Epidemiology of limb reduction defects as registered in the Medical Birth Registry of Norway, 1970-2016: Population based study.

BACKGROUND: Following the Thalidomide disaster, the Medical Birth Registry of Norway (MBRN) was established in 1967, with epidemiological surveillance of congenital anomalies as one main aim. Limb reduction defects (LRD) constitute a rare and heterogeneous anomaly group, where correct registration and classification is important for surveillance and research. We aimed at reviewing and recoding LRD cases in the MBRN using the same classification system for all years, and evaluate time trends, characteristics and risk factors, 1970-2016. METHODS: After reviewing and recoding LRD cases using International Classification of Diseases (ICD), 10th version, for all years, time trends, association with major anomalies, risk factors and infant outcomes were calculated. Generalized linear models for the binomial family with log link gave relative risks (RR) with 95% confidence intervals (CI). Classification of LRD as suggested by European surveillance of congenital anomalies (EUROCAT) was attempted. RESULTS: Overall LRD prevalence, 1970-2016, was 4.4 per 10 000, slightly increasing during 1970-1981, followed by relatively stable rates. There were more defects in upper than lower limbs. Defects in hands/fingers were most common, but unspecific descriptions prevented classification of LRD according to EUROCAT. A majority of cases had associated anomalies, the most common being other limb defects, followed by cardiac defects and anomalies in the nervous and digestive systems. From 1999, 26% of LRD cases were terminated, more than 90% of these had associated major anomalies. Stillbirth, neonatal and infant mortality were higher among infants with LRD, also related to associated anomalies. Pre-gestational diabetes was associated with a more than three times increased risk of offspring total LRD, while no association with maternal epilepsy was found. Taking folate/multivitamin supplements before and/or during pregnancy was associated with lower risk of offspring LRD (adjusted RR 0.7; 95% CI 0.6-0.9), while daily smoking did not significantly increase the risk. CONCLUSION: The MBRN now has information on LRD coded by ICD-10 from 1970, but information is not specific enough to use other recommended classification systems. Collecting radiographic descriptions and/or more details from hospital records would improve the quality of the registry data. Taking folate supplements before/during pregnancy may reduce the risk of offspring LRD.

De novo truncating variants in PHF21A cause intellectual disability and craniofacial anomalies.

Potocki-Shaffer syndrome (PSS) is a contiguous gene syndrome caused by 11p11.2 deletions. PSS is clinically characterized by intellectual disability, craniofacial anomalies, enlarged parietal foramina, and multiple exostoses. PSS occasionally shows autism spectrum disorder, epilepsy, and overgrowth. Some of the clinical features are thought to be associated with haploinsufficiency of two genes in the 11p11.2 region; variants affecting the function of ALX4 cause enlarged parietal foramina and EXT2 lead to multiple exostoses. However, the remaining clinical features were still yet to be linked to specific genetic alterations. In this study, we identified de novo truncating variants in an 11p11.2 gene, PHF21A, in three cases with intellectual disability and craniofacial anomalies. Among these three cases, autism spectrum disorder was recognized in one case, epilepsy in one case, and overgrowth in two cases. This study shows that PHF21A haploinsufficiency results in intellectual disability and craniofacial anomalies and possibly contributes to susceptibility to autism spectrum disorder, epilepsy, and overgrowth, all of which are PSS features.

Intergenerational birth weight associations by mother's birth order - the mechanisms behind the paradox: a population-based cohort study.

BACKGROUND: Mother's birth order is inversely associated with offspring birth weight despite positively associated with the mother's own birth weight. The causes behind this relation have not been elucidated. AIMS: To investigate the relation between mother's birth order and birth weight of her offspring, with emphasis on possible mechanisms behind the findings. STUDY DESIGN: Population based cohort study over two generations. SUBJECTS: Data were from the Medical Birth Registry of Norway, based on all births in Norway, 1967-2006 (2.3 million births). Units where both mothers and offspring were singletons and offspring were first born were included, forming 272,674 mother-offspring units for the analyses. OUTCOME MEASURE: Birth weight in the second generation. RESULTS: Mother's birth weight increased steadily with increasing birth order from 3369 g for first born to 3538 g for fourth or later born mothers. In contrast, there was a monotonic decrease in offspring mean birth weight with increasing mother's birth order (9.1 g per birth order (95% C.I.; 6.8, 11.4)). First born mothers tended to be older, to have higher education, to more often be married or cohabiting, and to smoke less than later born mothers at the time of their first pregnancy. CONCLUSION: The general reduction in mean birth weight among first born mothers was not observed in the next generation. We suggest that first born mothers have the same biologically potential for achieving similar sized offspring as later born mothers, and that social factors account for the inverse relation.

Maternal and paternal contribution to intergenerational recurrence of breech delivery: population based cohort study.

OBJECTIVE: To investigate intergenerational recurrence of breech delivery, with a hypothesis that both women and men delivered in breech presentation contribute to increased risk of breech delivery in their offspring. DESIGN: Population based cohort study for two generations. SETTING: Data from the medical birth registry of Norway, based on all births in Norway 1967-2004 (2.2 million births). PARTICIPANTS: Generational data were provided through linkage by national identification numbers, forming 451,393 mother-offspring units and 295,253 father-offspring units. We included units where both parents and offspring were singletons and offspring were first born, forming 232,704 mother-offspring units and 154,851 father-offspring units for our analyses. MAIN OUTCOME MEASURE: Breech delivery in the second generation. RESULTS: Men and women who themselves were delivered in breech presentation had more than twice the risk of breech delivery in their own first pregnancies compared with men and women who had been cephalic presentations (odds ratios 2.2, 95% confidence interval 1.8 to 2.7, and 2.2, 1.9 to 2.5, for men and women, respectively). The strongest risks of recurrence were found for vaginally delivered offspring and were equally strong for men and women. Increased risk of recurrence of breech delivery in offspring was present only for parents delivered at term. CONCLUSION: Intergenerational recurrence risk of breech delivery in offspring was equally high when transmitted through fathers and mothers. It seems reasonable to attribute the observed pattern of familial predisposition to term breech delivery to genetic inheritance, predominantly through the fetus.