Assisted reproductive technologies (ARTS) are used for more than 30 years to help infertile couples. Concerns about long-term health of children conceived following ART have led to start follow-up studies. Despite methodological limitations and discrepant results, many of the studies and meta-analyses have reported an increased risk of birth defects after ART. Etiologies may be multiple births, a major drawback of ART, parents' subfertility, or technologies themselves. Prematurity and intrauterine growth retardation (IUGR) seem to cause most of the pathologies reported in ART children. Nevertheless, epigenetic disorders need to be followed up since increases of imprinting diseases were reported. Consequently, alteration of gametes and early embryo development with ART may have consequences on children health since periconceptional period is critical for long-term development. Yet general condition of most of children conceived with ART is reassuring, but long-term followup is still strongly needed.
Currently, more than 3 500 000 children were born following assisted reproductive technologies (ARTS) [
Since Louise Brown was born in 1978,
In 1992, a new technology, intracytoplasmic sperm injection (ICSI), had been developed and had spread throughout the world [
Other technologies have emerged like embryo cryopreservation with slow freezing protocols and more recently vitrification. Preimplantation genetic diagnosis (PGD) or screening (PGS) used to detect and eliminate embryos with single-gene disorders or aneuploidy is quite invasive and demand more embryo handling and may be at risk of altered embryo and fetal developments.
Concerns about long-term health of people conceived with ART still remain, and many studies have been conducted worldwide. Despite methodological limitations, different designs of these studies and other bias may have led to contradictory results, and many of the studies and meta-analyses reported from the followup of children born after ART concluded an increased risk of birth defects.
Multiple pregnancies are a major drawback of ART, leading to serious obstetrical risks. After spontaneous conception, multiple pregnancy risk is about 1% whereas it is about 25% following ART. Higher risks of prematurity, low birth weight, perinatal death, and neurologic sequelae (learning disability, language problems, etc.) have been reported concerning multiple births. To avoid such drawbacks, a policy of elective single embryo transfer (eSET) has been developed by many countries [
Even if multiple pregnancy risks are well known, it was also highlighted that pregnancy risks are more frequent in singleton conceived with ART. Data reported in 3 meta analyses have demonstrated that singletons born following ART (IVF, ICSI, GIFT) have twofold risks of low or very low birth weight, prematurity, and intrauterine growth retardation (IUGR) compared to singleton conceived spontaneously [
Furthermore, a link between time to conceive (as an index of subfertility of the parents) and risk of prematurity and low birth weight has been established [
In a multicentre study conducted on 1 515 five-year-old children, Bonduelle et al. showed an increased risk of major and minor malformations detected from the neonatal period up to 5 years [
No different temperaments and behaviour issues were observed in IVF or ICSI children compared to naturally conceived children. However, psychological testing on parents has underlined that mother who conceived child with ICSI seems to have a more commitment to parenting [
Several reports have observed, studying subfertile couples, a small increase of chromosomal abnormalities especially in males with deep infertility [
Many steps are needed to achieve pregnancy with ART. All the stages are critical and may influence long-term health of the conceptus.
Induction of ovulation with high doses of gonadotrophin alters oocyte maturation process and creates an artificial environment in oviduct and uterus, which can influence fertilisation and preimplantation embryos.
With IVF success, many concerns about embryo culture appeared. Embryos developed
When ICSI was started, many risks were highlighted. First of all, it was obvious that there were more chromosomal abnormalities and gene disorders in spermatozoa used for ICSI. These defects can impact on embryo development, and chromosomal abnormality can be transmitted in case of sperm aneuploidy. Offspring run a risk of gene abnormalities related to fertility issue inheritance [
Furthermore, when ICSI is performed, a spermatozoon is injected directly into the cytoplasm of each oocyte. Then, first steps of fertilization are bypassed leading to a loss of selection of morphologically normal spermatozoon, even if data on this specific topic showed that there is no selection of spermatozoon in spontaneous conception [
Finally, even if the injection of spermatozoon with chromosomal abnormalities is the most probable cause of higher incidence of chromosomal abnormalities in fetus, risk may be linked to the process of ICSI itself. The breaking of the zona pellucida and cytoplasmic membrane could lead to injuries of internal structures of the oocyte and have deleterious consequences such as aneuploidy and chromosomal abnormalities [
Few followups of children conceived with cryopreserved embryo transfer are available. However, more major malformations were observed in ICSI children born after cryopreserved embryo transfer. Furthermore, children conceived with cryopreserved embryos tended to have more chromosomal abnormalities and have significant higher birthweight than children conceived with fresh embryos [
However, Wennerholm et al. published a recent review concerning the long-term outcome of children conceived with cryopreserved embryo transfer. Their results were reassuring despite an increasing risk of low birthweight and prematurity following the slow freezing method, and they conclude that data on children conceived with embryo cryopreserved with vitrification are needed [
Germ cell and preimplantation embryo developments are critical stages for epigenetic events. Indeed, DNA methylation is erased in primordial germ cells and reapposed during spermatozoon and oocyte maturation in a sex-specific manner. After fertilization, the epigenetic resetting of the gamete genome leads to the activation of developmental genes and allows pluripotency, but imprinting genes are protected from demethylation. Imprinting genes are functionally haploid and are expressed in a parent-of-origin-specific manner (expression from a single parental allele). To date, 100 imprinting genes are known and play a critical role in embryo development and fetus growth.
Epigenetic disruptions may take root during gametogenesis, fertilization, and preimplantation embryo development. Gamete and embryo exposure to artificial conditions may lead to epimutation and altered imprinting genes with consequences on fetal development.
In human sperm, altered methylations of H19 DMR (differentially methylated regions) were observed in patients with oligozoospermia, teratozoospermia, or oligoasthenoteratozoospermia [
It was demonstrated in mouse and human that ovarian stimulation may alter methylation of imprinting genes. Despite H19 is a maternally expressed gene only methylated on the paternal chromosome, methylation was found in H19 DMRs of superovulated mouse oocyte and of human superovulated immature oocytes [
Consequently, culture medium composition can affect the expression of imprinted genes and influence phenotype of the conceptus.
The mechanisms of epimutations are still unknown.
A link between imprinting disorders and ART is known for a few years [
An association between Angelman syndrome (AS) and ICSI was also observed [
Epigenetic disorders were identified in majority of cases of AS and BWS after ART, and defect of maternal allele methylation was detected in all cases of AS and BWS caused by epigenetic disorders [
Very few data are available to link ART with other imprinting diseases such as Prader-Willi syndrome and Russel-Silver syndrome, and more epidemiological studies are needed.
Nevertheless, some other large epidemiological studies [
Many studies have highlighted an increased risk of cancer in children born following IVF-ICSI [
Furthermore, long-term studies would be necessary to highlight an increased risk of adult cancer.
Discrepant data are available on this topic and have underlined that neurological abnormalities and cerebral palsy may be more frequent or not in ARTchildren. A recent systematic review taking account of methodological bias concluded that children conceived after IVF/ICSI do not have impaired neuromotor, cognitive, language, and behavioural development compared to naturally conceived children [
Very few data concerning cardiovascular outcomes of ART children are available and are strongly needed. In 2007, Painter and Roseboom emphasized the lack of information about this subject [
Followup of ART children should be proceeded by all ART centres but is time-consuming, and researchers are confronted by methodological difficulties. Indeed, researchers need to contact families many years after birth and can create a risk of stigmatization of ART children. High rate of nonparticipation is reported in many studies, depending on cultural influences and legal rules of each country that could generate a bias of selection because of numerous refusal or lost to followup [
There are clear evidences of birth defects after ART. Periconceptional and prenatal periods are critical for long-term development. Several etiologies may involve parents’ subfertility or technologies. To date, multiple births represent the major risk of ART defects, and, reducing the number of embryo transferred to minimize, this drawback should be a strong priority. ART singletons are also at risk of impaired development since slightly increase of childhood illness and more hospital admission are reported. Nevertheless, prematurity and IUGR seem to be causes of most of the pathologies reported in ART children. On the other hand, researchers need to continue paying attention of imprinting diseases. Finally, general condition of most of children conceived with ART is reassuring, but parents undergoing ART should be aware of such existing risks. Long-term followups are still strongly needed.
Currently, first IVF people are now more than 30 years old, and some of them have conceived children. We can wonder if children born from parents conceived following ART are at risk of altered development. Indeed, epidemiological studies on nutrition and fetal programming have suggested that exposure of paternal grandfathers to famine influences obesity and cardiovascular disease in subsequent generations [