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Twin and multiple births have negative effects on the performance and health of cows and calves. To decipher the genetic architecture of this trait in the two Swiss Brown Swiss cattle populations, we performed various association analyses based on de-regressed breeding values. Genome-wide association analyses were executed using ~600 K imputed SNPs for the maternal multiple birth trait in ~3500 Original Braunvieh and ~7800 Brown Swiss animals. Significantly associated QTL were observed on different chromosomes for both breeds. We have identified on chromosome 11 a QTL that explains ~6% of the total genetic variance of the maternal multiple birth trait in Original Braunvieh. For the Brown Swiss breed, we have discovered a QTL on chromosome 15 that accounts for ~4% of the total genetic variance. For Original Braunvieh, subsequent haplotype analysis revealed a 90-kb window on chromosome 11 at 88 Mb, where a likely regulatory region is located close to the ID2 gene. In Brown Swiss, a 130-kb window at 75 Mb on chromosome 15 was identified. Analysis of whole-genome sequence data using linkage-disequilibrium estimation revealed possible causal variants for the identified QTL. A presumably regulatory variant in the non-coding 5' region of the ID2 gene was strongly associated with the haplotype for Original Braunvieh. In Brown Swiss, an intron variant in PRDM11, one 3' UTR variant in SYT13 and three intergenic variants 5' upstream of SYT13 were identified as candidate variants for the trait multiple birth maternal. In this study, we report for the first time QTL for the trait of multiple births in Original Braunvieh and Brown Swiss cattle. Moreover, our findings are another step towards a better understanding of the complex genetic architecture of this polygenic trait.

Multiple birth is one of several perinatal factors associated with increased risk for autism spectrum disorder (ASD); however, complexity in its relationship to ASD symptoms and developmental functioning remains. The present study investigated perinatal risk factors for ASD, primarily focusing on birth status, within a large early intervention sample. In particular, the relationship between ASD, perinatal factors, and the effect of birth status on developmental functioning and ASD symptom severity were examined in youth with and without ASD classification who were born singly or were the product of a multiple birth. Overall, the presence of other perinatal risk factors, including prematurity, low birth weight, and advanced parental age, was primarily related to birth status and not to ASD classification, while severity of ASD symptoms and developmental impairments were primarily related to ASD classification and not to birth status. Study findings and implications for early screening of children with developmental delays are discussed.

Background The naturally occurring male-to-female (M/F) ratio at birth is 1.05. Higher ratios found primarily in countries across Asia have been attributed to prenatal sex selection due to son preference. There is growing evidence that sex-selective practices continue following migration; however, little is known about these practices following migration to Australia. Methods In this population-based study we assessed M/F ratios at birth per mother’s country of birth for all registered births 1999–2015 in Victoria, Australia (n = 1 191 250). We also compared the M/F ratio among births to mothers born elsewhere to that of mothers born in Australia, stratified by time period and parity. Results Compared with the naturally occurring M/F ratio as well as to the M/F ratio among births to mothers born in Australia, there was an increased ratio of male births to mothers born in India, China and South-East Asia, particularly at higher parities and in more recent time periods (elevated M/F ratios ranged from 1·079 to 1·248, relative risks of male birth ranged from 1·012 to 1·084 with confidence intervals between 1·001 and 1·160 and P-values between 0·005 and 0·039). The most male-biased sex ratios were found among multiple births to Indian-born mothers, and parity of two or more births to Indian and Chinese-born mothers in 2011–15. Conclusions The male-biased sex ratios observed in this study indicate that prenatal sex selection may be continuing following migration to Australia from countries where these practices have been documented. The excess of males among multiple births raises the question as to what role assisted reproduction plays. Findings also suggest that systematic discrimination against females starts in the womb.

Objective: Parents of newborn twins are at risk for both shortened sleep duration and sleep discontinuity. The purpose of this study was to characterize weekday and weekend sleep duration, sleep continuity, and awakenings in both mothers and fathers of newborn twins during the first 3 months at home. Material and Methods: Sleep-wake parameters were assessed at two time points using self-report diaries and actigraphy in 75 families with newborn twins. To assess sleep on weekdays and weekends with minimal subject burden, actigraphy recordings of both parents commenced at 9:00 p.m. Saturday and terminated at 9:00 p.m. Tuesday. Results: Mean sleep duration over 24 hours for parents of twins ranged between 6.7 and 7.5 hours during the first 3 months postpartum and did not significantly differ on weekdays or weekends for mothers. Weekend sleep was more fragmented for fathers at both one month and three months with more awakenings, compared to weekday sleep. Mothers had more fragmented night sleep compared to fathers at one month. In contrast, at three months postpartum fathers had shorter total sleep time and night sleep time, but fewer night awakenings on weekdays than mothers. No differences were observed in weekend sleep duration or sleep patterns between mothers and fathers at three months. Discussion: Consolidated sleep periods for both parents averages three hours or less during the first three months postpartum and sleep for both parents is fragmented. In families with newborn twins, the extent of sleep disruption for mothers and fathers is similar.

Research question What are the trends in patient characteristics, effectiveness and safety of assisted reproductive technology (ART) performed in Latin America over the past three decades, as well as the detailed outcomes of procedures initiated in 2018? Design Retrospective collection of multinational data including epidemiology and outcomes of ART performed between 1990 and 2018. Results Over these 30 years we report 955,117 initiated cycles, 191,191 deliveries and 238,045 live births. In 1990, 66.5% of women were ≤34 years and 8.7% ≥40 years; in 2018, 26.4% of women were ≤34 years and 32.0% were ≥40 years. In 1990, 60.4% of transfers included ≥3 embryos, falling to 13.5% in 2018, and single embryo transfer (SET) increased from 13.8% to 30.4% between 1990 and 2018. Delivery rate per fresh transfer increased from approximately 17% in the 1990s to 25% in 2018, with a meaningful drop in high-order multiples, from 5–9% in the 1990s to 0.4% in 2018. This drop is associated with increasing use of frozen embryo transfer (FET) (57% in 2018) compared with 10% in 2000. In 2018, delivery rate in FET was 28.3%, reaching 31.2% in freeze-all cycles; and the cumulative live birth rate (fresh + FET) was 41.9%. Elective SET also increased, from 0.9% in 2010 to 10% in 2018. The delivery rate in elective SET (31.7%) was only 5.4% lower than elective double embryo transfer (DET) (37.1%); however, multiple births increased from 2.1% to 25.5% twins and 0.4% triplets in elective DET. Conclusion The Latin American Registry of Assisted Reproduction (RLA) celebrates 30 years of voluntary reporting from a total of nearly 200 centres in 15 countries. This South–South Cooperation network has proven to be an efficient and safe system for technological transfer and regional growth.

Objective The aim of this study is to compare neonatal mortality and morbidity in multiple and singleton preterm/very low birthweight (PT/VLBW) multiethnic Asian infants. Study Design Cohort study of 676 singleton and 299 multiple PT/VLBW infants born between 2008 and 2012 at KK Women's and Children's Hospital, the largest tertiary perinatal center in Singapore with further stratification by gestational ages 23 to 25 (Group 1), 26 to 28 (Group 2), and ≥29 (Group 3) weeks. Outcome measures included predischarge mortality and major neonatal morbidity. Results Overall survival to discharge was comparable for singletons 611/676 (90%) and multiples 273/299 (91%). Use of assisted reproductive technologies (47 vs. 4%), antenatal steroids (80 vs. 68%), and delivery by cesarean section (84 vs. 62%) were significantly higher (p Conclusion Neonatal mortality and morbidity were comparable in our cohort of PT/VLBW singletons and multiple births, but preterm multiple births ≤25 weeks had a higher incidence of neonatal morbidity. Key Points

Background and Objective: Although rates of breastfeeding initiation for multiples may be similar to those of singletons, breastfeeding duration falls short. Evidence-based interventions tailored t...

OBJECTIVE To explore the current practice and perceptions of health visitors in supporting multiple birth families. DESIGN AND SAMPLE Practicing health visitors across the United Kingdom were invited to complete a cross-sectional, descriptive, online survey. The questionnaire covered multiple birth caseload, education received about multiples and the experience of working with families. Two-hundred and ninety health visitors completed the questionnaire. Descriptive and inferential statistics were used for analysis of the quantitative components and thematic analysis for the qualitative data. RESULTS Most health visitors had twins on their current workload. Most health visitors had not received any specific training or continuing professional development regarding the needs of multiple birth families. Supporting the families within the confines of reduced time and increased workload was challenging. Daily tasks of caring for multiples were the main areas that health visitors and parents wanted more information about. CONCLUSIONS In the United Kingdom, health visitors are uniquely positioned to support multiple birth families, in particular during the more challenging early years. However, the findings of this study suggest that many health visitors are aware that the care and support that they are able to provide multiple birth families falls short of meeting their needs.

Background Whether infertility treatment predicts severe maternal morbidity in both singleton and twin pregnancies is controversial. We conducted this nationwide population-based cohort study to compare pregnancies conceived through assisted reproductive technology treatments, such as intrauterine insemination or in vitro fertilization, with unassisted pregnancies. Methods This study included 269,930 women who experienced childbirth in 2018, using data of the National Health Insurance Service National Delivery Cohort in Korea. The primary outcome was assessed using a severe maternal morbidity algorithm developed by the Centers for Disease Control and Prevention in the United States. A modified Poisson regression was used to estimate the adjusted risk ratio of severe maternal morbidity. Results Severe maternal morbidity occurred in 6,333 (2.3%) of 280,612 deliveries investigated. The risk of severe maternal morbidity was approximately 1.5-fold higher among women who received in vitro fertilization (risk ratio: 1.51, 95% confidence interval: 1.36–1.68) than among fertile women. However, no significant association between intrauterine insemination and maternal morbidity was identified. Via subgroup analysis, in vitro fertilization increased the risk of severe maternal morbidity by 1.6- and 1.3-fold in singleton and multiple births, respectively (singleton: risk ratio: 1.62, 95% confidence interval: 1.43–1.83; multiple birth: risk ratio: 1.31, 95% confidence interval: 1.07–1.60). Conclusions This study suggested that in vitro fertilization was associated with the risk of severe maternal morbidity in both singleton and multiple births. Further research should identify patient- and treatment-specific factors that may mitigate or prevent adverse maternal health risks.

OBJECTIVE The proportion of multiple births has risen rapidly worldwide. Multiple births are likely to affect birth weight, which results in low birth weight (LBW) of less than 2500 g, possibly, because multiples are more likely to be born prematurely or less than 37 weeks into pregnancy. Using data from South Korea, this study aims to estimate the contribution of the rise in multiples to the rise in LBW incidence. METHODS Based on data from 2000 to 2017, we estimated the effect of multiples on LBW rates using linear regression analysis. Based on the regression analysis and the change in the proportion of multiples during this period, we calculated the contribution of the rise in multiples to the rise in LBW incidence using the total differential. In other words, we divided the change in LBW during the period due to the change in multiples by the total change during the period. The data are from the birth registry of the National Statistical Office, which contains information on the 8.4 million live births during the period 2000-2017. RESULTS We found that a 1 percentage point increase in multiples increases the proportion of LBWs by 0.495 percentage points. In addition, because the changes in the proportion of multiples and LBWs from 2000 to 2017 are 2.2 and 2.4 percentage points, respectively, 1.1 percentage points or 45.8% of the increase in LBWs over the period is due to the increase in multiples. CONCLUSION Since the Korean government introduced a measure to reduce the number of transferred embryos recently, one may expect that multiples in Korea would reduce in the near future, as it did in other countries. Subsequently, the incidence of LBW children is also likely to reduce, which is desirable in terms of the children's health outcomes.

Study question What are the factors that could predict the number of embryos to be transferred in order to diminish risk of multiple pregnancies? Summary answer Single embryo transfer (SET) is advisable for What is known already Multiple pregnancies are associated to increased maternal and perinatal complications. Risks associated to multiple implantations are significantly reduced with SET policy. However, while SET is more assertive with a lesser negative impact in younger patients ( Study design, size, duration A retrospective study from the national French data registry provided and approved by the Agence de la Biomédecine was performed. A total of 196530 fresh and 68913 frozen cycles from women aged 18–43 year-old were included (2014–2017). Risk factors assessed included women’s age, number of attempts, number of oocytes, fertilization rate, embryo stage, number of embryos transferred, number of supernumerary embryos frozen. Secondary infertility, oocyte donor, oocyte freezing, PGT, freeze-all and IVM cycles were excluded. Participants/materials, setting, methods Cumulative cycles derived from 65% of ICSI, 32% of IVF and 3,2% IVF/ICSI. The distribution of patients age at oocyte retrieval was 60% < 35, 21% < 38, 11% < 40, and 8% ≥ 40 years old. Multivariable logistic regression was conducted to calculate adjusted odds ratios with 95% confidence intervals for live birth chance and multiple live birth risk associated with each risk factor. Main results and the role of chance The chances of obtaining a cumulative live birth decreases with increased patients age (OR 0.71 for 35–38 years and 0.47 for 38–40 years, p 18, p 40% (OR 1.29, p 1, OR 13.08 for >2, and OR 16.92 for >6, p 2 embryos, p In case of live birth, the risks of multiple births when two embryos were transferred decreases in patients aged >38 years (OR 0.50, p 60% (OR 1.30, p 1.30, p Limitations, reasons for caution This study is limited in only providing a risk-benefit balance for multiples on the choice of transferring one or two embryos. Clinical data such as stimulation protocols and doses of gonadotropins were not considered in this evaluation. Wider implications of the findings: This study provides help to develop a strategy for the medical staff in the decision making for the number of embryos to be transferred. It may also serve as a patient’s information aid and help to improve their chances of achieving a health singleton if pregnant. Trial registration number Not applicable

Aim:To describe the birth prevalence, temporal trends, and clinical outcomes of twins, triplets, or quadruplets with cerebral palsy (CP).Method:This was a cross-sectional study using data for twins, triplets, and quadruplets with prenatally or perinatally acquired CP and pooled from the Surveillance of Cerebral Palsy in Europe network (born 1992–2009) and Australian Cerebral Palsy Register (born 1993–2009). Children were at least 4 years old at time of registration. Children born in regions with population ascertainment and available denominator data were included in prevalence calculations (n=1033 twins, 81 triplets, and 11 quadruplets). Clinical data from children registered in all participating registers were described, including 2163 twins (56% male), 187 triplets (59% male), and 20 quadruplets (45% male).Results:The birth prevalence of CP was higher with increasing plurality (twins 6.5 per 1000 live births [95% confidence interval {CI} 6.1–6.9], triplets 17.1 [95% CI 13.6–21.2], quadruplets 50.7 [95% CI 25.6–88.9]); however, prevalence by gestational age was similar across all pluralities. Between 1992–1994 and 2007–2009, prevalence of CP among twins declined (p=0.001) but prevalence of CP among triplets did not change significantly over time (p=0.55). The distributions of Gross Motor Function Classification System, epilepsy, and impairments of intellect, vision, and hearing were similar regardless of plurality.Interpretation:The data combined from two CP register networks indicated that triplets and quadruplets had increased risk of CP compared to twins. The higher prevalence of CP in triplets and quadruplets is due to their higher risk of preterm birth. Prevalence of CP among twins significantly declined in Europe and Australia. Clinical outcomes were similar for all multiple births.

BACKGROUND There are limited data available on the survival and early complications of preterm infants with less than 500 g birthweight. To estimate the outcomes for these infants, it is important for caregivers to be aware of perinatal factors that may affect survival. OBJECTIVES We assessed the mortality and certain early complications of preterm infants born with less than 500 g in Hungary between 2006 and 2015. METHODS We reviewed data of 486 infants from the database of the Hungarian Central Statistical Office and in parallel of 407 infants from the "NICU database." The study period was divided into two epochs: 2006-2010 and 2011-2015. RESULTS The survival was 27.1% in the first epoch and 39.1% in the second epoch, and the incidence of early complications was slightly higher in the second epoch. In the surviving group (first and second epoch combined), gestational age (25.1 vs 23.7 weeks), birthweight (458 vs 447 g) antenatal steroid treatment (66.3% vs 52.3%), surfactant therapy (95.1% vs 84.3%), median Apgar scores (6 vs 3 and 8 vs 5 at 1 and 5 minutes, respectively) and proportion of caesarean delivery (89.3% versus 68.5%) were higher than in the non-surviving group (first and second epoch combined). The proportion of multiple births was lower in the surviving group (15.7% vs 33.4%). CONCLUSIONS Survival of infants with less than 500 g improved between 2006-2010 and 2011-2015 in Hungary. The slightly higher occurrence of early complications might be associated with improving survival.

Background We aimed to compare cardiometabolic indicators in singletons and multiples at age 7 and explore the birthweight mediation effect. Methods We studied 5431 singletons and 103 sets of multiples from Generation XXI birth cohort. Anthropometric measurements, body composition, and fasting blood samples were obtained. Age- and sex-specific z-scores were calculated (additionally height-specific for blood pressure). Adjusted regression coefficients and respective 95% confidence intervals [β (95%CI)] were computed using path analysis. Results Multiples had lower weight [− 0.419 (− 0.616;-0.223)], height [− 0.404 (− 0.594;-0.213)], BMI [− 0.470 (− 0.705;-0.234)], fat mass index [− 0.359 (− 0.565;-0.152)], waist circumference [− 0.342 (− 0.537;-0.147)], and waist-to-height ratio [− 0.165 (− 0.326;-0.003)] z-scores. These results were explained by the indirect effect via birthweight, which was also negative and significant for all the aforementioned cardiometabolic indicators, while no direct effect was present. There were also significant indirect effects regarding fat-free mass index, glucose, insulin, and blood pressure, though the total effects were not significant, due to the balance between direct and indirect effects. The only significant direct effect was regarding diastolic blood pressure [− 0.165 (− 0.302;-0.028)]. Conclusions At age 7, multiples presented better cardiometabolic indicators explained by lower weight at birth, except for the lower blood pressure which was independent of an effect via birthweight.

Exclusive breastfeeding is currently recommended until at least 6 months of postnatal age, due to maternal breast milk (BM) unique composition and beneficial properties. In fact, BM modifies itself according to gestational age (GA) at birth, adapting its composition to neonatal requests during lactation. Multiple births represent about 3% of the whole pregnancies; such neonates result more vulnerable than full-term newborns, due to lower GA and birth weight (BW) and the higher incidence of perinatal complications. Although an adequate nutrition is fundamental for twins and other multiples, studies on this topic are lacking. We collected and analyzed BM from mothers of 19 twins and 5 triplets showing GA < 33 weeks and BW < 1500 g, comparing it to a control group of 28 preterm singletons. As a result, at GA ≤ 28 weeks, we observed that protein content is higher in BM for multiples (1.53 vs. 1.29 g per 100 ml), lactose concentration is greater in BM for singletons (6.72 vs. 6.34 g per 100 ml) and GA results the most relevant factor influencing BM protein composition. BM for multiples results higher in proteins and lower in lactose, if compared with singleton’s samples; this could promote and sustain growth and organ development in this vulnerable category. BM from multiples shows a trophic and immunologic role, since these neonates often show lower GA and BW instead of singletons. These findings could help in optimizing nutritional strategies and improving BM individualized fortification.

Objective Limitations on the number of embryos transferred have been recommended worldwide to reduce the number of medically assisted multiple births. Our aim was to evaluate the impact of this recommendation for embryo transfer limitation on perinatal outcomes of multiple births. Study design A retrospective and population-based study compared all multiple births in Shiga prefecture of Japan in 2014–2015 (2015 group) with those in 2007–2008 (2008 group). The perinatal background and neonatal outcomes of multiple births were compared. Results The number of multiple pregnancies in the 2015 group (n = 251) was almost the same as in the 2008 group (n = 245). The proportion of multiple pregnancies conceived through assisted reproductive technology significantly decreased to 23% in the 2015 group compared to 31% in the 2008 group. In contrast, the rate of ovulation induction significantly increased to 24% in the 2015 group from 15% in the 2008 group. There was no significant difference in the outcome of multiple-birth infants between the two groups. Conclusion The method of conception in multiple pregnancies markedly shifted from in vitro fertilization to non-in vitro fertilization after the issuance of a recommendation for limits on embryo transfer. It should be necessary for the assessment of the impact of this recommendation to monitor closely multiple pregnancies via non-in vitro fertilization as well as via in vitro fertilization.

Background Brazil experienced important progress in maternal and child health in recent decades. We aimed at describing secular trends as well as socioeconomic and ethnic inequalities in reproductive history indicators (birth spacing, previous adverse perinatal outcome, parity and multiple births) over a 33-year span. Methods Four population-based birth cohort studies included all hospital births in 1982, 1993, 2004 and 2015 in Pelotas, Southern Brazil. Information on reproductive history was collected through interviews. Indicators were stratified by family income quintiles and skin colour. Absolute and relative measures of inequality were calculated. Results From 1982 to 2015, the proportion of primiparae increased from 39.2% to 49.6%, and median birth interval increased by 23.2 months. Poor women were more likely to report short intervals and higher parity, although reductions were observed in all income and ethnic groups. History of previous low birthweight was inversely related to income and increased by 7.7% points (pp) over time—more rapidly in the richest (12.1 pp) than in the poorest quintile (0.4 pp). Multiple births increased from 1.7% to 2.7%, with the highest increase observed among the richest quintile and for white women (220% and 70% increase, respectively). Absolute and relative income and ethnic-related inequalities for short birth intervals increased, whereas inequalities for previous low birthweight decreased over time. Conclusions In this 33-year period there were increases in birth intervals, multiple births and reports of previous low-birthweight infants. These trends may be explained by increased family planning coverage, assisted reproduction and a rise in preterm births, respectively. Our results show that socioeconomic and ethnic inequalities in health are dynamic and vary over time, within the same location.

The objective of this study was to review the results of umbilical cord drug screening in twins and triplets (multiples) to compare the detected drug(s) and/or drug metabolite(s). Results that did not agree between multiples were considered mismatched and investigated. A retrospective analysis was conducted using de-identified data from a national reference laboratory, and results were compared with data from an academic medical center, where detailed medical chart review was performed. Umbilical cord was analyzed for stimulants, sedatives, opioids and other drugs and metabolites. For the reference laboratory dataset, 23.3% (n = 844) of 3,616 umbilical cords from twins (n = 3,550) or triplets (n = 66) were positive for one or more drugs and/or metabolites. Of these, mismatched results were identified for 37 sets of twins (2.1%) and no sets of triplets. The most frequent mismatches were found in opioids (n = 24), with morphine (n = 5) being the most mismatched of any single analyte in the panel. Mismatches for the marijuana metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (9-COOH-THC) in the reference laboratory dataset occurred in 6 of 737 sets of twins (0.8%) and no triplets. For the academic medical center dataset, 21.9% (n = 57) of 260 umbilical cords tested positive for one or more drugs and/or metabolite(s). Of these, four mismatches (3.2%) were identified, including 9-COOH-THC (n = 2), phentermine (n = 1) and oxycodone (n = 1), all involving twins. All involved cases where the discrepant analyte was likely present in the negative twin but either slightly below the reporting cutoff threshold or failed analytical quality criteria. Mismatched results of umbilical cord drug screening occur in less than 4% of twins and most often occur when the analyte is slightly above the reporting cutoff in just one infant.

Objectives-This report presents 2019 data on U.S. births according to a wide variety of characteristics. Trends in fertility patterns and maternal and infant characteristics are described and interpreted. Methods-Descriptive tabulations of data reported on the birth certificates of the 3.75 million births that occurred in 2019 are presented. Data are presented for maternal age, livebirth order, race and Hispanic origin, marital status, tobacco use, prenatal care, source of payment for the delivery, method of delivery, gestational age, birthweight, and plurality. Selected data by mother's state of residence and birth rates by age are also shown. Trend data for 2010 through 2019 are presented for selected items. Trend data by race and Hispanic origin are shown for 2016-2019. Results-A total of 3,747,540 births were registered in the United States in 2019, down 1% from 2018. The general fertility rate declined from 2018 to 58.3 births per 1,000 women aged 15-44 in 2019. The birth rate for females aged 15-19 fell 4% between 2018 and 2019. Birth rates declined for women aged 20-34 and increased for women aged 35-44 for 2018-2019. The total fertility rate declined to 1,706.0 births per 1,000 women in 2019. Birth rates declined for both married and unmarried women from 2018 to 2019. The percentage of women who began prenatal care in the first trimester of pregnancy rose to 77.6% in 2019; the percentage of all women who smoked during pregnancy declined to 6.0%. The cesarean delivery rate decreased to 31.7% in 2019 (Figure 1). Medicaid was the source of payment for 42.1% of all births in 2019. The preterm birth rate rose for the fifth straight year to 10.23% in 2019; the rate of low birthweight was essentially unchanged from 2018 at 8.31%. Twin and triplet and higher-order multiple birth rates both declined in 2019 compared with 2018.

Purpose Initial genetic alterations in the development of childhood leukemia occur in utero or before conception; both genetic and environmental factors are suspected to play a role. We aimed to investigate the associations between childhood leukemia and perinatal characteristics including birth order, birth interval to older siblings, parental age, birth weight, and multiple birth. Methods We identified cases diagnosed between 1981 and 2015 and born in Switzerland between 1969 and 2015 from the Swiss Childhood Cancer Registry and randomly sampled five controls per case from national birth records matched on date of birth, sex, and municipality of residence at birth. We used conditional logistic regression to investigate associations between perinatal characteristics and leukemia at ages 0–15 and 0–4 years, and the subtypes acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Results The study included 1,403 cases of leukemia. We observed increased risks associated with high birth weight (adjusted OR 1.37, 95% CI 1.12–1.69) and multiple birth (1.89, 1.24–2.86). These associations were similar for ALL and stronger for leukemia at ages 0–4 years. For AML, we observed an increased risk for higher birth order (3.08, 0.43–22.03 for fourth or later born children). We found no associations with other perinatal characteristics. Conclusion This register-based case–control study adds to the existing evidence of a positive association between high birth weight and risk of childhood leukemia. Furthermore, it suggests children from multiple births are at an increased risk of leukemia.

In the early years of in vitro fertilization, overall pregnancy rates were low, and it was considered necessary to transfer more than one embryo to increase the chances of pregnancy. It was not until advances in assisted reproductive technologies resulting in increased pregnancy rates that the concept of transferring just one embryo was considered possible. A consequence of improvements in implantation rates was also an increase in multiple pregnancies when more than one embryo was transferred. Although some countries have reduced the number of embryos transferred, international data show that in many parts of the world high twin and higher order multiple pregnancy rates still exist. Even in developed countries these problems persist depending on clinical practice, funding of health services, and patient demands. Perinatal and other outcomes are significantly worse with twins compared with singleton pregnancies and there is an urgent need to reduce multiple pregnancy rates to at least 10%. This has been achieved in several countries and clinics by introducing single embryo transfer but there are many barriers to the introduction of this technique in most clinics worldwide. We discuss the background to the high multiple rate in assisted reproduction and the factors that contribute to its persistence even in excellent clinics and in high-quality health services. Practices that may promote single embryo transfer are discussed.

Multiple births (twins or higher order multiples) are increasing in developed countries and may present higher risk for cerebral palsy (CP). However, few studies can reliably investigate trends over time because these outcomes are relatively rare.ObjectiveWe pooled data from European CP registers to investigate CP birth prevalence and its trends among single and multiple births born between 1990 and 2008.DesignPopulation cohort study.Setting12 population-based registers from the Surveillance of Cerebral Palsy in Europe collaboration.Participants4 446 125 single and multiple live births, of whom 8416 (0.19%) had CP of prenatal or perinatal origin.Main outcomesCP diagnosis ascertained in childhood using harmonised methods; CP subtype; Motor impairment severity among CP cases.ResultsThe rate of multiple births increased from 1990. Multiples displayed higher risk for CP (RR=4.27, 95% CI 4.00 to 4.57). For singletons and multiples alike, risk for CP was higher among births of lower gestational age (GA) or birth weight (BW). However, CP birth prevalence declined significantly among very preterm (ConclusionsBetween 1990 and 2008, CP birth prevalence decreased steadily among multiples with low GA or BW. Furthermore, multiples with CP display similar profiles of severe motor impairment compared with CP singletons. Improvements in management of preterm birth since the 1990s may also have been responsible for providing better prospects for multiples.

Objectives-This report presents 2018 data on U.S. births according to a wide variety of characteristics. Trends in fertility patterns and maternal and infant characteristics are described and interpreted. Methods-Descriptive tabulations of data reported on the birth certificates of the 3.79 million births that occurred in 2018 are presented. Data are presented for maternal age, live-birth order, race and Hispanic origin, marital status, tobacco use, prenatal care, source of payment for the delivery, method of delivery, gestational age, birthweight, and plurality. Selected data by mother's state of residence and birth rates by age also are shown. Trend data for 2010 through 2018 are presented for selected items. Trend data by race and Hispanic origin are shown for 2016-2018. Results-3,791,712 births were registered in the United States in 2018, down 2% from 2017. Compared with rates in 2017, the general fertility rate declined to 59.1 births per 1,000 women aged 15-44. The birth rate for females aged 15-19 fell 7% in 2018. Birth rates declined for women aged 20-34 and increased for women aged 35-44. The total fertility rate declined to 1,729.5 births per 1,000 women in 2018. Birth rates for both married and unmarried women declined from 2017 to 2018. The percentage of women who began prenatal care in the first trimester of pregnancy rose to 77.5% in 2018; the percentage of all women who smoked during pregnancy declined to 6.5%. The cesarean delivery rate decreased to 31.9% in 2018 following an increase in 2017. Medicaid was the source of payment for 42.3% of all 2018 births, down 2% from 2017. The preterm birth rate rose for the fourth straight year to 10.02% in 2018; the rate of low birthweight was unchanged at 8.28%. Twin and triplet and higher-order multiple birth rates declined in 2018 (Figure 1).

There is a global recognition of the need to reduce multiple pregnancies following assisted reproductive technology. Complications of multiple pregnancies can be simply avoided by replacing one embryo at a time. Most policies to reduce the number of double or higher order embryo transfers involve predicting which patients are at most risk by using a multiple birth minimisation strategy. These frequently consider factors such as patient age, previous treatments and embryo quality. However, with improvements in methods of embryo culture, embryo selection and cryopreservation, this chapter will question whether, at present, it is time to move to single embryo transfer (SET) for all.

Background Hepcidin is a systemic regulator of iron homeostasis. Little is known about the relative role of maternal compared with cord hepcidin on neonatal iron homeostasis. Objective This study was undertaken to evaluate inter- and intrauterine variance in neonatal iron status, vitamin B-12, folate, and inflammatory markers in a cohort of twins (n = 50), triplets (n = 14), and quadruplets (n = 1) born to 65 women. Methods Umbilical cord blood was obtained from 144 neonates born at 34.8 ± 2.7 wk of gestation with a mean birth weight of 2236 ± 551 g (means ± SDs). Cord hemoglobin and cord serum measures of ferritin (SF), soluble transferrin receptor (sTfR), hepcidin, erythropoietin (EPO), iron, vitamin B-12, folate, interleukin 6, and C-reactive protein were evaluated. Results Intraclass correlation coefficient (ICC) analyses were used to examine inter- and intrauterine variance in neonatal iron indicators. A greater variability in cord hepcidin (ICC = 0.39) was found between siblings. Cord hepcidin had the greatest association with cord iron indicators because cord hepcidin alone captured 63.8%, 48.4%, 44.4%, and 31.3% of the intrauterine variance in cord hemoglobin, SF, sTfR, and EPO, respectively, whereas maternal hepcidin had no effect on cord iron indicators. Significantly greater differences in cord SF (P = 0.03), sTfR (P = 0.03), hepcidin (P = 0.0003), and EPO (P = 0.03) were found between di- and trichorionic siblings than between monochorionic siblings. In contrast, cord folate (ICC = 0.79) and vitamin B-12 (ICC = 0.74) exhibited a greater variability between unrelated neonates. Conclusions In summary, fetally derived hepcidin might have more control on intrauterine variance in iron indicators than maternal hepcidin and appears to be capable of regulating fetal iron status independently of maternal hepcidin. The use of a multiple-birth model provides a unique way to identify factors that may contribute to placental nutrient transport and iron stores at birth.

To establish the annual and cumulative multiyear contribution of delayed childbearing to the national plural birth excess.Using publicly available national birth data reported by the National Center for Health Statistics, we estimated the contribution of delayed childbearing to the national plural birth excess through 2016. To this end, the observed as well as the maternal age- and race-adjusted national plural birth rates were assessed before (1949-1966; n=71,570,717) and during (1971-2016; n=166,817,655) the assisted reproduction era. Comparable estimates through 2025 relied on simulated projections.The relative risk estimates of unassisted plural births by maternal age before the assisted reproduction era (1949-1966) proved unimodal and race-dependent. The risk of unassisted plural births in 35- to 39-year-old black women proved 2.75-fold higher than that of 15- to 19-year-old counterparts (39.81/1,000 to 14.48/1,000; 95% CI 2.67-2.83). A 2.47-fold risk increment was noted for comparably aged white women (28.76/1,000 to 11.63/1,000; 95% CI 2.43-2.52). Similar age-dependent risk increments were obtained for twin and higher order births. An increasingly prominent delayed childbearing trend during the assisted reproduction era (1971-2016) gave rise to 255,964 (95% CI 134,746-375,581) and 66,271 (95% CI 34,099-96,197) unassisted plural births by white and black women, respectively. In 2016 alone, delayed childbearing accounted for 24% (95% CI 15-32%) and 38% (95% CI 28-47%) of the national plural birth excess for white and black women, respectively. By 2025, delayed childbearing could account for as much as 46% (95% CI 32-60%) and 40% (95% CI 30-53%) of the national plural birth excess for white and black women, respectively.Delayed childbearing, a growing contributor to the national plural birth excess previously solely ascribed to assisted reproduction, warrants greater consideration in future clinical, analytic, and policy deliberations as well as in individual family planning decisions.

The East Flanders Prospective Twin Survey (EFPTS) is a registry of multiple births in the province of East Flanders, Belgium. Since its start in 1964, over 10,000 twin-pairs have been registered. EFPTS has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are recruited at birth; basic perinatal data are recorded; chorion type and zygosity are established; since 1969, placental biopsies have been taken and frozen at -20°C for future research. Since its origin, the EFPTS has included placental data and allows differentiation of three subtypes of monozygotic twins based on the time of the initial zygotic division: the dichorionic-diamniotic pairs (early, with splitting before the fourth day after fertilization), the monochorionic-diamniotic pairs (intermediate, splitting between the fourth- and the seventh-day postfertilization) and the monochorionic-monoamniotic pairs (late, splitting after the eighth day postfertilization). Studies can be initiated taking into account primary biases, those originating 'in utero'. Such studies could throw new light on the consequences of early embryological events and the gene-environment interactions as far as periconceptional and intrauterine environment are concerned. ispartof: TWIN RESEARCH AND HUMAN GENETICS vol:22 issue:6 pages:454-459 ispartof: location:England status: published

Objective Pulmonary hemorrhage (PH) is a severe complication in preterm neonates. This study aims to identify risk factors and comorbidities of PH. Study Design A single-center cohort study on medical records including all preterm neonates of Results In this study, 344 preterm neonates were included, of whom 36 suffered from PH (10.5%). The mean time of the first occurrence was the third day of life (standard deviation [SD]: 1.2). On average, the patients suffered from 1.5 incidents (SD: 0.8) of PH, of whom 50% were severe. Preterm neonates born as multiples (95% confidence interval [CI]: 3.1, 26.9) and those who suffered from IVH (95% CI: 2.7, 18.9) had a significantly increased risk of PH. ICSI was not an independent risk factor. Conclusion PH is significantly associated with IVH and multiple births but not with ICSI. The identification of patients at risk allows to apply prophylactic strategies of ventilation and pharmacological treatment.

Background/aim: This study aimed to compare the incidence of any stage of retinopathy of prematurity (ROP) and type 1 ROP between extremely preterm multiple- and single-birth infants. Materials and methods: In this retrospective study, we included extremely preterm infants who were ≤27 weeks of gestational age at birth. The screened infants were divided into two groups: single and multiple births. The incidence of any stage of ROP and type 1 ROP was compared between the groups. Results: This study included 301 infants; 225 were in the single-birth group and 76 were in multiple-birth group. The incidences of any stage of ROP and type 1 ROP among all infants were 70.7% (213 of 301) and 16.6% (50 of 301), respectively. Regression analysis showed that lower birth weight (OR = 0.99, P = 0.004) and longer length of stay in hospital (OR = 1.02, P = 0.002) were significantly correlated with any stage of ROP. Compared to single-birth infants, the risk of any stage of ROP and type 1 ROP did not statistically increase for multiple-birth infants (P > 0.05). Conclusion: This study showed that multiple birth had no significant correlation with ROP development in extremely preterm infants.

In our recent paper1 we provided estimates of length of stay for very preterm (24–31 weeks gestational age) singleton babies admitted for neonatal care in units within England. As with much neonatal research, we chose to exclude multiples (twins, triplets and higher order; in this letter referred to as ‘multiples’) from this initial work. However, as around 1 in 10 twins are born before 32 weeks, compared with around 1 in 100 singleton births,2 it is important to be able to also estimate the length of stay for these babies to aid the planning of healthcare resources and facilitate the counselling of their parents. We were interested in whether the estimates of length of stay from the singleton population could be applied to multiples without the need to calculate new estimates. Data related to multiples admitted to neonatal units in England equivalent to the singletons was extracted from the National Neonatal Research Database. A total of 7496 babies met the inclusion criteria as described elsewhere1: 6755 twins and 741 triplets or higher order. We calculated the observed median (25th, 75th centiles) length of stay for multiples by week of gestational age at birth and compared it with that estimated previously for singletons (table 1). Across all gestational ages, the median length of stay for multiples was very similar to their singleton …

BACKGROUND Congenital cytomegalovirus (cCMV) infection is an important cause of hearing loss and neurodevelopment delay. While data on vertical transmission and neonatal outcome after singleton pregnancy with cCMV are well established, only scarce reports have addressed cCMV in multiple birth pregnancies. Furthermore, no studies have yet compared the outcome after birth and long-term follow-up of children with cCMV born after a singleton versus multiple pregnancies. METHODS Infant outcome after birth of symptomatic versus asymptomatic infection was compared for infants born with cCMV after multiple (study group) and singleton (control group) pregnancies in a 1:2 ratio. RESULTS Of 508 infants diagnosed with cCMV, 25 (4.9%) were born after a multiple pregnancy. Children in the study and control groups did not differ in terms of specific prenatal CMV investigations including amniocentesis and brain magnetic resonance imaging studies. However, prematurity rates were significantly higher in the study compared with control group (52% vs. 4%, P < 0.001). There was a higher rate of symptomatic cCMV infection in the study group than in the controls (48% vs. 14%, P < 0.001). Hearing impairment at birth was also more frequent in the study group (32% vs. 8%, P = 0.016). A long-term follow-up demonstrated that children in the study group had higher rates of neurologic sequelae (hearing impairment or neurodevelopmental delay) compared with children in the control group (20% vs. 4%, P = 0.016). CONCLUSIONS Infants with cCMV born after multiple birth pregnancies are born earlier and have a higher risk of symptomatic disease at birth and worse long-term neurologic outcome than those born after a singleton pregnancy. This important group of children warrants meticulous prenatal and postnatal care.