status in pregnant women. Knowledge about the Rh negative state during pregnancy and post delivery administration of anti-D to non-sensitized women may reduced the risk of isoimmunization to the D antigen in the next pregnancy but may not totally prevent isoimmunization from other Rh or minor blood group antigents. It is prudent for each community to determine the prevalence of various blood groups and to consider antenatal screening for those commonly occurring antigens that may lead to hemolytic disease of the newborn. In her present pregnancy she was found to have a high anti-D antibody titre at 16 weeks gestation. However since the indirect Coomb's test, spectrophotometric analysis of amniotic fluid, bilirubin level and serial ultrasound examination may not predict the development of hydrops fetalis, investigations were deferred until 28 weeks gestation.2,3 Earlier ultrasound examination could have detected the hydropic changes of the fetus sooner.
At present the overall survival of hydropic fetuses due to Rh (D) alloimmunization following intrauterine therapy is around 70%.4 Intravascular transfusion is the preferred modality of treatment before fetal maturity is reached at around 36 weeks gestation. The technique, frequency and the amount of blood needed to be transfused to maintain the desired level of fetal haematocrit has been well documented.5 Following these recommendations we were able to maintain fetal haematocrit level around 40%. The improvement in fetal hydropic condition and fetal non-stress test has been observed following transfusion. It was also noted that maternal pre-eclampsia and renal function improved following fetal therapy. Although it is recommended that the delivery of these fetuses be deferred until 36-38 weeks gestation, after discussion with the neonatologist and the parents we decided against taking further risk of transfusion and delivered the baby at 34 weeks gestation.
During the neonatal period, the infant did not develop severe neonatal jaundice because most of the native fetal erythrocytes possessing the sensitizing antigen had been replaced by donor blood. This replacement partially corrected fetal anaemia and hence suppressed fetal erythropoiesis, and thereby decreased fetal haemolysis. This is similar to experience reported by Newnham and his co-workers in that severe cases of Rh isoimmunization often required multiple in-utero blood transfusions and do not require exchange transfusion after birth.6 Yet less severe cases who do not require prenatal transfusion often required repeated exchange transfusions after birth. This baby also had very protracted postnatal anaemia with absence of reticulocytosis. The postnatal anaemia was related to the persistence of sensitizing antibody, so that erythrocytes produced postnatally were quickly destroyed in the peripheral circulation. The haemolysis, however, was not compensated by reticulocytosis, possibly due to low erythropoietin level, as previously reported.7 In postnatal life the transfused adult haemoglobin may facilitate tissue oxygen delivery, thereby decreasing stimulation of erythropoietin. Intrauterine transfusion may also delay the normal maturational shift of erythropoietin production from liver to kidney. Therefore it is important to closely monitor the haemoglobin level of these babies who had been successfully treated by intrauterine transfusion. In spite of the severe in-utero anaemia of haemoglobin of 2.4 gm/dl in this baby, long term neurological follow up showed favourable developmental outcome.
The incidence of Rh- mother is low in southern Chinese and hydrops fetalis due to Rh (D) alloimmunization is rare. Nevertheless, clinicians should be aware of this complication and routinely screen for Rh group in these women. The importance of anti-D immunoglobulin prophylaxis cannot be over-emphasized. Early diagnosis and timely prenatal intervention significantly improve the outcome. Protracted postnatal anaemia can occur in babies treated by in utero transfusion. Hence it is important to monitor the haemoglobin level postnatally.
1. Mak KH,Yan KF, Cheng SS, et al. Rh phenotypes of Chinese Blood donors in Hong Kong, with special reference to weak D antigens. Transfusion 1993;33(4):348-51.
2. Bowman JM, Pollock JM. Amniotic fluid spectrophotometry and early delivery in the management of erythroblastosis fetalis. Pediatrics 1965 ;35:815-20.
3. Nicholaides KH, Rodeck CH, Mibashan RS, Kemp JR. Have Liley charts outlived their usefulness? Am J Obstet Gynecol 1986;155:90-6.
4. Rodeck CH, Santolaya, Nicolini U. The fetus with immune hydrops. The Unborn Patient - Prenatal diagnosis and treatment. second edition 1990;215-27.
5. Nicholaides KH, Soothill PW, Rodeck CH, Clewell W. Rh disease: Intravascular fetal blood transfusion by cordocentesis. Fetal Ther 1986;1:185-90.
6. Newnham JP, Phillips JM. Intrauterine intravascular transfusion for fetal haemolytic anaemia: the Western Australian experience. The Medical Journal of Australia 1992;157:660-5.
7. Millard DD, Gidding SS. Effects of intravascular intrauterine transfusion on prenatal and postnatal haemolysis and erythropoiesis in severe fetal Isoimmunization. J Pediatr 1990;117:447-54.
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