School-age outcomes among IVF-conceived children: A population-wide cohort study.

BACKGROUND: In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. METHODS AND FINDINGS: Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring <10th percentile in ≥2/5 developmental domains (physical health and wellbeing, social competence, emotional maturity, language and cognitive skills, communication skills, and general knowledge). The second, educational outcome at age 7 to 9, was assessed using National Assessment Program-Literacy and Numeracy (NAPLAN) data (n = 342,311) and defined by overall z-score across 5 domains (grammar and punctuation, reading, writing, spelling, and numeracy). Inverse probability weighting with regression adjustment was used to estimate population average causal effects. The study included 412,713 children across the 2 outcome cohorts. Linked records were available for 4,697 IVF-conceived cases and 168,503 controls for AEDC, and 8,976 cases and 333,335 controls for NAPLAN. There was no causal effect of IVF-conception on the risk of developmental vulnerability at school-entry compared with spontaneously conceived children (AEDC metrics), with an adjusted risk difference of -0.3% (95% CI -3.7% to 3.1%) and an adjusted risk ratio of 0.97 (95% CI 0.77 to 1.25). At age 7 to 9 years, there was no causal effect of IVF-conception on the NAPLAN overall z-score, with an adjusted mean difference of 0.030 (95% CI -0.018 to 0.077) between IVF- and spontaneously conceived children. The models were adjusted for sex at birth, age at assessment, language background other than English, socioeconomic status, maternal age, parity, and education. Study limitations included the use of observational data, the potential for unmeasured confounding, the presence of missing data, and the necessary restriction of the cohort to children attending school. CONCLUSIONS: In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians.

The incidence of hypertensive disorders of pregnancy following sperm donation in IVF: an Australian state-wide retrospective cohort study.

STUDY QUESTION: Does IVF using donor sperm increase the risk of hypertensive disorders of pregnancy and fetal growth restriction (FGR)? SUMMARY ANSWER: IVF conceptions arising from sperm donation are not associated with an increased risk of hypertensive disorders of pregnancy or FGR. WHAT IS KNOWN ALREADY: It has been hypothesized that the absence of prior exposure to factors within the paternal ejaculate increases the risk of preeclampsia and FGR among nulliparous women or women with a new partner-the concept of 'primipaternity'. It remains unclear which element of the ejaculate is responsible: the sperm cell or the constituents of seminal fluid. IVF pregnancies arising from donor sperm where the seminal fluid is absent provide a unique opportunity to test the theory of primipaternity and the relative contribution of the sperm cell. Pregnancies conceived via artificial reproductive technology are at increased risk of preeclampsia and FGR. STUDY DESIGN, SIZE, DURATION: Theories about the development of preeclampsia and the relative contribution of spermatic factors were explored by comparing the risk of hypertensive disorders of pregnancy and FGR among IVF pregnancies conceived with autologous gametes (own eggs and partner sperm) and those conceived with donor sperm, donor egg (and partner sperm) and donor embryo. To do this, we performed a retrospective cohort analysis of pregnancy outcomes among singleton pregnancies (n = 15 443) conceived through fertility clinics within Australia between 2009 and 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All pregnancies resulting in a singleton pregnancy delivering after 20 weeks' gestation were included. The cohort was divided into donor sperm, donor egg and donor embryo (where both gametes came from a donor to create an embryo, or in a surrogate pregnancy) groups. We also compared the data with a control group, defined as IVF-conceived pregnancies from autologous cycles. A multivariable regression model was used to calculate an adjusted odds ratio (aOR). MAIN RESULTS AND THE ROLE OF CHANCE: The final cohort contained 1435, 578 and 239 pregnancies conceived by donor sperm, donor egg and donor embryo, respectively, and 13 191 controls. There were a very small number of women lost to follow-up (31 women; 0.2% of total cohort). Compared to control pregnancies, there was no increase in the risk of hypertensive disorders among pregnancies conceived via donor sperm (aOR 0.94; 95% CI 0.73-1.21). Subgroup analysis was performed for a cohort where parity was known (n = 4551), and of these, 305 multigravida pregnancies were conceived via donor sperm. Among this cohort, no increased risk of preeclampsia or pregnancy-induced hypertension was found (aOR 1.18; 95% CI: 0.69-2.04) as a result of primipaternity (new sperm donor).A significantly increased risk for hypertensive disorders of pregnancy was associated with the use of donor eggs (but partner sperm; aOR 2.34; 95% CI 1.69-3.21). However, the association was no greater among pregnancies conceived with donor embryos (i.e. donated egg and sperm; aOR 2.0; 95% CI 1.25-3.17) than among the donor oocyte group. The overall incidence of FGR (defined as birthweight <10th centile) was 18%. There were no significant differences observed between donor sperm, or donor embryo pregnancies; however, egg donation was associated with a 1.5-fold increase in FGR. LIMITATIONS, REASONS FOR CAUTION: This study was limited by a lower than expected rate of hypertensive disorders of pregnancy (n = 862, 5.6%), which is contrary to the well-established increased risk among women using IVF. However, this is likely to be evenly distributed across the study groups and, therefore, unlikely to have introduced significant bias. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that exposure to new sperm may not be implicated in the pathogenesis of preeclampsia. The mechanism of increased risk seen in conceptions arising from egg or embryo donation remains unclear. Further investigation is required to elucidate these mechanisms and, ultimately, improve pregnancy outcomes following IVF. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Australian Commonwealth Government-Graduate Research Scheme (A.K.). Salary support was provided by the National Health and Medical Research Council of Australia (S.T.), Mercy Foundation (A.L.), and the Department of Obstetrics and Gynaecology at the University of Melbourne (R.H.). There are no competing interests.

Identification of the optimal growth charts for use in a preterm population: An Australian state-wide retrospective cohort study.

BACKGROUND: Preterm infants are a group at high risk of having experienced placental insufficiency. It is unclear which growth charts perform best in identifying infants at increased risk of stillbirth and other adverse perinatal outcomes. We compared 2 birthweight charts (population centiles and INTERGROWTH-21st birthweight centiles) and 3 fetal growth charts (INTERGROWTH-21st fetal growth charts, World Health Organization fetal growth charts, and Gestation Related Optimal Weight [GROW] customised growth charts) to identify which chart performed best in identifying infants at increased risk of adverse perinatal outcome in a preterm population. METHODS AND FINDINGS: We conducted a retrospective cohort study of all preterm infants born at 24.0 to 36.9 weeks gestation in Victoria, Australia, from 2005 to 2015 (28,968 records available for analysis). All above growth charts were applied to the population. Proportions classified as <5th centile and <10th centile by each chart were compared, as were proportions of stillborn infants considered small for gestational age (SGA, <10th centile) by each chart. We then compared the relative performance of non-overlapping SGA cohorts by each chart to our low-risk reference population (infants born appropriate size for gestational age [>10th and <90th centile] by all intrauterine charts [AGAall]) for the following perinatal outcomes: stillbirth, perinatal mortality (stillbirth or neonatal death), Apgar <4 or <7 at 5 minutes, neonatal intensive care unit admissions, suspicion of poor fetal growth leading to expedited delivery, and cesarean section. All intrauterine charts classified a greater proportion of infants as <5th or <10th centile than birthweight charts. The magnitude of the difference between birthweight and fetal charts was greater at more preterm gestations. Of the fetal charts, GROW customised charts classified the greatest number of infants as SGA (22.3%) and the greatest number of stillborn infants as SGA (57%). INTERGROWTH classified almost no additional infants as SGA that were not already considered SGA on GROW or WHO charts; however, those infants classified as SGA by INTERGROWTH had the greatest risk of both stillbirth and total perinatal mortality. GROW customised charts classified a larger proportion of infants as SGA, and these infants were still at increased risk of mortality and adverse perinatal outcomes compared to the AGAall population. Consistent with similar studies in this field, our study was limited in comparing growth charts by the degree of overlap, with many infants classified as SGA by multiple charts. We attempted to overcome this by examining and comparing sub-populations classified as SGA by only 1 growth chart. CONCLUSIONS: In this study, fetal charts classified greater proportions of preterm and stillborn infants as SGA, which more accurately reflected true fetal growth restriction. Of the intrauterine charts, INTERGROWTH classified the smallest number of preterm infants as SGA, although it identified a particularly high-risk cohort, and GROW customised charts classified the greatest number at increased risk of perinatal mortality.