Celocentesis for early prenatal diagnosis of hemoglobinopathy.

OBJECTIVE: Celocentesis is an invasive technique that can provide prenatal diagnosis of single-gene disorders, from as early as 7 weeks' gestation. The objective of this study was to examine the safety of celocentesis. METHODS: In this prospective study, celocentesis was performed for prenatal diagnosis of hemoglobinopathy in 402 singleton pregnancies in which both parents were carriers of ß-thalassemia or sickle cell disease trait. We assessed procedure-related maternal discomfort or pain, success of sampling and obtaining results, pregnancy outcome and postnatal follow-up. RESULTS: First, celocentesis was carried out at a median gestational age of 8.6 (range, 6.9-9.9) weeks and celomic fluid was successfully aspirated in 99.8% of cases. Second, 67% of women had no or only mild discomfort, 18% had moderate discomfort, 12% had mild-to-moderate pain and 3% had severe pain. Third, prenatal diagnosis from analysis of the celomic fluid was successful in 93.8% cases, and in the last 121 cases, it was always successful. Fourth, in all cases of successful sampling and analysis of celomic fluid, the diagnosis was concordant with results obtained from additional prenatal or postnatal testing. Fifth, in addition to diagnosis of hemoglobinopathy, quantitative fluorescence polymerase chain reaction analysis, which was performed to evaluate maternal contamination using several markers for chromosomes X, Y, 21, 18 and 13, led to the accurate diagnosis of chromosomal aneuploidy. Sixth, in all cases of an affected fetus diagnosed by celocentesis in which the parents chose termination of pregnancy, this was carried out < 10 weeks' gestation. Seventh, in 97.1% (298/307) of the continuing pregnancies there was live birth, in seven (2.3%) there was miscarriage and in two (0.7%) there was loss to follow-up. Eighth, fetal abnormalities were diagnosed in three (1%) cases, including unilateral transverse amputation of the forearm, unilateral moderate hydronephrosis and small-bowel duplication. All neonates were examined by a pediatrician and were found to be phenotypically normal, except for the three cases with a prenatally diagnosed defect. CONCLUSIONS: Celocentesis can be used for early prenatal diagnosis of genetic abnormalities, and the procedure-related risk of pregnancy complications appears to be low. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Maternal serum hCG, PAPP-A and AFP as predictors of hemoglobin Bart disease at mid-pregnancy.

OBJECTIVE: To evaluate the ability of maternal serum-free ß-human chorionic gonadotrophin (ß-hCG), pregnancy-associated plasma protein-A (PAPP-A), and alpha fetoprotein (AFP) levels in the screening of fetuses with hemoglobin (Hb) Bart's disease among pregnancies at risk. MATERIALS AND METHODS: Pregnancies at risk for fetal Hb Bart's disease scheduled for cordocentesis at 18 to 22 weeks were recruited into the study. Maternal serum-free ß-hCG, PAPP-A, and AFP concentrations were measured before cordocentesis, and the final fetal diagnosis of Hb Bart disease was based on fetal Hb typing using high-performance liquid chromatography. RESULTS: Of 57 recruited pregnancies, 11 had fetal Hb Bart's disease and 46 were unaffected. Maternal serum alpha-fetoprotein (MSAFP) concentrations were significantly higher in women with fetal Hb Bart's disease than those with unaffected fetuses (median 99.53 vs 50.83, P < 0.001), whereas the concentrations of free ß-hCG and PAPP-A were not significantly different between the two groups (P = 0.543 and 0.777, respectively). CONCLUSION: Second-trimester MSAFP may be clinically a useful screening test for fetal Hb Bart's disease among pregnancies at risk.

High fetal splenic artery peak velocity in fetuses with hemoglobin Bart disease: a preliminary study.

OBJECTIVE: The purpose of this study was to evaluate the role of the splenic artery (SPA) peak systolic velocity (PSV) in identifying fetuses with hemoglobin (Hb) Bart disease among pregnancies at risk for the disease. METHODS: Pregnancies at risk for fetal Hb Bart disease scheduled for cordocentesis at 18 to 25 weeks' gestation at Maharaj Nakorn Chiang Mai Hospital were recruited into the study. The SPA PSV was measured before cordocentesis, and the final fetal diagnosis of Hb Bart disease was based on fetal Hb typing using high-performance liquid chromatography. RESULTS: Seventy-six singleton pregnancies at risk for fetal Hb Bart disease were sonographically evaluated for the SPA PSV and underwent cordocentesis for fetal blood analysis. Among the 76 recruited pregnancies, 17 fetuses with Hb Bart disease were finally diagnosed by fetal blood analysis with high-performance liquid chromatography, and the remainder had no abnormalities or had the alpha-thalassemia 1 trait and were defined as unaffected fetuses. The mean SPA PSVs +/- SD for the unaffected and affected fetuses were significantly different: 21.17 +/- 3.7 cm/s (range, 13.8-29.9 cm/s) and 26.12 +/- 3.6 cm/s (range, 20.4-31.5 cm/s) respectively. The SPA PSV of the affected fetuses was higher than that of the unaffected ones (Wilcoxon signed rank test, P < .001). CONCLUSIONS: Splenic artery PSV assessment at mid pregnancy may have a potential role in identifying fetuses with Hb Bart disease. Further studies to evaluate the effectiveness of the SPA PSV in differentiating affected from unaffected fetuses among pregnancies at risk are desirable.

A pilot study of 'fast track' antenatal screening for haemoglobinopathies.

The NHS Plan launched in 2000 advocated a linked antenatal and neonatal screening programme for haemoglobinopathies. Currently screening practices vary widely across the UK and patient sampling is generally performed in a hospital setting. The process is flawed and frequently fails to provide accurate and timely information. In this study we demonstrate that organisational changes can improve the efficiency and quality of screening. The primary care screening process described here has increased partner testing rates and allowed early identification of at risk couples.

ACOG technical bulletin. Hemoglobinopathies in pregnancy. Number 220--February 1996 (replaces no. 185, October 1993). Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists.

Hemoglobinopathies, while relatively uncommon among obstetric patients, can be associated with a variety of effects on the mother, fetus, or newborn. The effects range from absence of clinical disease to severe morbidity and death. Through the obstetrician-gynecologist's high index of suspicion based on clinical history and a close working relationship with a consultant hematologist, pregnancy outcome in patients with these disorders can be improved. Since most hemoglobinopathies are inherited as autosomal recessive conditions, screening, counseling, and prenatal diagnosis are important components of prenatal care for these women.

Symmetrical terminal transverse limb defects: report of a twenty-week fetus.

A 20-week gestation hydropic Thai fetus is reported who had symmetrical absence of each hand and forefoot with persistence of digit-like nubbins on each limb. The histologic studies showed there was calcified acellular material in the digit-like nubbins, consistent with infarcted blood vessels, and cartilaginous structures that represented possibly the distal metacarpal articulating surface. The red blood cell indices of both parents were consistent with their being heterozygous for a hemoglobinopathy, such as alpha-thalassemia, which is common in Thais. The infarcted blood vessels could be the result of thrombosis of the digital arteries in the fetus due to a hemoglobinopathy such as hemoglobin Bart's, just as rabbit fetuses homozygous for brachydactyly have transverse terminal digit amputations following digital vessel occlusions due to macrocytic anemia. This was the only child with symmetrical absence of the hands and feet identified among 123,489 liveborn and stillborn infants surveyed for major malformations.

Prenatal diagnosis of hemoglobinopathies.

Hemoglobinopathies are the most frequent and severe inherited diseases worldwide. Prenatal diagnosis is an effective way of controlling severe hemoglobin disorders for which effective treatments are not yet available everywhere. It is a multidisciplinary process requiring knowledge of the spectrum of molecular defects and involving laboratory investigations and genetic counseling. Hematological screening for these disorders is simple, rapid, and reliable. Carrier screening in populations at risk and genetic counseling are part of a number of European health programs, offering many couples at risk the chance of having a healthy child. This article describes the current molecular biology techniques for prenatal diagnosis of hemoglobinopathies.

Cardiac blood flow studies in fetuses with haemoglobin Bart's disease.

Blood flow across the atrioventricular valves and outflow tracts was measured in 55 normal fetuses and 32 fetuses with haemoglobin (Hb) Bart's disease between 18 and 26 weeks of gestation. The mean velocities remained unchanged in both normal and affected fetuses over the gestations studied. The volume flow across both atrioventricular valves and outflow tracts increased as the gestation advanced in both normal and affected fetuses, but was significantly higher in affected than in normal fetuses. The same magnitude of increased flow was found in both hydropic and non-hydropic fetuses with Hb Bart's disease. These findings suggest that fetuses with severe and long-standing anaemia have a remarkable cardiac compensatory mechanism for the maintenance of tissue oxygenation. In response to anaemia and circulatory loading, the cardiac chambers and outflow tracts enlarge proportionately up to twice the normal values. Because of this response and the operation of the Frank-Starling mechanism, the heart is able to maintain a normal mean velocity of propulsion and the net output is increased to two to three times that in normal fetuses. Hydropic changes in these anaemic fetuses appear unrelated to cardiac failure as cardiac failure is not observed at the time that hydropic changes develop.

Haemoglobin Bart's hydrops syndrome in Greece.

A case of haemoglobin Bart's hydrops syndrome was characterised in a Greek family with a history of three other fetuses with hydrops. Family studies showed that both the mother and father carried alpha-thalassaemia genes, and globin-chain synthesis analysis of the present fetus showed a total absence of alpha-chain production. The haemoglobin composition of the fetus was similar to that seen in cases in south-east Asia, and analysis of DNA from the Greek case confirmed the total deletion of the alpha-chain genes. The extent of the deletion, however, differed from that seen in south-east Asian cases and included the loss of one of the embryonic zeta-chain genes. Thus the severe form of alpha-thalassaemia occurs in Greece but has arisen independently from the similar condition in south-east Asia. The condition must be considered in any woman of this racial background who gives a history of unexplained stillbirths.