Fetal nuchal translucency: ultrasound screening for chromosomal defects in first trimester of pregnancy.

OBJECTIVE--To examine the significance of fetal nuchal translucency at 10-14 weeks'' gestation in the prediction of abnormal fetal karyotype. DESIGN--Prospective screening study. SETTING--The Harris Birthright Research Centre for Fetal Medicine, King''s College Hospital, London. SUBJECTS--827 fetuses undergoing first trimester karyotyping by amniocentesis or chorionic villus sampling. MAIN OUTCOME MEASURE--Incidence of chromosomal defects. RESULTS--The incidence of chromosomal defects was 3% (28 of 827 cases). In the 51 (6%) fetuses with nuchal translucency 3-8 mm thick the incidence of chromosomal defects was 35% (18 cases). In contrast, only 10 of the remaining 776 (1%) fetuses were chromosomally abnormal. CONCLUSION--Fetal nuchal translucency > or = 3 mm is a useful first trimester marker for fetal chromosomal abnormalities.     

Effect of chorionic villus sampling and early pregnancy counselling on uptake of prenatal diagnosis.

An early pregnancy counselling clinic was introduced to improve the uptake of prenatal diagnosis and to offer chorionic villus sampling to women aged 38 and over by their expected date of delivery. Ninety eight (62%) unselected older mothers were seen before 11 weeks'' gestation, and 23 (32%) of those with viable pregnancies elected to undergo chorionic villus sampling compared with 38 (52%) electing amniocentesis. A quarter of the patients booking before 11 weeks had a miscarriage. Because of the future potential demand for chorionic villus sampling counselling during pregnancy and referral of eligible patients should occur as early as possible.     

Antenatal diagnosis of thalassaemia major.

Haemoglobin synthesis was studied in fetal blood samples obtained at 17 to 20 weeks'' gestation in 22 women at risk of carrying a fetus with homozygous beta-thalassaemia. A presumptive diagnosis of homozygous beta-thalassaemia was made in four cases, and the pregnancy was terminated. An inconclusive answer was obtained in one case, and the patient also chose to have her pregnancy terminated. Two fetuses were lost as a result of the procedure. Of the remaining 15 pregnancies, 13 proceeded to term and two to 36 weeks; in each case a normal infant or one heterozygous for beta-thalassaemia was delivered. Current efforts should be directed towards improving the blood sampling technology so that fetal blood sampling can be used widely in those countries where thalassaemia is a major problem.     

Non-invasive early prenatal molecular diagnosis using retrieved transcervical trophoblast cells

Fetal DNA was recovered from 17 of 39 (44%) transcervical cell (TCC) samples obtained between 7 and 9 weeks of gestation by endocervical canal flushing. Trophoblast retrieval was adequate for polymerase chain reaction (PCR) amplification of Y chromosome-specific DNA sequences and detection of paternal-specific microsatellite alleles. The fetal sex predicted by PCR in TCCs was confirmed in all cases by karyotype analysis of chorionic villi at 10 weeks of gestation. The absence of the disease-associated paternal alleles in TCC samples from two pregnancies at risk for spinal muscular atrophy and myotonic dystrophy predicted unaffected fetuses in agreement with subsequent results on chorionic villi and newborns' leukocytes. A trisomy 21 fetus was diagnosed in TCCs using fluorescent in situ hybridization (FISH) and semiquantitative PCR analysis of superoxide dismutase-I (SOD 1). Present experience indicates that TCC sampling is a promising technique for early prenatal monitoring of Mendelian disorders and chromosome aneuploidy.     

Continuous-flow plasmapheresis in management of severe rhesus disease.

Eight patients with severe rhesus disease and expected fetal loss were treated by intensive plasmapheresis using a continuous-flow cell separator. Plasmapheresis was started at 16-27 weeks'' gestation, and continued until planned intrauterine transfusion or until the infant was delivered or the rhesus disease became uncontrolled again. Altogether 24 to 2371 of plasma was exchanged over periods ranging from seven to 16 weeks. In seven of the eight patients the anti-D concentration fell during the period of plasmapheresis. Amniotic fluid spectrophotometry values remained below those recorded in the preceding pregnancy in six out of seven women. In five patients an attempt was made to control the rhesus disease by plasmapheresis alone, and two of these women delivered infants who survived. In the other three cases the infants died, one from the idiopathic respiratory distress syndrome and the other two in utero. These preliminary findings suggest that intensive plasmapheresis with a cell separator may reduce fetal haemolysis is delivered. Nevertheless, plasmapheresis may best be used to reduce haemolysis until intrauterine transfusions may be given more safely after 30 weeks'' gestation.     

Sampling pure fetal blood by fetoscopy in second trimester of pregnancy.

A technique for fetal blood-sampling in the second trimester of pregnancy (between 16 and 22 weeks'' gestation) combining fetoscopy with real-time ultrasound was used in 48 attempts at fetal blood-sampling. Specimens containing fetal red cells with or without amniotic fluid or maternal blood, and adequate for diagnosing haemoglobinopathies, were obtained in 45 of the 48 fetoscopies. Sampling was successful in all 18 patients with a posterior placenta, and in 27 of the 30 with an anterior placenta. In 22 of the last 27 consecutive fetoscopies pure fetal blood was taken; the placenta was anterior in 16 and posterior in six. Out of 17 cases sampled between 18 and 22 weeks'' gestation pure fetal blood was obtained in 16. The volume of the samples varied from 50 to 500 microliter. The ability to obtain pure fetal blood consistently even when the placenta is anterior will increase knowledge of fetal physiology and the scope of prenatal diagnosis.     

Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies)

OBJECTIVE: To determine whether treatment with low dose aspirin and heparin leads to a higher rate of live births than that achieved with low dose aspirin alone in women with a history of recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies), lupus anticoagulant, and cardiolipin antibodies (or anticardiolipin antibodies). DESIGN: Randomised controlled trial. SETTING: Specialist clinic for recurrent miscarriages. SUBJECTS: 90 women (median age 33 (range 22-43)) with a history of recurrent miscarriage (median number 4 (range 3-15)) and persistently positive results for phospholipid antibodies. INTERVENTION: Either low dose aspirin (75 mg daily) or low dose aspirin and 5000 U of unfractionated heparin subcutaneously 12 hourly. All women started treatment with low dose aspirin when they had a positive urine pregnancy test. Women were randomly allocated an intervention when fetal heart activity was seen on ultrasonography. Treatment was stopped at the time of miscarriage or at 34 weeks'' gestation. MAIN OUTCOME MEASURES: Rate of live births with the two treatments. RESULTS: There was no significant difference in the two groups in age or the number and gestation of previous miscarriages. The rate of live births with low dose aspirin and heparin was 71% (32/45 pregnancies) and 42% (19/45 pregnancies) with low dose aspirin alone (odds ratio 3.37 (95% confidence interval 1.40 to 8.10)). More than 90% of miscarriages occurred in the first trimester. There was no difference in outcome between the two treatments in pregnancies that advanced beyond 13 weeks'' gestation. Twelve of the 51 successful pregnancies (24%) were delivered before 37 weeks'' gestation. Women randomly allocated aspirin and heparin had a median decrease in lumbar spine bone density of 5.4% (range -8.6% to 1.7%). CONCLUSION: Treatment with aspirin and heparin leads to a significantly higher rate of live births in women with a history of recurrent miscarriage associated with phospholipid antibodies than that achieved with aspirin alone.     

Changing prognosis for babies of less than 28 weeks' gestation in the north of England between 1983 and 1994. Northern Neonatal Network.

OBJECTIVE: To investigate the changing prognosis for babies of less than 28 weeks'' gestation. DESIGN: A prospective, collaborative, population based survey. SETTING: The former Northern Regional Health Authority. SUBJECTS: All the births between 1983 and 1994 at 22 to 27 completed weeks'' gestation to women normally resident in the region. MAIN OUTCOME MEASURES: Miscarriage, stillbirth, death in the first year of life, and disability in survivors. RESULTS: There were 479070 registered births in the study period. No baby of 22 weeks'' gestation survived; only eight (4%) of the 197 babies of 23 weeks who were alive at the onset of labour survived for a year-a proportion that did not change during the study period. Survival among other babies of less than 28 weeks improved progressively between 1983-6 and 1991-4, but administration of artificial surfactant to babies requiring ventilation from mid-1990 was associated with further improvement in survival only in those over 25 weeks'' gestation. Babies of 24 weeks required three times as much high dependency care per survivor as babies of 27 weeks (76 v 26 days). The rate of severe disability in the one year survivors of less than 26 weeks'' gestation (30/123; 24%) was similar to that seen in the sampled survivors of 26 and 27 weeks (29/108; 27%); the proportion disabled did not change significantly during the study period. All the children born in 1983, 1987, and 1991 were later reassessed in greater detail: 10% (13/136) seemed destined for a continuing life of total dependency. CONCLUSIONS: Gestation, if accurately assessed, can give a woman facing very preterm delivery a clear indication of the prognosis for her baby and help her judge the appropriateness of accepting obstetric intervention and sustained perinatal support.     

Randomised controlled comparative study of methyldopa and oxprenolol in treatment of hypertension in pregnancy.

One hundred pregnant women with hypertension (defined as diastolic blood pressure at or above 95 mm Hg) were allocated at random to treatment with methyldopa or oxprenolol and were compared with nonhypertensive controls matched according to parity and gestation at delivery. The patients were also stratified into those entering the study early (before 32 weeks'' gestation) and those entering late (after 32 weeks'' gestation). Although there were no differences in diastolic blood pressure between the hypertensive groups before or during treatment, in the early entry group the systolic blood pressure at entry of those allocated to oxprenolol was significantly higher than that of those receiving methyldopa; this difference remained throughout the treatment period. Also in the early entry group further increments of drug treatment were required to control blood pressure of patients receiving oxprenolol than in those receiving methyldopa. The eventual fetal outcome for all patients treated with methyldopa was the same as that for those treated with oxprenolol; birth weight, placental weight, head circumference, and Apgar score were not significantly different and there were no stillbirths in either group.     

A cytogenetic study of the human chorion for the purpose of the prenatal diagnosis of hereditary diseases

Cytogenetical investigation of 50 diagnostic chorionic villus samples from women with a high risk of giving birth to babies with chromosomal and genic pathology, and of 128 chorionic samples obtained from medical abortions, both on the 8-12th weeks of gestation was performed by means of original direct chromosomal analysis. Chromosomal anomalies were found in 6 cases of diagnostic chorion biopsies (12%) and in 4 cases (3%) of medical abortions. The former group included 5 embryos with autosomal trisomy (4--Ts21 and 1--Ts13) and one embryo with monosomy 18. The latter group contained 2 embryos with X-chromosome monosomy and 2 other with chromosomal mosaicism. A significant prevalence of the female sex was found in the diagnostic group (sex ratio 0.56), but not in the medical abortion one (sex ratio 1.0). Analysis of routine chromosomal preparations and those after in situ hybridization with X-chromosome alfoid-probe YAP 1-10 revealed polyploidy in average in 0.8-1% chorion cells. The feasible causes of sex ratio distortion in embryos of diagnostic group and factors responsible for the rate of polyploidy are discussed. High reliability of originally elaborated direct "shaking-blotting" method of chromosomal preparations from chorionic villus samples is stressed.     

Five Years' Experience with Intrauterine Transfusion

Five years'' experience with intrauterine transfusion involving 94 transfusions on 50 fetuses forms the basis of the paper. Twenty-three fetuses survived, which represents an overall salvage of 46%. Of 22 fetuses who received intrauterine transfusions before 28 weeks'' gestation, seven (31.9%) survived, which justifies the attempt. Of 28 fetuses who received intrauterine transfusions after 28 weeks'' gestation, 16 (57.1%) survived, which compares favourably with other series. A comparison of two different procedural techniques shows no statistically significant difference in ultimate results. Indications for amniocentesis are outlined and intrauterine transfusion was advised if the optical density difference fell in Liley''s zone III (or a very high zone II) and rose at a rate which anticipated a zone III reading prior to 32 weeks'' gestation. A pediatric assessment and therapeutic management of the 33 live births are presented. Twenty-eight babies received exchange transfusions. Five were excluded for reasons outlined in the text. Ten of the live-born died neonatally. The 23 survivors continue to thrive mentally and physically and follow-up continues.     

Endpiece: The noble profession

ObjectivesTo assess whether bacterial vaginosis or chlamydial infection before 10 weeks'' gestation is associated with miscarriage before 16 weeks.DesignProspective cohort study.Setting32 general practices and five family planning clinics in south London.Participants1216 pregnant women, mean age 31, presenting before 10 weeks'' gestation.Results121 of 1214 women (10.0%, 95% confidence interval 8.3% to 11.7%) miscarried before 16 weeks. 174 of 1201 women (14.5%, 12.5% to 16.5%) had bacterial vaginosis. Compared with women who were negative for bacterial vaginosis those who were positive had a relative risk of miscarriage before 16 weeks'' gestation of 1.2 (0.7 to 1.9). Bacterial vaginosis was, however, associated with miscarriage in the second trimester at 13-15 weeks (3.5, 1.2 to 10.3). Only 29 women (2.4%, 1.5% to 3.3%) had chlamydial infection, of whom one miscarried (0.32, 0.04 to 2.30).ConclusionBacterial vaginosis is not strongly predictive of early miscarriage but may be a predictor after 13 weeks'' gestation. The prevalence of Chlamydia was too low to assess the risk, but it is unlikely to be a major risk factor in pregnant women.

What is already known on this topic

Miscarriages are common and associated with considerable morbidity and costsBacterial vaginosis is associated with miscarriage after 16 weeks'' gestation and preterm birth but the role of chlamydial infection is uncertain

What this study adds

Bacterial vaginosis is not a strong predictor of miscarriage before 16 weeks'' gestation but may be associated with miscarriage at 13-15 weeks'' gestationThe prevalence of chlamydial infection was too low for it to be a major risk factor for miscarriage in this population of healthy pregnant womenNon-invasive screening for bacterial vaginosis and chlamydial infection by using self administered vaginal swabs is feasible in pregnant women in the community     

Prognosis for infants born at 23 to 28 weeks' gestation.

The survival and neurodevelopmental outcome of 356 extremely preterm infants born at 23 to 28 weeks'' gestation were reported by week of gestation. Their corrected 1 year survival improved from 7% at 23 weeks to 75% at 28 weeks. The overall incidence of impairment was 19% and of major disability 12%. Boys had a significantly lower normal survival than girls. Multiple births had a significantly lower survival and higher incidence of impairment than singleton births. Predictions of outcome were made before delivery, after resuscitation, and at 1 week to aid the development of guidelines on when perinatal intensive care is justified, whether obstetric intervention for fetal reasons is warranted, and what initial and ongoing prognoses to give to parents. Intensive care for progressively smaller and more immature infants, many of whom were previously considered non-viable, needs to be carefully monitored by every perinatal centre.     

Deliberate delays in offering abortion to pregnant women with fetal anomalies after 24 weeks' gestation at a centre in South Africa

South Africa has an abortion law which codifies the broad themes of reproductive rights set out in the Constitution of South Africa, other laws and national guidelines. Certain wording of the conditions in the Choice Act for abortion after 20 weeks' gestation, are open to interpretation, being ‘severe malformation of the fetus’ and ‘risk of injury to the fetus’. From 24 weeks onwards, abortion is carried out by feticide/induced fetal cardiac asystole (‘IFCA’) and subsequent induction of labour in South Africa. Some maternal-fetal units have developed guidelines to assist clinicians and patients in decision-making around eligibility for abortion after 20 weeks' gestation, given the broad terms in the law. We consider the guideline used by an institution in the Western Cape for abortion after 23 weeks and 6 days gestation, in terms of its alignment with the law on reproductive rights and its compliance with fair and transparent procedures. We also note its effect on respect for patients and on staff professionalism.     

Obstetric importance,diagnosis, and management of fetal tachycardias.

During 1980-7, 23 pregnancies of 22-38 weeks'' duration were investigated for fetal tachycardia. Twelve were cases of supraventricular tachycardia, eight of atrial flutter, and three cases in which the rhythm varied between supraventricular tachycardia and atrial flutter. In 11 cases the fetus had developed non-immune fetal hydrops before referral; 12 cases were non-hydropic at referral but one of this group of fetuses became hydropic during treatment. No relation was found between the rate or type of arrhythmia and the presence or absence of intrauterine heart failure. One non-hydropic infant was delivered electively prematurely. Maternal antiarrhythmic treatment was instituted in the remaining 22 cases. Conversion of the arrhythmia was achieved with digoxin alone in five cases and with a combination of digoxin and verapamil in nine. Control of the arrhythmia was achieved in seven of the 10 non-hydropic fetuses, and all were delivered at term with no deaths. Of the 12 hydropic fetuses, control was achieved in seven. Only three of the hydropic fetuses were delivered close to term. There were two deaths, both in the hydropic group. Of the whole group, five neonates suffered severe complications of prematurity. In this series the main benefit of treatment appeared to be in prolonging gestation of those hydropic fetuses in which conversion was achieved.     

Detection of confined placental mosaicism in trisomy 18 conceptions using interphase cytogenetic analysis

Fluorescence in situ hybridization provides a rapid and accurate technique for detecting chromosomal aneuploidy. It is an excellent method for identifying mosaicism in placental tissues following prenatal diagnosis. Mosaicism, in the form of confined placental mosaicism, occurs im approximately 1%–2% of viable pregnancies studied by chorionic villus sampling at 9–11 weeks of gestation. It has been detected in pregnancies with both diploid and trisomic fetuses and appears to have an important effect on the intrauterine fetal survival. Using both standard cytogenetic analysis and fluorescence in situ hybridization, we have studied 12 placentas from pregnancies with trisomy 18 for the presence of chromosomal mosaicism. These included 2 that were spontaneously aborted, 5 that were terminated after prenatal diagnosis, and 4 that were delivered as either stillborn or liveborn. Significant levels of mosaicism, confined exclusively to cytotrophoblast, were detected in 7 pregnancies. This study demonstrates the usefulness of interphase cytogenetic analysis of uncultured tissues as an alternative method for the detection of mosaicism.     

First trimester fetal karyotyping: one thousand diagnoses

Summary Cytogenetic investigations for diagnostic purposes were performed on 1000 first trimester samples of chorionic villi (CVS) in two laboratories using similar techniques. Fetal karyotyping was the primary indication for CVS in 912 and maternal age was the major indication in 758 of them. The risk category previous child/fetus with chromosome abnormality included 74 diagnoses, while the category chromosome abnormality in one of the parents included 38 diagnoses. Sex determination was the primary indication for CVS in 53 pregnancies. The overall incidence of chromosomal abnormalities was 70, of which 47 were balanced and 23 unbalanced. The results are detailed for each of the risk categories and the incidence of abnormal karyotypes is given for each year of maternal age. In the maternal age of 35–37 years the incidence of unbalanced karyotypes was 2.9% and in the years 38 onwards it was 6.6%. The incidence of unbalanced karyotypes was about 4% when the sampling was made in the weeks 9 to 12 but six abnormal karyotypes were found among 39 CVS performed at the eight week of gestation. The 11 trisomies of the type not found at birth were clustered between the 8th and the 10th week of pregnancy. The technical problems encountered in this experience and the preliminary estimates of fetal loss are discussed.     

Early onset pre-eclampsia: recognition of underlying renal disease.

A follow up study of 84 patients with early onset pre-eclampsia (before 37 weeks'' gestation) showed a high prevalence of underlying renal disease. Renal abnormalities were found in 33 of the 49 primiparas (67%) and in 22 of the 35 multiparas (63%). Two thirds of the multiparas with pre-eclampsia before 37 weeks with a diagnosis of either essential hypertension or renal disease had recurrent pre-eclampsia. Maternal morbidity and fetal mortality were greater in the group with early onset pre-eclampsia than in a group with late onset disease. Idiopathic pre-eclampsia occurred in 10% of primiparas in the early onset group, whereas it was the main condition in over three quarters of primiparas in the late onset group. A presumptive diagnosis of idiopathic pre-eclampsia is likely to be correct only in primiparas who develop the disease after 37 weeks of pregnancy; in all other cases careful search will almost certainly detect an underlying abnormality, predominantly renal.     

Prenatal diagnosis for recessive dystrophic epidermolysis bullosa in 10 families by mutation and haplotype analysis in the type VII collagen gene (COL7A1).

BACKGROUND: Epidermolysis bullosa (EB) is a group of heritable diseases that manifest as blistering and erosions of the skin and mucous membranes. In the dystrophic forms of EB (DEB), the diagnostic hallmark is abnormalities in the anchoring fibrils, attachment structures beneath the cutaneous basement membrane zone. The major component of anchoring fibrils is type VII collagen, and DEB has been linked to the type VII collagen gene (COL7A1) at 3p21, with no evidence for locus heterogeneity. Due to life-threatening complications and significant long-term morbidity associated with the severe, mutilating form of recessive dystrophic EB (RDEB), there has been a demand for prenatal diagnosis from families with affected offspring. MATERIALS AND METHODS: Intragenic polymorphisms in COL7A1 and flanking microsatellite markers on chromosome 3p21, as well as detection of pathogenetic mutations in families, were used to perform PCR-based prenatal diagnosis from DNA obtained by chorionic villus sampling at 10-15 weeks or amniocentesis at 12-15 weeks gestation in 10 families at risk for recurrence of RDEB. RESULTS: In nine cases, the fetus was predicted to be normal or a clinically unaffected carrier of a mutation in one allele. These predictions have been validated in nine cases by the birth of a healthy child. In one case, an affected fetus was predicted, and the diagnosis was confirmed by fetal skin biopsy. CONCLUSIONS: DNA-based prenatal diagnosis of RDEB offers an early, expedient method of testing which will largely replace the previously available invasive fetal skin biopsy at 18-20 weeks gestation.     

Delayed elimination of caffeine by women in the last 2 weeks of pregnancy.

Caffeine elimination was studied in 15 women at 38 to 40 weeks'' gestation. The mean hourly caffeine clearance, 37 ml/kg, determined from assays of saliva, was only 39% of the value previously reported for nonpregnant adults (94 ml/kg). Reassessment in four of the women 2 to 12 weeks post partum showed that in each woman the caffeine clearance had increased more than threefold and that the mean caffeine concentration in the saliva after no intake of caffeine for 24 hours was now much lower (0.07 v. 0.84 microgram/ml).