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Assisted Reproductive Technology and Birth Defects: Effects of Subfertility and Multiple Births.

ABSTRACT: Assisted reproductive technology (ART) has been associated with birth defects, but the contributions of multiple births and underlying subfertility remain unclear. We evaluated the effects of subfertility and mediation by multiple births on associations between ART and nonchromosomal birth defects.We identified a retrospective cohort of Massachusetts live births and stillbirths from 2004 to 2010 among ART-exposed, ART-unexposed subfertile, and fertile mothers using linked information from fertility clinics, vital records, hospital discharges, and birth defects surveillance. Log-binomial regression was used to estimate prevalence ratios and 95% confidence intervals (CIs). Mediation analyses were performed to deconstruct the ART-birth defects association into the direct effect of ART, the indirect effect of multiple births, and the effect of ART-multiples interaction.Of 17,829 ART-exposed births, 355 had a birth defect, compared with 162 of 9431 births to subfertile mothers and 6183 of 445,080 births to fertile mothers. The adjusted prevalence ratio was 1.5 (95% CI, 1.3-1.6) for ART and 1.3 (95% CI, 1.1-1.5) in subfertile compared with fertile deliveries. We observed elevated rates of several birth defects with ART, including tetralogy of Fallot and hypospadias. Subfertility and multiple births affect these associations, with multiple births explaining 36% of the relative effect of ART on nonchromosomal birth defects.Although the risk of birth defects with ART is small, a substantial portion of the relative effect is mediated through multiple births, with subfertility contributing an important role. Future research is needed to determine the impact of newer techniques, such as single embryo transfer, on these risks. Birth Defects Research 109:1144-1153, 2017. © 2017 Wiley Periodicals, Inc.

SUBMITTER: Liberman RF

PROVIDER: S-EPMC5555800 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Assisted Reproductive Technology and Birth Defects: Effects of Subfertility and Multiple Births.

Liberman Rebecca F RF Getz Kelly D KD Heinke Dominique D Luke Barbara B Stern Judy E JE Declercq Eugene R ER Chen Xiaoli X Lin Angela E AE Anderka Marlene M

Birth defects research 20170621 14

<h4>Background</h4>Assisted reproductive technology (ART) has been associated with birth defects, but the contributions of multiple births and underlying subfertility remain unclear. We evaluated the effects of subfertility and mediation by multiple births on associations between ART and nonchromosomal birth defects.<h4>Methods</h4>We identified a retrospective cohort of Massachusetts live births and stillbirths from 2004 to 2010 among ART-exposed, ART-unexposed subfertile, and fertile mothers u ...[more]

PMID: 28635008

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Project description:BackgroundIt has been consistently shown in several meta-analyses that infants born after ART have an excess of birth defects compared with those after spontaneous conception, however, the prevalence of birth defects among ART offspring in China is incompletely studied. Moreover, it is unclear to what extent the risk of birth defects is associated with parental infertility characteristics, specific ART procedures and twinning.MethodsIn the prospective cohort study, we included women who participated in the cohort, and had pregnancies of at least 20 gestational weeks between August 2016 and May 2019, and followed them until their children reached 1 year of age. Exposures of interest were ART, as well as infertility-related characteristics, certain ART procedures and specific medication usage. The primary outcome was birth defects including both major and minor defects, which we analysed with logistic generalized estimating equations to investigate the association with ART and certain ART characteristics.FindingsA total of 1,825 women with ART-pregnancy and 3,483 women with spontaneous-pregnancy were included in the analysis. The prevalence of any defects was significantly higher among ART-births than their non-ART counterparts at each follow-up, specifically at prenatal screening (2•2% vs. 1•2%), at delivery (4•9% vs. 2•9%), at 6 months (10•4% vs. 5•3%) and 1 year of age (13•9% vs. 7•0%), and the associations between ART and increased risk of birth defects at each follow-up were similarly robust. Among ART-births, GnRH antagonist regimen for ovulation induction in women was associated with an increased risk of birth defects in their offspring after taking into account potential influencing factors (Multivariable model: adjusted risk ratio [aRR] 1•47, 1•04-2•07). Additionally, mediation through twinning accounted for 31•1% of the risk of ART-associated birth defects.InterpretationThe results suggest that ART confers an increased risk for birth defects in offspring. The risk is partly attributable to infertility characteristics, certain ovulation induction regimen, and to some extent mediated by twinning. Our findings highlight the importance of long-term follow-up of children conceived via ART for health conditions.FundingNational Key Research and Development Program of China, National Natural Science Foundation of China and Natural Science Foundation of Jiangsu Province.

Project description:ObjectiveTo determine the maternal demographic, health, and fertility variables underlying prematurity.DesignRetrospective: Society for Assisted Reproductive Technology Clinic Outcome Reporting System data linked to Massachusetts birth certificates and hospital stays.SettingNot applicable.PatientsWe included 166,963 privately insured, singleton, first births to women ≥18 years of age between 2004 and 2013. Deliveries were as follows: assisted reproductive technology (ART) when linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System, medically assisted reproduction (MAR) when fertility treatment was indicated on the birth certificate, unassisted subfertile (USF) when there were indications of subfertility but no treatment, and fertile if none of the above.InterventionNone.Main outcome measuresLate preterm birth (LPTB; 34-36 weeks) and early preterm birth (EPTB; <34 weeks) were compared with term deliveries (≥37 weeks). Covariates that statistically significantly influenced prematurity in binary analysis were modeled by using multinomial logistic regression. Backward elimination and mediation analysis were used to determine the influence of single parameters on outcomes of others.ResultsLPTB was increased in the USF (adjusted odds ratio [AOR] 1.32, 95% confidence interval [CI] 1.06-1.65) and ART (AOR 1.42, 95% CI 1.30-1.56) but not MAR (AOR 1.16, 95% CI 0.98-1.37). ETPB was increased in all (USF: AOR 1.67, 95% CI 1.21-2.31; MAR: AOR 1.67, 95% CI 1.31-2.12; ART: AOR 1.40, 95% CI 1.21-1.61). The strongest effectors of prematurity were placental problems (LPTB: AOR 4.02; EPTB: AOR 10.28), pregnancy hypertension (LPTB: AOR 2.14; EPTB: AOR 2.88), and chronic hypertension (LPTB: AOR 1.85; EPTB: AOR 2.79). Mediation analysis demonstrated a statistically significant indirect effect of placental problems for ART and subfertility.ConclusionThe greatest effectors of prematurity were placental problems and hypertensive disorders. ART and, to a lesser extent, subfertility were both associated with preterm birth directly and indirectly mediated by placenta problems.

Project description:Study questionWhat are the socio-demographic characteristics of families in Norway who have children after assisted reproductive technology (ART), and have these characteristics changed over time?Summary answerParents who conceive through ART in Norway tend to be advantaged families, and their socio-demographic profile has not changed considerably over the period 1985-2014.What is known alreadyA small number of studies show that couples who conceive through ART tend to be socio-economically advantaged.Study design, size, durationNorwegian Population Register, the Medical Birth Register and the national data bases were linked to study all live births in Norway between 1985 and 2014.Participants/materials, setting, methodsThe sample consisted of 1?757?768 live births. Simple bivariate analyses were performed to describe the socio-demographic characteristics of parents who conceived through ART and changes in these characteristics over the time period 1985-2014. We used linear probability models to estimate the association between parental income and giving birth after ART from 2000 to 2014, before and after adjustment for maternal age at delivery, education and area of residence.Main results and the role of chanceParents conceiving through ART were more likely to be older, with the highest levels of income and education, and married. Their socio-demographic profiles did not change considerably during the period 1985-2014. In the unadjusted model, parents belonging to the top income quartile were 4.2 percentage points more likely (95% CI: 4.1 to 4.3) to have conceived through ART than parents who belonged to the bottom income quartile. Adjustment for maternal age only partially reduced the income disparities (for the top income quartile by 35% (??=?2.7 with 95% CI: 2.5 to 2.8)). Additional adjustment for maternal education, marital status and area of residence did not further attenuate the associations.Limitations, reasons for cautionThe data does not enable us to tell whether the lower numbers of children conceived through ART amongst more disadvantaged individuals is caused by lower success rates with ART treatment, lower demand of ART services or barriers faced in access to ART. The study focuses on Norway, a context characterised by high subsidisation of ART services.Wider implications of the findingsEven though in Norway access to ART services is highly subsidised, the results highlight important and persisting social inequities in use of ART. The results also indicate that children born after ART grow up in resourceful environments, which will benefit their development and well-being.Study funding/competing interest(s)This work was supported by European Research Council agreement n. 803959 (to A.G.), by Economic and Social Research Council grant ES/M001660/1 and by the Research Council of Norway through its Centres of Excellence funding scheme, project number 262700. The authors have no conflict of interest to declare.Trial registration numberNot applicable.

Project description:ObjectivesTo compare the differences in the prevalence of birth defects among offspring conceived by assisted reproductive technology (ART) and conceived spontaneously (non-ART), and assess the contribution of ART to birth defects.DesignA population-based retrospective cohort study.SettingBeijing.ParticipantsPregnant women whose expected date of childbirth was verified as occurring between October 2014 and September 2015, and were registered on the Beijing Maternal and Child Health Information Network System, were the recorded pregnancy outcomes. 2699 ART offspring and 191 368 non-ART offspring (live births, stillbirths and medical terminations) were included in our study.InterventionsNone.Outcome measuresRisk ratios (RR) for birth defects were calculated among ART conceptions and non-ART conceptions with confounding factors by using logistic regression models.Results194 067 offspring were included in the present study, and 2699 (1.4%) were conceived using ART. Among all the births, the prevalence of any birth defect in the ART offspring (5.5%) was significantly higher than in the non-ART offspring (3.8%) (crude RR, 1.49, 95% CI 1.26 to 1.76). After adjusting for confounding factors, ART use was still associated with an increased risk of any birth defect (5.4% vs 3.5% in ART and non-ART group, adjusted RR (aRR), 1.43, 95% CI 1.08 to 1.90), especially for chromosomal abnormalities (0.5% vs 0.2% in ART and non-ART group, aRR, 3.11, 95% CI 1.28 to 7.58), in singleton births to mothers <35 years. Circulatory system malformations and musculoskeletal system malformations were observed to have a non-significant increase in offspring conceived by ART. However, the associations between ART and birth defects were not detected in multiple births or mothers ≥35 years.ConclusionsThis study confirmed a small but significant association between ART and birth defects. However, the risk tends to be non-significant under the conditions of advanced maternal age or multiple pregnancies.

Project description:ObjectiveTo compare incidence, risk factors, and etiology of women's deaths in fertile, subfertile, and undergoing assisted reproductive technology (ART) in the years after delivery.DesignRetrospective cohort.SettingUniversity hospital.Patient(s)Women who had delivered in Massachusetts.Intervention(s)This study used data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System linked to vital records, hospital stays, and the Massachusetts death file. Mortality of patients delivered from 2004-2013 was evaluated through 2015. The exposure groups, determined on the basis of the last delivery, were ART-treated (linked to Society for Assisted Reproductive Technology Clinic Outcome Reporting System), subfertile (no ART but with indicators of subfertility including birth certificate checkbox for fertility treatment, prior hospitalization for infertility [International Classification of Disease codes 9 628 or V23], and/or prior delivery with checkbox or ART), or fertile (neither ART nor subfertile). Numbers (per 100,000 women-years) and causes of death were obtained from the Massachusetts death file.Main outcome measure(s)Mortality of women after delivery in each of the three fertility groups and the most common etiology of death in each.Result(s)We included 483,547 women: 16,429 ART, 11,696 subfertile, and 455,422 fertile among whom there were 1,280 deaths with 21.1, 25.5, and 44.7 deaths, respectively, per 100,000 women-years. External causes (violence, accidents, and poisonings) were the most common reasons for death in the fertile group. Deaths occurred on average 46 months after delivery. When external causes of death were removed, there were 19.1, 17.0, and 25.6 deaths per 100,000 women-years and leading causes of death in all groups were cancer and circulatory problems.Conclusion(s)The study presents reassuring data that death rates within 5 years of delivery in ART-treated and subfertile women do not differ from those in fertile women.

Project description:Live-birth rates after treatment with assisted reproductive technology have traditionally been reported on a per-cycle basis. For women receiving continued treatment, cumulative success rates are a more important measure.We linked data from cycles of assisted reproductive technology in the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database for the period from 2004 through 2009 to individual women in order to estimate cumulative live-birth rates. Conservative estimates assumed that women who did not return for treatment would not have a live birth; optimal estimates assumed that these women would have live-birth rates similar to those for women continuing treatment.The data were from 246,740 women, with 471,208 cycles and 140,859 live births. Live-birth rates declined with increasing maternal age and increasing cycle number with autologous, but not donor, oocytes. By the third cycle, the conservative and optimal estimates of live-birth rates with autologous oocytes had declined from 63.3% and 74.6%, respectively, for women younger than 31 years of age to 18.6% and 27.8% for those 41 or 42 years of age and to 6.6% and 11.3% for those 43 years of age or older. When donor oocytes were used, the rates were higher than 60% and 80%, respectively, for all ages. Rates were higher with blastocyst embryos (day of transfer, 5 or 6) than with cleavage embryos (day of transfer, 2 or 3). At the third cycle, the conservative and optimal estimates of cumulative live-birth rates were, respectively, 42.7% and 65.3% for transfer of cleavage embryos and 52.4% and 80.7% for transfer of blastocyst embryos when fresh autologous oocytes were used.Our results indicate that live-birth rates approaching natural fecundity can be achieved by means of assisted reproductive technology when there are favorable patient and embryo characteristics. Live-birth rates among older women are lower than those among younger women when autologous oocytes are used but are similar to the rates among young women when donor oocytes are used. (Funded by the National Institutes of Health and the Society for Assisted Reproductive Technology.).

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Assisted Reproductive Technology and Birth Defects: Effects of Subfertility and Multiple Births.

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Assisted Reproductive Technology and Birth Defects: Effects of Subfertility and Multiple Births.

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