Interpregnancy weight change and adverse pregnancy outcomes: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the effect of interpregnancy body mass index (BMI) change on pregnancy outcomes, including large-for-gestational-age babies (LGA), small-for-gestational-age babies (SGA), macrosomia, gestational diabetes mellitus (GDM) and caesarean section (CS). DESIGN: Systematic review and meta-analysis of observational cohort studies. DATA SOURCES: Literature searches were performed across Cochrane, MEDLINE, EMBASE, CINAHL, Global Health and MIDIRS databases. STUDY SELECTION: Observational cohort studies with participants parity from 0 to 1. MAIN OUTCOME MEASURES: Adjusted ORs (aORs) with 95% CIs were used to evaluate the association between interpregnancy BMI change on five outcomes. RESULTS: 925 065 women with singleton births from parity 0 to 1 were included in the meta-analysis of 11 studies selected from 924 identified studies. A substantial increase in interpregnancy BMI (>3 BMI units) was associated with an increased risk of LGA (aOR 1.85, 95% CI 1.71 to 2.00, p<0.001), GDM (aOR 2.28, 95% CI 1.97 to 2.63, p<0.001), macrosomia (aOR 1.54, 95% CI 0.939 to 2.505) and CS (aOR 1.72, 95% CI 1.32 to 2.24, p<0.001) compared with the reference category, and a decreased risk of SGA (aOR 0.83, 95% CI 0.70 to 0.99, p=0.044). An interpregnancy BMI decrease was associated with a decreased risk of LGA births (aOR 0.70, 95% CI 0.55 to 0.90, p<0.001) and GDM (aOR 0.80, 95% CI 0.62 to 1.03), and an increased risk of SGA (aOR 1.31, 95% CI 1.06 to 1.63, p=0.014). Women with a normal BMI (<25kg/m2) at first pregnancy who have a substantial increase in BMI between pregnancies had a higher risk of LGA (aOR 2.10, 95% CI 1.93 to 2.29) and GDM (aOR 3.10, 95% CI 2.74 to 3.50) when compared with a reference than women with a BMI ≥25 kg/m2 at first pregnancy. CONCLUSIONS: Gaining weight between pregnancies increases risk of developing GDM, CS and LGA, and reduces risk of SGA in the subsequent pregnancy. Losing weight between pregnancies reduces risk of GDM and LGA and increases risk of SGA. Weight stability between first and second pregnancy is advised in order to reduce risk of adverse outcomes. TRIAL REGISTRATION NUMBER: CRD42016041299

The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Ovarian reserve in women with sickle cell disease

<div><p>Background</p><p>It has been proposed that ovarian sickling and/or iron overload in women with sickle cell disease (SCD) could contribute to gonadal dysfunction, but there are very few published studies. We hypothesised that the above phenomena might impair ovarian reserve.</p><p>Methods</p><p>A total of 50 SCD patients were case-matched by age, ethnicity, and presence of regular cycles (28±5 days) with 73 patients without a known haemoglobinopathy who required anti-Müllerian hormone (AMH) assessment in a gynaecology clinic. SCD patients had AMH levels taken as part of routine care. The patients were case-controlled and matched with patients who had no haemoglobinopathy in a tertiary centre over a period of one year.</p><p>Results</p><p>The mean AMH in the SCD case group was 7.6 pmol/l compared with 13.4 pmol/l in the control group (p<0.001). The AMH distributions were subsequently categorised. This showed that SCD patients had a significantly higher chance of having lower AMH in comparison with the control group (OR 2.6 (CI 1.1–6.5, P = 0.02). The proportion of women with AMH > 20 pmol/l was significantly lower in the SCD group (6%) in comparison with the control group (19%) (P = 0.04).</p><p>Conclusions</p><p>This is the first study showing that women of reproductive age with SCD are more likely to have a low ovarian reserve at a younger age in comparison with patients with no haemoglobinopathy.</p></div