Ovulation induction and subfertile untreated conception groups offer improved options for interpreting risks associated with ART.

PURPOSE: To identify and characterise appropriate comparison groups for population studies of health outcomes in ART-conceived births: ovulation induction (OI), subfertile untreated and fertile natural conceptions. Our secondary objective was to examine whether known risks of pregnancy complications and adverse birth outcomes in ART births are elevated in comparison with subfertile (untreated and OI) conception groups. METHODS: We linked State and Commonwealth datasets to identify all live and stillbirths (≥ 20 weeks) in Western Australia from 2003 to 2014 by method of conception. Demographic characteristics, maternal pre-existing conditions, adverse obstetric history and pregnancy complications were compared across conception groups. Generalised estimating equations were used to estimate adjusted risk ratios (aRRs) and 95% confidence intervals (CI) for pregnancy complications and birth outcomes in singletons. RESULTS: We identified 9456 ART, 3870 OI, 11,484 subfertile untreated and 303,921 fertile naturally conceived deliveries. OI and subfertile untreated groups more closely resembled the ART group than the fertile group; however, some differences remained across parity, maternal age, pre-existing conditions and obstetric history. In multivariate analyses, ART singletons had greater risks of placental problems (e.g. placenta praevia aRR 2.42 (95% CI 1.82-3.20)) and adverse birth outcomes (e.g. preterm birth aRR 1.38 (95% CI 1.25-1.52)) than the subfertile untreated group, while OI singletons were more similar to the subfertile group with higher risk of preeclampsia and gestational diabetes. CONCLUSION: OI and subfertile untreated conception groups offer improved options for interpreting health outcomes in ART births. Pregnancy complications (particularly placental disorders) and adverse outcomes at delivery are more common following ART.

Surfacing undiagnosed disease: consideration, counting and coding.

The diagnostic odyssey for people living with rare diseases (PLWRD) is often prolonged for myriad reasons including an initial failure to consider rare disease and challenges to systemically and systematically identifying and tracking undiagnosed diseases across the diagnostic journey. This often results in isolation, uncertainty, a delay to targeted treatments and increase in risk of complications with significant consequences for patient and family wellbeing. This article aims to highlight key time points to consider a rare disease diagnosis along with elements to consider in the potential operational classification for undiagnosed rare diseases during the diagnostic odyssey. We discuss the need to create a coding framework that traverses all stages of the diagnostic odyssey for PLWRD along with the potential benefits this will have to PLWRD and the wider community.

Severe Congenital Heart Defects and Cerebral Palsy.

OBJECTIVE: To report the prevalence of cerebral palsy (CP) in children with severe congenital heart defects (sCHD) and the outcome/severity of the CP. METHODS: Population-based, data linkage study between CP and congenital anomaly registers in Europe and Australia. The EUROCAT definition of severe CHD (sCHD) was used. Linked data from 4 regions in Europe and 2 in Australia were included. All children born in the regions from 1991 through 2009 diagnosed with CP and/or sCHD were included. Linkage was completed locally. Deidentified linked data were pooled for analyses. RESULTS: The study sample included 4989 children with CP and 3684 children with sCHD. The total number of livebirths in the population was 1 734 612. The prevalence of CP was 2.9 per 1000 births (95% CI, 2.8-3.0) and the prevalence of sCHD was 2.1 per 1000 births (95% CI, 2.1-2.2). Of children with sCHD, 1.5% (n = 57) had a diagnosis of CP, of which 35 (61%) children had prenatally or perinatally acquired CP (resulting from a brain injury at ≤28 days of life) and 22 (39%) children had a postneonatal cause (a brain injury between 28 days and 2 years). Children with CP and sCHD more often had unilateral spastic CP and more intellectual impairments than children with CP without congenital anomalies. CONCLUSIONS: In high-income countries, the proportion of children with CP is much higher in children with sCHD than in the background population. The severity of disease in children with CP and sCHD is milder compared with children with CP without congenital anomalies.

Trends in prenatal diagnosis of congenital anomalies in Western Australia between 1980 and 2020: A population-based study.

BACKGROUND: Advances in screening and diagnostics have changed the way in which we identify and diagnose congenital anomalies. OBJECTIVE: To examine changes in rates of prenatal diagnosis of congenital anomalies over time and by demographic characteristics. METHODS: We undertook a population-based retrospective cohort study of all children born in Western Australia between 1980 and 2020 and diagnosed with a congenital anomaly. Age at diagnosis (prenatal, neonatal, infancy, early childhood or childhood) prevalence (all-type and type-specific), and prevalence ratios (PR) were calculated. We fit joinpoint regression models to describe the average annual percentage change (APC) in prenatal diagnosis over time, and log-binomial regression models to estimate the association between prenatal diagnosis and demographic characteristics. RESULTS: Prenatal diagnosis prevalence between the first (1980-1989: 28.3 per 10,000 births) and last (2005-2014: 156.1 per 10,000 births) decades of the study increased 5.5-fold (95% confidence interval [CI] 5.0, 5.9). Substantial increases were observed for cardiovascular (PR 10.7, 95% CI 8.0, 14.6), urogenital (PR 10.5, 95% CI: 8.7, 12.6) and chromosomal anomalies (PR 7.0, 95% CI 5.9, 8.3). Prenatal diagnosis was positively associated with the birth year (adjusted risk ratio [RR] 1.04, 95% CI 1.03, 1.04), advanced maternal age (RR 1.14, 95% CI 1.11, 1.18), multiple anomalies (RR 2.86, 95% CI 2.77, 2.96) and major anomalies (RR 3.75, 95% CI 3.36, 4.19), and inversely associated with remoteness (RR 0.89, 95% CI: 0.83, 0.95) and Aboriginality (RR 0.90, 95% CI 0.83, 0.97). CONCLUSIONS: Increases in prenatal diagnosis of congenital anomalies were observed in Western Australia from 1980 to 2020, reflecting advances in screening. Prenatal diagnosis was less common in remote regions and in Aboriginal children, strengthening calls for increased provision of antenatal care services for these populations.

Insights Gained into the Use of Individual Development Plans as a Framework for Mentoring NIH Postbaccalaureate Research Education Program (PREP) Trainees.

This study examines the use of individual development plans (IDPs) in a structured mentoring program as an effective mechanism for reducing identity-related anxiety for underrepresented trainees and increasing their learner agency. Social cognitive theory served to provide the theoretical framework for our implementation of IDPs and our investigation of the effects of completing IDPs on trainees attaining academic goals and subsequent success in enrolling in competitive PhD programs. Results suggest that IDPs are also an effective tool that can allow faculty mentors to provide the social support necessary for trainees to persist in accomplishing their short- and long-term learning goals. Additionally, trainee self-agency, in the use of the IDP and mentoring, seemed to provide an alternative narrative to ability as a sole predictor of STEM achievement. We also found that IDPs helped foster social support networks, providing stability, predictability, and a sense of belonging. Specifically, IDPs helped foster the emotional and informational support necessary for trainees to persist, despite obstacles, as they strived to attain their learning goals.

Microcephaly in Australian infants: A retrospective audit.

AIM: To describe clinical characteristics, outcomes and causes of microcephaly in children whose condition was identified within the first year of life. METHODS: Retrospective review of medical records of microcephalic children born between 2008 and 2018 and admitted for any reason during the same period to a tertiary paediatric hospital. Microcephaly was defined as occipitofrontal circumference (OFC) more than two standard deviations below the mean (>-2 SD). RESULTS: Between January 2008 and September 2018, 1083 medical records were retrieved. Of the children, 886 were ineligible and 197 were confirmed cases of microcephaly. Of cases, 73 (37%) had primary microcephaly (at birth) and 72 (37%) had severe microcephaly (OFC > -3 SD). Of microcephalic children, 192 (98%) had congenital anomalies, of whom 93% had major anomalies, mostly cardiovascular or musculoskeletal. Neurological signs or symptoms were reported in 148 (75%), seizures being the most common. Of the 139 children with abnormal central nervous system (CNS) imaging, one or more structural brain abnormalities were identified in 124 (89%). Failure to reach developmental milestones was observed in 69%, visual impairment in 41% and cerebral palsy in 13%. Microcephaly was idiopathic in 51% and 24% had diagnosed genetic disorders. There was no association between developmental outcomes or structural brain anomalies and severity of microcephaly or timing of diagnosis. CONCLUSION: Our results suggest the need for a systematic investigative approach to diagnosis, including a careful history, examination, genetic testing and neuroimaging, to determine the underlying cause of microcephaly, identify co-morbidities, predict prognosis and guide genetic counselling and therapy.

Late-in-life treadmill training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

Protein quality control mechanisms decline during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs. adult mice. As expected, 24-month-old male C57BL/6J mice (old) exhibited repressed autophagosome formation and protein aggregate accumulation in the heart, systolic and diastolic dysfunction, and reduced exercise capacity vs. 8-month-old (adult) mice (all p < 0.05). To investigate the influence of late-in-life exercise training, additional cohorts of 21-month-old mice did (old-ETR) or did not (old-SED) complete a 3-month progressive resistance treadmill running program. Body composition, exercise capacity, and soleus muscle citrate synthase activity improved in old-ETR vs. old-SED mice at 24 months (all p < 0.05). Importantly, protein expression of autophagy markers indicate trafficking of the autophagosome to the lysosome increased, protein aggregate clearance improved, and overall function was enhanced (all p < 0.05) in hearts from old-ETR vs. old-SED mice. These data provide the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and contractile performance in mouse hearts.

Birth prevalence of congenital heart defects in Western Australia, 1990-2016.

AIM: To describe the birth prevalence and characteristics of congenital heart defects in a geographically defined Australian population. METHODS: This descriptive, population-based study examined congenital heart defects in live births, stillbirths and pregnancy terminations ascertained by the Western Australian Register of Developmental Anomalies, 1990-2016. Birth prevalence (per 1000 births) was stratified by severity, known cause, maternal and birth characteristics, and primary diagnosis; and prevalence ratios were calculated for Aboriginal versus non-Aboriginal births. Temporal trends in prevalence, diagnosis age and infant mortality were examined. RESULTS: For births 1990-2010 (allowing 6 years for complete case ascertainment by 2016), 6419 cases were identified; prevalence was 11.5 per 1000 births (95% confidence interval (CI), 11.2-11.8). Severe defects were ascertained in 2.5 per 1000 births (95% CI 2.4-2.7). Most cases were liveborn (5842, 91.0%), and 28.9% had other birth defects. Prevalence was slightly higher in Aboriginal births (prevalence ratio 1.1; 95% CI 1.0-1.2); and the infant mortality rate more than doubled (13.4% vs. 5.8%, P < 0.001). Prenatal diagnosis increased over time but, in remote areas, was significantly lower for Aboriginal versus non-Aboriginal cases (3.1% vs. 9.3%; P = 0.008). A cause was identified in 920 cases (14.3%), more often for severe defects (347, 24.4%); 63% of known causes were rare diseases. Congenital heart defects associated with fetal alcohol spectrum disorder were much more common in Aboriginal births (prevalence ratio 82; 95% CI 28-239). CONCLUSIONS: Earlier detection of congenital heart defects and improved survival has occurred over time, although discrepancies between ethnic groups and regions warrant further investigation and strategic action.

Microcephaly in Australian children, 2016-2018: national surveillance study.

OBJECTIVE: To describe infants aged <12 months reported with microcephaly to the Australian Paediatric Surveillance Unit (APSU) following emergence of Zika virus infection internationally. DESIGN, SETTING AND PATIENTS: National, active, monthly surveillance for microcephaly using the APSU. Microcephaly was defined as occipitofrontal circumference (OFC) of more than 2 SDs below the mean for age, gender and gestation. MAIN OUTCOME MEASURES: Clinical spectrum, aetiology and birth prevalence of microcephaly reported by paediatricians. RESULTS: Between June 2016 and July 2018, 106 notifications were received, with clinical details provided for 96 (91%). After excluding ineligible notifications, 70 cases were confirmed, giving an annual birth prevalence of 1.12 (95% CI 0.88 to 1.42) per 10 000 live births. Of the total number of cases, 47 (67%) had primary microcephaly (at birth); and 25 (36%) had severe microcephaly (OFC >3 SDs). Birth defects were reported in 42 (60%). Of 49 infants with developmental assessment details available, 25 (51%) had failed to reach all milestones. Vision impairment was reported in 14 (26%). The cause of microcephaly was unknown in 60%: 13 (19%) had been diagnosed with genetic disorders; 22 (39%) had anomalies on neuroimaging. No congenital or probable Zika infection was identified. Severe microcephaly was more often associated with hearing impairment than microcephaly of >2 SDs but ≤3 SDs below the mean (p<0.007). Indigenous children and children with socioeconomic advantage were over-represented among children with microcephaly. CONCLUSION: Novel national data on microcephaly highlight the high proportion of idiopathic cases. This has implications for prevention and management and suggests the need for a standardised diagnostic approach and ongoing surveillance mechanism in Australia.

Data Linkage: Canadian and Australian Perspectives on a Valuable Methodology for Intellectual and Developmental Disability Research.

Data linkage holds great promise for generating new information about people with intellectual and developmental disabilities (IDD) as a population, yet few centers have developed the infrastructure to utilize this methodology. Two examples, from Canada and Australia, describe their efforts in building data linkage capabilities, and how linked databases can be used to identify persons with IDD and used for population-based research. The value of data linkage is illustrated through new estimates of prevalence of IDD; health service utilization patterns; associations with sociodemographic characteristics, and with physical and mental health conditions (e.g., chronic diseases, injury, fertility, and depression); and findings on equity in medical treatments. Examples are provided of findings used for governmental policy and program planning.

Congenital Anomalies in Children With Cerebral Palsy: A Systematic Review.

Congenital anomalies are a strong risk factor for cerebral palsy, particularly for children born at term. This systematic review aimed to address gaps in our understanding of the association between congenital anomalies and cerebral palsy. Eight population-based studies (n = 10 081) were identified. Congenital anomalies were reported in 12% to 32% of children with pre/perinatal brain injury and 20% of children with postneonatal brain injury. Variation between studies included study cohort inclusion criteria and the definitions and classification of included anomalies. The most common cerebral anomalies were microcephaly and hydrocephaly, whereas circulatory system anomalies were the most common noncerebral anomalies. The proportion of congenital anomalies was higher in children born at term than preterm. Synthesizing the highest quality data published, this review identified that congenital anomalies are common in cerebral palsy. New collaborative research, addressing sources of variation, is vital to identify pathways to cerebral palsy that include specific congenital anomalies, and explore opportunities for prevention.

Intellectual Disability in Children Conceived Using Assisted Reproductive Technology.

OBJECTIVES: To examine whether children conceived using assisted reproductive technology (ART) have a higher risk of intellectual disability (ID) compared with non-ART-conceived children and describe known causes of ID in these groups. METHODS: We linked ID and ART data from population-based registers in Western Australia. Our cohort included live births from 1994 to 2002 (n = 210 627) with at least 8 years of follow-up. The prevalence of ID was compared between ART- and non-ART-conceived children, and risk of ID was estimated using Poisson regression with robust SEs. We also stratified by plurality and gestation at delivery. RESULTS: Children conceived using ART had a small increased risk of ID (risk ratio 1.58; 95% confidence interval 1.19-2.11) even when analyses were restricted to singleton births (risk ratio 1.56; 95% confidence interval 1.10-2.21). The risk of ID was more than doubled for those born very preterm, for severe ID, and after intracytoplasmic sperm injection (ICSI) treatments. Children conceived using ICSI had a greater risk of ID than those conceived using in vitro fertilization and were more likely to have a known genetic cause for ID (27.6% vs 12.9% in vitro fertilization and 11.9% non-ART). CONCLUSIONS: The risk of ID was increased in children born after ART in Western Australia from 1994 to 2002. More recent cohorts should be examined to assess the impact of important changes in ART clinical practice. Our results are particularly pertinent because multiple embryo transfers are routinely performed in many countries, increasing the risk of preterm birth, and ICSI use rates are high.

Association between male genital anomalies and adult male reproductive disorders: a population-based data linkage study spanning more than 40 years.

BACKGROUND: The male genital anomalies hypospadias and undescended testes have been linked to adult male reproductive disorders, testicular cancer, and decreased fertility. Few population-based studies have evaluated their effects on adult fertility outcomes and, in the case of undescended testes, the importance of early corrective surgery (orchidopexy). METHODS: We did a population-based cohort study of all liveborn boys in Western Australia in 1970-99, and followed them up until 2016 via data linkage to registries for hospital admissions, congenital anomalies, cancer, and assisted reproductive technologies (ART). Study factors were hypospadias or undescended testes, and study outcomes were testicular cancer, paternity, and use of ART for male infertility. Cox regression was used to calculate hazard ratios (HRs) for the associations between genital anomalies and testicular cancer or paternity, and log-binomial regression was used to calculate relative risks (RRs) for the associations between genital anomalies and use of ART. FINDINGS: The cohort comprised 350 835 boys, of whom 2484 (0·7%) had been diagnosed with hypospadias and 7499 (2·1%) with undescended testes. There were 505 (0·1%) cases of testicular cancer, 109 471 (31·2%) men had fathered children, and 2682 (0·8%) had undergone fertility treatment with ART. Undescended testes was associated with a more than two times increase in risk of testicular cancer (HR 2·43, 95% CI 1·65-3·58) and hypospadias with an almost 40% increase (1·37, 0·51-3·67), although this increase was not significant. Both hypospadias and undescended testes were associated with a 21% reduction in paternity (adjusted HR 0·79 [95% CI 0·71-0·89] for hypospadias and 0·79 [0·74-0·85] for undescended testes). Undescended testes was associated with a two times increase in use of ART (adjusted RR 2·26, 95% CI 1·58-3·25). For every 6 months' delay in orchidopexy, there was a 6% increase in risk of testicular cancer (HR 1·06, 95% CI 1·03-1·08), a 5% increase in risk of future use of ART (1·05, 1·03-1·08), and a 1% reduction in paternity (RR 0·99, 95% CI 0·98-0·99). INTERPRETATION: Undescended testes is associated with an increased risk of testicular cancer and male infertility, and decreased paternity. We provide new evidence to support current guidelines for orchidopexy before age 18 months to decrease the risk of future testicular cancer and infertility. FUNDING: National Health and Medical Research Council and Sydney Medical School Foundation.

Cerebral palsy after assisted reproductive technology: a cohort study.

AIM: To calculate the birth prevalence of cerebral palsy (CP) after assisted reproductive technology (ART) and compare the clinical outcomes of children with CP after ART or natural conception. METHOD: This cohort study used linked CP and ART register data from live births in Western Australia (1994-2002). Birth prevalence was calculated and data analysed using descriptive statistics and logistic regression. It was adjusted for confounding variables and stratified by plurality and gestational age. RESULTS: In total, 211 660 live births were included; prevalence of CP was increased in children born after ART (7.2/1000 live births compared with naturally conceived births, 2.5/1000). Odds of CP were doubled for singletons; when stratified by gestational age odds were only increased in the under 32-week group. Prevalence of CP was increased in ART (9.9/1000 live births) and naturally conceived twins (8.4/1000 live births). Clinical outcomes were similar between ART and naturally conceived children. INTERPRETATION: The birth prevalence of CP is increased two-fold after ART. After stratification for gestational age and plurality, residual risk remains in singletons born very preterm. Birth prevalence of CP will be tracked over time to identify any impact of changes to clinical practice. WHAT THIS PAPER ADDS: In Western Australia, assisted reproductive technology (ART) increases birth prevalence of cerebral palsy (CP), mediated mostly by preterm and multiple births. Preterm birth alone does not account for the doubled odds of CP for ART singletons born very preterm. Clinical outcomes are similar between ART and naturally conceived children with CP.

Prevalence of microcephaly in an Australian population-based birth defects register, 1980-2015.

OBJECTIVES: To describe the prevalence and characteristics of microcephaly in a geographically defined Australian population. DESIGN, SETTING AND PARTICIPANTS: Descriptive epidemiological study of microcephaly cases ascertained by the Western Australian Register of Developmental Anomalies, 1980-2015, defining microcephaly as an occipito-frontal head circumference below the third percentile or more than two standard deviations below the mean sex- and age-appropriate distribution curve. MAIN OUTCOME MEASURES: Microcephaly prevalence (per 10 000 births) was calculated for cases with known and unknown causes, and by demographic characteristics. Temporal trends were analysed, and prevalence ratios (PRs) and 95% CIs calculated for Aboriginal and non-Aboriginal births. RESULTS: For births during 1980-2009 (ie, with at least 6 years' follow-up and therefore complete case ascertainment), 416 cases were identified, a prevalence of 5.5 per 10 000 births (95% CI, 4.95-6.02), or 1 in 1830 births. There was no significant temporal trend in prevalence (P = 0.23). Most cases were in live-born children (389, 93.5%), and other major birth defects were diagnosed in 335 of the affected children (80%). Prevalence was higher in Aboriginal births (PR, 4.5; 95% CI, 3.55-5.73). A cause of microcephaly was identified in 186 cases (45% of cases), and more often for Aboriginal (64 cases, 70%) than non-Aboriginal births (122 cases, 38%). The most frequent known cause of microcephaly in Aboriginal births was fetal alcohol spectrum disorder (FASD; 11 per 10 000 births); monogenic (0.68 per 10 000) and chromosomal conditions (0.59 per 10 000 births) were the most common causes in non-Aboriginal births. CONCLUSIONS: These data provide a baseline for prospective surveillance of microcephaly. We identified a high proportion of cases without known cause, highlighting the need for clinicians to carefully investigate all possibilities, including emerging infections. FASD is an important cause of microcephaly in the Aboriginal population.

What counts? A mixed-methods study to inform evaluation of shelters for abused women.

Shelters for abused women have expanded from "safe havens" to providing a range of residential and outreach services, and face increasing pressure to demonstrate "value for money" by providing evaluation metrics that may or may not reflect what they actually do. We conducted interviews and surveys with 68 shelter directors in Ontario, Canada, and found that differences in service philosophy and how abuse is defined influence decisions about who receives services and the shelter's role in the broader community; these in turn affect how the work of shelters is positioned. Implications for shelter service evaluation are discussed.

Hospital costs of multiple-birth and singleton-birth children during the first 5 years of life and the role of assisted reproductive technology.

IMPORTANCE: The unprecedented increase in multiple births during the past 3 decades is a major public health concern and parallels the uptake of medically assisted conception. The economic implications of such births are not well understood. OBJECTIVES: To conduct a comprehensive economic and health services assessment of the frequency, duration, and cost of hospital admissions during the first 5 years of life for singleton, twin, and higher-order multiple (HOM) children and to examine the contribution of assisted reproductive technology (ART) to the incidence and cost of multiple births. DESIGN, SETTING, AND PARTICIPANTS: A retrospective population cohort study using individually linked birth, hospital, and death records among 233,850 infants born in Western Australia between October 1993 and September 2003, and followed up to September 2008. EXPOSURES: Multiple-gestation delivery and ART conception. MAIN OUTCOMES AND MEASURES: Odds of stillbirth, prematurity and low birth weight, frequency and length of hospital admissions, the mean costs by plurality, and the independent effect of prematurity on childhood costs. RESULTS: Of 226,624 singleton, 6941 twin, and 285 HOM infants, 1.0% of singletons, 15.4% of twins, and 34.7% of HOM children were conceived following ART. Compared with singletons, twins and HOMs were 3.4 and 9.6 times, respectively, more likely to be stillborn and were 6.4 and 36.7 times, respectively, more likely to die during the neonatal period. Twins and HOMs were 18.7 and 525.1 times, respectively, more likely to be preterm, and 3.6 and 2.8 times, respectively, more likely to be small for gestational age. The mean hospital costs of a singleton, twin, and HOM child to age 5 years were $2730, $8993, and $24,411 (in 2009-2010 US dollars), respectively, with cost differences concentrated in the neonatal period and during the first year of life. Almost 15% of inpatient costs for multiple births could have been avoided if ART twins and HOMs had been born as singletons. CONCLUSIONS AND RELEVANCE: Compared with singletons, multiple-birth infants consume significantly more hospital resources, particularly during the neonatal period and first year of life. A significant proportion of the clinical and economic burden associated with multiple births can be prevented through single-embryo transfer. Increasing ART use worldwide and persistently high ART multiple-birth rates in several countries highlight the need for strategies that encourage single-embryo transfer. The costs from this study can be generalized to other settings.

The impact of assisted reproductive technologies on intra-uterine growth and birth defects in singletons.

Pooled odds ratios from meta-analyses of infants born following assisted reproductive technologies (ART) compared with non-ART singletons show increases in low birth weight, preterm birth, small for gestational age, and birth defects. Although there have been small reductions in recent data, odds associated with these outcomes are still higher for ART singletons. Both ART procedures and underlying infertility contribute to these increased risks. Outcomes appear better for frozen-thawed compared with fresh embryo transfers, but are poorer than for non-ART infants. There is a concerning increase in large-for-gestational-age infants born following frozen-thawed embryo transfer and limited data on the effects of embryo vitrification used instead of slow-freezing techniques. Using large datasets, we now need to investigate risks of individual birth defects and disentangle the inter-related effects of different types of infertility and the multiple aspects of ART. Greater understanding of the causes of adverse ART outcomes and identification of modifiable risk factors may lead to further reductions in the disparities in outcome between ART and non-ART infants.

Assisted reproductive technology and birth defects: a systematic review and meta-analysis.

BACKGROUND: It has been 10 years since we carried out a systematic search of the literature on birth defect risk in infants born following assisted reproductive technology (ART) compared with non-ART infants. Because of changes to ART practice since that review and the publication of more studies the objective of this review was to include these more recent studies to estimate birth defect risk after ART and to examine birth defect risk separately in ART singletons and multiples. METHODS: We searched Medline, Embase and Current Contents databases (1978-2012). We used the same data extraction sheet and questionnaire we had used previously with the addition of a quality score to the questionnaire. Pooled relative risk (RR) estimates were calculated using a random effects model. All data were analysed using Comprehensive Meta-Analysis V2. RESULTS: There were 45 cohort studies included in this review. ART infants (n = 92 671) had a higher risk of birth defects [RR 1.32, 95% confidence interval (CI) 1.24-1.42] compared with naturally conceived infants (n = 3 870 760). The risk further increased when data were restricted to major birth defects (RR 1.42, 95% CI 1.29-1.56) or singletons only (RR 1.36, 95% CI 1.30-1.43). The results for ART multiples were less clear. When all data for multiples were pooled the RR estimate was 1.11 (95% CI 0.98-1.26) but this increased to 1.26 (0.99-1.60) when the analysis was restricted to studies of ART twins where some adjustment was made for differences in zygosity distribution between ART and non-ART multiples. CONCLUSIONS: Birth defects remain more common in ART infants. Further research is required to examine risks for important subgroups of ART exposure.