Prenatal detection of orofacial clefts in Denmark from 2009 to 2018.

OBJECTIVE: To investigate the overall and type-specific prenatal detection rates (DRs) of orofacial clefts in a national cohort in Denmark. METHODS: This study was based on data from the Danish Fetal Medicine Database and included all fetuses and children from singleton pregnancies diagnosed with an orofacial cleft prenatally and/or postnatally between 2009 and 2018. The types of cleft included unilateral, bilateral or median cleft lip (CL); unilateral, bilateral or median cleft lip with secondary cleft palate (CLP); and cleft palate (CP). The clefts were grouped as cleft lip with or without cleft palate (CL(P)) or as all clefts (including CP). All cases with discordance between prenatal and postnatal diagnoses were validated in the local patient files (Astraia). Cases without prenatal validation of the postnatal diagnosis were marked as undetected. Postnatally diagnosed cases with a strong prenatal suspicion of a cleft but without an International Classification of Diseases-10 code were registered as prenatally detected. Termination of pregnancy and intrauterine death were registered as true positives even if no autopsy could be performed. Liveborn cases with a prenatal diagnosis but without a postnatal validation were excluded. RESULTS: A total of 994 cases were included in the study, of which 933 were liveborn. The prevalence of orofacial cleft was 1.6 per 1000 live births. There were no differences in the baseline characteristics between detected and undetected cases. The DR for CL(P) was 71.7% (95% CI, 64.8-78.9%), with an increase from 60.0% in 2009 to 73.0% in 2018 (P = 0.018). The type-specific DRs for the entire period were 56.4% (95% CI, 45.0-67.6%) for unilateral CL; 76.6% (95% CI, 71.7-82.9%) for unilateral CLP; 70.5% (95% CI, 52.1-87.6%) for bilateral CL; 82.3% (95% CI, 70.6-93.6%) for bilateral CLP; 0% (0/6) for median CL; 75.0% (3/4) for median CLP; and 3.3% (95% CI, 0.6-5.7%) for CP. A total of 20.9% (208/994) of the cases had associated findings, of which 33.2% (69/208) were genetic aberrations. CONCLUSIONS: The DR for CL(P) has improved in Denmark over the last decade. The DR for CLP is high, with the highest DR for bilateral CLP. However, prenatal detection of CP remains a challenge. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prevalence and detection rate of major congenital heart disease in twin pregnancies in Denmark.

OBJECTIVE: To investigate the national prevalence and prenatal detection rate (DR) of major congenital heart disease (mCHD) in twin pregnancies without twin-to-twin transfusion syndrome (TTTS)-associated CHD in a Danish population following a standardized prenatal screening program. METHODS: This was a national registry-based study of data collected prospectively over a 10-year period. In Denmark, all women with a twin pregnancy are offered standardized screening and surveillance programs in addition to first- and second-trimester screening for aneuploidies and malformation, respectively: monochorionic (MC) twins every 2 weeks from gestational week 15 and dichorionic (DC) twins every 4 weeks from week 18. The data were retrieved from the Danish Fetal Medicine Database and included all twin pregnancies from 2009-2018, in which at least one fetus had a pre- and/or postnatal mCHD diagnosis. mCHD was defined as CHD requiring surgery within the first year of life, excluding ventricular septal defects. All pregnancy data were pre- and postnatally validated in the local patient files at the four tertiary centers covering the entire country. RESULTS: A total of 60 cases from 59 twin pregnancies were included. The prevalence of mCHD was 4.6 (95% CI, 3.5-6.0) per 1000 twin pregnancies (1.9 (95% CI, 1.3-2.5) per 1000 live births). The prevalences for DC and MC were 3.6 (95% CI, 2.6-5.0) and 9.2 (95% CI, 5.8-13.7) per 1000 twin pregnancies, respectively. The national prenatal DR of mCHD in twin pregnancies for the entire period was 68.3%. The highest DRs were in cases with univentricular hearts (100%) and the lowest with aortopulmonary window, total anomalous pulmonary venous return, Ebstein's anomaly, aortic valve stenosis and coarctation of the aorta (0-25%). Mothers of children with prenatally undetected mCHD had a significantly higher body mass index (BMI) compared to mothers of children with a prenatally detected mCHD (median, 27 kg/m2 and 23 kg/m2 , respectively; P = 0.02). CONCLUSIONS: The prevalence of mCHD in twins was 4.6 per 1000 pregnancies and was higher in MC than DC pregnancies. The prenatal DR of mCHD in twin pregnancies was 68.3%. Maternal BMI was higher in cases of prenatally undetected mCHD. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prevalence of chromosomal disorders in cases with congenital heart defect: registry-based study from Denmark between 2008 and 2018.

OBJECTIVE: To estimate the prevalence of chromosomal conditions in all fetuses and children with major congenital heart defect (CHD) in Denmark between 2008 and 2018. METHODS: This was a national registry-based study including all singleton pregnancies with a prenatally or postnatally diagnosed major CHD usually requiring surgery within the first year after birth and a due date between July 2008 and December 2018 in Denmark. Data were retrieved from the Danish Fetal Medicine Database (DFMD) and the Danish Cytogenetic Central Register (DCCR) in October 2020. The DCCR contains information on all prenatal and postnatal genetic analyses, including karyotyping, chromosomal microarray, polymerase chain reaction, multiplex ligation-dependent probe amplification and fluorescence in-situ hybridization. All cases were reviewed by a clinical geneticist, and genetic changes were classified as pathogenic, likely pathogenic, variant of uncertain significance, likely benign or benign. Pathogenic and likely pathogenic variants were considered to be abnormal. Cases with CHD without any registered chromosomal analysis reported were considered genetically normal. Isolated CHD was defined as a case with major CHD without any other structural malformations detected prenatally or postnatally. Results are given as n (%). Comparisons between isolated and non-isolated cases were performed using logistic regression analysis, and data are presented as odds ratios (ORs) with 95% CIs. RESULTS: A total of 8482 cases with any cardiovascular diagnosis were retrieved from the DFMD. Twins (n = 112) and minor CHD cases (n = 6921) were excluded, resulting in 1449 cases with major CHD. Of the included cases, 918 (63.4%) underwent chromosomal analysis. An abnormal test result was found in 187 cases, giving a prevalence of a chromosomal condition of 12.9% (95% CI, 11.2-14.7%) among all cases with major CHD. The highest prevalence of a chromosomal condition was found in cases with pulmonary atresia with intact ventricular septum and those with truncus arteriosus (both 28.6%), while the lowest prevalence was found in cases with transposition of the great arteries (2.2%) and congenitally corrected transposition of the great arteries (0%). In isolated cases of transposition of the great arteries, the prevalence of a chromosomal condition was 0.6%. The overall OR for a chromosomal condition in non-isolated cases compared with isolated cases was 2.72 (95% CI, 1.90-3.88). CONCLUSIONS: We found an overall prevalence of a chromosomal condition of 12.9% among cases with major CHD in a national cohort with a high participation rate in first- and second-trimester screening, without employing whole genome and whole exome sequencing. The prevalence of a chromosomal condition varied considerably according to CHD diagnosis and presence of associated extracardiac malformations. These findings are important for prenatal counseling. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prenatal cardiac biometry and flow assessment in fetuses with bicuspid aortic valve at 20 weeks' gestation: multicenter cohort study.

OBJECTIVE: To investigate prenatal changes in cardiac biometric and flow parameters in fetuses with bicuspid aortic valve (BAV) diagnosed neonatally compared with controls with normal cardiac anatomy. METHODS: This analysis was conducted as part of the Copenhagen Baby Heart Study, a multicenter cohort study of 25 556 neonates that underwent second-trimester anomaly scan at 18 + 0 to 22 + 6 weeks' gestation and neonatal echocardiography within 4 weeks after birth, in Copenhagen University Hospital Herlev, Hvidovre Hospital and Rigshospitalet in greater Copenhagen, between April 2016 and October 2018. From February 2017 (Rigshospitalet) and September 2017 (Herlev and Hvidovre hospitals), the protocol for second-trimester screening of the heart was extended to include evaluation of the four-chamber view, with assessment of flow across the atrioventricular valves, sagittal view of the aortic arch and midumbilical artery and ductus venosus pulsatility indices. All images were evaluated by two investigators, and cardiac biometric and flow parameters were measured and compared between cases with BAV and controls. All cases with neonatal BAV were assessed by a specialist. Maternal characteristics and first- and second-trimester biomarkers were also compared between the two groups. RESULTS: Fifty-five infants with BAV and 8316 controls with normal cardiac anatomy were identified during the study period and assessed using the extended prenatal cardiac imaging protocol. There were three times as many mothers who smoked before pregnancy in the group with BAV as in the control group (9.1% vs 2.7%; P = 0.003). All other baseline characteristics were similar between the two groups. Fetuses with BAV, compared with controls, had a significantly larger diameter of the aorta at the level of the aortic valve (3.1 mm vs 3.0 mm (mean difference, 0.12 mm (95% CI, 0.03-0.21 mm))) and the pulmonary artery at the level of the pulmonary valve (4.1 mm vs 3.9 mm (mean difference, 0.15 mm (95% CI, 0.03-0.28 mm))). Following conversion of the diameter measurements of the aorta and pulmonary artery to Z-scores and Bonferroni correction, the differences between the two groups were no longer statistically significant. Pregnancy-associated plasma protein-A (PAPP-A) multiples of the median (MoM) was significantly lower in the BAV group than in the control group (0.85 vs 1.03; P = 0.04). CONCLUSIONS: Our findings suggest that fetuses with BAV may have a larger aortic diameter at the level of the aortic valve, measured in the left-ventricular-outflow-tract view, and a larger pulmonary artery diameter at the level of the pulmonary valve, measured in the three-vessel view, at 20 weeks' gestation. Moreover, we found an association of maternal smoking and low PAPP-A MoM with BAV. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Long-term effects of prenatal progesterone exposure: neurophysiological development and hospital admissions in twins up to 8 years of age.

OBJECTIVES: To perform a neurophysiological follow-up at 48 or 60 months of age in children exposed prenatally to progesterone compared with a placebo and evaluate their medical histories up to 8 years of age. METHODS: In this study, Danish participants of the PREDICT study, including 989 surviving children from 498 twin pregnancies, were followed-up. PREDICT was a placebo-controlled randomized clinical trial examining the effect of progesterone for prevention of preterm delivery in unselected twin pregnancies. Medical histories of the children were reviewed and neurophysiological development was evaluated by the parent-completed Ages and Stages Questionnaire (ASQ) at either 48 or 60 months after the estimated date of delivery. We used the method of generalized estimating equation to account for the correlation within twins. RESULTS: A total of 492 children had been exposed prenatally to progesterone and 497 to placebo. There was no difference in the number of admissions to or length of stay in hospital between the treatment groups, and we found no overall difference in the rates of diagnoses made. However, the odds ratios (ORs) for a diagnosis concerning the heart was 1.66 (95% CI, 0.81-3.37), favoring placebo, among all children, 2.38 (95% CI, 1.07-5.30) in dichorionic twins and 8.19 (95% CI, 1.02-65.6) in all children when excluding diagnoses made at outpatient clinic visits. ASQ scores were available for 437 children (progesterone, n = 225; placebo, n = 212). Mean ASQ score was slightly higher in the progesterone group compared with the placebo group (P = 0.03). In dichorionic twins, the risk of having a low ASQ score (< 10(th) centile) was decreased in the progesterone group (OR, 0.34 (95% CI, 0.14-0.86)). CONCLUSION: Second- and third-trimester exposure of the fetus to progesterone does not seem to have long-term harmful effects during childhood, but future studies should focus on cardiac disease in the child. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.