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.

Should intrauterine human chorionic gonadotropin infusions ever be used prior to embryo transfer?

PURPOSE: The aim of this study was to explore the factors that influence the outcome of intrauterine human chorionic gonadotropin (hCG) infusion at the time of embryo transfer (ET), in particular, the effect of hCG infusions on fresh and frozen embryo transfers (FETs) and whether prior recurrent implantation failure (RIF) impacts upon outcomes. METHOD: This was a case-control study based on a standardized database from a multi-site in vitro fertilization clinic. The analysis contains 458 cases and 749 matched controls, with an intervention group of those given intrauterine hCG prior to ET and a control group of patients receiving no hCG infusion. Outcomes were defined as clinical pregnancy and live birth rates. Two analyses were performed. The first separated FETs (cases n = 224, controls n = 325) and fresh ETs (cases n = 234, controls n = 424), with outcomes calculated in each group. The second analysis divided patients into those with RIF (cases n = 149, controls n = 200) and those without (cases n = 309, controls n = 549). RESULTS: Results in fresh ETs demonstrated a 5.8% reduction (adjusted odds ratio (AOR) = 0.60, p = 0.041) in clinical pregnancy rates with the use of intrauterine hCG. In those without defined RIF, clinical pregnancy rates were reduced by 8.1% (AOR = 0.61, p = 0.023) and live birth rates by 7.2% (AOR = 0.56, p = 0.32) with intrauterine hCG use. There were no significant differences in outcomes in FETs and in the RIF cohort. CONCLUSION: Intrauterine hCG at the time of ET not only seems to have no benefit, but rather a negative effect in fresh ETs and those without RIF.

The Effects of Adjuvant Therapies on Embryo Transfer Success.

BACKGROUND: Many adjuvant therapies are employed during IVF treatment in an attempt to improve outcomes. The objective of our study was to evaluate the impact of thirteen adjuvants (Intralipid, steroids, melatonin, coenzyme Q10, Filgrastim, testosterone, DHEA, growth hormone, antibiotics, hCG infusion, aspirin, enoxaparin/heparin and dopamine agonists) on the success of embryo transfers. METHODS: This is a retrospective cohort study of all embryo transfers between January 2010 and April 2015 from a multi-site IVF clinic. To ensure data independence, random number was applied to each included transfer and used to pick an individual transfer for each patient (n=13,372). Outcomes were clinical pregnancy, live birth and pregnancy loss. Univariate comparison with Chi square testing and logistic regression analysis were used. The level of significance was p<0.05. RESULTS: Steroid use was significantly associated with both reduced clinical pregnancy loss (aOR 0.39, CI 0.19-0.76) and improved live birth rates (aOR 1.40, CI 1.11-1.77). While aspirin was associated with improved live birth rates (aOR 1.48, CI 1.08-2.02), melatonin was linked with reduced rates (aOR 0.66, CI 0.45-0.96). Analyses for all other adjuvant therapies did not reach statistical significance after logistic regression. CONCLUSION: Many of the interventions investigated in this study fail to significantly demonstrate any effects on the success of embryo transfers. Our analysis results show negative effects with the use of melatonin; however, use of aspirin or steroids demonstrated promising, potentially beneficial outcomes. Additional exploration is needed to guide evidence-based practice.

The success rate of IVF has significantly improved over the last decade.

AIM: To demonstrate that success rates with in vitro fertilisation (IVF) have been improving despite decreasing the number of embryos transferred. MATERIALS AND METHODS: This was a retrospective cohort study comparing live birth outcomes for women who started IVF between 2001 and 2005 with women who started between 2006 and 2010, using life table analysis to allow for the fact that women had differing number of cycles of treatment. The data were obtained from a single IVF centre, Monash IVF Geelong, Victoria. The 2001-2005 cohort consisted of 233 women, and the 2006-2010 cohort consisted of 453 women who started IVF between the specified dates. The main outcome measure was a live birth. Life table analysis was used to estimate the cumulative probability of a live birth after each cycle. RESULTS: The estimate of cumulative live birth probability demonstrated that the chance of a live birth by cycle five was 75.8% in the 2001-2005 cohort, which significantly increased to 80.1% by cycle five in the 2006-2010 cohort (P = <0.05). There was a mean of 1.8 embryos transferred per embryo transfer in the 2001-2005 cohort, which decreased to a mean of 1.3 embryos transferred per embryo transfer in the 2006-2010 cohort. This was associated with a significant decrease in the multiple birth rate from 24.7% in the 2001-2005 cohort to 7.5% in the 2006-2010 cohort. CONCLUSION: The IVF success rate has significantly improved despite the number of embryos transferred being reduced. This study provides further support for elective single embryo transfers.

Can you ever collect too many oocytes?

STUDY QUESTION: Does the chance of pregnancy keep improving with increasing number of oocytes, or can you collect too many? SUMMARY ANSWER: Clinical pregnancy (CP) and live birth (LB) rates per embryo transfer varied from 10.2 and 9.2% following one oocyte collected to 37.7 and 31.3% when >16 oocytes were collected. Regression modelling indicated success rates increased or at least stayed the same with number of oocytes collected. WHAT IS KNOWN ALREADY: It has been suggested that if >15 oocytes are collected, the success rate for fresh embryo transfers decreases. As this is counterintuitive, as more oocytes should result in more embryos, with a better choice of quality embryos, we decided to analyse the recent experience in a busy IVF unit. STUDY DESIGN, SIZE DURATION: A retrospective analysis of clinical pregnancy and live birth outcome, with respect to number of oocytes collected at Monash IVF for the 2-year period between August 2010 and July 2012, where patients under the age of 45 years underwent a fresh embryo transfer. This included 7697 stimulated cycles for IVF and ICSI. PARTICIPANT/MATERIALS, SETTING, METHODS: Statistical analysis involved data tables and graphs comparing oocyte number with outcome. Results of women who had their first oocyte collection with an embryo transfer within the reference period were analysed by logistic regression analysis including other covariates that might influence pregnancy outcome. Analysis was also carried out of all the 7679 oocyte collections undertaken, resulting in fresh embryo transfers by generalized estimating equations to allow for the within subject correlation in outcomes for repeated treatments. MAIN RESULTS AND THE ROLE OF CHANCE: The number of oocytes collected varied from 1 to 48. Clinical pregnancy and live birth rates per embryo transfer varied from 10.2 and 9.2% when only one oocyte was collected to 37.7 and 31.3% when >16 oocytes were collected. Regression modelling indicated success rates increased or at least stayed the same or with the number of oocytes collected. The percentage of women with embryos cryopreserved increased from under 20% with <4 oocytes collected to over 70% with >16 oocytes collected. There was a slight increase (from 18 to 22%) in oocyte immaturity and a more marked increase (from 0 to 3%) in cancelling fresh transfers to prevent Ovarian Hyperstimulation Syndrome (OHSS) with increase in number of oocytes collected above 16. The results of this study suggest that you cannot collect too many oocytes as both clinical pregnancy and live birth rates do not decrease with high numbers of oocytes collected. However, once >15 oocytes are collected, everything gets quite uncertain. LIMITATIONS, REASONS FOR CAUTION: As the data become sparse above 15 oocytes, we could not demonstrate a significant increase in pregnancy rates above this number. Larger studies would be required to answer the question whether there is a plateau, or rates continue to increase. The negative of aggressive stimulation to produce many oocytes is that the risk of OHSS increases, and this is the most serious complication of ovarian stimulation. STUDY FUNDING/COMPLETING OF INTERESTS: No funding was required. There is no conflict of interest, except that G.K., V.M. and C.M. are shareholders in Monash IVF Pty Ltd.

Outcome of pregnancies achieved by in vitro fertilisation techniques and diagnosed as twins at the 6 week ultrasound.

BACKGROUND: To bring the success rate of in vitro fertilisation (IVF) procedures to an acceptable level, multiple embryos have historically been replaced. This has resulted in an 'epidemic' of multiple births. The pendulum has now swung full circle and the number of embryos transferred is now being limited. Such high numbers of IVF twins will not be produced in the future. AIM: To review retrospectively the outcome of a series of pregnancies achieved by IVF where the 6 week ultrasound showed the presence of two sacs. METHODS: Retrospective study in a university IVF programme that produced 746 IVF pregnancies with twins at 6 weeks of gestation (1991-1999). RESULTS: The main outcome measures were perinatal mortality, pregnancy outcome, gestation at delivery and obstetrics complications reported. Interestingly, by 20 weeks gestation, 184 (24.7%) of pregnancies spontaneously reduced to a singleton, whereas 49 (6.6%) lost both twins. Of the 513 (68.8%) viable twin pregnancies (>20 weeks), 154 (20.6%) went on to term (>37 weeks), whereas 250 (33.5%) delivered between 33 and 36 weeks gestation. The perinatal mortality per 1000 births was 6.5 over 37 weeks, 8.0 for 33-36 weeks, 41.7 for 29-32 weeks and 500 for under 28 weeks.

What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST endpoint for assisted reproduction.

Assisted reproduction programmes do not report success consistently. Rates vary with the definition used. Success must reflect delivery of healthy babies, and the burden of treatment to couples. We report the singleton, term gestation, live birth rate of a baby per assisted reproductive technology cycle initiated for a large IVF programme. We defined assisted reproductive technology cycles as those initiated with the intention of oocyte collection. We examined cycles conducted through Monash IVF in 2001. All women with positive pregnancy tests had first trimester ultrasonography. Obstetric outcomes were recorded. All babies had neonatal examinations conducted by paediatricians. A total of 644 positive pregnancy tests were recorded in 2600 cycles; 509 showed fetal heart motion. Of 448 deliveries, 328 were singleton and 120 were multiple. There were 290 singleton deliveries at term gestation. In 2001, a couple had an 11.1% chance of delivering a singleton, term gestation, live baby per assisted reproductive technology cycle begun. We suggest that delivery of a single, term gestation, live baby per cycle initiated is the most relevant standard of success. This statistic was 11.1% at Monash IVF. We encourage programmes to report this BESST (Birth Emphasizing a Successful Singleton at Term) outcome.

Replacement of one selected embryo is just as successful as two embryo transfer, without the risk of twin pregnancy.

The transition of in vitro fertilization from research to standard clinical practice has, to a great extent, been as a result of the use of controlled ovarian hyper stimulation. A disadvantage of the availability of multiple embryos has been the replacement of several embryos leading to an epidemic of multiple pregnancies. This retrospective review of 2606 fresh embryo transfers between 2001 and 2003, where either one or two selected embryos were replaced from an available cohort of at least four, shows that single embryo transfers have a similar pregnancy rate without the risk of multiple pregnancy.