Michèle Hansen

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.

Twins born following assisted reproductive technology: perinatal outcome and admission to hospital

BACKGROUND Compared with spontaneously conceived (SC) singletons, adverse perinatal outcome, neonatal intensive care unit (NICU) admission and hospital admission in infancy are more common in those born following Assisted Reproductive Technology (ART). Similar comparisons for twins have shown conflicting results. METHODS We investigated perinatal outcome and hospital admission during the first 3 years of life for all twin children born in Western Australia between 1994 and 2000 [700 ART, 4097 SC]. RESULTS ART twins had a greater risk of adverse perinatal outcome including preterm birth, low birthweight and death compared with SC twins of unlike-sex. In their first year of life, ART twins had a longer birth admission; were 60% more likely to be admitted to a NICU; and had a higher risk of hospital admission. The increased risk of hospital admission continued in the second and third year but was not statistically significant in the third year. CONCLUSIONS Couples undertaking ART should be aware that in addition to the known increased perinatal risks associated with a twin birth, ART twins are more likely than SC twins to be admitted to a NICU and hospitalized in the first 3 years of life.

Assisted reproductive technologies and birth outcomes: overview of recent systematic reviews

Several systematic reviews have been published recently on birth outcomes of infants conceived through assisted reproductive technologies (ART), compared with infants conceived spontaneously. These outcomes include perinatal mortality, preterm birth, low birthweight and birth defects. Methodological limitations of many of the individual studies (including small sample size, potential for bias in ascertainment of outcomes and considering singletons and multiples together) were obviated in these reviews by excluding studies where methods were considered inadequate, by conducting meta-analyses using data from all methodologically sound studies (small and large) and by examining singletons separately. Overall, the reviews indicate few differences between outcomes in ART twins compared with twins conceived spontaneously. However, in singleton ART infants, there are around two-fold increases in risk of perinatal mortality, low birthweight and preterm birth, about a 50% increase in small for gestational age and a 30-35% increase in birth defects, compared with singletons conceived spontaneously. Couples considering ART should be counselled about the increased risk of adverse outcomes. Epidemiologists, in conjunction with clinical and laboratory colleagues, should now focus on large, methodologically sound studies with long-term follow up that seek to identify the reasons for these increased risks and their long-term consequences, whether they are associated with particular technologies and causes of infertility, and how they might be reduced.

The risk of birth defects in children born after assisted reproductive technologies

Purpose of review This review addresses the question of whether there is evidence of an increased risk of birth defects in children born following assisted reproductive technologies compared with spontaneously conceived children. Recent findings Three recent studies added relatively little new information given their modest size (56-472 assisted reproductive technology children). We therefore considered all published papers that compared birth defects in children born following assisted reproductive technologies with those in children born following spontaneous conception. Overall, only six of the 26 relevant papers concluded there was an increased risk of birth defects following assisted reproductive technologies. The interpretation of many studies was based on statistical significance testing alone. When results showed a greater proportion of defects in the assisted reproductive technology group compared with the spontaneous group, but the results were not statistically significant, this was often interpreted as showing no increase in risk, rather than an increase in risk that may have been due to chance. The vast majority of individual studies were too small to have sufficient power to detect, as statistically significant, clinically relevant results. We found that although only eight (30%) of the studies had statistically significant results, 24 (89%) had an odds ratio estimate comparing assisted reproductive technology with spontaneously conceived children of over 1.0; 19 (70%) had an estimate of 1.20 or greater; and 14 (52%) had an estimate of 1.5 or greater. Summary Current evidence suggests there is an elevated risk of birth defects in children born following assisted reproductive technologies. Whilst others may disagree with our interpretation, one certainly cannot exclude this possibility on the basis of the current evidence.

Admission to hospital of singleton children born following assisted reproductive technology (ART)

BACKGROUND Adverse perinatal outcomes are more common in singletons born following assisted reproductive technology (ART) and this would predict an increase in hospitalization during infancy and early childhood. METHODS We investigated hospital admissions during the first 3 years of life for all singleton children born in Western Australia between 1994 and 2000 [1328 ART, 162 350 spontaneously conceived (SC)]. RESULTS ART infants had a significantly longer birth admission and were four times more likely to be admitted to neonatal intensive care units (NICU) than SC infants. ART children had a 60% greater risk of one or more admissions in their first year and an equal risk of admission in their second and third years. Their length of stay in hospital was longer in each age period. Maternal, infant and socio-economic confounders accounted for most of the increased admission risk in the first year. However, after adjustment, a 20% increase in the risk of admission to NICU (P < 0.05) and admission to hospital during the first year (P < 0.05) remained. CONCLUSIONS Couples undertaking ART should be aware that ART infants are more likely to be admitted to a NICU, to be hospitalized in the first year of life and to stay in hospital longer than other children.

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.

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

Hospital utilization, costs and mortality rates during the first 5 years of life: a population study of ART and non-ART singletons

2730,

Cerebral palsy after assisted reproductive technology: a cohort study

8993, and

Application of Population-Based Linked Data to the Study of Intellectual Disability and Autism

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.