Successful intrauterine treatment and good long-term outcome in an extremely severe case of fetal hemolytic disease.

A 34-year-old multiparous woman presented with anti-Rh-D antibodies (1: 512) and fetal hydrops at the 21(st) week of gestation. Ultrasound revealed massive fetal skin edema, ascites, hepatomegaly, placentomegaly, and anhydramnios. No fetal movements were observed. Fetal heart was enlarged, with reportedly decreased contractibility. The Doppler parameters were abnormal: the peak systolic velocity in median cerebral artery (MCA PSV) was increased (84 cm/s, 3 MoM), and absent end diastolic flow (AEDF) was reported in the umbilical artery. Ultrasound examination indicated severe fetal anemia and heart failure. Umbilical vein puncture was performed and the fetal blood count was determined (RBC 0.01 × 10(6)/µl, Ht 0.1%, PLT 67 × 10(3)/µl, WBC 2.1 × 10(3)/µl, indeterminable hemoglobin level). Packed red blood cells (0 Rh-, 30 ml) were immediately transfused to the fetus. Altogether, seven intrauterine transfusions were performed. Fetal hydrops disappeared gradually during the next few weeks. The male neonate (1860 g, 45 cm, Apgar score 3-4) was delivered after the last transfusion at 34(th) week of gestation due of intrauterine asphyxia. The infant was discharged after 21 days, in good condition, on breastfeeding. There was one 10 mm focus of periventricular leukomalacia in the brain, diagnosed based on trans-fontanel ultrasound, without any signs of damage to other organs. At the age of 5 years, the child is healthy, with no abnormalities in his neurodevelopmental parameters.

Introduction

Generalized fetal hydrops is a serious complication of fetal hemolytic disease. It is a symptom of serious anemia, with concomitant heart failure, hypoxia and multiorgan damage(. The prognosis for the survival of a fetus w ith hydrops depends on the gestational age at the diagnosis, fetal blood parameters and, on the effectiveness of prenatal therapy. Fetal anemia caused by hemolytic disease does not usually cause intrauterine growth restriction, or the redistribution of flow indicating fetal asphyxia, which are typical, for example, for fetuses with hypotrophy resulting from placental insufficiency. Fetuses with hemolytic anemia are usually of normal growth and centralization of fetal circulation is not observed even in the most severe cases of hydrops. The main abnormality in Doppler examination is an acceleration of peak systolic blood flow, which can be typically tested in fetal median cerebral artery. Severe fetal anemia usually causes hydrops with ascites, skin edema, cardio-, hepato-, placentomegaly and polydramnios.

It is well established, that the effectiveness of fetal therapy is very high and gives the chance of survival for most of the fetuses with hemolytic disease(. Nevertheless, doubts arise regarding the long-term neurodevelopmental outcome of children which experience profound intrauterine anemia. In hereby presented case, it was difficult to estimate the prognosis for the fetus, because profound anemia and associated hypoxia could lead to irreversible changes in the fetal brain. The literature data concerning this issue are scarce; nevertheless, they indicate that fetal tolerance to chronic hypoxia due to hemolytic disease is quite high(. We present a case of a successful prenatal treatment of a fetus with advanced hydrops, heart failure, anhydramnios and extremely low blood count.

Case report

A 34-year-old multigravida was referred by her obstetrician to the 2nd Department of Obstetrics and Gynecology Department in Bielanski Hospital in Warsaw due to ultrasonographic evidence of fetal hydrops in the 21st week of gestation. In the past the patient had delivered a baby weighting 1800 g in the 35th week of gestation due to PPROM. In the current pregnancy, she was closely monitored by her obstetrician because of the growing level of anti-D antibodies. On admission to the hospital, the level of antibodies was 1: 512. The visualization of the fetus was poor due to the anhydramnios and fetal compression. Advanced hydrops with ascites, massive skin edema, cardio-, hepato-, and placentomegaly were documented (figs. 1 and 2). The mother did not report the evidence of any fetal movements. The results of the Doppler examination were abnormal, with absent end diastolic flow in the umbilical artery (AEDF) and peak systolic velocity in the MCA equal to 81 cm/s, which accounted for 3 MoM (fig. 3). We performed a diagnostic cordocentesis and took a blood sample for blood count determination. The results indicated poor fetal condition. There was profound anemia (RBC 0.01 × 106/µl, Ht 0.1%, PLT 67 × 103/µl, WBC 2.1 × 103/µl), and the hemoglobin level was undetectable using routine techniques.

Fig. 1

Cardiomegaly and cardiac effusion in the fetus with severe anemia at 21 weeks

Fig. 2

Anhydramnios, giant placentomegaly, fetal head compression and skin edema at 21 weeks

Fig. 3

Abnormal MCA flow in the fetus with profound anemia and compression of the head due to anhydramnios

Generally, it was questionable, whether the fetus with such poor parameters qualified for prenatal therapy at all. The mother was informed about increased risk of cerebral palsy and other potential future neurological consequences of fetal anemia. However, she was determined to undergo the treatment.

After diagnostic cordocentesis, we transfused 30 ml of 0 Rh– blood to the fetus, with no arising complications (fig. 4). Three days after introducing the treatment, the volume of amniotic fluid was normal, and the mother started to feel fetal movements (fig. 5). Consecutive intrauterine transfusions to the free umbilical loop (n = 7) were performed approximately every 2 weeks. Fetal hydrops g radually resolved during 4 weeks a fter commencing the treatment. A male neonate (1860 g, 45 cm, Apgar score 3– 4) was delivered via cesarean section at 34th week due to post-transfusion intrauterine asphyxia, which was caused by an unintended circulation overload (there was damage of the device measuring fetal hemoglobin level). The neonate required mechanical ventilation for a short period of time, and was hospitalized at the intensive care unit for 10 days. A partial exchange transfusion was performed on the first day, due to increasing hyperbilirubinemia and high hematocrit. After this procedure, the condition of the neonate improved rapidly. He was discharged after 21 days, i n good condition a nd on breastfeeding. At that time, one 10 mm focus of periventricular leucomalacia was observed on trans-fontanel ultrasound. There were no abnormalities in the child's physical condition and laboratory parameters. However, routine controls in specialist clinics were recommended due to prematurity. The child received 2 complementing transfusions due to secondary anemia in the first year of life. Currently, he is 5-year-old and develops normally, but still remains under regular neurological, cardiologic and ophthalmologic control. No abnormalities are observed on vision and hearing testing, and in echocardiography. According to the NMR examination, the central nervous system is normal. The detailed tests evaluating the child's neurological status were not performed due to lack of developmental abnormalities.

Fig. 4

Blood flow in the transfusion needle and in the umbilical vein in the color Doppler

Fig. 5

The cross section similar to presented in fig. 2. The 3rd day after the first intrauterine transfusion. Normal amniotic fluid volume, persistent skin edema and placentomegaly

Discussion

Untreated fetal anemia can lead to serious complications, such as heart failure, hydrops, intrauterine fetal death or death after delivery, and many neurological complications, including cerebral palsy(. Therefore, it should be treated prenatally, with intrauterine intravascular transfusions of red blood cell concentrates. The treatment is very effective, and the prognosis is good in most cases, with survival rates over 90%(. Although even the most severe anemia can be corrected with intravascular transfusions, the further neurological development in the affected fetuses raises some concerns. The largest meta-analysis regarding intrauterine therapy in fetal anemia was published in 2011. It revealed that 2.4% (13/549) of babies treated in utero develop cerebral palsy, and 6.2% (26/422) show other neurological abnormalities(. Although data on the long-term development of such patients are still insufficient, there is consensus that the risk factors of neurological disorders include severe fetal hydrops, multiple intrauterine transfusions, low hematocrit at delivery, perinatal asphyxia, and low level of parental education(. To the best of our knowledge, no papers reporting successful treatment of a fetus with such severe anemia and hydrops were published to date. In hereby presented case, ultrasound findings suggested terminal fetal condition. The hydropic changes in the fetus and placenta were advanced; furthermore, we observed heart failure, pathological umbilical artery flow, renal hipoperfusion and anhydramnios. However, despite many risk factors for poor long-term neurological outcome, the baby has been developing normally thus far. Our patient presented with an extremely severe case of fetal hydrops, which was treated at a very advanced stage. Usually such cases are treated at earlier stages. Also in this case, hydrops was observed already at 19th week, but the patient was refused treatment in two specialists centers close to her place of residence due to the early gestational age. She was informed that the intrauterine therapy can be performed no earlier than after the 24th w eek. A lthough t he t herapy c onducted at our center was not optimal, because the baby was delivered prematurely, this case documents the purpose and effectiveness of treatment even in the most severe, seemingly hopeless cases of fetal hemolytic disease.

Conclusions

Even in the most severe cases of hemolytic disease, fetal therapy should be considered, after discussing its possible benefits and risks with the parents.

Fetal compensation mechanisms can allow protection of the central nervous system even in cases of very severe anemia.

In fetuses with hemolytic disease, if there are clear indications to fetal therapy, intrauterine transfusions can be performed regardless of gestational age.