Advanced maternal age at birth is considered a major risk factor for birth outcomes. It is unclear to what extent this association is confounded by maternal characteristics. To test whether advanced maternal age at birth independently increases the risk of low birth weight (<2,500 g) and preterm birth (<37 weeks’ gestation), we compared between-family models (children born to different mothers at different ages) with within-family models (children born to the same mother at different ages). The latter procedure reduces confounding by unobserved parental characteristics that are shared by siblings. We used Finnish population registers, including 124,098 children born during 1987–2000. When compared with maternal ages 25–29 years in between-family models, maternal ages of 35–39 years and ≥40 years were associated with percentage increases of 1.1 points (95% confidence intervals: 0.8, 1.4) and 2.2 points (95% confidence intervals: 1.4, 2.9), respectively, in the probability of low birth weight. The associations are similar for the risk of preterm delivery. In within-family models, the relationship between advanced maternal age and low birth weight or preterm birth is statistically and substantively negligible. In Finland, advanced maternal age is not independently associated with the risk of low birth weight or preterm delivery among mothers who have had at least 2 live births.

Background Children born after medically assisted reproduction (MAR) are at higher risk of adverse birth outcomes than naturally conceived children. It is not known to what extent the excess risk should be attributed to harmful effects of the treatment or to pre-existing parental characteristics that confound the association. Methods We analysed birth weight, gestational age, risk of low birth weight, and risk of preterm birth among MAR-and naturally conceived children using Finnish population registers covering 65,634 children born in 1995-2000. First, we estimated the differences in birth outcomes by mode of conception in the general population using standard multivariate methods that controlled for observed factors (e.g., multiple birth, birth order, and parental socio-demographic characteristics). Second, we used a sibling-comparison approach that has not been used before in MAR research. We compared MAR-conceived children to their naturally conceived siblings, and thus controlled for all observed and unobserved factors shared by siblings. The latter analysis included 1245 children. Findings MAR-conceived children had worse outcomes than naturally conceived children for all outcomes, even after adjustments for observed child and parental characteristics (e.g., 60gr [95% CI:-34 to-86] lower birth weight; 2.2-percentage point [95% CI: 1•1 to 2•2] increased risk of preterm delivery). In the sibling comparison, the gap in birth outcomes was attenuated, such that the relationship between MAR and adverse birth outcomes was statistically and substantively weak for all outcomes (e.g., 31gr [95% CI:-22 to 85] lower birth weight; 1.6 percentage points [95% CI:-1•3% to 4•4%] increased risk of preterm delivery). Interpretation MAR-conceived children face an elevated risk of adverse birth outcomes. However, our results indicate that this increased risk is largely attributable to factors other than the MAR treatment itself. Funding European Research Council, the Academy of Finland, and the Signe and Ane Gyllenberg Foundation. Research in context Evidence before this study We searched for studies analysing the association between Medically Assisted Reproduction and birth outcomes within families who had at least one child conceived through MAR and one child conceived naturally, published in any language up until March 2018 (with no specified earliest date). We searched in PubMed and Google Scholar using relevant terms ("Medically Assisted Reproduction", "Assisted Reproductive Technology", "birth outcomes", "low birth weight", "preterm", "siblings", "within family"). We found only three studies that compared MAR-and naturally conceived children from the same families. These studies, which reported mixed findings, suffered from two major limitations. First, they relied on random-effects models, which are biased when unobserved random effects (e.g., measuring health) are correlated with observed covariates (e.g., maternal age, socioeconomic status). Second, they focused on children conceived through IVF only, and included chil...

IMPORTANCEChildren who are placed in out-of-home care may have poorer outcomes in adulthood, on average, compared with their peers, but the direction and magnitude of these associations need clarification.OBJECTIVE To estimate associations between being placed in out-of-home care in childhood and adolescence and subsequent risks of experiencing a wide range of social and health outcomes in adulthood following comprehensive adjustments for preplacement factors. DESIGN, SETTING, AND PARTICIPANTSThis cohort and cosibling study of all children born in Finland between 1986 and 2000 (N = 855 622) monitored each person from their 15th birthday either until the end of the study period (December 2018) or until they migrated, died, or experienced the outcome of interest. Cox and Poisson regression models were used to estimate associations with adjustment for measured confounders (from linked population registers) and unmeasured familial confounders (using sibling comparisons). Data were analyzed from October 2020 to August 2021.EXPOSURES Placement in out-of-home care up to age 15 years. MAIN OUTCOMES AND MEASURESThrough national population, patient, prescription drug, cause of death, and crime registers, 16 specific outcomes were identified across the following categories: psychiatric disorders; low socioeconomic status; injuries and experiencing violence; and antisocial behaviors, suicidality, and premature mortality.RESULTS A total of 30 127 individuals (3.4%) were identified who had been placed in out-of-home care for a median (interquartile range) period of 1.3 (0.2-5.1) years and 2 (1-3) placement episodes before age 15 years. Compared with their siblings, individuals who had been placed in out-of-home care were 1.4 to 5 times more likely to experience adverse outcomes in adulthood (adjusted hazard ratio [aHR] for those with a fall-related injury, 1.40; 95% CI, 1.25-1.57 and aHR for those with an unintentional poisoning injury, 4.79; 95% CI, 3.56-6.43, respectively). The highest relative risks were observed for those with violent crime arrests (aHR, 4.16; 95% CI, 3.74-4.62; cumulative incidence, 24.6% in individuals who had been placed in out-of-home care vs 5.1% in those who had not), substance misuse (aHR, 4.75; 95% CI,; cumulative incidence, 23.2% vs 4.6%), and unintentional poisoning injury (aHR 4.79; 95% CI, 3.56-6.43; cumulative incidence, 3.1% vs 0.6%). Additional adjustments for perinatal factors, childhood behavioral problems, and traumatic injuries, including experiencing violence, did not materially change the findings.CONCLUSIONS AND RELEVANCE Out-of-home care placement was associated with a wide range of adverse outcomes in adulthood, which persisted following adjustments for measured preplacement factors and unmeasured familial factors.

STUDY QUESTION Does the risk of low birth weight and premature birth increase with age among mothers who conceive through medically assisted reproduction (MAR)? SUMMARY ANSWER Among MAR mothers, the risk of poorer birth outcomes does not increase with maternal age at birth except at very advanced maternal ages (40+). WHAT IS KNOWN ALREADY The use of MAR treatments has been increasing over the last few decades and is especially diffused among women who conceive at older ages. Although advanced maternal age is a well-known risk factor for adverse birth outcomes in natural pregnancies, only a few studies have directly analysed the maternal age gradient in birth outcomes for MAR mothers. STUDY DESIGN, SIZE, DURATION The base dataset was a 20% random sample of households with at least one child aged 0–14 at the end of 2000, drawn from the Finnish population register and other administrative registers. This study included children who were born in 1995–2000, because the information on whether a child was conceived through MAR or naturally was available only from 1995 onwards. PARTICIPANTS/MATERIALS, SETTING, METHODS The outcome measures were whether the child had low birth weight (LBW, &lt;2500 g at birth) and whether the child was delivered preterm (&lt;37 weeks of gestation). Conceptions through MAR were identified by examining data on purchases of prescription medication from the National Prescription Register. Linear probability models were used to analyse and compare the maternal age gradients in birth outcomes of mothers who conceived through MAR or naturally before and after adjustment for maternal characteristics (i.e. whether the mother suffered from acute/chronic conditions before the pregnancy, household income and whether the mother smoked during pregnancy). MAIN RESULTS AND THE ROLE OF CHANCE A total of 56 026 children, 2624 of whom were conceived through MAR treatments, were included in the study. Among the mothers who used MAR to conceive, maternal age was not associated with an increased risk of LBW (the overall prevalence was 12.6%) at ages 25–39. For example, compared to the risk of LBW at ages 30–34, the risk was 0.22 percentage points lower (95% CI: −3.2, 2.8) at ages 25–29 and was 1.34 percentage points lower (95% CI: −4.5, 1.0) at ages 35–39. The risk of LBW was increased only at maternal ages ≥40 (six percentage points, 95% CI: 0.2, 12). Adjustment for maternal characteristics only marginally attenuated these associations. In contrast, among the mothers who conceived naturally, the results showed a clear age gradient. For example, compared to the risk of LBW (the overall prevalence was 3.3%) at maternal ages 30–34, the risk was 1.1 percentage points higher (95% CI: 0.6, 1.6) at ages 35–39 and was 1.5 percentage points higher (95% CI: 0.5, 2.6) at ages ≥40. The results were similar for preterm births. LIMITATIONS, REASON FOR CAUTION A limited number of confounders were included in the study because of the administrative nature of the data used. Our ability to reliably distinguish mothers based on MAR treatment type was also limited. WIDER IMPLICATIONS OF THE FINDINGS This is the first study to analyse the maternal age gradient in the risk of adverse birth outcomes among children conceived through MAR using data from a nationally representative sample and controlling for important maternal health and socio-economic characteristics. This topic is of considerable importance in light of the widespread and increasing use of MAR treatments. STUDY FUNDING/COMPETING INTEREST(S) Funding for this project was provided by the European Research Council (grant no. 803959 MARTE to Alice Goisis and grant no. 336475 COSTPOST to Mikko Myrskylä). E.S. reports personal fees from Theramex, personal fees from Merck Serono, personal fees from Health Reimbursement Arrangement, non-financial support from Merck Serono and grants from Ferring, grants from Theramex, outside the submitted work. The remaining authors have no competing interests. TRIAL REGISTRTION NUMBER N/A

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