Confidential inquiry into families with two siblings with cystic fibrosis

OBJECTIVE—To audit the care that had been provided to couples before the birth of a child with cystic fibrosis where a sibling had been previously diagnosed.
DESIGN—Retrospective review of case notes.
SAMPLE—Families where at least one affected child had been born between 1 January 1991 and 30 June 1995 and the diagnosis in the first child was made before the second affected pregnancy reached 20 weeks. The combination of information on these families with data from the prenatal diagnosis register allowed the reconstruction of a cohort of pregnancies in women with a previous affected child.
MAIN RESULTS—Forty six eligible families with a second affected child were identified. Details from the paediatrician who had diagnosed the first affected child were obtained in 43 cases: all 43 couples were offered genetic counselling, but where provided by a paediatrician this was difficult to assess as no couple was sent a summary letter. Details were obtained from the obstetrician in the subsequent affected pregnancy in 42 cases: prenatal diagnosis was not offered in 10 (24%), offered and declined in 24 (57%), offered and accepted but termination declined in eight (19%). In the overall cohort of at risk pregnancies, the estimated rate of prenatal diagnosis offer was 97%, prenatal diagnosis uptake 86%, false negative prenatal diagnosis rate 0%, and uptake of termination 95%.
CONCLUSIONS—(1) Parental choice was an important determinant of second affected births. (2) Despite widespread availability, prenatal diagnosis was not offered in an estimated 3% of at risk pregnancies. (3) There were shortcomings in counselling documentation, in particular failure to send a summary letter to counselled couples.

     

Community-wide screening for cystic fibrosis carriers could replace newborn screening for the diagnosis of cystic fibrosis

Most babies with cystic fibrosis (CF) are born to parents who did not know they were carriers until their baby was diagnosed with CF, usually by newborn screening. It is only after the birth of their first child with CF that couples are offered genetic counselling and reproductive choices. Most use this information for prenatal testing of subsequent pregnancies. With the high uptake of first trimester screening for Down syndrome (80% in Victoria) most couples have had screening during the CF affected pregnancy. Yet screening for CF carrier status is available, costs are similar to that for Down syndrome screening and CF carrier screening only ever needs to be done once. Waiting for couples to have a baby with CF before they are identified as carriers denies them choice. A national policy on CF carrier screening in Australia, and determination to equitably fund such a programme, is required.     

Prenatal diagnosis of beta-thalassemia in Egypt: implementing accurate high-tech methods did not reflect much on the outcome

The clinical severity of thalassemia major makes it a priority genetic disease for prevention programs through prenatal diagnosis for carrier couples. Incorporation of automated DNA sequencing that enables the characterization of mutations not detected by other mutation specific detection procedures was a prime goal of this work. Automated DNA sequencing was offered on fetal tissues in 30 pregnancies during the year 2005. The pregnancies were at high risk for homozygosity or compound heterozygosity for beta-thalassemia based on mutation analysis of both parents before prenatal diagnosis. Both parents have beta-thalassemia trait. Fetal samples were collected by chorionic villus sampling (CVS) in the first trimester and by amniocentesis in the second trimester. The point mutations were characterized by PCR (ARMS). The absence of the expected fragment with all the mutant ARMS primers insinuated an uncharacterized DNA segment that was further subjected to direct automated fluorescent DNA sequencing in an attempt to know if the fetus was affected by parents' mutations. If no mutation was detected using the PCR ARMS, the sample was further analyzed using direct automated fluorescent DNA sequencing. The mean gestation when carrying out the invasive procedure was 14 (10 -18) weeks. All mothers had a previous affected pregnancy, and 13 had two or more previous affected pregnancies. Pregnancies were: 8 carrier fetuses (trait) and 22 affected fetuses in which 2 were homozygous and 20 double heterozygous. Fourteen parents of affected fetuses preferred to continue pregnancy and the babies were born as diagnosed. The other 8 parents decided on termination and DNA of the abortuses proved to be as previously diagnosed by DNA sequencing. The use of PCR amplification and direct sequencing have permitted the accurate characterization of unidentified alleles and successfully solved 100% of the examined samples. However, it has resulted in minor changes of the outcome as the majority of couples preferred continuation of pregnancy.     

PRENATAL DIAGNOSIS OF β-THALASSEMIA IN EGYPT: Implementing Accurate High-Tech Methods Did not Reflect Much on the Outcome

The clinical severity of thalassemia major makes it a priority genetic disease for prevention programs through prenatal diagnosis for carrier couples. Incorporation of automated DNA sequencing that enables the characterization of mutations not detected by other mutation specific detection procedures was a prime goal of this work. Automated DNA sequencing was offered on fetal tissues in 30 pregnancies during the year 2005. The pregnancies were at high risk for homozygosity or compound heterozygosity for β-thalassemia based on mutation analysis of both parents before prenatal diagnosis. Both parents have β-thalassemia trait. Fetal samples were collected by chorionic villus sampling (CVS) in the first trimester and by amniocentesis in the second trimester. The point mutations were characterized by PCR (ARMS). The absence of the expected fragment with all the mutant ARMS primers insinuated an uncharacterized DNA segment that was further subjected to direct automated fluorescent DNA sequencing in an attempt to know if the fetus was affected by parents’ mutations. If no mutation was detected using the PCR ARMS, the sample was further analyzed using direct automated fluorescent DNA sequencing. The mean gestation when carrying out the invasive procedure was 14 (10 –18) weeks. All mothers had a previous affected pregnancy, and 13 had two or more previous affected pregnancies. Pregnancies were: 8 carrier fetuses (trait) and 22 affected fetuses in which 2 were homozygous and 20 double heterozygous. Fourteen parents of affected fetuses preferred to continue pregnancy and the babies were born as diagnosed. The other 8 parents decided on termination and DNA of the abortuses proved to be as previously diagnosed by DNA sequencing. The use of PCR amplification and direct sequencing have permitted the accurate characterization of unidentified alleles and successfully solved 100% of the examined samples. However, it has resulted in minor changes of the outcome as the majority of couples preferred continuation of pregnancy.     

Prenatal diagnosis of congenital nephrosis in 23 high-risk families.

The efficacy of maternal serum and amniotic fluid alpha-fetoprotein (AFP) estimation for the prenatal detection of congenital nephrosis was assessed in 23 pregnancies of couples with a previously affected child. At 15 to 18 weeks' gestation, amniotic fluid AFP concentration was elevated in seven of 23 cases, and maternal serum AFP level in five of these. Legal abortion was carried out at 18 to 19 weeks in all those cases where he amniotic fluid AFP concentration was abnormally high, and in all cases the fetus was found to be affected. The diagnosis of intrauterine congenital nephrosis was obvious by electron microscopic examination of the fetal kidney, but not by light microscopy. The child was born without congenital nephrosis in all 16 cases where amniotic fluid AFP level was normal, and in 16 of 18 cases (89%) where maternal serum AFP concentration was normal. Thus, the amniotic fluid AFP assay is more reliable and is recommended whenever congenital nephrosis is suspected on the basis of family history.     

Reasons for trisomy 13 or 18 births despite the availability of prenatal diagnosis and pregnancy termination

BACKGROUND: Few studies have evaluated the reasons why lethal chromosomal anomalies continue to occur despite the importance of this question for maximizing perinatal care. AIMS: To determine why trisomy 13 or 18 births continue to occur in Alaska. STUDY DESIGN: Case series involving review of maternal and infant medical records. SUBJECTS: All 28 known infants and fetuses that died with trisomy 13 or 18 during 1992-2001 and their mothers. OUTCOME MEASURES: The proportion of mothers that declined or received a variety of routine prenatal tests, the results of prenatal testing, and the impact of testing on decisions related to pregnancy. RESULTS: Seventeen women declined pregnancy termination or amniocentesis, 10 had no prenatal risk factors and were not offered these procedures, and one woman had an amniocentesis but was not offered pregnancy termination. Twenty-six women had >/=1 prenatal ultrasounds; for 17 women, these were interpreted as normal throughout pregnancy (n=11) or until after 30 weeks gestation (n=6) despite substantial fetal malformations. Fourteen of 15 women with an abnormal ultrasound had an amniocentesis compared to one of eight women whose only risk factor was advanced maternal age. CONCLUSIONS: Most trisomy 13 or 18 deliveries occurred to women who declined amniocentesis or pregnancy termination. Failure to identify abnormalities on prenatal ultrasound may have contributed to the decision not to have these procedures.     

Counselling of a couple faced with a prenatal diagnosis of Klinefelter syndrome

When a prenatal diagnosis of Klinefelter syndrome (KS) is made, a couple is faced with an unfamiliar and unexpected diagnosis. The aim of this article is to give clues to prenatal counselling in this situation. The information provided to couples facing a prenatal diagnosis of KS should ideally be based on longitudinal studies of unselected individuals, including those diagnosed prenatally. Indeed, there are several reasons to think that the phenotype of individuals diagnosed prenatally is globally less severe than in those diagnosed postnatally. Based on these studies, the evidence to be explained to couples to help them make an informed decision about the pregnancy is the following: except for rather tall height, generally normal appearance throughout life; increased risk of learning disabilities; spontaneous puberty, reduced testicular size, usual need for testosterone supplementation from adolescence onward; increased risk of gynecomastia; sexual orientation similar to the general male population; infertility, but with the possibility of having biological offspring with assisted reproductive techniques. In this article, we review the evidence about the phenotype of KS according to the circumstances of diagnosis and its use in counselling couples faced with a prenatal diagnosis of this common condition. CONCLUSION: Cohort studies including individuals with KS diagnosed prenatally are still lacking.     

Multidisciplinary management of fetal surgical anomalies: the impact on maternal anxiety.

AIM: To assess the impact on maternal anxiety of a multidisciplinary approach in prenatal management of fetal surgical anomalies. DESIGN: A case-control study was undertaken: Group A (cases) consisted of 16 couples receiving a prenatal multidisciplinary counselling, Group B (controls) was represented by 16 couples, who received diagnosis of the fetal anomaly and the relevant counselling by an obstetrician only. The fetuses were affected by the following gastrointestinal anomalies: gastroschisis, omphalocele, intestinal atresia. METHODS: The Italian version of the Spielberger State-Trait Anxiety Inventory was utilized to assess maternal anxiety. In Group A maternal anxiety level was assessed after the first antenatal counselling and at birth, whereas in Group B only at birth. RESULTS: At birth, Group A presented STAI-S scores significantly lower than after the first antenatal consultation with the team (Mean +/- SD = 39.87 +/- 6.46 versus 68.93 +/- 5.81; p < 0.01). At the end of the first day spent with the baby in the Neonatal Surgery Unit, Group A presented STAI-S scores significantly lower than Group B (Mean +/- SD = 39.87 +/- 6.46 versus 70.62 +/- 4.12; p < 0.01). CONCLUSIONS: This study provides evidence of the positive impact on maternal anxiety of a multidisciplinary approach in prenatal management of fetal surgical anomalies.     

Diagnostic trap and difficulties of genetic counseling in a family with neuromuscular disease carriers]

BACKGROUND: Recent advances in the field of molecular genetics have provided useful tools for the diagnosis of neuromuscular disorders. Genetic counselling for many of these conditions may, however, be fraught with difficulties. CASE REPORT: The patient, two paternal uncles and a paternal aunt presented with clinical and electromyographic evidence of type III spinal muscular atrophy despite an autosomal dominant-like pedigree. The diagnosis was confirmed by genetic testing for the SMN deletion. As the proband's mother was pregnant at the time of presentation of the affected child, a prenatal diagnostic test was performed. The deletion was not found in the DNA extracted from the trophoblast and the pregnancy proceeded to full term, and a normal child. At the same time, a first cousin of the proband was found to have a clinically similar condition. He had not the SMN deletion. He presented with electrophysiological and pathological features of limb-girdle muscular dystrophy. Genetic testing revealed a homozygote del T521 mutation of the gama-sarcoglycan gene. CONCLUSION: To provide accurate genetic counselling, it is essential to get precise data on family background and diagnostic confirmation for each affected relative to avoid missing the possibility, albeit rare, of several neuromuscular disorders within a family.     

Anterior abdominal wall defects.

A total of 48 infants with abdominal wall defects referred to the South West Regional Neonatal Surgical Centre over a period of six years were reviewed. There were 27 (56%) infants with gastroschisis and 21 (44%) infants with exomphalos. At the regional centre, four pregnancies with gastroschisis were terminated following a prenatal diagnosis, one child was stillborn, and one with exomphalos and trisomy 13 died soon after birth. Of the remaining 42 live births, the one year survival for babies born with a gastroschisis was 95% (21/22) and with an exomphalos was 81% (17/20). All deaths, except one, were due to factors other than the abdominal defect. The effect on outcome of prenatal diagnosis, parental counselling, in utero transfer, mode of delivery, and methods of surgical closure was reviewed.     

Reproductive decisions after neonatal screening identifies cystic fibrosis

AIMS: To document the reproductive choices made by women in New South Wales, Australia, after neonatal screening has identified cystic fibrosis (CF). METHODS: A sample of women attending cystic fibrosis clinics in New South Wales who had a child (or children) diagnosed by neonatal screening between 1981 and 1996 were interviewed. RESULTS: Two thirds of the women chose to avoid having another child with CF. The uptake of prenatal diagnosis was 66% in women who had a subsequent pregnancy; of these 69% terminated or would have terminated an affected fetus. Fifty nine per cent of the women who decided against a further pregnancy made this decision in order to avoid having another child with CF. CONCLUSIONS: These data show that having a child with CF influenced subsequent reproductive choices. In addition to the medical advantages of an early diagnosis offered by neonatal screening, this also allows informed future reproductive decisions.     

Molecular prenatal diagnosis in families with fetal mitochondrial trifunctional protein mutations

OBJECTIVES: To evaluate the feasibility of molecular prenatal diagnosis in families with mitochondrial trifunctional protein (TFP) mutations and prospectively study the effects of fetal genotype on pregnancy outcome. TFP catalyzes the last 3 steps in mitochondrial long-chain fatty acid oxidation. STUDY DESIGN: We performed molecular prenatal diagnosis in 9 pregnancies, 8 in 6 families with isolated long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency and one in a family with complete TFP deficiency. Analyses were performed on chorionic villous samples in 7 pregnancies and on amniocytes in 2. RESULTS: Molecular prenatal diagnosis successfully identified the fetal genotype in all 9 pregnancies. Two fetuses were affected, and both pregnancies were terminated by family decision. Two other fetuses had normal genotype and 5 others were heterozygotes. These 7 pregnancies were uncomplicated, and all the offspring are alive and apparently healthy. Genotypes of the aborted fetuses and neonates were confirmed by molecular analysis and enzymatic assays. CONCLUSIONS: Molecular prenatal diagnosis is possible and valid in guiding management of pregnancies in families with known TFP defects. Women heterozygous for TFP alpha-subunit mutations who carry fetuses with wild-type or heterozygous genotypes have uncomplicated pregnancies.     

The effect of electronic job aid assisted one‐to‐one counselling to support exclusive breastfeeding among 0–5‐month‐old infants in rural Bangladesh

Exclusive breastfeeding (EBF) for the first 6 months has established benefits, yet had slow improvements globally. Little is known about electronic job aid‐assisted counselling to support EBF. As a secondary outcome of a cluster randomized controlled trial in Bangladesh, we assessed the effect of electronic job aid‐supported nutrition counselling and practical demonstration on EBF. We randomized pregnant women to one of five study arms in the trial and followed mother–child dyads until 2 years of age. Community health workers (CHWs) provided breastfeeding counselling with or without prenatal and complementary nutrient supplements in all four intervention arms. The comparison arm continued with the usual practice where mothers could receive nutrition counselling at routine antenatal and postnatal care, and during careseeking for childhood illnesses. We assessed breastfeeding indicators at birth and monthly until the child was 6 months old, in both intervention and comparison arms. To evaluate the effect of nutrition counselling on breastfeeding, we combined all four intervention arms and compared them with the comparison arm. Intervention newborns had half the risk (relative risk [RR]: 0.54, 95% confidence interval [CI]: 0.39, 0.76) of receiving prelacteal feeds than those in the comparison arm. EBF declined steeply in the comparison arm after 3 months of age. EBF was 16% higher in the intervention than the comparison arm at 4 months (RR: 1.16, 95% CI: 1.08, 1.23) and 22% higher at 5 months of age (RR: 1.22, 95% CI: 1.12, 1.33). Maternal background and household characteristics did not modify the intervention effect, and we observed no difference in EBF among caesarean versus vaginal births. Breastfeeding counselling and practical demonstration using an electronic job aid by CHWs are promising interventions to improve EBF and are scalable into existing community‐based programmes.     

Parental attitudes: antenatal diagnosis of cystic fibrosis.

In order to understand attitudes to antenatal diagnosis of cystic fibrosis (CF), we interviewed parents from 19 families, who already had one child with CF. Nine women had chorion villus sampling in a subsequent pregnancy and 6/19 said they would consider termination of pregnancy if the result confirmed CF. These results differ from the results of antenatal screening studies of previously unaffected families, where most couples opt for termination.     

Prenatal Diagnosis of Hypoplastic Left Heart Syndrome: Impact of Counseling Patterns on Parental Perceptions and Decisions Regarding Termination of Pregnancy

An online survey for parents of children with congenital heart disease (CHD) was developed to study parents?? experiences at the time of diagnosis. The survey was distributed to online support groups. A total of 841 responses from parents of children with CHD were received during a 4-week period. The current study examined those respondents (211 [25?%]) who reported their child??s diagnosis as hypoplastic left heart syndrome (HLHS). Among these, 138 (65?%) reported receiving the diagnosis prenatally. 32?% of those receiving a prenatal diagnosis reported that after they declined to terminate the pregnancy, termination was mentioned again by their physicians. Parents who had termination mentioned again after their initial decline reported significantly lower optimism regarding their child??s life expectancy than those who did not have it mentioned again (66 vs. 94?%, p?<?0.001); were more likely to interpret the term ??rare?? to mean ??little or no chance of survival?? (34 vs. 13?%, p?=?0.01); and were more likely to change pediatric cardiologists (PCs) (43 vs. 12?%, p?<?0.001). Similarly, 22?% of respondents receiving a prenatal diagnosis reported feeling pressure to terminate the pregnancy by the PC. Those who felt pressure to terminate reported lower optimism about their child??s life expectancy than respondents who did not feel pressure (48 vs. 88?%, p?<?0.001) and were more likely to choose a new PC (48 vs. 17?%, p?<?0.001). In our cohort of parents, when termination of pregnancy was mentioned after the parents declined it, or if the parents felt pressure to terminate, the parents perceived a lower chance of survival, felt less optimistic about their child??s life expectancy, and were more likely to choose another PC for long-term follow-up care. Our study could not determine whether repeated discussions of the possibility for termination of pregnancy independently impacts parental optimism regarding prognosis or whether those who counsel with repeated discussions of termination tend to have more guarded notions of the prognosis of children with HLHS. Further study is warranted to identify the implications of counseling patterns on parental perceptions and decisions regarding termination of pregnancy.     

Parental attitudes: antenatal diagnosis of cystic fibrosis

In order to understand attitudes to antenatal diagnosis of cystic fibrosis (CF), we interviewed parents from 19 families, who already had one child with CF. Nine women had chorion villus sampling in a subsequent pregnancy and 6/19 said they would consider termination of pregnancy if the result confirmed CF. These results differ from the results of antenatal screening studies of previously unaffected families, where most couples opt for termination.     

Genetic counseling. Indications, problems and prospects

From their personal experience, the authors demonstrate that, in spite of increased requests in general, couples in underprivileged socio-cultural classes are insufficiently concerned by genetic counselling; on the contrary it is too often requested by women who are already pregnant. They emphasize the necessity of providing information to all at risk couples and the essential part taken by family doctors. They discuss the difficulties of geneticists when consulters do not express a real question or wait to be given a rule of behaviour. Antenatal diagnosis (proposed to 2 of every 5 couples in 1983) changed the concept of genetic counselling by replacing a probability (the risk) by a certainty (the child presents with the disease or is normal). However, one should not look to either genetic counselling or antenatal diagnosis for a considerable decrease in the incidence of affected children.     

Urinary tract ultrasonography in newborns with late oligohydramnios]

BACKGROUND AND AIM: The aim of this study was to evaluate the value of neonatal renal ultrasonography in the diagnosis of urinary tract malformation pathologies in newborns from pregnancies complicated by late oligohydramnios. METHODS: During the period January 1994-October 1997, 119 newborns from pregnancies complicated by oligohydramnios occurring in the third trimester of pregnancy underwent ultrasonography of the urinary tract at our Centre. All newborns had previously undergone prenatal ultrasonography. RESULTS: Ultrasonography revealed calicopyelic dilatation < 10 mm in 7 newborns (5.8%), 5 of whom had already been reported at the prenatal ultrasonography. One new-born (0.8%) also showed the presence of an ectopic kidney that had not been diagnosed at the prenatal scan. By the next follow-up all the calico-pyelic dilatations had become normal. CONCLUSIONS: Neonatal ultrasonography did not show any alterations to the urinary tract that might be responsible for the reduction of amniotic liquid. We therefore feel that is useful to perform neonatal ultrasonography in those situations in which the onset of oligohydramnios occurred in the second trimester of pregnancy and in cases in which no scan was performed during the prenatal period.     

Chromosomal basis of recurrent fetal losses

Chromosome abnormalities constitute the single most etiological factor in spontaneous abortions and other fetal losses and include sporadic chromosome abnormalities such as monosomy, trisomy, triploidy, tetraploidy and chromosomal mosaicism. These errors either originate during gametogenesis or after fertilization during the early zygotic divisions. Based upon the information now available it is apparent that if a couple has had two fetal losses, the karyotypes of the abortuses are most likely to be concordant either both being normal or both being abnormal. Fetal losses may also be due to a chromosome abnormality carried by a parent in a clinically silent form such as a balanced translocation. A compilation of cytogenetic data from 17,112 parents (8,743 females and 8,369 males) revealed 517 instances of chromosome abnormalities, an incidence of 3 per cent (6% of couples). Approximately 50 per cent of all chromosome abnormalities detected were balanced reciprocal translocations, followed by balanced Robertsonian translocations (23%) and sex chromosome mosaicism in females (14%). Parental chromosome abnormalities are known to be factors in abnormal gametogenesis and zygote formation, and, therefore, prenatal diagnosis should be considered in future pregnancies. Further, even when parental karyotypes are normal, prenatal diagnosis should be offered to couples who have had two or more fetal losses due to their increased risk of having a fetus with a chromosome abnormality.     

Assessment and follow-up of suspected child abuse in preschool children with fractures seen in a general hospital emergency department

OBJECTIVE: To evaluate the emergency department assessment and follow-up of possible child abuse in children with fractures. METHODS: A retrospective audit was conducted of children up to 3 years of age who presented with a fracture to a general hospital emergency department over a 2-year period. RESULTS: In the 98 cases included, there was no documentation of complete physical examination in 57% of cases, whether the injury was witnessed in 54%, or time of injury in 18%. In 27% of cases the history documented was too brief to assess consistency of the injury with the history. Seventy-five per cent of children with known prior injuries did not have their past history documented. In 80% of all cases there was no indication that the emergency department doctor had considered the possibility of child abuse. Emergency doctors did not recognize four out of 16 cases (25%) with inconsistent histories. There was poor follow-up of patients in whom abuse was suspected: 46% of children less than 2 years had neither a skeletal survey nor bone scan. Patients referred to a paediatrician by the emergency department were significantly more likely to have a skeletal survey performed and to have the diagnosis of child abuse confirmed. CONCLUSIONS: Emergency department staff in a general hospital do not document or assess for all of the indicators of child abuse in a high-risk population and they do not document consideration of the diagnosis in the majority of cases. Emergency department staff need more training and more resources to allow for full assessment of child abuse. Suspected child abuse cases should be referred to a paediatrician to improve investigation and follow-up.