Yung Hang Lam

Early ultrasound prediction of pregnancies affected by homozygous α-thalassaemia-1

Homozygous α‐thalassaemia‐1 is conventionally diagnosed by invasive testing on all at‐risk pregnancies. We evaluated the diagnostic efficacy of non‐invasive abdominal ultrasonographic cardiothoracic ratio measurement in 62 pregnancies at 13–14 weeks and 75 pregnancies at 17–18 weeks. This performed better than placental thickness measurement. Using a cardiothoracic ratio cut‐off level of ≥0·5, 75 per cent of affected pregnancies were detected at 13–14 weeks and all cases were detected at 17–18 weeks. False‐positive rates were 7 and 8 per cent, respectively. There was no false‐positive diagnosis if the cardiothoracic ratio was ≥0·53. With this approach, invasive procedures can be selectively performed and fewer pregnancies will be lost unnecessarily. The reduction in medical expenses is likely to be substantial.

Nuchal translucency in pregnancies conceived after assisted reproduction technology

Levels of maternal serum markers of fetal Down syndrome in pregnancies conceived after assisted reproduction are different from those of normal spontaneous pregnancies. The present study examined the effects of conventional in‐vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and embryo cryopreservation on nuchal translucency (NT) thickness.

Second-trimester maternal serum alpha-fetoprotein and human chorionic gonadotrophin screening for Down's syndrome in Hong Kong

Second‐trimester maternal serum screening for fetal Downs syndrome is well established in many Western countries. Its usefulness and acceptability is unknown in the Asian countries. Between June 1994 and December 1996, we offered second‐trimester serum AFP and hCG screening to pregnant women in Hong Kong who were less than 35 years old and without other risk factors for chromosomal abnormalities. Each woman was assigned a risk of having a Downs syndrome term pregnancy by using a computer software program that took into account her age, weight, AFP and hCG MOMs. All those with a risk of one in 250 or greater were designated screen‐positive, subject to the revision of gestation by ultrasound examination. 9177 women with singleton pregnancies (93 per cent were Chinese) were screened. The uptake of screening was 75 per cent. 281 women (three per cent) were initially classified to be screen‐positive. After revision of the gestation by ultrasound examination, 183 women (two per cent) were ‘true’ screen‐positive and 164 (90 per cent) accepted the offer of amniocentesis. Eight of these pregnancies were affected by Downs syndrome and all the women elected pregnancy termination. The odds of being affected, given a positive screening result, were one in 23. Six Downs syndrome pregnancies were missed by the screening programme. The detection rate was 57 per cent. The study showed that second‐trimester serum screening for fetal Downs syndrome was feasible and acceptable in the Hong Kong population.

Middle cerebral artery Doppler study in fetuses with homozygous α‐thalassaemia‐1 at 12–13 weeks of gestation

Fetuses affected by homozygous α‐thalassaemia‐1 are anaemic from the first trimester of pregnancy. We investigated middle cerebral artery Doppler velocimetry in these affected fetuses at 12–13 weeks of gestation to assess its use in predicting fetal anaemia.

Second-trimester maternal serum inhibin-A screening for fetal Down syndrome in Asian women.

Case–control studies in the Caucasian population showed that maternal serum inhibin‐A is elevated in Down syndrome pregnancies and may be a useful second‐trimester marker in addition to human chorionic gonadotrophin (hCG) and alpha‐fetoprotein (AFP). Data in the Asian population are lacking. We measured inhibin‐A levels in the stored maternal sera of 49 Down syndrome pregnancies and 341 controls with a commercially available assay and expressed them as the multiples of the median of the gestational week. The log means and standard deviations for case and control inhibin‐A MOMs were 0.209, 0.226, and 0.002 and 0.177, respectively. Median inhibin‐A MOM in Down syndrome cases was elevated to 1.62 (95 per cent confidence interval, 1.29–1.82). 36 per cent of Down syndrome cases were expected to be detected at a 5 per cent false‐positive rate. However, inhibin‐A MOMs were strongly correlated with hCG MOMs in the cases (r=0.73, p<0.001) and the controls (r=0.56, p<0.001). This will diminish the value of adding inhibin‐A to the existing hCG and AFP screening protocol. Copyright

The Risk of α‐Thalassaemia in Offspring of β‐Thalassaemia Carriers in Hong Kong

Couples in whom one is heterozygous for α‐thalassaemia‐1 and the other is heterozygous for β‐thalassaemia are assumed not to be at risk of having offspring with homozygous α‐thalassaemia‐1 or homozygous β‐thalassaemia. We retrospectively reviewed the genetic outcome of 189 pregnancies of 178 couples in whom the partners were diagnosed to be discordant heterozygotes of α‐thalassaemia and β‐thalassaemia on haematological tests. ζ gene mapping was performed on 158 β‐thalassaemia carriers to diagnose the presence of co‐existing α‐thalassaemia‐1. Eleven patients (7 per cent) were found to be compound α‐ and β‐thalassaemia heterozygotes. They accounted for 16 pregnancies, of which five were diagnosed to be affected by homozygous α‐thalassaemia‐1. Our results show that couples presumed to be discordant heterozygotes of α‐ and β‐thalassaemia on haematological testing are at risk of having offspring with homozygous α‐thalassaemia‐1 if the ζ gene mapping of the heterozygous β‐thalassaemia partner shows co‐inheritance of α‐thalassaemia‐1. Prenatal diagnosis of homozygous α‐thalassaemia‐1 should be performed on these at‐risk pregnancies.

Limb reduction defects in fetuses with homozygous α-thalassaemia-1

Limb reduction defect is a rare event. Its exact pathogenesis is unknown. We retrospectively reviewed the outcome of 130 fetuses affected by homozygous α‐thalassaemia‐1 and found that 11 of them (8 per cent; 95 per cent confidence interval: 4–13 per cent) had terminal transverse limb reduction defects. Chromosome study was available in ten fetuses with limb defects and the results were normal. We postulate that the strong association between homozygous α‐thalassaemia‐1 and limb reduction is related to the hypoxic insult in early gestation. This may be the final common pathway in the pathogenesis of other forms of limb reduction defects.

Prenatal diagnosis of haemoglobin bart's disease by cordocentesis at 12-14 weeks' gestation

Couples with α‐thalassaemia‐1 face a 25 per cent risk of having fetuses with haemoglobin (Hb) Barts disease. Prenatal diagnosis is conventionally performed by DNA studies of chorionic villi or amniocytes obtained from chorionic villus biopsy or amniocentesis. DNA studies are expensive and time‐consuming. We identified 11 affected pregnancies on abdominal ultrasound examination at 12–14 weeks when the placental thickness exceeded the mean plus 2 SD measurement for the gestational week and the cardiothoraic ratio was more than 0·5. Cordocentesis was then performed with a free hand technique. The procedures were successful in ten cases using a 26‐gauge spinal needle with a 20‐gauge introducer. Hb Barts disease was confirmed in all cases by Hb electrophoresis. The procedure was unsuccessful in one case when a 22‐gauge spinal needle was used. Hb study of fetal blood collected at abortion also confirmed Hb Barts disease. In conclusion, ultrasound findings of concomitant placentomegaly and cardiomegaly at 12–14 weeks is highly specific of disease in pregnancies at risk of Hb Barts disease. Cordocentesis and Hb study in pregnancies with these sonographic manifestations may be an alternative prenatal diagnostic approach. This diagnostic approach is of particular value in areas where resources for molecular studies are limited.

Acceptability of serum screening as an alternative to cytogenetic diagnosis of down syndrome among women 35 years or older in Hong Kong.

The addition of second trimester serum markers to maternal age increases the efficacy of screening for Down syndrome by maternal age alone. Among women aged 35 years or older, serum screening makes a large proportion of amniocentesis unnecessary. However, there are ethical and medicolegal concerns about serum screening in ‘old’ women, largely because some of the pregnancies affected by Down syndrome and other chromosomal abnormalities may not be detected. We investigated the acceptability of serum screening in women aged 35 years or older when it was offered as an alternative to prenatal cytogenetic diagnosis after detailed counselling. Women referred for prenatal diagnosis of Down syndrome because of advanced maternal age were given the options of cytogenetic diagnosis by chorionic villus sampling (CVS) or amniocentesis. As an alternative, they could choose to undergo second trimester serum human chorionic gonadotrophin (hCG) and alpha‐fetoprotein (AFP) screening first before deciding on whether to undergo amniocentesis. Between January 1997 and October 1999, 3419 subjects were recruited. 1807 women (52.9%) chose to undergo serum screening, 1516 women (44.3%) chose to have amniocentesis and 96 women chose to have CVS (2.8%). The proportion of women who chose serum screening rose steadily from 38.8% in the year of 1997 to 63.4% in 1999. Significantly fewer Chinese women chose serum screening than non‐Chinese. The decision as to whether to undergo an invasive diagnostic procedure or to be content with the relatively safer but less accurate screening test varies, being affected by the womens background and culture. Copyright

Risk of neural tube defects in the offspring of thalassaemia carriers in Hong Kong Chinese

The risk of having an offspring with neural tube defect is negatively correlated with early pregnancy maternal folate levels. Thalassaemia carriers often have subnormal folate levels. We postulate that their offspring may be at increased risk of having neural tube defect. We retrospectively reviewed the records of 1961 Chinese women referred to a tertiary centre for prenatal diagnosis between January 1997 and August 1998. Women with a mean corpuscular volume greater than 80 fl were assumed not to be α‐thalassaemia‐1 or β‐thalassaemia heterozygotes. α‐ and β‐thalassaemia heterozygotes were diagnosed by haemoglobin studies. Of the 1961 women studied, pregnancy outcome was not available in 20 and thalassaemia screening was not available in 109 and these were excluded from the final analysis. Two‐hundred‐and‐six women were α‐thalassaemia‐1 heterozygotes, 102 women were β‐thalassaemia heterozygotes and one woman had HbE disease. Three α‐thalassaemia carriers and one β‐thalassaemia carrier had a pregnancy affected by anencephaly (odds=1:76). In the 1523 non‐carriers, five pregnancies were affected by spina bifida (odds=1:304). The odds ratio (95 per cent confidence interval) for neural tube defects in the α‐ and β‐thalassaemia carriers was 3.99 (1.07 to 14.94; p<0.05, Chi‐square test). Because of the small number of affected pregnancies studied, the finding needs to be substantiated by a larger series. If the increased risk is genuine, women need to be screened for thalassaemia before conception and the thalassaemia carriers should be given periconceptional folate supplement to reduce the occurrence of neural tube defects. Copyright