In many countries, 1 to 3% or more of newborn
infants are conceived by assisted reproductive
technology (ART) (
Despite the success of ART, the risk of major congenital malformations (MCM) due to various parental factors or treatment may be increased. International studies show the high rate of prematurity,
low birth weight and infant mortality in ART conceived births (
"A widely accepted definition of major malformations was used, namely malformations that
generally cause functional impairment or require
surgical correction. Malformations were considered synonymously with structural malformation" (
Historical cohort study of major congenital malFarhangniya et al.
formationswas reformedin 978 births from January 2008 to December 2010. In our study, the incidence of MCMs among 326 ART infants (exposed
group) was compared with 652 infants who were
not born after ART (non-exposed group). We studied two naturally conceived (NC) infants for each
ART infant. This retrospective record linkage cohort study used data set: The ART database (exposed group) was obtained from Child Health and
Development Research Centre (CHDRC) which
is a subset of Iranian Academic Centre for Education, Culture and Research (ACECR); all the
mothers have been treated by Royan Institute for
Reproductive Biomedicine (RI-RB). Both groups
of exposed and unexposed infants were obtained
from CHDRC. We used an acceptable definition of
major malformations as a criteria for consideration
of diseases in this study as a major malformations
The CHDRC is the only centre in Tehran, Iran, to issues health certificate for children in different ages. For this reason, many infants and children from different areas of Tehran are referred to this centre so as to gain full visiting rights and observation for many years. Therefore, this group could be representative of infants who live in Tehran but may also be referred because of known health problems in the family.
So our inclusion criteria were as follows: i. the infants with the complete medical records from CHDRC obtained after the examination during two different time periods at the centre as follows: the first visit by 6 months of age, and the second visit between 6 and 18 months, ii. no history of major genetic disorders in the infant’s family, iii. residence in Tehran, and iv. first born child; and mothers without history of drugs and medicine usage during pregnancy, exposure to X-ray radiation during pregnancy, trauma to abdomen during pregnancy, and parental family relationships.
In addition, the Demographic information and the results from two visits included; mother’s age, infant’s sex, reproductive technique, type of delivery, history of stillbirth and abortion in mothers, report of first clinical visit, report of second clinical visit, and congenital malformation were extracted from children’s files.
stics to determine the prevalence of MCMs in both ART and NC groups.
We also performed multiple logistic regression analyses with SPSS-18 software to calculate the odds ratio (OR) and 95% confidence intervals (CI) for the independent association of ART on each outcome. Difference at the 5% level of significance was considered the threshold of significance. In addition to ART, each model included mother’s age, infant’s sex, reproductive technique, type of delivery, stillbirth and abortion as independent variables. Mothers’ age, type of delivery, history of stillbirth and abortion in mothers has been entered to the model to see whether they should be considered as confounding factors or not. For each of the above-mentioned outcomes, we conducted stratified analyses to examine potential confounding and/or effect modification of the ART-outcome associations by mothers’ age and infants’ sex.
The Research Ethics Committee of ACECR and Royan’s Institutional Review Board approved the study.
Of 978 infants who selected from CHDRC, 326 ART infants were chosen from CHDR Center and 652 NC infants (control group) were also selected from the same centre from 2008 to 2010.
Table 1 shows the prevalence rate of MCM in ART and NC groups. It also presents the comparison of MCM rate between the exposed and unexposed groups. Also this table shows the distribution of the data for ART infants by maternal age and infant’s sex compared with the NC infants. No statistically significant differences in the rate of malformations were noted for age groups and infant’s sex. In the two groups, NC mothers had an average age of 30.3 years, while ART mothers showed an average age of 30.6 years. We had 51% boys and 49% girls in both groups, as shown in table 1.
Prevalence of demographic and some important variables in ART and NC infants
In comparison with NC infants, we found that
ART infants had a 1.94-fold increased risk of MCM
which is statistically significant [p=0.017; 95% CI:
(1.13-3.34)]. When we entered stillbirths, abortion during pregnancy, and delivery methods in the
both univariate and multivariate models, we did not
find any effects on the risk of MCM. Table 1 shows
MCM analysed according to specific risk factors in
both ART and NC infants. This table also presents
these malformations separately for IVF and ICSI.
Major Congenital malformations compared in reproductive techniques and other important factors
shows in table 2. In addition, we sorted those according to different organ systems which are shown
in table 3. Overall musculoskeletal, genitourinary
and cardiovascular malformations were seen more
commonly in our study infants. On the other hand,
in comparison between ART and NC infants, in ART
infants, Developmental Dysplasia of the Hip (DDH),
hypospadias, rickets and Cardiovascular Heart Disease (CHD) and in NC infants; CHD have more frequency among other malformations (
The prevalence rate for ICSI was 6.5%, and for
IVF was 15.9%, which is 2.73 fold higher than
ICSI (p=0.018; 95% CI: 1.18-6.3,
Major congenital malformations compared in reproductive techniques and other important factors
|Variable||MCM||OR (95% CI)||P value||OR (95% CI)||P value|
|NC||623 (95.6%)||29 (4.4%)||Reference||Reference|
|ART||299 (91.7%)||27 (8.3%)||1.94 (1.13-3.34)||2.04 (0.92-4.5)|
|Male||473 (94.4%)||28 (5.6%)||Reference||Reference|
|Female||449 (94.1%)||28 (5.9%)||1.05 (0.61-1.81)||1.04 (0.61-1.08)|
|<35||738 (94.4%)||44 (5.6%)||Reference||Reference|
|≥35||184 (93.9%)||12 (6.1%)||1.09 (0.57-2.11)||1.05 (0.54-2.03)|
|No||907 (94.3%)||55 (5.7%)||Reference||Reference|
|≥1||15 (93.8%)||1 (6.3%)||1.1 (0.14-8.48)||1.02 (0.13-7.9)|
|No||551 (95.2%)||28 (4.8%)||Reference||Reference|
|≥1||371 (93%)||28 (7%)||1.48 (0.86-2.55)||1.14 (0.5-2.5)|
|Normal||111 (96.5%)||4 (3.5%)||Reference||Reference|
|Cesarean||810 (94%)||52 (6%)||1.64 (0.64-4.2)||1.3 (0.49-3.45)|
Prevalence of organs and systems’ major malformations in ART and NC infants
Prevalence of normality and major congenital malformations in ART and NC infants
|Result of 2 visits1||n||%||n||%||n||%|
*Children with two or more malformations counted once for all congenital malformations but counted for each malformation in related subgroup.
Major congenital malformations (MCM) in IVF technique compared with ICSI techniqueP value
|53 (84.1%)||10 (15.9%)||Reference|
|246 (93.5%)||17 (6.5%)||2.73 (1.18-6.3)|
|299 (91.7%)||27 (8.3%)|
Our study shows an overall increase in MCM after ART (8.3%) compared to naturally conceived infants (4.4%), with an odds ratio of 1.94. After adjustment for maternal age and infant’s sex (because ART mothers get pregnant on average 5 years later than NC mothers, and there are some possible differences in risk between girls and boys), and also adjusting for stillbirth, abortion and type of delivery, we found a relatively small difference in risk of MCM (OR=2.04; 95% CI: 0.92-4.5).
In fact after adjustment for mention variables, we noted nearly the same association between ART and MCM. The odds ratio of MCM had no changes with attending to the role of some variables like infants’ sex, maternal ages and stillbirth.
In this study, the majority (94.3%) of all infants
were normal, but 5.7% of infants had at least one
type of MCM. In comparison with studies in other
countries, our incidence of MCMs in ART infants
is similar to Germany (8%) (
We also found evidence of a difference in risk of
MCM between IVF and ICSI with an adjusted OR
of 2.73, especially when we compared these two
ART groups, we found 15.9% of IVF infants and
6.5% of ICSI infants had major congenital malformations. This finding is consistent with several
other studies (
After analysis of results by affected anatomical
organ system, the most frequently reported MCMs
in ART infants were musculoskeletal (2.8%) and
urogenital (2.3%) malformations. Another Iranian
study showed IVF infants had higher numbers of
congenital heart disease, developmental dysplasia
of the hip and hydronephrosis with renal reflux
Comparing malformations in ART and NC infants has some well recognised limitations. The
ART population is often not comparable to the
general population because the underlying infertility may be associated with factors leading to a
higher incidence of malformations. Another problem is that ART usually requires ovulation induction, which in itself poses an increased risk of
pregnancy loss. The last problem in this kind of
study is the potential confounding variables which include underlying maternal disease, maternal
drug exposure and nutrition (
Unless infants are examined without knowledge of how they were conceived, doctors may make a more careful examination of ART infants, thereby detecting and reporting more malformations than in NC infants. This is an important source of potential bias in this type of study, possibly resulting in differential misclassification and reducing external validity of the study. By selecting the unexposed group from the same centre, we anticipated that infants would be seen by the same paediatrician in order to reduce the likelihood of bias.
The strength of this study is that we controlled
some biases occurred in many previous studies (
It is noted that we ignore the possible role of
genotype and other unknown factors in increasing
incidence of malformations in ART infants. On the
other hand, among mothers using ART, there are
some well-defined and other less defined factors
which may cause infertility, and ultimately, lead
to an increased risk of congenital malformations
in this group (
In this study, we report a greater risk of MCMs in ART infants compared to naturally conceived infants in Iran. We also found evidence of a difference in risk of MCMs between IVF and ICSI. Musculoskeletal and urogenital malformations were the most reported MCMs in ART infants according to organs and systems classification. More musculoskeletal, cardiovascular and endocrine abnormalities have often been reported in ART infants than in NC infants while more visual, nervous and genetic disorders have been reported in NC than in ART infants.