A meta-analysis of the impact of IVF and ICSI on major malformations after adjusting for the effect of subfertility

Purpose The aim of this study was to provide a comprehensive follow-up of fetal and perinatal outcome and the incidence of congenital anomalies in babies born after fresh embryo transfers compared to those conceived spontaneously in infertile couples. Methods Retrospective comparative analysis of all clinical pregnancies from fresh cleavage-stage embryo transfer cycles (IVF and ICSI) compared with infertile patients who conceived spontaneously in the same time period (control). Congenital anomalies were classified following the European Surveillance of Congenital Anomalies (EUROCAT) classification. Results A total of 2414 assisted reproductive technology (ART) pregnancies were compared to 582 spontaneous conceptions in the control infertile group representing 2306 deliveries. No significant differences were found in pregnancy outcome between the two groups (delivery rate, abortion rate, ectopic pregnancies, medical abortions for fetal anomalies, single and twins mean gestational age, and weight at delivery). A significant difference (p < 0.001) was found in the twin (21.3 vs 2.3 %) and triplet rates (2.3 vs 0 %). A total of 2351 babies were delivered in the ART group and 449 in the control group. A total of 90 babies (3.8 %) were diagnosed with a major congenital anomaly in the ART group and 15 (3.3 %) in the control group (p = ns). The overall rate of major congenital anomalies (105/2800) in ART and spontaneous pregnancies in infertile couples was significantly higher when compared to the EUROCAT 2.0 versus 3.75 % (p = 0.0002). Discussion Babies born after ART treatments and from spontaneous conception in infertile couples had rates of congenital anomalies higher than those recorded by the EUROCAT. However, the rates of anomalies were not different within the infertile population whether conceived by ART or spontaneously. These data suggest that the diagnosis of infertility in itself is the common denominator for the increase in the rates of anomalies seen in both ART and spontaneous conceptions.

Section: Discussionsupporting

confidence: 90%

Obstetric outcome and incidence of congenital anomalies in 2351 IVF/ICSI babies

Levi-Setti

Moioli

Smeraldi

et al. 2016

“…We would like to raise some concerns about the methods used to 'adjust' for the effect of subfertility in the metaanalysis of ART and major birth defects in the recent paper by Rimm et al [1] Having also published a systematic review and meta-analysis of ART and birth defects (BDs) [2], we are concerned both by the methods used and some of the statements made in the Rimm et al paper.…”

Section: To the Editormentioning

confidence: 99%

“…In their recent meta-analysis, Rimm et al [1] attempt to 'adjust' the study-specific estimates of BD risk for couples conceiving by ART for the proportion they estimate to be due to underlying subfertility, by subtracting the risk for couples who conceived naturally after more than 12 months (based on Zhu et al [3]). In doing so, they have assumed that the underlying causes of infertility in couples who managed to conceive spontaneously after 12+ months of trying were the same (and of equal severity) as those in couples who required ART to conceive.…”

Section: To the Editormentioning

confidence: 99%

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mentioning

confidence: 99%

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ART, birth defects and subfertility—what should prospective patients be told?

Hansen

Milne

Klerk

et al. 2011

To the EditorWe would like to raise some concerns about the methods used to 'adjust' for the effect of subfertility in the metaanalysis of ART and major birth defects in the recent paper by Rimm et al. [1] Having also published a systematic review and meta-analysis of ART and birth defects (BDs) [2], we are concerned both by the methods used and some of the statements made in the Rimm et al. paper.Assumptions underlying the adjustment method:In their recent meta-analysis, Rimm et al.[1] attempt to 'adjust' the study-specific estimates of BD risk for couples conceiving by ART for the proportion they estimate to be due to underlying subfertility, by subtracting the risk for couples who conceived naturally after more than 12 months (based on Zhu et al. [3]). In doing so, they have assumed that the underlying causes of infertility in couples who managed to conceive spontaneously after 12+ months of trying were the same (and of equal severity) as those in couples who required ART to conceive. We think this is unlikely since many couples who proceed to ART treatment, such as those where the female partner has blocked or absent fallopian tubes or is unable to ovulate, or where the male partner has very low or no sperm in his ejaculate, would have little or no chance of conceiving spontaneously.Meta-analysis is a statistical technique used to summarise the results from many different studies identified through systematic review on the premise that we should look at the body of evidence rather than any study in isolation. Rimm et al. have adjusted the results of the many ART studies they identified (with OR estimates ranging from 0.54 to 15.4) based on an estimate of subfertility derived from a single study, ignoring any of the uncertainty around the single estimate they use. The fact that there are limited data on subfertility and BD risk does not make this valid or appropriate.Inconsistencies in data presented: There appear to be errors in some of the adjustments made to the ORs in this meta-analysis.Although the OR estimates for individual studies are not listed in the original , the ORs presented in the forest plot increase in size from left to right. When these ORs are compared with those in the more recent paper, it is evident that the OR for Place et al. [5] is lower than the one included in the first meta-analysis. Using information in the Place et al. paper, we estimate the OR for major BDs among IVF and ICSI children combined to be 1.36, compared with the OR of 1.24 used in the second Rimm meta-analysis. It is not clear how this was calculated. Moreover, many of the adjusted ORs in Table 1 of the second meta-analysis appear to have been incorrectly calculated (eg MRC, Isaksson, Place, Sutcliffe 1995) so that the hierarchical position of the studies on the second forest plot has changed even further from the original. Some studies also appear to have been incorrectly labelled on the forest plot (eg the OR for Ludwig appears to have been labelled Zadori and vice-versa).Capsule Clinicians who counsel prospective...

“…For example, infertility is associated with abnormal sperm parameters and in turn men with azospermia or oligospermia have constitutional chromosomal abnormalities that may contribute to the development of birth defects [8,9]. Along this line, the frequency of birth defects has been shown to be increased among women who conceived spontaneously after a history of infertility [10,11,3,4].…”

Section: Introductionmentioning

confidence: 99%

The risk of birth defects after assisted reproduction

Parazzini

Cipriani

Bulfoni

et al. 2015

Purpose Aim of this study was to investigate the association between congenital malformations and type of conception (spontaneous or medically assisted). Methods This is a population based study using data from the regional data base of Lombardy, a Northern Italian Region with a population of about 10 million inhabitants. Included in the study were 277,043 neonates born in Lombardy during the study period 2010-2012. Adjusted and unadjusted odds ratios (OR), and corresponding 95 % confidence intervals (CI), of congenital abnormalities were calculated using unconditional multiple logistic regression. Results A total of 7057 births (2.5 %) were reported after non spontaneous conception. Overall, the frequency of birth defects was 4.4 % among births after spontaneous conception and 6.7 % among births after non spontaneous ones (OR= 1.67, 95%CI=1.5-1.9). The association disappeared after taking into account the confounding effect of maternal age and factors associated with non spontaneous conception. The crude OR of abnormalities was higher than unity for any defect (OR=1.67, 95%CI=1.5-1.9), multiple defects (OR=1.76, 95%CI=1.3-2.3), cardiovascular (OR=2.05, 95%CI=1.8-2.4), musculoskeletal (OR=2.05, 95%CI=1.7-2.5) and metabolic system abnormalities (OR=1.97, 95%CI=1.1-3.5). Almost all these associations, however, disappeared after taking into account potential confounding with the exception of musculoskeletal defects (adjusted OR=1.31, 95%CI=1.1-1.6). In this case also, if adjustment for multiple comparison is taking into account, results did not reach statistical significance. Conclusions The results of this analysis confirm the recently emerging view that the increased frequency of birth defects observed after ART/medically induced ovulation only is largely due to confounders.