ABSTRACT
This large retrospective study was conducted to compare the risk for birth defects among infants conceived by in vitro fertilization (IVF) with that among infants conceived by intracytoplasmic sperm injection (ICSI) and to explore the effect of frozen embryo transfer (FET) on the risk for birth defects among infants born by IVF and ICSI. All patients who received assisted reproductive technology (ART) treatment and who underwent childbirth during the period January 2005–August 2017 were included in this study. There were 18,221 births after ART included in the analysis; of these births, 12,649 were conceived by IVF, and 5,572 were conceived by ICSI. In the study, the prevalence of any birth defect in singleton infants was 1.15% with the use of IVF and 1.38% with the use of ICSI, and that in twin infants increased to 2.74% by IVF and 2.58% by ICSI. However, no significant difference between IVF and ICSI was found among all infants, singleton births or twin births. Additionally, in assessing ART infants born after FET, we did not detect a difference in the risk for birth defects between infants born by IVF and those born by ICSI. These results indicate that among the entire cohort of children conceived from ART and among the children conceived from FET, the risk for birth defects after ICSI is similar to that after IVF.Abbreviations: IVF: in vitro fertilization; ICSI: intracytoplasmic sperm injection; FET: frozen embryo transfer; ART: assisted reproductive technology; ET: embryo transfer; BMI: body mass index; OHSS: ovarian hyperstimulation syndrome; CMOH: Chinese Ministry of Health; ICD-10: International Classification of Diseases, 10th edition; PTB: preterm birth; OR: odds ratio; aOR: adjusted odds ratio; CI: confidence interval
Introduction
Assisted reproductive technology (ART), which includes in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), is a common medical practice for infertile women of reproductive age (Kissin et al. Citation2014). Clinically, IVF has been widely used for many categories of infertile couples since the first child was born by IVF in 1978. After the first birth of an infant by ICSI in 1992, ICSI was increasingly used for couples with severe male infertility disease, and the scope of ICSI application has expanded greatly to patients without male factor infertility. With more than 5 million infants born via ART globally, the safety of ART has been a worldwide concern. Birth defects (also called congenital anomalies or congenital malformations), the major cause of death and disability in infants, is a severe global public health problem. There has been an increasing number of research studies focusing on birth defects among children after ART, since a series of reports indicated that infants conceived with the use of ART was associated with an increased risk for birth defects compared to those conceived naturally (Davies et al. Citation2012; Wen et al. Citation2012; Hansen et al. Citation2013; Heisey et al. Citation2015). Although many studies reported no significant difference in the risk for birth defects between infants conceived by ICSI compared and those conceived by IVF, other studies concluded that infants conceived by ICSI had a 1.5–4 times increased risk for chromosomal abnormalities, imprinting disorders, and other birth defects compared to those conceived by IVF (Bonduelle et al. Citation2002; Lie et al. Citation2005; Zhu et al. Citation2006; Amor and Halliday Citation2008; Belva et al. Citation2008; Gjerris et al. Citation2008; Davies et al. Citation2012; Wen et al. Citation2012; Boulet et al. Citation2015).
Frozen embryo transfer (FET) has become a routine procedure for IVF and ICSI treatment. Emerging as an alternative to fresh embryo transfer (ET), FET has many advantages in ART treatment. It helps to improve the cumulative pregnancy rate while decreasing the risk for ovarian hyperstimulation syndrome and additional ovarian stimulation and oocyte retrieval (Barnhart Citation2014). However, a concern with FET is whether it has adverse effects on births and whether its effects are different between IVF and ICSI. The results from previous studies comparing the risk for birth defects between infants with IVF-FET and those with ICSI-FET are inconsistent. A large population-based study in South Australia showed no significant difference in the risk for any birth defect among births resulting from IVF-FET compared with those from ICSI-FET (Davies et al. Citation2012). However, a hospital-based study evaluating the safety of infants after IVF or ICSI found a higher birth defect rate in the ICSI-FET group compared with the IVF-FET group (Belva et al. Citation2008). In addition, there is limited research on the risk for birth defects with the use of other ART procedures, such as embryo stage at transfer, and the number of embryos transferred.
We conducted this study to evaluate the risk for birth defects following specific ART procedures. The aim of our study was to assess the risk for overall birth defect and specific birth defects among infants conceived by IVF compared to those conceived by ICSI and to examine the risk for overall birth defect among different types of ART procedures for infants conceived with IVF or ICSI.
Results
There were 18,221 births after ART included in the analysis; of these births, 12,649 were conceived by IVF, and 5572 were conceived by ICSI. Compared with ICSI, IVF had higher frequencies of twins and a gestation of less than 32 weeks (). The average birth weight of infants conceived by IVF was lower than that of infants conceived by ICSI. Mothers of ICSI infants were more likely to be younger than 30 years or older than 40 years and were more likely to have primary infertility and male factor infertility than mothers of IVF infants. There was no difference in the distribution of body mass index (BMI) between the mothers of ICSI infants and mothers of IVF infants.
Table 1. Characteristics of births conceived with IVF or ICSI, 2005–2017.
Among all births, the prevalence of any birth defect was 1.57% (n = 199) for births conceived by IVF, compared with 1.67% (n = 93) for ICSI births; however, no significant difference in the risk for any birth defect was found between the two groups (adjusted odds ratio (aOR): 0.97; 95% confidence interval (CI): 0.72–1.30) (). The prevalence of multiple birth defects was 0.09% (n = 12) for IVF infants and 0.07% (n = 4) for ICSI infants, but the type of ART was not significantly associated with the risk for multiple birth defects (aOR: 0.78; 95% CI: 0.22–2.74). For subcategories of birth defects, the risk for birth defects was not significantly different between IVF infants and ICSI infants.
Table 2. Logistic regression for birth defects of infants conceived with ICSI compared with IVF, 2005–2017.
For singleton infants, the prevalence of any birth defect was 1.15% in infants conceived by IVF and 1.38% for infants conceived by ICSI, and it increased for twin infants, to 2.74% for those conceived by IVF, and to 2.58% ICSI (). Stratified by plurality (singleton vs. twins), the multivariate analysis showed the risk for having at least one birth defect or having multiple birth defects did not differ between IVF and ICSI infants for both singleton and twin births. For singleton births, the only subcategory of birth defects for which there was a significantly increased risk was circulatory abnormalities (aOR: 1.82; 95% CI: 1.06–3.12), whereas for twin births, there was no significant association between the type of ART (IVF or ICSI) and risk for any subcategory of birth defects.
Table 3. Logistic regression for birth defects of singleton and twins infants conceived with ICSI compared with IVF, 2005–2017.
When the study population was restricted to whole IVF births, there was no significant increase in the risk for any birth defect between births resulting from FET and births from fresh ET (aOR: 1.15; 95% CI: 0.53–2.53) (). The abovementioned associations also existed among singleton IVF infants and twin IVF infants. For those conceived by ICSI, no significant association of type of cycle (FET or fresh ET) with any birth defect was found among the whole ICSI infants or singleton and twin ICSI infants. The risk for any birth defect in specific ART procedures, including frozen embryo transfer and embryo transfer, was not different between the IVF group and ICSI group for whole births and singleton and twin births. It is worth noting that there was one birth defect in 34 monozygotic infants.
Table 4. Risk of any birth defects among infants born after fresh and frozen-thawed embryo transfer in the IVF and ICSI, 2005–2017.
summarizes the relationship of any birth defect with specific ART procedures after FET among infants. The stage of embryo transfer was not associated with the risk for any birth defect among the whole IVF-FET infants and ICSI-FET infants. Similar associations were also noted in singleton and twin births. When comparing IVF-FET with ICSI-FET for any birth defect, no differences in the protocol of cleavage stage embryo transfer and blastocyst transfer used were observed for all births, singletons or twins.
Table 5. Risk of any birth defects among infants born after frozen-thawed embryo transfer in the IVF and ICSI, 2005–2017.
Discussion
This retrospective analysis did not identify a significantly increased risk for any birth defect or multiple birth defects among infants conceived by ICSI when compared with those conceived by IVF. As far as specific organ system defects were concerned, no differences in the risk for any subcategory of birth defect were shown between infants conceived by IVF and those conceived by ICSI. Our findings are in accordance with those of other studies. A large population-based cohort study in three American States reported that infants born after ICSI did not have a higher risk for selected nonchromosomal birth defects than infants born after conventional IVF (Boulet et al. Citation2016). Lie et al. reported no significantly increased risk for major birth defects in ICSI as compared with IVF (odds ratio (OR) = 1.12, 95% CI: 0.97–1.28) based on a meta-analysis of four studies (Lie et al. Citation2005). Wen et al., based on the results of 24 studies, estimated that the pooled risk ratio for birth defects in ICSI infants compared with IVF infants was 1.05 (95% CI: 0.91–1.20)(Wen et al. Citation2012). However, the results from a population-based study conducted in South Australia between 1986 and 2002 are in contrast to those of previous studies. In that study, Davies et al. found a higher risk for birth defects among infants conceived by ICSI than those conceived by IVF (OR = 1.47, 95% CI: 1.15–1.89) (Davies et al. Citation2012). The inconsistency of results may be related to many factors, such as different measurement methods for birth defects and the different study populations. Pinborget et al. pointed out that the recent studies were likely to show a lower birth defect risk for ICSI children since the application range of ICSI has been expanded from being used for couples with severe male infertility to those with nonmale factor infertility (Pinborg et al. Citation2012).
Stratified by plurality (singleton vs. twins), no significantly increased risk for any subcategory of birth defects were shown in singleton infants by ICSI compared with singleton infants by IVF, with the exception of circulatory abnormalities (aOR: 1.82; 95% CI: 1.06–3.12). For twin births, there was no difference in risk for birth defects between IVF and ICSI for any birth defect subcategory. The reason for this relationship between circulatory abnormalities and ICSI is unknown, but Ericson et al. speculated that it may be caused by paternal subfertility with a genetic background (Ericson and Kallen Citation2001). Therefore, this result hinted that further research exploring this association should include adjusting for the sex of infants.
With significant technological advances in cryopreservation, the frozen embryos were well-preserved in terms of quality and potential for implantation (Herrero et al. Citation2011; Cobo et al. Citation2012). FET has been a routine procedure of ART and an alternative to fresh ET when dyssynchrony between endometrial receptivity and the development stage of the embryo was present. With this method, embryos were transferred into the more favorable uterine environment, which improved the pregnancy rates and live birth rates and reduced the prevalence of ovarian hyperstimulation syndrome (OHSS) (Aflatoonian et al. Citation2010; Maheshwari et al. Citation2012; Roque et al. Citation2013). For the birth defects, our study did not indicate a significant difference between births after FET and births after fresh ET. The results from most previous studies are similar to this result, except for one study that found a higher risk for birth defects among births by FET (Belva et al. Citation2008; Davies et al. Citation2012; Pinborg et al. Citation2013; Pelkonen et al. Citation2014). In general, our result indicated that FET is a safe, convenient, effective method to use during ART treatment. However, the drawbacks of FET, such as the financial costs associated with FET cycles, including cryopreservation costs and endometrial priming costs, the emotional distress from deferred embryo transfer, and the physical costs related to endometrium preparation treatments also should be considered. Thus, before widespread adoption of FET, more research studies are needed to weigh the potential benefits against the costs.
The few available studies comparing the risk for birth defects in infants after IVF-FET with that in infants after ICSI-FET have conflicting results. Davies et al. did not detect a difference in the risk for birth defects between infants born by IVF-FET and those born by ICSI-FET, which is a result that is consistent with the results of our study (Davies et al. Citation2012). However, Belva et al. found a twofold increase of major birth defects in ICSI-FET infants compared with IVF-FET infants (Belva et al. Citation2008). Many factors related the FET procedure, such as the cryopreservation method, quality of transferred frozen-thawed embryos, and protocol for endometrial preparation, as well as ethnic differences, may affect the prevalence of birth defects. Differences in the abovementioned factors among studies may partly explain their inconsistent results. In addition, we did not find a significant association between any birth defect and the stage or number of embryos transferred between infants conceived by IVF-FET and those conceived by ICSI-FET. Similarly, for any specific ART procedure, there was no increased risk for birth defects in the ICSI-FET infants compared with the IVF-FET infants. However, this result should be interpreted with caution because we have no information on birth defects among women suffering miscarriage.
From our perspective, this was a large population-based study with a large amount of detailed information on the type of ART procedure. We compared the risk for birth defects by ICSI with that by IVF in infants after whole ART and after FET. In addition, the significantly higher proportion of male factor etiology within the ICSI cohort reflected the more judicious and appropriate use of ICSI regulated in China, so that it is more likely that the data specifically reflect any ICSI-associated birth defects. However, our study has several limitations. First, we had no information about the occurrence of birth defects among women suffering miscarriage due to fetal abnormality, which may result in an underestimation of the true prevalence of birth defects (Samadirad et al. Citation2012; Svensson et al. Citation2014). Second, we were unable to adjust for various potential confounding variables, such as prenatal screening for fetal abnormalities, family history of birth defects, maternal smoking, and environmental exposures (Hackshaw et al. Citation2011; Deng et al. Citation2015; Rocheleau et al. Citation2015).
In summary, this study showed that the risk for birth defects after ICSI is similar to that of IVF among an entire cohort of children conceived from ART and among children conceived from FET. However, more studies evaluating long-term outcomes of children conceived by ICSI and IVF are needed.
Materials and methods
Details of ART treatment were provided by the Department of Assisted Reproduction of Shanghai Ninth People’s Hospital affiliated with Jiaotong University School of Medicine (a large, hospital-based reproductive tertiary care center in Shanghai, China). The study was approved by the ethics committee (institutional review board) of Shanghai Ninth People’s Hospital. Informed written consent in accordance with the ethics committee protocol was obtained from all patients. Any birth in the hospital resulting from ART was recorded according to the requirements of the Technical Standard for Human Assisted Reproduction issued by the Chinese Ministry of Health (CMOH). All patients who received ART treatment and underwent childbirth at this hospital during the period January 2005–August 2017 were included in this study.
The collection of data in this study was similar to that in earlier follow-up studies and has been extensively described in previous publications (Chen et al. Citation2015). Briefly, the couples completed a telephone interview during each stage of pregnancy and until 1 month after delivery to provide data on: a wide range of preconception and pregnancy exposures; gestational weeks; pregnancy complications; mode of delivery; birthdate and birth locality; birth weight and length; infant gender; and neonatal diseases, if any. Pertinent information on the questionnaire was researched through family planning service agencies when attempts to contact couples failed. Data on pregnancies, deliveries, and neonatal histories were retrieved from written information obtained from the gynecologists, pediatricians, and parents. Information obtained from the gynecologists/pediatrician was double-checked with the parents and completed with additional information on hospital admissions, surgery, and medication intake. The births included in the study were those, whether live or not, that were conceived with the use of ART and that had a gestational age of at least 23 weeks and a birthweight no less than 500 g. In the present study, we mainly excluded minor birth defects, except for those that required treatment or were disfiguring. Birth defects were ascertained by the submission of discharge records with the birth defect diagnosis from the birth hospital or pediatric care center, and the birth defects were classified and coded according to the International Classification of Diseases, 10th Revision (ICD-10), including structural abnormalities, biochemical abnormalities, and chromosomal or genetic abnormalities. Information on congenital anomalies was retrieved from medical documents and included results from genetic tests and pathology reports. If diagnosis was in question, a pediatric geneticist reviewed the records to determine the diagnosis after consulting the diagnosing physician, if necessary. In total, 13 subcategories of birth defects and two additional categories, ‘any birth defect’ and ‘multiple birth defects’, were created and used in this study. Each patient was counted only once in each subgroup, but a patient with multiple birth defects may have been included in more than one subgroup.
We described the distribution of demographic characteristics for the IVF and ICSI births. The demographic variables included plurality, birth weight, gestational age, maternal age, female infertility type, infertility causes, and maternal body mass index (BMI). Preterm birth (PTB) was defined as birth before 37 weeks of gestation, and that in < 32 weeks defined early PTB. Maternal ages were categorized into five age groups (<30, 30–34, 35–37, 38–40, and >40 years). The total patient population was divided into three different groups according to BMI (BMI < 25, 25–29, and >29). We also compared the prevalence of any birth defect and multiple birth defects and that of the different subcategories of birth defects for all births conceived by IVF and ICSI, stratified by singleton and twin births.
Next, we evaluated the prevalence of any birth defect in infants for certain ART procedures, including the type of cycle (FET or fresh ET) and number of embryos transferred (1 or ≥2), stratified by type of ART (IVF or ICSI) and plurality (singleton vs. twins). Because the proportion of frozen embryo transfer was more than 85% among all embryo transfer cycles, we further restricted the analysis population to infants conceived from IVF-FET or ICSI-FET and examined the prevalence of any birth defect by stage of embryo transferred (cleavage stage or blastocyst stage), number of embryos transferred (1 or ≥2), and other certain procedures combining the stage of embryo transferred and number of embryos transferred (transfer of one embryo at cleavage stage, transfer of one embryo at blastocyst stage, transfer of two embryos at cleavage stage, or transfer of two embryos at blastocyst stage). We conducted the abovementioned analyses for all births by IVF-FET or ICSI-FET and for singleton or twin births.
Differences in the distribution of demographic variables, using the chi-square test for categorical variables and using student’s t test for continuous variables, were studied. A logistic regression model was used to compute the OR for associations between the use of IVF or ICSI and birth defects. This study was conducted to compare the risk for birth defects among infants conceived by IVF with that among infants conceived by ICSI, so we used IVF as reference. The model was adjusted for maternal age, type of infertility, causes of infertility, and year of birth. We did not adjust for gestational age and birthweight in the model, as they were likely to be potential intermediate factors for birth defects. The results are reported as the aOR with 95% CI. We used the same approach to estimate the adjusted odds ratio for the relationships of the specified ART procedures with any birth defects. Two-tailed p values less than 0.05 were considered significant. All statistical analyses were performed using the statistical package Stata, version 12.
Acknowledgments
The material contained in the manuscript is original and has not been published elsewhere. Furthermore, it has not been submitted and is not going to be submitted elsewhere. The authors are solely responsible for the content and writing of the article. No funding was received for the study.
Disclosure statement
No potential conflict of interest was reported by the authors.
Additional information
Funding
Notes on contributors
Yanping Kuang
Conceived and designed the experiments: YK, YW; analyzed the data: JZ, QZ, BW, QL; wrote the manuscript: JZ, QZ.
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