Gestational diabetes mellitus and adverse maternal and perinatal outcomes in twin and singleton pregnancies: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the risk of adverse maternal and perinatal complications between twin and singleton pregnancies affected by gestational diabetes mellitus and the respective group without gestational diabetes mellitus (controls). DATA SOURCES: A literature search was performed using MEDLINE, Embase, and Cochrane from January 1980 to May 2023. STUDY ELIGIBILITY CRITERIA: Observational studies reporting maternal and perinatal outcomes in singleton and/or twin pregnancies with gestational diabetes mellitus vs controls were included. METHODS: This was a systematic review and meta-analysis. Pooled estimate risk ratios with 95% confidence intervals were generated to determine the likelihood of adverse pregnancy outcomes between twin and singleton pregnancies with and without gestational diabetes mellitus. Heterogeneity among studies was evaluated in the model and expressed using the I2 statistic. A P value of <.05 was considered statistically significant. The meta-analyses were performed using Review Manager (RevMan Web). Version 5.4. The Cochrane Collaboration, 2020. Meta-regression was used to compare relative risks between singleton and twin pregnancies. The addition of multiple covariates into the models was used to address the lack of adjustments. RESULTS: Overall, 85 studies in singleton pregnancies and 27 in twin pregnancies were included. In singleton pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.85; 95% confidence interval, 1.69-2.01), induction of labor (relative risk, 1.36; 95% confidence interval, 1.05-1.77), cesarean delivery (relative risk, 1.31; 95% confidence interval, 1.24-1.38), large-for-gestational-age neonate (relative risk, 1.61; 95% confidence interval, 1.46-1.77), preterm birth (relative risk, 1.36; 95% confidence interval, 1.27-1.46), and admission to the neonatal intensive care unit (relative risk, 1.43; 95% confidence interval, 1.38-1.49). In twin pregnancies with gestational diabetes mellitus, compared with controls, there were increased risks of hypertensive disorders of pregnancy (relative risk, 1.69; 95% confidence interval, 1.51-1.90), cesarean delivery (relative risk, 1.10; 95% confidence interval, 1.06-1.13), large-for-gestational-age neonate (relative risk, 1.29; 95% confidence interval, 1.03-1.60), preterm birth (relative risk, 1.19; 95% confidence interval, 1.07-1.32), and admission to the neonatal intensive care unit (relative risk, 1.20; 95% confidence interval, 1.09-1.32) and reduced risks of small-for-gestational-age neonate (relative risk, 0.89; 95% confidence interval, 0.81-0.97) and neonatal death (relative risk, 0.50; 95% confidence interval, 0.39-0.65). When comparing relative risks in singleton vs twin pregnancies, there was sufficient evidence to suggest that twin pregnancies have a lower relative risk of cesarean delivery (P=.003), have sufficient adjustment for confounders, and have lower relative risks of admission to the neonatal intensive care unit (P=.005), stillbirths (P=.002), and neonatal death (P=.001) than singleton pregnancies. CONCLUSION: In both singleton and twin pregnancies, gestational diabetes mellitus was associated with an increased risk of adverse maternal and perinatal outcomes. In twin pregnancies, gestational diabetes mellitus may have a milder effect on some adverse perinatal outcomes and may be associated with a lower risk of neonatal death.

On the Unknown Proteins of Eukaryotic Proteomes.

To study unknown proteins on a large scale, a reference system has been set up for the three better studied eukaryotic kingdoms, built with 36 proteomes as taxonomically diverse as possible. Proteins from 362 other eukaryotic proteomes with no known homologue in this set were then analyzed, focusing noteworthy on singletons, that is, on such proteins with no known homologue in their own proteome. Consistently, for a given species, no more than 12% of the singletons thus found are known at the protein level, according to Uniprot. In addition, since they rely on the information found in the alignment of homologous sequences, predictions of AlphaFold2 for their tridimensional structure are poor. In the case of metazoan species, the number of singletons rarely exceeds 1000 for the species the closest to the reference system (divergence times below 75 Myr). Interestingly, in the cases of viridiplantae and fungi, larger amounts of singletons are found for such species, as if the timescale on which singletons are added to proteomes were different in metazoa and in other eukaryotic kingdoms. In order to confirm this phenomenon, further studies of proteomes closer to those of the reference system are, however, needed.

Perinatal characteristics and neonatal outcomes of singletons and twins in Chinese very preterm infants: a cohort study.

BACKGROUND: The prevalence of preterm birth has been rising, and there is a paucity of nationwide data on the perinatal characteristics and neonatal outcomes of twin deliveries of very preterm infants (VPIs) in China. This study compared the perinatal characteristics and outcomes of singletons and twins admitted to neonatal intensive care units (NICUs) in China. METHODS: The study population comprised all infants born before 32 weeks in the Chinese Neonatal Network (CHNN) between January 2019 and December 2019. Three-level and population-average generalized estimating equation (GEE)/alternating logistic regression (ALR) models were used to determine the association of twins with neonatal morbidities and the use of NICU resources. RESULTS: During the study period, there were 6634 (71.2%) singletons and 2680 (28.8%) twins, with mean birth weights of 1333.70 g and 1294.63 g, respectively. Twins were significantly more likely to be delivered by caesarean section (p < 0.01), have antenatal steroid usage (p = 0.048), have been conceived by assisted reproductive technology (ART) (p < 0.01), have a higher prevalence of maternal diabetes (p < 0.01) and be inborn (p < 0.01) than singletons. In addition, twins had a lower prevalence of small for gestational age, maternal hypertension, and primigravida mothers than singletons (all p < 0.01). After adjusting for potential confounders, twins had higher mortality rates (adjusted odds ratio [AOR] 1.28, 95% confidence interval [CI] 1.10-1.49), higher incidences of short-term composite outcomes (AOR 1.28, 95% CI 1.09-1.50), respiratory distress syndrome (RDS) (AOR 1.30, 95% CI 1.12-1.50), and bronchopulmonary dysplasia (BPD) (AOR 1.10, 95% CI 1.01-1.21), more surfactant usage (AOR 1.22, 95% CI 1.05-1.41) and prolonged hospital stays (adjusted mean ratio 1.03, 95% CI 1.00-1.06), compared to singletons. CONCLUSION: Our work suggests that twins have a greater risk of mortality, a higher incidence of RDS and BPD, more surfactant usage, and longer NICU stays than singletons among VPIs in China.

On the equivalence of one-inflated zero-truncated and zero-truncated one-inflated count data likelihoods.

One-inflation in zero-truncated count data has recently found considerable attention. There are currently two views in the literature. In the first approach, the untruncated model is considered as one-inflated whereas in the second approach the truncated model is viewed as one-inflated. Here, we show that both models have identical model spaces as well as identical maximum likelihoods. Consequences of population size estimation are illuminated, and the findings are illustrated at hand of two case studies.

The contribution of genetics to dental caries, oral habits and occlusal traits in Turkish twins: A comparative study.

OBJECTIVE: The aims of this study were to investigate and compare the prevalence of dental caries and the frequency of oral habits, molar relationships and occlusal traits between children of multiple births, and singletons, and to determine the relative contributions of genetics and environmental factors to these parameters by using twin study design. METHODS: The study group consisted of 345 multiple births (34 monozygotic and 122 dizygotic twin pairs, 11 sets of triplets) and 345 singletons between the ages of 2 and 17. The prevalence of dental caries, and the frequency of tooth brushing, the children's oral habits, molar relationships, and occlusal traits were recorded. RESULTS: The percentage of children who brushed their teeth more than twice daily was statistically significantly higher in multiple births than in singletons. Higher correlation coefficients were found in dental caries index, except for decayed, filled (df) (2-5 age group) and filled (f) (6-11 age group), in the monozygotic twin pairs compared to those in the dizygotic twin pairs. In children between the ages of 6 and 11 years, mouth breathing, bruxism, lip biting, and pencil biting were higher in singletons than in children of multiple births. There were statistically significant differences between children of multiple births and singletons, with increased overjet in the 2-5 year age group being observed. CONCLUSION: When analyzing these parameters, environmental factors must also be investigated. Due to the low incidence of twin births, longitudinal follow-up studies with more twin pairs are necessary to determine whether these results are generalizable.

Speech processing performance of Hungarian-speaking twins and singletons.

Studying speech processing in twins versus their singleton peers provides opportunities to study both genetic and environmental effects on how children acquire these aspects of their speech and - by extension - their phonological systems. Our study focused on speech processing in typically developing Hungarian-speaking twins and their singleton peers between 5 and 9 years of age. Participants included 384 monolingual Hungarian-speaking children (192 twins, and 192 singletons). Data from four tasks - repetition of synthesised monosyllables, nonsense words, well-formed noisy sentences, and well-formed phonologically complex sentences - were analysed. There was a main effect for birth status, and singletons outperformed their twin peers on the majority of the speech processing tasks. Age and task also had effects on the performance of the participants, and there was a three-way task by age by twin versus singleton status indicating that the speech processing performance of twins versus singletons is interdependent with the type of task and age. Our results also indicate that monolingual Hungarian-speaking twins may be at higher risk for developmental speech delays relative to their singleton peers.

Whole-genome analyses reveal a novel prophage and cgSNPs-derived sublineages of Brachyspira hyodysenteriae ST196.

BACKGROUND: Brachyspira (B.) hyodysenteriae is a fastidious anaerobe spirochete that can cause swine dysentery, a severe mucohaemorragic colitis that affects pig production and animal welfare worldwide. In Switzerland, the population of B. hyodysenteriae is characterized by the predominance of macrolide-lincosamide-resistant B. hyodysenteriae isolates of sequence type (ST) ST196, prompting us to obtain deeper insights into the genomic structure and variability of ST196 using pangenome and whole genome variant analyses. RESULTS: The draft genome of 14 B. hyodysenteriae isolates of ST196, sampled during a 7-year period from geographically distant pig herds, was obtained by whole-genome sequencing (WGS) and compared to the complete genome of the B. hyodysenteriae isolate Bh743-7 of ST196 used as reference. Variability results revealed the existence of 30 to 52 single nucleotide polymorphisms (SNPs), resulting in eight sublineages of ST196. The pangenome analysis led to the identification of a novel prophage, pphBhCH20, of the Siphoviridae family in a single isolate of ST196, which suggests that horizontal gene transfer events may drive changes in genomic structure. CONCLUSIONS: This study contributes to the catalogue of publicly available genomes and provides relevant bioinformatic tools and information for further comparative genomic analyses for B. hyodysenteriae. It reveals that Swiss B. hyodysenteriae isolates of the same ST may have evolved independently over time by point mutations and acquisition of larger genetic elements. In line with this, the third type of mobile genetic element described so far in B. hyodysenteriae, the novel prophage pphBhCH20, has been identified in a single isolate of B. hyodysenteriae of ST196.

The risks of birth defects and childhood cancer with conception by assisted reproductive technology.

STUDY QUESTION: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer? SUMMARY ANSWER: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects. WHAT IS KNOWN ALREADY: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Does underlying infertility in natural conception modify the epigenetic control of imprinted genes and transposable elements in newborns?

RESEARCH QUESTION: Does the epigenetic control of imprinted genes and transposable elements at birth differ according to time to conception in natural conception and after intrauterine insemination (IUI)? DESIGN: A total of 144 singletons were included in four groups: 50 natural pregnancies obtained within 6 months after stopping contraception (group 1); 34 natural pregnancies with infertility period between 6 and 12 months (group 2); 36 pregnancies with an infertility period of more than 12 months (group 3) and 24 pregnancies obtained after IUI (group 4). RESULTS: The placental DNA methylation levels of H19/IGF2 and KCNQ1OT1 were lower in groups 2, 3 and 4 than in group 1 (P = 0.025 in the overall comparison). The DNA methylation rate for LINE-1 was higher in placentas from group 2 than in group 1 (P = 0.022). In cord blood, DNA methylation levels were not significantly different between groups except for H19/IGF2 for which the DNA methylation levels were higher in group 2 than in group 1 (H19/IGF2-seq1 and seq2: P = 0.023 and P = 0.002, respectively). In placenta tissue, compared with group 1, relative expression for SNRPN and for LINE-1 was significantly higher in group 2 (P = 0.002 and P < 0.001, respectively). The relative expression of KCNQ1 in placenta was lower in group 4 than in group 1 (P = 0.013). In cord blood, compared with group 1, the relative expression for H19 was significantly higher in group 3 (P = 0.026), and the relative expression of LINE-1 was higher in groups 2 and 3 and in group 4 (P < 0.001). CONCLUSIONS: Infertility itself, and not only ART techniques, could contribute to potential epigenetic risks for children.

The role of maternal age on the risk of preterm birth among singletons and multiples: a retrospective cohort study in Lombardy, Norther Italy.

BACKGROUND: All over the world, especially in the developed countries, maternal age at birth is rising. This study aimed to assess the role of maternal age on the occurrence of preterm birth (PTB) in a large birth cohort of Lombardy Region, Northern Italy. METHODS: This population-based study used data from regional healthcare utilization databases of Lombardy to identify women who delivered between 2007 and 2017. PTBs were defined as births before 37 completed weeks of gestation and considered according to the gestational age (two categories: < 32 weeks and 32 to 36 weeks). Six maternal age groups were defined (< 20, 20-24, 25-29, 30-34, 35-39, ≥40 years). Logistic regression models were fitted to estimate the crude and adjusted odds ratio (aOR) and the corresponding 95% confidence interval (CI) for PTB among different maternal age groups. Analyses were separately performed according to type of pregnancy (singletons and multiples). Reference group was the age group with the lowest frequency of PTB. RESULTS: Overall, 49,759 (6.6%) PTBs were observed, of which 41,807 were singletons and 7952 were multiples. Rates of PTB were lowest in the women aged 25-29 years among singletons and in the 30-34 years old group among multiples. Our results described a U-shaped association between maternal age and risk of PTB. In particular, the risk of a singleton PTB between 32 and 36 weeks was significantly higher for women aged less than 20 years (aOR = 1.16, CI 95%: 1.04-1.30) and more than 40 years (aOR = 1.62 CI 95%: 1.54-1.70). The highest risk of a multiple delivery between 32 and 36 weeks was observed among women aged less than 25 years and more than 40 years (aOR = 1.79, CI 95%: 1.01-3.17, aOR = 1.47, CI 95%: 1.16-1.85 and aOR = 1.36, CI 95%: 1.19-1.55 respectively for < 20, 20-24 and > 40 age categories). PTB before 32 completed weeks occurred more frequently in the same age categories, except that among multiples no association with advanced maternal age emerged. CONCLUSION: Our study suggested that, after adjustment for potential confounders, both advance and young maternal age were associated with an increased risk of PTB.

Cytoplasmic mRNPs revisited: Singletons and condensates.

Cytoplasmic messenger ribonucleoprotein particles (mRNPs) represent the cellular transcriptome, and recent data have challenged our current understanding of their architecture, transport, and complexity before translation. Pre-translational mRNPs are composed of a single transcript, whereas P-bodies and stress granules are condensates. Both pre-translational mRNPs and actively translating mRNPs seem to adopt a linear rather than a closed-loop configuration. Moreover, assembly of pre-translational mRNPs in physical RNA regulons is an unlikely event, and co-regulated translation may occur locally following extracellular cues. We envisage a stochastic mRNP transport mechanism where translational repression of single mRNPs-in combination with microtubule-mediated cytoplasmic streaming and docking events-are prerequisites for local translation, rather than direct transport.

Uniform International Method to Measure Cervical Length: Are We There Yet?

INTRODUCTION: Cervical length is an important predictor of spontaneous preterm birth. So far, the best way to measure cervical length has not been established. We aimed to compare the incidence of short cervical length between three methods of cervical length measurement with and without the inclusion of cervico-isthmic complex (CIC) (six methods in total) and to determine the positive predictive value for spontaneous preterm birth. MATERIAL AND METHODS: We performed a prospective single-center cohort study in women with a singleton pregnancy between August 2014 and December 2018. During the routine fetal anomaly scan (18-22 weeks), women were offered transvaginal ultrasound for cervical length measurement to screen for the risk of spontaneous preterm birth. Each cervix was measured in six different ways: single-line, two-line, and tracing method between the internal and external os of the cervix with and without CIC. We evaluated the predictive value of the different measurements for spontaneous delivery before 37 weeks using positive predictive values. RESULTS: Our final study population comprised 1,691 women. The overall rate of preterm birth <37 weeks was 8.0% (4.6% spontaneous, 3.4% iatrogenic preterm birth). The mean gestational age at cervical length measurement was 19+6 weeks. The different measuring techniques resulted in significant different cervical lengths, showing a maximum difference of >8 mm between the techniques (41.04 mm [SD 7.1] with one-line without CIC and 49.18 [SD 9.05] mm with trace with CIC) with an incidence of short cervical length below <25 mm ranging from 0.4% to 1.1% (p = 0.18). The positive predictive values for spontaneous preterm birth <37 weeks ranged from 42.9% to 20.0%. CONCLUSION: Different measurement methods for cervical length resulted in statistically significant differences in measured cervical length. Depending on the chosen cut-off this translates to different incidences of short cervical length and influences the number of women designated as high risk for preterm birth and receiving treatment. For interpretation and comparability between (inter-) national studies, it is important to adequately report on the employed technique. Future research should focus on determining the optimal measuring technique and a universal method of measurement.

A Modal Interpretation of Quantum Spins and Its Application to Freudian Theory.

In the present paper, we aim to develop a formal quantum logic theory of the interplay between conscious and unconscious processes of the human mind, a goal that has already been envisaged in quantum cognition; in doing so, we will show how the interplay between formal language and metalanguage allows for characterizing pure quantum states as infinite singletons: in the case of the spin observable, we obtain an equation defining a modality that is then re-interpreted as an abstract projection operator. By including a temporal parameter in the equations and by defining a modal negative operator, we derive an intuitionistic-like negation, for which the non-contradiction law is seen as an equivalent of the quantum uncertainty. Building on the psychoanalytic theory of Bi-Logic by Matte Blanco, we use modalities in interpreting the emergence of conscious representations from an unconscious one, and we demonstrate that this description fits well with Freud's view of the role of negation in mental processes. Psychoanalysis, where affect plays a prominent role in shaping not only conscious, but also unconscious representations, is therefore seen as a suitable model to expand the domain of quantum cognition to the broader field of affective quantum cognition.

Do in vitro fertilization, intrauterine insemination or female infertility impact the risk of congenital anomalies in singletons? A longitudinal national French study.

STUDY QUESTION: Do IVF, IUI or female infertility (i.e. endometriosis, polycystic ovary syndrome [PCOS] and primary ovarian insufficiency [POI]) lead to an increased risk of congenital anomalies in singletons? SUMMARY ANSWER: After multivariable adjustments, the increased risks of congenital defects associated with IUI were no longer significant, but the underlying maternal infertility presented a potential emental risk, in addition to the risk associated with IVF. WHAT IS KNOWN ALREADY: Most epidemiological studies suggest that singletons born from ART have a higher risk of birth defects, specifically musculoskeletal, cardiovascular and urogenital disorders. However, most of these studies were established on data obtained at birth or in the neonatal period and from relatively small populations or several registries. Moreover, to our knowledge, female infertility, which is a potential confounder, has never been included in the risk assessment. STUDY DESIGN, SIZE, DURATION: Using data from the French National Health System database, we conducted a comparative analysis of all singleton births (deliveries ≥22 weeks of gestation and/or >500 g of birthweight) in France over a 5-year period (2013-2017) resulting from fresh embryo or frozen embryo transfer (fresh-ET or FET from IVF/ICSI cycles), IUI and natural conception (NC). Data were available for this cohort of children at least up to early childhood (2.5 years old). PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 3 501 495 singleton births were included (3 417 089 from NC, 20 218 from IUI, 45 303 from fresh-ET and 18 885 from FET). Data were extracted from national health databases and used to identify major birth defects. Malformations were classified according to the 10th revision of the International Classification of Disease. To analyse the effect of mode of conception, multivariable analyses were performed with multiple logistic regression models adjusted for maternal age, primiparity, obesity, smoking, history of high blood pressure or diabetes and female infertility. MAIN RESULTS AND THE ROLE OF CHANCE: In our cohort of children, the overall prevalence of congenital malformations was 3.78% after NC, 4.53% after fresh-ET, 4.39% after FET and 3.91% after IUI (132 646 children with major malformations). Compared with infants conceived naturally, children born after fresh-ET and after FET had a significantly higher prevalence of malformations, with an adjusted odds ratio (aOR) of 1.15 [95% CI 1.10-1.20, P < 0.0001] and aOR of 1.13 [95% CI 1.05-1.21, P = 0.001], respectively. Among the 15 relevant subgroups of malformations studied, we observed a significantly increased risk of eight malformations in the fresh-ET group compared with the NC group (i.e. musculoskeletal, cardiac, urinary, digestive, neurological, cleft lip and/or palate and respiratory). In the FET group, this increased risk was observed for digestive and facial malformations. The overall risk of congenital malformations, and the risk by subtype, was similar in the IUI group and the NC group (overall risk: aOR of 1.01 [95% CI 0.94-1.08, P = 0.81]). In addition, there was an overall independent increase in the risk of congenital defects when the mothers were diagnosed with endometriosis (1.16 aOR [95% CI 1.10-1.22], P < 0.0001), PCOS (1.20 aOR [95% CI 1.08-1.34], P = 0.001) or POI (1.52 aOR [95% CI 1.23-1.88], P = 0.0001). Chromosomal, cardiac and neurological anomalies were more common in the three maternal infertility groups. LIMITATIONS, REASONS FOR CAUTION: Male infertility, the in vitro fertilization method (i.e. in vitro fertilization without or with sperm injection: conventional IVF vs ICSI) and embryo stage at transfer could not be taken into account. Furthermore, residual confounding cannot be excluded as well as uncertainties regarding the diagnostic criteria used for the three female infertilities. Findings for specific malformations should be interpreted with caution because the number of cases was small in some sub-groups (potentially due to the Type I error or multiple testing). WIDER IMPLICATIONS OF THE FINDINGS: In this large study, after multivariable maternal adjustments, a moderately increased risk of defects subsisted after IVF, while those associated with IUI were no longer significant. In addition, our results showed that underlying maternal infertility could contribute to the increased risk of defects associated with IVF. These novel findings highlight the importance of taking into account the ART treatment methods and the type of infertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Agency of Biomedicine. The authors have no competing interests to disclose. TRIAL REGISTRATION NUMBER: NA.

The risk of birth defects with conception by ART.

STUDY QUESTION: What is the association between ART conception and treatment parameters and the risk of birth defects? SUMMARY ANSWER: Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively. WHAT IS KNOWN ALREADY: Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved. STUDY DESIGN, SIZE, DURATION: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017. LIMITATIONS, REASONS FOR CAUTION: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility. WIDER IMPLICATIONS OF THE FINDINGS: The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study. STUDY FUNDING/COMPETING INTEREST(S): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts. TRIAL REGISTRATION NUMBER: N/A.

The Prevalence of Nonsyndromic Oral Clefts in Twins Compared to Singletons: The Association With Birth Weight.

PURPOSE: To examine the prevalence of nonsyndromic oral clefts in twins compared to singletons in the United States and to evaluate the association between birth weight and nonsyndromic oral clefts. DESIGN: A large population-based cross-sectional study was performed using the data from the US National Center for Health Statistics database in 2017. PARTICIPANTS: Our sample consisted of 128 310 twins and 3 723 273 singletons. METHODS: The variables collected were sociodemographic variables, environmental predictors, and clinical measures. Descriptive analysis, bivariate, and multivariate logistic regression were performed. MAIN OUTCOME MEASURE: The main outcome variable in our study is nonsyndromic oral clefts. RESULTS: The prevalence of nonsyndromic oral clefts was 5.22 per 10 000 in twins and 5.12 per 10 000 in singletons. Results show no significant risk of nonsyndromic oral clefts in twins compared to singletons (P = .92). There was a significant relationship between birth weight and infant diagnosed with nonsyndromic oral clefts (P = .01). Unadjusted odds ratio for birth weight was 2.52 (95% CI: 2.25-2.82). Adjusted odds for potential confounders such as mother's age, race, mother's education, gender of the infant, APGAR 5-minute score, gestational age, prenatal smoking, number of prenatal care visits, and mother's body mass index were resulted in similar but with a slightly lower odds of 2.11 (95% CI: 1.78-2.50). CONCLUSION: Compared to singletons, twins did not have higher risk of nonsyndromic oral clefts. Infants with low birth weight were more prone to have nonsyndromic oral clefts.

Effect of sex and dyad composition on speech and gesture development of singleton and twin children.

Children's early vocabulary shows sex differences - with boys having smaller vocabularies than age-comparable girls - a pattern that becomes evident in both singletons and twins. Twins also use fewer words than their singleton peers. However, we know relatively less about sex differences in early gesturing in singletons or twins, and also how singletons and twins might differ in their early gesture use. We examine the patterns of speech and gesture production of singleton and twin children, ages 0;10-to-3;4, during structured parent-child play. Boys and girls - singleton or twin - were similar in speech and gesture production, but singletons used a greater amount and diversity of speech and gestures than twins. There was no effect of twin dyad type (boy-boy, girl-girl, boy-girl) on either speech or gesture production. These results confirm earlier research showing close integration between gesture and speech in singletons in early language development, and further extend these patterns to twin children.

The pan-genome of Treponema pallidum reveals differences in genome plasticity between subspecies related to venereal and non-venereal syphilis.

BACKGROUND: Spirochetal organisms of the Treponema genus are responsible for causing Treponematoses. Pathogenic treponemes is a Gram-negative, motile, spirochete pathogen that causes syphilis in human. Treponema pallidum subsp. endemicum (TEN) causes endemic syphilis (bejel); T. pallidum subsp. pallidum (TPA) causes venereal syphilis; T. pallidum subsp. pertenue (TPE) causes yaws; and T. pallidum subsp. Ccarateum causes pinta. Out of these four high morbidity diseases, venereal syphilis is mediated by sexual contact; the other three diseases are transmitted by close personal contact. The global distribution of syphilis is alarming and there is an increasing need of proper treatment and preventive measures. Unfortunately, effective measures are limited. RESULTS: Here, the genome sequences of 53 T. pallidum strains isolated from different parts of the world and a diverse range of hosts were comparatively analysed using pan-genomic strategy. Phylogenomic, pan-genomic, core genomic and singleton analysis disclosed the close connection among all strains of the pathogen T. pallidum, its clonal behaviour and showed increases in the sizes of the pan-genome. Based on the genome plasticity analysis of the subsets containing the subspecies T pallidum subsp. pallidum, T. pallidum subsp. endemicum and T. pallidum subsp. pertenue, we found differences in the presence/absence of pathogenicity islands (PAIs) and genomic islands (GIs) on subsp.-based study. CONCLUSIONS: In summary, we identified four pathogenicity islands (PAIs), eight genomic islands (GIs) in subsp. pallidum, whereas subsp. endemicum has three PAIs and seven GIs and subsp. pertenue harbours three PAIs and eight GIs. Concerning the presence of genes in PAIs and GIs, we found some genes related to lipid and amino acid biosynthesis that were only present in the subsp. of T. pallidum, compared to T. pallidum subsp. endemicum and T. pallidum subsp. pertenue.

Genome-based analysis for the bioactive potential of Streptomyces yeochonensis CN732, an acidophilic filamentous soil actinobacterium.

BACKGROUND: Acidophilic members of the genus Streptomyces can be a good source for novel secondary metabolites and degradative enzymes of biopolymers. In this study, a genome-based approach on Streptomyces yeochonensis CN732, a representative neutrotolerant acidophilic streptomycete, was employed to examine the biosynthetic as well as enzymatic potential, and also presence of any genetic tools for adaptation in acidic environment. RESULTS: A high quality draft genome (7.8 Mb) of S. yeochonensis CN732 was obtained with a G + C content of 73.53% and 6549 protein coding genes. The in silico analysis predicted presence of multiple biosynthetic gene clusters (BGCs), which showed similarity with those for antimicrobial, anticancer or antiparasitic compounds. However, the low levels of similarity with known BGCs for most cases suggested novelty of the metabolites from those predicted gene clusters. The production of various novel metabolites was also confirmed from the combined high performance liquid chromatography-mass spectrometry analysis. Through comparative genome analysis with related Streptomyces species, genes specific to strain CN732 and also those specific to neutrotolerant acidophilic species could be identified, which showed that genes for metabolism in diverse environment were enriched among acidophilic species. In addition, the presence of strain specific genes for carbohydrate active enzymes (CAZyme) along with many other singletons indicated uniqueness of the genetic makeup of strain CN732. The presence of cysteine transpeptidases (sortases) among the BGCs was also observed from this study, which implies their putative roles in the biosynthesis of secondary metabolites. CONCLUSIONS: This study highlights the bioactive potential of strain CN732, an acidophilic streptomycete with regard to secondary metabolite production and biodegradation potential using genomics based approach. The comparative genome analysis revealed genes specific to CN732 and also those among acidophilic species, which could give some insights into the adaptation of microbial life in acidic environment.

Early styles of interaction in mother-twin infant dyads and maternal mental health.

Transition to parenthood is considered a critical process for mothers of twins. There are, however, few studies on the subject. This study aims to evaluate the differences between mother-twin infant dyads and mother-singleton infant dyads with regard to maternal depression, anxiety, parenting stress, and the quality of mother-infant interaction. Mothers of twin infants (N = 40) were compared to mothers of singletons (N = 72). At infant 3 months, maternal depression, anxiety, and parenting stress were assessed via a questionnaire and styles of interaction with the Care-Index. The results indicated that mothers of twins (vs mothers of singletons) had significantly higher state anxiety and higher scores on the Difficult Child Scale of the Parenting Stress Index at infant 3 months. No significant differences between the two groups were found with regard to maternal depression. Mothers of twins had significantly lower sensitivity and were more unresponsive than mothers of singletons. Twin infants had significantly more difficult and compliant behaviours than singleton infants. Assisted reproductive treatment (ART) and prematurity had no effect on any of the examined variables. State anxiety was shown to partially mediate the relationship between twin parenthood and maternal sensitivity and to completely mediate the relationship between twin parenthood and infant difficult style. Maternal unresponsiveness was shown to be exclusively linked to being the parent of twins. The study shows that twin parenthood has a significant effect on maternal mental health and on the quality of mother-infant interaction and highlights the importance of early prevention programmes for twin parents.