Exploring the diagnostic utility of genome sequencing for fetal congenital heart defects.

OBJECTIVE: The diagnostic yield for congenital heart defects (CHD) with routine genetic testing is around 10%-20% when considering pathogenic CNVs or aneuploidies as positive findings. This is a pilot study to investigate the utility of genome sequencing (GS) for prenatal diagnosis of CHD. METHODS: Genome sequencing (GS, 30X) was performed on 13 trios with CHD for which karyotyping and/or chromosomal microarray results were non-diagnostic. RESULTS: Trio GS provided a diagnosis for 4/13 (30.8%) fetuses with complex CHDs and other structural anomalies. Findings included pathogenic or likely pathogenic variants in DNAH5, COL4A1, PTPN11, and KRAS. Of the nine cases without a genetic etiology by GS, we had outcome follow-up data on eight. For five of them (60%), the parents chose to keep the pregnancy. A balanced translocation [46,XX,t(14; 22)(q32.33; q13.31)mat] was detected in a trio with biallelic DNAH5 mutations, which together explained the recurrent fetal situs inversus and dextrocardia that was presumably due to de novo Phelan-McDermid syndrome. A secondary finding of a BRCA2 variant and carrier status of HBB, USH2A, HBA1/HBA2 were detected in the cohort. CONCLUSIONS: GS expands the diagnostic scope of mutation types over conventional testing, revealing the genetic etiology for fetal heart anomalies. Patients without a known genetic abnormality indicated by GS likely opted to keep pregnancy especially if the heart defect could be surgically repaired. We provide evidence to support the application of GS for fetuses with CHD.

Down syndrome in monochorionic twins.

Down syndrome in monochorionic twins has rarely been reported. We report such a case diagnosed prenatally. Maternal serum screening was performed at 15 weeks for a twin pregnancy which indicated a risk of greater than 1:50 for Down syndrome. The review of early ultrasonography confirmed monochorionic twins. Amniocentesis at 17 weeks' gestation was performed on one of the twin sacs, which confirmed Down syndrome. A screening scan at 19 weeks' gestation showed isolated absent nasal bones in both twins. Termination of pregnancy was performed subsequently.

Non-surgical interventions for threatened and recurrent miscarriages.

Many surgical and non-surgical interventions are used in the management of threatened and recurrent miscarriages. Evidence-based management of recurrent miscarriages requires investigations into the underlying aetiology. When a specific cause is identified, directed treatment may reduce miscarriage rates. Combined aspirin and heparin for antiphospholipid syndrome, and screening and treatment of bacterial vaginosis between ten and 22 weeks of pregnancy with clindamycin, are the only interventions proven to be useful in randomised controlled trials (RCTs). The use of periconceptional metformin for polycystic ovarian (PCO) syndrome is promising, though data from RCTs are still required. The use of heparin in inherited thrombophilias, bromocriptine in hyperprolactinaemia and luteinising hormone suppression in fertile patients with PCO syndrome are more controversial. In threatened miscarriages, or when no cause is found, treatment becomes empirical. Supportive care may reduce miscarriage rates. Dydrogesterone, a progesterone derivative, may further reduce miscarriage rates. Bed rest and avoidance of sexual intercourse, though commonly advised, are of no proven benefit. Use of uterine relaxing agents, human chorionic gonadotrophin, immunotherapy and vitamins remain controversial in idiopathic recurrent miscarriages.

Intestinal atresia of co-twin after spontaneous cessation of blood flow through an acardiac twin.

A 33-year-old woman was diagnosed at 15 weeks gestation with a twin pregnancy complicated by an acardiac acephalic foetus. The patient opted for expectant management with close foetal surveillance. Serial ultrasonography showed polyhydramnios at 22 weeks gestation. However, subsequent scans over the next two weeks showed cessation of blood flow in the acardiac foetus, decreasing size of the foetal mass, as well as gradual resolution of the polyhydramnios. Subsequent follow-up was rather uneventful and she underwent an uncomplicated elective caesarean section at 35 weeks, resulting in a healthy 2,820 g girl. The baby was found to have intestinal atresia at birth. She underwent surgery successfully and was well when discharged. The possible causes and pathophysiology of intestinal atresia are discussed.

The amniotic sheet: a truly benign condition?

OBJECTIVE: Amniotic sheets are the result of uterine synechiae that have been encompassed by the expanding chorion and amnion. Radiologically they are seen as 'shelves' in the amniotic cavity. The benign nature of such amniotic sheets has been documented in many case series in the literature. The objective of this study was to determine the characteristics (if any) of amniotic sheets that predict fetal outcome. METHODS: Between January 2001 and December 2002, detailed scans were performed in 30 476 singleton pregnancies at 18-32 weeks' gestation. Of these, 44 cases of amniotic sheets were detected. The characteristics studied were site of amniotic sheet and whether the amniotic sheet was complete (i.e. no free edge seen on ultrasound) or incomplete (i.e. presence of free edge seen on ultrasound). The primary fetal outcome studied was stillbirth. RESULTS: The incidence of amniotic sheets was 0.14%. Two were complete and 42 were incomplete. Of the 38 cases with known outcomes there were two intrauterine deaths. There was no association between fetal outcome and the uterine location of the amniotic sheet (i.e. upper two-thirds vs. lower third, P = 0.5). There was, however, an association between the completeness of the amniotic sheets and intrauterine death (P = 0.002). Both instances of intrauterine death occurred in the two cases with complete amniotic sheets. Postmortem examination suggested that cord accidents were the cause of intrauterine death in both cases. CONCLUSIONS: This study supports the view that incomplete amniotic sheets are benign. It also suggests for the first time that complete amniotic sheets may be associated with intrauterine death.

Birth defects in Singapore: 1994-2000.

INTRODUCTION: To study characteristics of birth defect cases among live births, stillbirths and abortions in Singapore between 1994 and 2000. METHODS: Index cases for the National Birth Defects Registry (NBDR) were obtained from all neonatal nurseries in Singapore, all hospital discharge summaries, cytogenetic and pathology reports from all pathology laboratories in Singapore, and from the compulsory reporting of all termination of pregnancy cases and stillbirths delivered. Further information was obtained from case notes retrieved from the medical record offices, antenatal clinics, cytogenetic laboratories, pathology departments and the Registry of Births and Deaths. The notified cases (live births, stillbirths and abortions) between 1994 and 2000 were extracted from the NBDR and analysed with regard to ethnicity, maternal age, trend over the seven years and types of birth defects using the British Paediatric Association Classification. RESULTS: Between 1994 and 2000, a total of 7,870 cases (6,278 births and 1,592 abortuses) were notified, giving a rate of 23.99 birth defect cases per 1000 live births. There was a decreasing trend in birth defect incidence (19.76 to 16.85 per 1,000 live births) among live births and stillbirths and an increasing trend of abortion (3.25 to 7.57 per 1,000 live births) for birth defects. Malays had a higher rate of congenital defects at birth (24.4/1,000 live births) compared to Chinese (18.4/1,000 births). The 25-29 years age group had the lowest overall rate (22.6/1,000 live births) compared to the 19 years and below group at 31.6/1,000 live births and the 45-49 years group at 126.6/1,000 live births. The five most common groups of anomalies (per 1,000 live births) were those of heart (9.07), musculoskeletal (4.98), chromosomal (4.35), urinary (3.12) and nervous systems (2.90). The five most common aborted anomalies (per 1,000 live births) were those of chromosomal (2.40), nervous (1.23), heart (0.95), musculoskeletal (0.85) and urinary systems (0.36). CONCLUSION: There was an increasing trend of abortion for birth defects, accompanied by a falling trend in the congenital anomalies of live births. Both extremes of maternal age were at higher risk of non-chromosomal birth defects while advanced maternal age was at higher risk of chromosomal defects.

Outcomes of twin-twin transfusion syndrome managed by a specialised twin clinic.

INTRODUCTION: To determine the perinatal outcomes of monochorionic (MC) pregnancies complicated by the twin-twin transfusion syndrome (TTTS) that were managed in a specialised twin clinic at the KK Women's and Children's Hospital. METHODS: This was a 21-month retrospective study carried out from January 2002 to September 2003. MC pregnancies were followed up every two to three weeks with regular ultrasonographical and Doppler studies from the time monochorionicity was diagnosed. Standard criteria used for the diagnosis of TTTS are the presence of oligohydramnios/polyhydramnios sequence on ultrasonography. The severity of TTTS was staged according to Quintero's system. RESULTS: There were 77 sets of MC pregnancies in our database. 11 sets were diagnosed with TTTS, hence the incidence was 14.3 percent. The median gestation at diagnosis of TTTS was 17.4 (16.4 to 26) weeks. At first presentation, five were stage I, two were stage II, three were stage III and one was stage IV. Three pregnancies were terminated in the second trimester and one was lost to follow-up. Of the other seven, two were treated expectantly or delivered, four with amnioreduction/ septostomy and one with cord occlusion. The median gestation at delivery is 30.8 (26.7 to 36.9) weeks. Four (57 percent) were delivered before 32 weeks and these same four pairs required neonatal intensive care. The overall perinatal survival was 78 percent (11/14) and the median diagnosis to delivery interval was 10.7 (3.1 to 17.5) weeks. CONCLUSION: TTTS occurs in a significant proportion of MC pregnancies. The perinatal survival outcome of this group of patients managed in this clinic is comparable to that of other good centres.

Increased latency of absent end-diastolic flow in the umbilical artery of monochorionic twin fetuses.

OBJECTIVE: To determine if absent end-diastolic flow (AEDF) in the umbilical artery (UA) has a longer latency in monochorionic (MC) twin fetuses compared to singleton or dichorionic twin (DC) fetuses. METHODS: One hundred and eight pregnancies with a fetus with AEDF were reviewed: 47 MC and 17 DC twin pregnancies and 44 singletons. Because twin-twin transfusion syndrome (TTTS) is a potential confounder when determining latency, subgroup analysis was also performed on the 21 MC affected pregnancies without TTTS. Latency of AEDF (in days) was defined as the difference between the gestational age at diagnosis of AEDF and gestational age at delivery or intrauterine death. RESULTS: Latency was similar in MC twins (median, 39 days) and DC twins (30 days) but longer compared to singletons (11 days; P = 0.0001). After excluding pregnancies with TTTS, latency in non-TTTS MC twins (54 days) was longer than in both singletons and DC twins. This was due to an earlier gestational age at AEDF in non-TTTS MC twins of 20 weeks compared to 27 weeks in both singleton and DC twins because median gestational age at delivery was similar in MC twins, DC twins and singletons. CONCLUSIONS: The latency period of UA AEDF is longer in MC twins than in singletons. Our data suggest that in MC twin fetuses without TTTS, AEDF begins earlier and lasts about twice as long as in DC twin fetuses, which is consistent with placental insufficiency not being the sole factor mediating abnormal UA waveforms in MC placentation. This observation is important in counseling and managing twin pregnancies discordant for AEDF.

Occlusion of arterio-arterial anastomosis manifesting as acute twin-twin transfusion syndrome.

In vivo, ex vivo and modelling studies suggest that arterio-arterial anastomoses (AAAs) protect against haemodynamic imbalance in monochorionic twins and thus the development of TTTS. We report the acute onset of severe TTTS at 34 weeks' gestation in a patient with an antenatally visualized AAA which was shown at injection studies to have been obliterated, presumably by thrombosis. Computer modelling with the relevant clinical data confirmed that occlusion of the AAA alone was sufficient to reproduce the clinical manifestations. A study of the vascular configuration of AAA in the fixed placenta suggested that its small diameter and turbulent flow may have contributed to its occlusion. This case report shows that the unmasking of unbalanced AVA configurations by occlusion of a protective AAA can manifest as TTTS.

Acardiac twin: a systematic review of minimally invasive treatment modalities.

This review of the literature aimed to determine pregnancy outcomes after minimally invasive treatment for occluding vascular supply to acardiac twins. A MEDLINE search was performed until 2002 using the terms 'acardiac', 'acardius', 'twin reversed arterial perfusion (TRAP) sequence' and 'chorangiopagus parasiticus' and 207 articles published in the English-language literature were identified. These articles and the corresponding cited references in English were reviewed. We identified 32 reports involving 74 cases of acardiac twin treated by minimally invasive techniques. Seventy one cases were included for analysis including 40 treated by cord occlusion and 31 by intrafetal ablation. Cord occlusion was first attempted by embolization (n = 5), cord ligation (n = 15), laser coagulation (n = 10), bipolar diathermy (n = 7) and monopolar diathermy (n = 3). Intrafetal ablation was performed by alcohol (n = 5), monopolar diathermy (n = 9), interstitial laser (n = 4) and radiofrequency (n = 13). The overall median gestational ages at treatment and delivery were 21 (range, 14-28) weeks and 36 (range, 19-42) weeks, respectively, with a median treatment-delivery interval of 13 (range, 0-25) weeks. The overall pump twin survival rate was 76% (n = 54). Intrafetal ablation was associated with later median gestational age at delivery (37 vs. 32 weeks, P = 0.04) and higher median treatment-delivery interval (16 vs. 9.5 weeks, P = 0.02) compared with cord occlusion techniques. It was also associated with a lower technical failure rate (13% vs. 35%, P = 0.03), lower rate of premature delivery or rupture of membranes before 32 weeks (23% vs. 58%, P = 0.003) and higher rate of clinical success (77% vs. 50%, P = 0.02) than cord occlusion techniques. There were no statistically significant differences in terms of outcome between the subgroups of fetoscopic- or ultrasound-guided cord occlusion techniques. This review suggests that intrafetal ablation is the treatment of choice for acardiac twins because it is simpler, safer and more effective when compared with the cord occlusion techniques.