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Studies comparing risk of specific congenital malformations (CM) between multiple pregnancies resulting from IVF/intracytoplasmic sperm injection (ICSI) and those conceived naturally report conflicting results; furthermore, there is a lack of a complete overview. This meta-analysis aimed to address which types of CM are increased in IVF/ICSI multiple pregnancies compared with those conceived naturally. All studies testing the association between IVF/ICSI multiple pregnancies and specific CM identified in various databases were considered. The literature search yielded 856 records, of which 21 cohort studies were included for analysis. Overall, multiple pregnancies achieved with IVF/ICSI experienced a significantly higher risk of chromosomal defects (relative risk [RR] = 1.36; 95% confidence interval [CI]: 1.04–1.77), urogenital (RR = 1.18; 95% CI: 1.03–1.36) and circulatory (RR = 1.22; 95% CI: 1.01–1.47) system malformations. However, the remaining specific CM, such as cleft lip and/or palate, eye, ear, face and neck, respiratory, musculoskeletal, nervous and digestive system malformations, were similar in the two groups. No substantial heterogeneity was observed for most outcomes except for digestive (P = 0.094; I2 = 38.3%) and circulatory (P = 0.070; I2 = 35.2%) system malformations. These findings provide additional information on risks of IVF/ICSI for use when counselling patients.
Assisted reproductive technologies, including IVF and intracytoplasmic sperm injection (ICSI), are helping many infertile patients to build their family. To date, assisted reproductive technology procedures have contributed to the births of more than 5 million children worldwide (
). One of the consequences of the increasing popularity of assisted reproductive technologies is the progressive rise in the incidence of twin, triplet and multiple pregnancies because of increased requests for the transfer of two or three embryos to achieve a higher pregnancy rate (
Obstetric and neonatal outcomes of twin pregnancies conceived by assisted reproductive technology compared with twin pregnancies conceived spontaneously: a prospective follow-up study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2012; 165: 29-32
). Perinatal mortality and morbidity are well known to be more frequent in multiple than in singleton pregnancies. To effectively reduce the risks associated with multiple pregnancies, a policy of single-embryo transfer (SET) in stimulated cycles is currently being recommended in more and more countries (
Obstetric and neonatal outcomes of twin pregnancies conceived by assisted reproductive technology compared with twin pregnancies conceived spontaneously: a prospective follow-up study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2012; 165: 29-32
Congenital malformations (CM) are common and complex adverse pregnancy outcomes associated with perinatal or infant mortality and morbidity throughout the world (
Pregnancy-related complications and adverse pregnancy outcomes in multiple pregnancies resulting from assisted reproductive technology: a meta-analysis of cohort studies.
) has confirmed that the multiple pregnancies created with IVF/ICSI were significantly associated with the risk of developing CM in their offspring, when compared with their spontaneously conceived (SC) counterparts. However, it remains unknown which type of CM is significantly increased among the multiple pregnancies following IVF/ICSI. An improved understanding of this topic may have important clinical implications, given the fact that the assessment of risk for the specific CM is a fundamental step in adequate pre-conception counselling for infertile couples who selected IVF/ICSI to achieve a pregnancy, especially considering that 21.8% of all deliveries globally following assisted reproductive technologies occur in pregnancies with more than one fetus (
Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE).
) have investigated the association between IVF/ICSI multiple pregnancies and risk of specific CM, but the magnitudes of the association varied across studies and the results are often inconsistent, and a complete overview is missing. Again, dedicated care could be better planned and provided. With recently accumulating evidence, our goal was therefore to appraise the association between multiple pregnancies generated by IVF/ICSI and risk of specific CM by conducting a meta-analysis of cohort studies.
Materials and methods
The proposed PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed to report the present review (
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
A systematic literature search was conducted of PubMed, Embase, Google Scholar, Cochrane Libraries, and Chinese databases including China Biology Medicine disc, Chinese Scientific Journals Full-text Database, China National Knowledge Infrastructure and Wanfang on 1 July 2017, to identify studies testing the association between IVF/ICSI multiple pregnancies and specific CM. No restrictions were imposed. The reference lists of retrieved papers and recent reviews were also reviewed, but authors of the primary studies were not contacted for additional information. The following search strategy was used: ‘(assisted reproductive technology OR ART OR assisted conception OR assisted reproduction OR in vitro fertilization OR IVF OR test tube baby OR intracytoplasmic sperm injection OR ICSI OR embryo transfer) and (congenital malformation OR malformation OR abnormalities OR birth defect OR defect) and (cohort studies OR prospective studies OR follow-up studies) and (twin OR multiple)’.
Outcomes of interest
In this review, outcomes of interest were CM that were defined as abnormalities which were probably of prenatal origin, including structural, chromosomal and genetic defects. CM were classified into specific subtypes according to organs and systems classifications, which included cleft lip and/or palate, chromosomal defects, and eye, ear, face and neck, respiratory, musculoskeletal, urogenital, digestive, circulatory and nervous system malformations. Because the risk of total CM associated with IVF/ICSI has been assessed by previous reviews, the focus of this study was on specific CM.
Study selection
In our study, the IVF/ICSI multiple pregnancies were defined as the exposed group, and those conceived after natural conception as the unexposed group. The unexposed group included babies born to women who conceived naturally and in some studies this group may be contaminated by births resulting from ovulation induction (OI) and/or intrauterine insemination (IUI) treatment if they could not be identified and excluded. An initial screening of titles or abstracts was carried out, followed by a second screening based on full-text review. Studies were considered eligible if they met the following criteria: (i) the study design was a prospective or retrospective cohort study; (ii) the exposure of interest was IVF/ICSI multiple pregnancies and the control was SC multiple pregnancies; (iii) the outcome of interest was specific CM; (iv) relative risks (RR) and odd ratios (OR) with corresponding 95% confidence intervals (CI) (or data to calculate them) were reported; and (v) the study was published in English or Chinese.
Data extraction
Data extraction was performed using a standardized data collection form. Any reported RR or OR and their 95% CI of specific CM for multiple pregnancies created with IVF/ICSI compared with the reference group were extracted, as well as characteristics for each study. Data were recorded as follows: first author's name; year of publication; study period; geographic region; sample source (population versus clinic-based studies); study design (prospective versus retrospective cohort study); sample sizes of IVF/ICSI and SC multiple births, respectively; type of assisted reproductive technology; plurality (twins or multiples); whether patients who achieved a pregnancy with OI and IUI were included in the reference group (yes versus no); specific CM reported; length of follow-up; confounding factors matched or adjusted (matched or adjusted versus crude); quality score; whether CM were diagnosed only in live births; and whether dichorionic twins data were provided.
Assessment of study quality
The quality of each study was appraised using the Newcastle–Ottawa Scale (
). This scale is an eight-item instrument designed to assess study population and selection, study comparability, follow-up and assessment of outcomes. One or two points were awarded for each criterion and then points were added up to compare study quality in a quantitative manner. Total points of <7 and ≥7 were assigned for low and high quality of studies, respectively. Three authors (ZZ, TBY and JBQ) independently conducted the study selection, data extraction and quality assessment. Any disagreements were resolved through discussion among the authors until consensus was reached.
Data synthesis
RR was used as a common measure of the relationship between IVF/ICSI and risk of specific CM across studies. The OR and incidence density ratios were directly considered as RR. Homogeneity of effect size was tested using the Q statistic (significance level at P < 0.1), and the I2 statistic (significance level at I2 > 50%) was calculated to measure inconsistency across studies. The combined RR and the corresponding 95% CI were calculated using either fixed-effects models, or in the presence of heterogeneity, random-effects models.
Subgroup analyses were performed based on: whether the confounding factors were adjusted or matched, geographic region, sample sources, quality scores, type of assisted reproductive technology, whether patients who achieved a pregnancy with OI and IUI were included in the reference group, length of follow-up, whether CM were diagnosed only in live births, zygosity diagnosis and plurality, to assess the effect of these variables on outcomes. Sensitivity analysis was conducted to explore possible explanations for heterogeneity and examine the influence of various exclusion criteria on the overall risk estimate.
Potential publication bias was assessed by visual inspection of the Begg funnel plots. The Egger linear regression test and Begg rank correlation test were also used to assess potential publication bias (significance level at P < 0.1). Statistical analyses were performed in STATA version 12.0 (StataCorp LP, College Station, TX). A P-value <0.05 was considered statistically significant, except where otherwise specified.
Results
Literature search
The systematic literature search yielded 856 potential eligible records. Of these, the majority were excluded after the first screening based on titles or abstracts, mainly because they were reviews or comments, duplicates, not cohort studies, or unrelated to our topic. After full-text review of 116 studies, 37 studies without a control group of natural conception, nine studies in which the exposure was inconsistent with the interests of this study, 23 studies without twins or multiples data, and 24 studies not assessing the specific CM, were excluded. Additionally, two studies (
Characteristics of included studies, which involved 61,815 IVF/ICSI multiple births and 204,471 SC multiple births, and were published between 1997 and 2017, are summarized in Supplementary Table S1. Nine studies (42.9%) were conducted in Europe, six (28.6%) in Asia, four (19.0%) in North America and two (9.5%) in Australia. The number of IVF/ICSI and SC multiple births ranged between 128 and 31,260 and between 192 and 132,061 across studies, respectively. The sample sources were based on population (47.6%) in 10 studies, and clinics (52.4%) in 11 studies. Fourteen studies (66.7%) were considered of higher methodological quality, which contributed 96.8% of IVF/ICSI births and 99.1% of SC births.
One-third (33.3%) of studies monitored the occurrence of CM in the offspring at least 1 year after birth, and the remaining diagnosed CM only at birth. A total of nine (
) studies grouped IVF and ICSI infants together, and data for IVF and ICSI could not be extracted separately. There were 11 and three studies that assessed CM in IVF and ICSI multiple births, respectively. Seven studies (
) grouped all multiples together, and had data for twins that could not be extracted independently. Fifteen studies (71.4%) did not include patients who achieved a pregnancy with OI and IUI in the spontaneous conception group, but the remaining studies included these patients in the spontaneous conception group. Twelve studies (57.1%) did not adjust and/or match any factors in estimating the effect of IVF/ICSI multiples on specific CM; other studies adjusted and/or matched for some potential confounders.
) included live births, stillbirths and terminations of pregnancy for fetal anomaly, and the remaining included live births and stillbirths but no terminations of pregnancy for fetal anomaly (
). Total number of IVF/ICSI and SC multiple births involved for each specific CM is summarized in Supplementary Table S2.
IVF/ICSI and risk of cleft lip and/or palate, eye, ear, face and neck, and respiratory system malformations
Figure 2 shows the results from the fixed-effects model combining the RR for cleft lip and/or palate, eye, ear, face and neck, and respiratory system malformations. Overall, the IVF/ICSI multiple pregnancies did not have a significantly increased risk of developing cleft lip and/or palate (RR = 0.91; 95% CI: 0.54–1.52), eye, ear, face and neck (RR = 0.98; 95% CI: 0.79–1.22) and respiratory (RR = 1.09; 95% CI: 0.77–1.53) system malformations in their offspring compared with those after natural conception.
Figure 2Forest plot for IVF/intracytoplasmic sperm injection (ICSI) and risk of cleft lip and/or palate, eye, ear, face and neck, and respiratory system malformations in multiple pregnancies using the fixed-effects model.
Substantial heterogeneity was not found for these outcomes (all I2 ≤31.3%). Further analyses using the random-effects model yielded similar results (RR = 0.91 [95% CI: 0.54–1.52], 0.98 [95% CI: 0.79–1.22] and 1.26 [95% CI: 0.76–2.10], respectively).
IVF/ICSI and risk of musculoskeletal, urogenital and digestive system malformations
Figure 3 displays the results from the fixed-effects model combining the RR for musculoskeletal, urogenital and digestive system malformations. Overall, the IVF/ICSI multiple pregnancies compared with the reference group experienced a significantly higher risk of developing urogenital system malformations (RR = 1.18; 95% CI: 1.03–1.36), but there were not evidently increased risks for developing musculoskeletal (RR = 1.13; 95% CI: 0.96–1.34) and digestive (RR = 1.14; 95% CI: 0.94–1.39) system malformations.
Figure 3Forest plot for IVF/ICSI and risk of musculoskeletal, urogenital and digestive system malformations in multiple pregnancies using the fixed-effects model.
There was no evidence of heterogeneity for these outcomes apart from digestive system malformations (P = 0.094; I2 = 38.3%). Further analyses using the random-effects model yielded similar results (RR = 1.18 [95% CI: 1.03–1.36], 1.14 [95% CI: 0.95–1.37] and 1.04 [95% CI: 0.77–1.40], respectively).
IVF/ICSI and risk of chromosomal defects, and nervous system malformations
Figure 4 depicts the results from the fixed-effects model combining the RR for chromosomal defects and nervous system malformations. Overall, the risk of developing chromosomal defects (RR = 1.36; 95% CI: 1.04–1.77) was significantly higher in IVF/ICSI multiple pregnancies than those conceived naturally, but there was not a significantly increased risk for nervous system malformations (RR = 1.22; 95% CI: 0.96–1.55), without the evidence of heterogeneity (both I2 ≤ 2.5%). Additionally, the random-effects model yielded similar results (RR = 1.35 [95% CI: 1.02–1.79], and 1.22 [95% CI: 0.96–1.55], respectively).
Figure 4Forest plot for IVF/ICSI and risk of chromosomal defects and nervous system malformations in multiple pregnancies using the fixed-effects model.
IVF/ICSI and risk of circulatory system malformations
Figure 5 shows the results from the random-effects model combining the RR for circulatory system malformations. Overall, IVF/ICSI multiple pregnancies compared with the reference group were at a higher risk of developing circulatory system malformations (RR = 1.22; 95% CI: 1.01–1.47).
Figure 5Forest plot for IVF/ICSI and risk of circulatory system malformations in multiple pregnancies using the random-effects model.
Substantial heterogeneity was observed (P = 0.070; I2 = 35.2%). Further analyses using the fixed-effects model yielded similar results (RR = 1.13; 95% CI: 1.02–1.24).
Subgroup analysis
Subgroup analysis is summarized in Supplementary Table S3. After subgroup analysis, sample sources, whether CM were diagnosed only in live births, zygosity diagnosis, whether the confounding factors were adjusted or matched, length of follow-up, and whether patients who achieved a pregnancy with OI and IUI were included in the SC group were identified as the first six of the most relevant heterogeneity moderators. These differences for risks of developing circulatory system malformations in IVF/ICSI multiple pregnancies were statistically significant for sample sources (χ2 = 6.43; P = 0.01) and zygosity diagnosis (χ2 = 6.28; P = 0.01). Risks of respiratory system malformations in IVF/ICSI multiple pregnancies were significantly different for whether the confounding factors were adjusted or matched (χ2 = 4.30; P = 0.04), whether patients who achieved a pregnancy with OI and IUI were included in the SC group (χ2 = 4.15; P = 0.04), and length of follow-up (χ2 = 4.50; P = 0.03). Additionally, there were statistically significant differences for developing digestive system malformations in IVF/ICSI multiple pregnancies for whether CM were diagnosed only in live births (χ2 = 4.22; P = 0.04).
Sensitivity analysis
Sensitivity analyses were performed to explore potential sources of heterogeneity in the association between IVF/ICSI and risks of specific CM and to examine the influence of various exclusion criteria on the overall risk estimate. Exclusion of seven low-quality studies (
) yielded similar results (Supplementary Table S3), without substantial evidence of heterogeneity apart from circulatory system malformations (P = 0.06; I2 = 42%). Further exclusion of seven studies (
) that grouped all multiples together and had data for twins that could not be extracted independently showed similar results, without substantial evidence of heterogeneity apart from circulatory system malformations (P = 0.02; I2 = 52%). The influence of each included study on the pooled risk estimate was also assessed by repeating the meta-analysis after omitting each study in turn. The results suggested that the combined OR was not dominated by any single study (Supplementary Figure S1).
Publication bias
Visual inspection of the Begg funnel plot did not identify substantial asymmetry apart from respiratory, digestive and circulatory system malformations (Supplementary Figure S2). The Egger linear regression test and Begg rank correlation test indicated no evidence of publication bias apart from eye, ear, face and neck (P = 0.088 and 0.048, respectively), and circulatory (P = 0.035 and 0.063, respectively) system malformations.
Discussion
Assisted reproductive technology procedures are well recognized to significantly increase the risk of multiple gestations, which in turn is associated with a higher rate of perinatal mortality and morbidity (
). This meta-analysis, including 21 cohort studies and involving 61,815 IVF/ICSI multiple births and 204,471 SC multiple births, with sufficient statistical power, aimed to assess the risk of specific CM among multiple pregnancies following IVF/ICSI by comparison with those conceived after natural conception. An improved understanding of this issue may have important clinical implications that are useful for counselling assisted reproductive technology patients and properly designing consent forms.
Findings from the present study indicated that the multiple pregnancies generated by IVF/ICSI, when compared with those conceived naturally, were at a significantly higher risk of 18% for urogenital system malformations, 36% for chromosomal defects and 22% for circulatory system malformations, but the remaining specific CM, such as cleft lip and/or palate, eye, ear, face and neck, respiratory, musculoskeletal, nervous and digestive system malformations, were similar in the two groups. Substantial heterogeneity was not observed for most outcomes apart from digestive and circulatory system malformations.
Assisted reproductive techniques are generally considered safe, but rapid technological progress leading to treatment modifications makes it important to continually monitor the safety of assisted reproductive technologies for the rapidly growing population of users of the technology and infants conceived with its use (
Pregnancy-related complications and adverse pregnancy outcomes in multiple pregnancies resulting from assisted reproductive technology: a meta-analysis of cohort studies.
) suggested that multiple pregnancies resulting from IVF/ICSI experienced a significantly increased risk for total CM compared with those conceived spontaneously. Nevertheless, it was known which type of CM is significantly increased among the multiple pregnancies created with IVF/ICSI. This meta-analysis was an effort to address this issue. In contrast to previous reviews (
Pregnancy-related complications and adverse pregnancy outcomes in multiple pregnancies resulting from assisted reproductive technology: a meta-analysis of cohort studies.
), the present study only focused on the specific CM after IVF/ICSI multiple pregnancies considering that the risk of total CM has been confirmed by previous meta-analysis. By using a classification system that groups CM into body systems, a specific association was found between IVF/ICSI multiple pregnancies and specific CM.
Although the past few years have seen a rapidly growing interest in addressing the correlation between IVF/ICSI multiple pregnancies and risk of specific CM, study results are often inconsistent. For example,
reported a significantly increased risk of developing chromosomal defects, eye, ear, face and neck, musculoskeletal, urogenital and circulatory system malformations among multiple pregnancies created with IVF/ICSI compared with those conceived naturally;
) did not accept these findings, reporting that multiple pregnancies generated by IVF/ICSI compared with those conceived naturally had similar risks for specific CM. Therefore, the published literature has provided conflicting data, which may be attributed to differences in study population, methodology and management methods for multiple pregnancies (
So far, no systematic reviews or meta-analyses have been conducted to explore the association between IVF/ICSI multiple pregnancies and specific CM, which emphasizes the need for the present review. Our review showed that IVF/ICSI multiple pregnancies were at a significantly increased risk of circulatory, chromosomal and urogenital defects, compared with SC multiple pregnancies. Musculoskeletal and nervous system defects were also increased, although there was no statistically significant difference. A previous meta-analysis (
) that grouped singletons and multiples together supported that assisted reproductive technology pregnancies had a significantly higher risk of nervous, digestive, urogenital, circulatory, musculoskeletal, and eye, ear, face, and neck system defects when compared with those conceived spontaneously. However, for specific CM in assisted reproductive technologies versus SC singleton pregnancies, no review has been conducted. Some evidence could be found from cohort studies. For example,
reported a significantly increased risk of cleft lip and/or palate, eye, ear, face and neck, digestive, musculoskeletal, urogenital, circulatory, and nervous system malformations in IVF/ICSI singleton pregnancies than the reference group;
only found an increased risk of circulatory system malformations.
Postulated mechanisms to explain the observed associations between IVF/ICSI multiple pregnancies and specific CM included the advanced age of one or both partners of the infertile couple, factors causing the infertility in the mother or father, prior treatment for infertility, duration of infertility, environmental exposures, chronic disease such as obesity and diabetes, risk behaviours such as alcohol and smoking, the medications used to induce ovulation or to maintain the luteal phase, and the assisted reproductive technology procedures themselves such as the culture media composition, the length of time in culture, the freezing and thawing of embryos, the potential for polyspermic fertilization, the delayed fertilization of the oocyte, altered hormonal environment at the time of implantation, and the manipulation of gametes and embryos (
Mothers who used assisted reproductive technologies to achieve a pregnancy have been reported to have a higher proportion of obesity and diabetes before pregnancy compared with those who conceived naturally (
). Additionally, previous studies showed the medications used to induce ovulation or to maintain the luteal phase were significantly associated with urogenital system defects (
). For example, the use of progesterones during assisted reproductive technology treatments has been offered as one explanation for the increased risk of urogenital system defects such as hypospadias (
). Children exposed in utero to oestrogens and progesterones or only progesterones were found to have more genital malformations than non-exposed children (
). In this review, when compared with those conceived spontaneously, the risk of urogenital system defects was obviously higher in ICSI (RR = 1.39; 95% CI: 1.02–1.90) than IVF (RR = 1.15; 95% CI: 0.92–1.44) multiple pregnancies. Additionally, the risk of specific CM in IVF/ICSI multiple pregnancies may be associated with abnormal genomic imprinting. Recently, attention has been directed toward epigenetic errors that might be intrinsic in the infertile couple or stimulated as a consequence of the infertility treatment itself (
). Differential methylation of cytosine leading to expression of only one or two parental alleles is a mechanism of gene regulation known as genomic imprinting (
). Defects in imprinting might cause either over- or under-expression of certain genes, leading to birth defects. It has been reported that urogenital, neural tube, gastrointestinal and genitourinary system defects were associated with imprinting problems (
). However, the aetiology is rarely discussed by previous studies with regarding to the association between IVF/ICSI and specific CM and warrants further research.
The present study has important strengths compared with previous studies. It represents, to our knowledge, the first meta-analysis between multiple pregnancies created with IVF/ICSI and risk of specific CM. All the included original studies were cohort studies, which eliminates the possibility of reverse causation and minimizes recall and selection biases. No heterogeneity was observed for most specific CM apart from two outcomes. The most relevant heterogeneity moderators have been identified by subgroup analysis. Sensitivity analyses indicated that the results were stable and reliable. Again, with the accumulating evidence and enlarged sample size, we have enhanced statistical power to provide more precise and reliable risk estimates, especially considering that both IVF/ICSI and CM are infrequent events, and sufficiently powered studies are needed to assess association, particularly for specific CM.
This study had some potential limitations. First, it only included studies published in Chinese or English, and additional research in other populations, especially those from developing countries, is warranted to generalize the findings. Second, the classification of CM was different across studies, which may lead to classification bias. Because variations in the definition of malformations exist across countries and cultures, it is extremely difficult to define uniform standards. Not all included studies had defined specific CM and in such cases, it was necessary to rely on the outcome terminology in the original articles. Third, previous studies showed that the occurrence of monochorionicity among twin pregnancies following IVF/ICSI is quite rare, compared with SC twin pregnancies (about 2% versus 22%, respectively), and monochorionic pregnancies have worse perinatal outcomes (
Obstetric and neonatal outcomes of twin pregnancies conceived by assisted reproductive technology compared with twin pregnancies conceived spontaneously: a prospective follow-up study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2012; 165: 29-32
). The lower proportion of monochorionic twins in pregnancies after IVF/ICSI may therefore somewhat offset the adverse effect of IVF/ICSI in twins, which indicates that our results may be underestimated. In this study, when data were restricted in dichorionic twins, it was found that the risk estimates for circulatory, urogenital and musculoskeletal system defects increase substantially (although they were not statistically significant apart from circulatory and musculoskeletal defects), whereas there was no real difference in the magnitude of the risk estimates for chromosomal defects. Of note, although a subgroup analysis was performed according to zygosity diagnosis, the majority (71.4%) of included studies did not state the type of twins.
Fourth, some included studies may have considered pregnancies arising after OI and IUI to be in the spontaneously generated category. The result may have been an underestimation of the association between IVF/ICSI multiple pregnancies and specific CM, because pregnancies occurring after OI and IUI have been reported to more frequently have worse outcomes, compared with those conceived naturally (
Adverse obstetric and perinatal outcomes of singleton pregnancies may be related to maternal factors associated with infertility rather than the type of assisted reproductive technology procedure used.
) also supported this viewpoint. However, a subgroup analysis was performed based on whether patients who achieved a pregnancy with OI and IUI were included in the SC group. When studies were excluded in which patients who achieved a pregnancy with OI and IUI were included in the SC group, it was found that the risk of musculoskeletal, circulatory and respiratory system defects was slightly increased in IVF/ICSI multiple pregnancies.
Fifth, the review included seven low-quality studies. However, the results of this subgroup analysis of high-quality studies were very consistent with the overall results. In high-quality studies, estimates suggested that circulatory, chromosomal and urogenital defects were significantly increased in IVF/ICSI multiple pregnancies. In addition, many different analyses were performed (Supplementary Table S3), which may increase the possibility of chance findings. However, the subgroup analyses lay out considerations for an ideal study design to address the issue of CM risk in assisted reproductive technology multiples. When there are sufficient studies that address all of these criteria it should be possible to provide pooled data that is more meaningful for patient counselling purposes. Last but not least, potential publication bias may influence the findings. In this study, the Egger linear regression test and Begg rank correlation test indicated the evidence of publication bias for specific CM of the eye, ear, face and neck, and the circulatory system.
In conclusion, this meta-analysis, involving a large proportion of participants, with sufficient statistical power, aimed to address which type of CM is significantly increased among multiple pregnancies following IVF/ICSI, compared with those conceived naturally. Although the role of potential bias should be carefully evaluated, the study shows that chromosomal defects, urogenital and circulatory system malformations were more frequent among the multiple pregnancies generated by IVF/ICSI than those conceived after natural conception. These findings provide additional information on the risks of IVF/ICSI that could be used when counselling patients.
Acknowledgements
The authors would like to thank the editors and reviewers for their suggestions. This study was supported by the Project Funded by China Postdoctoral Science Foundation (2015M572248), Hunan Provincial Science and Technology Plan Project (2015RS4055) and the Natural Science Foundation of Hunan Province (2016JJ4047). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The corresponding author (JBQ) had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Appendix. Supplementary material
The following is the supplementary data to this article:
Sensitivity analysis was performed by removing each study in turn and recalculating the pooled relative risk estimates [(a) cleft lip and/or palate; (b) respiratory system malformations; (c) eye, ear, face and neck malformations; (d) musculoskeletal system malformations; (e) urogenital system malformations; (f) digestive system malformations; (g) nervous system malformations; (h) chromosomal defects; (i) circulatory system malformations].
Adverse obstetric and perinatal outcomes of singleton pregnancies may be related to maternal factors associated with infertility rather than the type of assisted reproductive technology procedure used.
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Obstetric and neonatal outcomes of twin pregnancies conceived by assisted reproductive technology compared with twin pregnancies conceived spontaneously: a prospective follow-up study.
Eur. J. Obstet. Gynecol. Reprod. Biol.2012; 165: 29-32
Assisted reproductive technology and intrauterine inseminations in Europe, 2005: results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE).
Pregnancy-related complications and adverse pregnancy outcomes in multiple pregnancies resulting from assisted reproductive technology: a meta-analysis of cohort studies.
Jiabi Qin is a researcher in the field of reproductive epidemiology at the School of Public Health, Central South University. He received his PhD from the School of Public Health in 2014, undertook postdoctoral work at the State Key Laboratory of Medical Genetics until August 2016, and has been hired as a professor at Central South University since July 1, 2017.
Key message
The present meta-analysis combined data from 21 cohort studies with the aim of addressing which type of congenital malformation is significantly increased among IVF/ICSI multiple pregnancies compared with those conceived naturally. Chromosomal, urogenital and circulatory system malformations were more frequent among IVF/ICSI multiple pregnancies than in the reference group.
Article info
Publication history
Published online: February 01, 2018
Accepted:
January 10,
2018
Received in revised form:
January 10,
2018
Received:
August 1,
2017
Declaration: The authors report no financial or commercial conflicts of interest.
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