Placenta
Volume 29, Supplement 2 , Pages 135-140, October 2008

Follow-up of Children Born after ART

Adolescent and General Paediatric Unit, Institute of Child Health, University College London, 250 Euston Road, 6th Floor, London NW1 2PQ, UK

Accepted 13 August 2008.

Article Outline

Abstract 

Assisted reproductive therapies (ART), namely in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), have become widely used in the treatment of human infertility. Children conceived using ART represent a substantial proportion of the population. Follow-up of these children is necessary in order to evaluate the risks of infertility treatment upon subsequently conceived offspring. In recent years there has been considerable work in this field. This review summarises current evidence regarding the health of children conceived following ART, encompassing neonatal outcomes, the risk of congenital malformations, neurodevelopmental outcome, physical health, psychosocial well being, and the risk of cancer. The main risks for the future well being of ART children remain multiple pregnancies and low birth weight. Evidence regarding the outcome of singletons born at term following ART is generally reassuring. It is essential that follow-up of ART children continues as they progress through adolescence into adulthood.

Keywords: Follow-up, Assisted reproductive therapies, ART, In vitro fertilisation, IVF, Intracytoplasmic sperm injection, ICSI

 

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1. Introduction 

Assisted reproductive technologies (ART), which may involve the manipulation of both eggs and sperm in the laboratory, are now widely used in the treatment of human infertility. Since the birth in 1978 of the first child (Louise Brown) to be conceived by in vitro fertilisation (IVF), it is likely that well over 1 million babies have been born worldwide using ART [1], [2]. During this time there have been rapid advances in assisted reproduction technologies. The introduction of embryo cryopreservation [3], and subsequently the more invasive ‘technique’ of intracytoplasmic sperm injection (ICSI) in 1992 [4], has improved the effectiveness of IVF considerably. Development of preimplantation genetic diagnosis (PGD) has facilitated identification and exclusion of genetically abnormal embryos, but involves significant manipulation of the embryo [5]. At present 1–3% of children born in developed countries are conceived through ART [6], [7].

There are various reasons why children conceived through ART might be exposed to greater health risks than naturally conceived children. ART carries a significantly increased risk of multiple pregnancies, which are associated with a higher rate of prematurity and low birth weights, and carry well-established risks of morbidity to the child [8]. The background biology of subfertile couples may confer health risks to ART children. Couples undergoing assisted reproduction are presently on average around 5 years older than those who conceive spontaneously [9]. Subfertility itself, without any fertility treatment, is recognised to be a risk factor for problems during gestation and birth [10], [11], [12]. Finally, procedural factors related to fertility treatments themselves may confer health risks to ART children. These include the artificial induction of ovulation with the possibility of changes in follicle milieu and oocyte structure, exposure of sperm and embryos to in vitro environments which might change their natural function, freezing and manipulation of oocytes and embryos (for example in PGD) [13], [14].

With children conceived through ART now forming a sizeable subgroup of the population, long-term follow-up studies of these children are required to assess the safety of ART. Many early outcome studies of ART children have common shortcomings, being small, uncontrolled, with poor follow-up rates. Despite IVF having been in practice for almost 30 years, most studies to date have only included newborns and young children, few having followed up ART children into early teenage years.

This review aims to summarise what is known about the health of children conceived using assisted reproductive techniques. We only briefly consider perinatal outcomes and the risk of congenital malformations following ART, as these are dealt with in detail elsewhere in this issue. In order to identify relevant articles we conducted a PubMed search with the terms: (“assisted reproduction” or IVF or ICSI) and (outcome or health or development). Only articles in the English language were included. We identified further relevant studies among the references citied in some of the articles returned by our search.

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2. Multiple births and perinatal outcome 

High multiple pregnancy rates continue to be the single greatest factor adversely impacting upon the outcome of ART pregnancies. Multiple birth rates of between 22.7 and 31.7% are being reported in Europe [15] and USA [6], respectively, following IVF and ICSI, compared to 1–2% of all births in the general population. Multiple pregnancy is a well-established risk factor for numerous adverse outcomes including preterm delivery, low birth weight, neonatal mortality, congenital malformation, and disability amongst survivors [16]. In the general population, the risk of preterm delivery is 5-fold in twins compared to singletons [17], and 50% of twins are born at a low birth weight (<2500g) compared to 6% of singletons [18]. However, most of the available evidence does not suggest that ART multiple pregnancies are at greater risk of adverse perinatal outcomes than non-ART multiple pregnancies [19].

In response to this problem, there has been a gradual trend over recent years to limit the number of embryos transferred into the uterine cavity per cycle of IVF/ICSI. In some Scandinavian countries single-embryo transfer (SET) has become the norm, resulting in a significant reduction in multiple birth rates in Sweden to ∼5% whilst maintaining pregnancy rates of 30–40% per transfer [20], [21]. A Cochrane review comparing the outcome of dual-embryo transfer in a single cycle vs. SET (combined with transfer of a single frozen–thawed embryo in a subsequent cycle if needed), identified similar pregnancy rates in both groups (odds ratio 1.19, 95% CI 0.87–1.62) with substantially greater multiple pregnancy rates following dual-embryo transfer (odds ratio 62.83, 95% CI 8.52–463.57) [22]. Kjellberg et al. [23] demonstrated significantly lower rates of premature delivery, low birth weight and paediatric complications requiring admission to a neonatal unit following SET compared to dual-embryo transfer.

However, elimination of multiple pregnancies will not totally eliminate the increased risk of adverse perinatal outcomes in ART pregnancies. Various meta-analyses have demonstrated that singleton children born after ART are at increased risk of preterm delivery, low birth weight, neonatal mortality, and neonatal intensive care unit admission when compared to spontaneously conceived singleton controls [19], [24], [25]. Underlying parental subfertility is likely to contribute to this risk, as significant correlations have been identified between time to pregnancy intervals of over 12 months and adverse outcomes including preterm birth, low birth weight, and perinatal mortality [26], [27], [28]. However, the relative contributions of parental subfertility, and other factors such as maternal age and procedural factors, towards the observed adverse perinatal outcomes in ART singleton pregnancies have yet to be established.

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3. Congenital malformations and birth defects 

Concerns were raised regarding the risk of congenital malformations following IVF as early as the 1980s, and intensified following the introduction of ICSI [29]. A number of meta-analyses have been published, reporting an increased risk of major malformations of between 29 and 41% in children born following ART when compared with naturally conceived children [25], [30], [31]. No significant difference in malformation rates between IVF and ICSI groups were found [31], [32]. More recent case–control studies and population-based registry studies have supported these findings [33], [34], [35], [36]. However, it is important to note that many of the studies on malformations after ART have significant methodological limitations, as recently reviewed by Sutcliffe and Ludwig [37]. These relate to imprecise definition and classification of congenital abnormalities, differences in method used to assess malformations, whether or not abortions and stillbirths are included, and differences in length of follow-up between groups.

A recent Danish registry-based study compared malformation rates in singletons born to fertile couples (time to pregnancy interval≤12 months), and singletons born to infertile couples (time to pregnancy interval of >12 months) who either conceived naturally or with infertility treatment [36]. Compared to children in the fertile group, singletons born to infertile couples had a higher rate of congenital malformations whether they were conceived naturally (OR 1.20, 95% CI 1.07–1.35) or after infertility treatment (OR 1.39, 95% CI 1.23–1.57), following adjustment for maternal age, BMI, smoking, and various other confounders. There was no significant difference in overall prevalence of malformations between the infertile group that conceived naturally and the infertile group that received treatment. These findings suggest that the increased risk of congenital malformations in ART children is largely due to the underlying parental background, rather than the treatment techniques themselves.

Concerns have also been raised regarding the risk of rare imprinting disorders following ART, with reports of increased risk of Beckwith–Wiedemann Syndrome (BWS) and Angelman's Syndrome [38], [39], [40]. The findings of subsequent surveys have been inconsistent; some reporting increased frequency of BWS in ART children [41], others not finding any association [42], [43], [44]. Due to the rarity of these conditions, much larger studies are required to reliably detect such associations.

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4. Neurodevelopmental outcome 

Numerous studies investigating the neurodevelopmental outcome (i.e. locomotor, cognitive, speech and language, and behaviour) in ART children have been published. The vast majority of these have been reassuring, not showing any significant difference in neurodevelopmental attainment between naturally conceived children and children conceived following various forms of ART. Early case-controlled studies were generally limited by small sample size, and only involved infants [45], [46], [47]. Subsequently, a number of authors have published larger, well-controlled studies of IVF and ICSI children at various ages.

Sutcliffe et al. performed a prospective study in children aged between 1 and 2 years, in which no difference in neurodevelopmental outcome (assessed using Griffiths Mental Development Scales) was found between 208 ICSI-conceived singletons and 221 matched spontaneously conceived (SC) singletons [48], [49]. Koivurova and colleagues did not identify any difference in psychomotor development (assessed using modified Bayley scales) between a cohort of 299 IVF children and 558 matched controls, assessed as part of the Finnish national screening programme at the ages of 12 months, 18 months, 2 years and 3 years [50]. Such standardised tests of mental development allow objective and quantifiable assessment of neurodevelopmental attainment at the age of examination, but may not have an accurate predictive value for future cognitive function at a latter age [51].

A number of studies have investigated neurodevelopmental outcomes in children aged 5 years. The largest of these involved collaboration between five European countries, and recruited 5-year-old singletons that were born ≥32 weeks of gestation; 511 ICSI-conceived, 424 IVF-conceived, and 488 SC controls [52]. Cognitive and motor development was assessed using Wechsler scales of intelligence and McCarthy motor scales. No significant differences were identified between the three groups. Other studies involving ICSI singletons aged between 4 and 6 years have reported similar results [53], two accounting for the potential confounder of preterm delivery by only including children born at term [54], [55]. A group in Belgium has followed up their cohort of ICSI children to the age of 10, showing similar cognitive and motor development between 109 ICSI singletons and 90 SC controls, at the ages of 8 and 10 [56], [57].

The first studies to investigate neurodevelopmental outcomes following preimplantation genetic diagnosis/screening (PGD) were recently published. Banerjee et al. found no difference in Griffiths Mental Development Scoring between 49 PGD children and 66 matched SC controls, in children aged between 3 months and 4 years [58]. A Belgian study reported similar mental and psychomotor outcomes between three groups of 2-year-old children: 70 born following PGD, 70 born following ICSI, and 70 matched SC controls [59].

However, a few studies have reported concerns regarding neurodevelopment in ART children. An Australian study suggested that 1-year-old children born following ICSI were more likely to exhibit delayed development than children born following IVF or natural conception [60]. However, this work had a number of significant methodological flaws, being statistically underpowered due to the small sample size, and failing to account for parental education level. A follow-up report of the same cohort of children at 5-years of age found them to be developmentally normal [61]. A recently published Dutch study has reported a lower mean IQ in 5–8 year old ICSI singletons (n=86) compared to naturally conceived singletons (n=85) [62]. However, there are weaknesses in the methodology of this study; it is small, used multiple examiners, and did not control for level of education of the parents.

In summary, the vast majority of the data available suggests that there is no difference in the neurodevelopmental well being of singleton ART children when compared to naturally conceived (NC) children, with the proviso that they are born at term and not from multiple births. Studies to the contrary are in a minority and are poorly constructed, but support the case for further follow-up of these children to continue as they grow older.

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5. Neurological outcome 

Four large registry-based cohort studies from Scandinavia have reported increased risks of cerebral palsy (CP) of between 1.6- and 3.7-fold in IVF children compared to naturally conceived children [44], [63], [64], [65]. Regression analysis of the data in two of these studies revealed that the increased risk is largely due to the higher frequency of multiple pregnancies, low birth weight, and prematurity in IVF children [63], [65]. No difference in the risk of CP between IVF twins and naturally conceived twins has been shown [63], [65], [66], although all multiple births are associated with a 4-fold greater risk of CP than singleton births [67]. Middleburg has published a recent review further exploring the risk of cerebral palsy and other neurodevelopmental handicaps in ART children [68].

There is evidence supporting a moderately increased risk of epilepsy in ART children. Using the Swedish national register of IVF pregnancies, Ericson and colleagues reported an increased risk of hospital admission with epilepsy in IVF children compared to spontaneously conceived children aged 1–11 years (odds ratio 1.54, 95% CI 1.10–2.15) [64]. In a seemingly separate study, the same group report that no difference in risk remains when only term children are included, or when figures are adjusted for a number of parental factors including years of unwanted childlessness [69]. More recently, Sun et al. published similar findings using the Danish national birth cohort between 1996 and 2002 [70]. They compared singletons conceived naturally by fertile couples (time to conception<6 months) with singletons born to subfertile couples (time to conception>12 months). Children were aged between 0 and 6 years. They found an increased risk of presentation to hospital with epilepsy in singletons born to subfertile couples, whether conceived spontaneously (odds ratio 1.38, 95% CI 1.00–1.89) or following treatment with IVF/ICSI (odds ratio 1.83, 95% CI 1.09–3.06). This difference lost statistical significance when preterm deliveries were excluded. Thus, the increased risk of epilepsy in ART children appears to be largely due to underlying parental subfertility and the risk of preterm delivery.

A number of prospective controlled studies, based upon interviews or neurological examination, did not find any difference in neurological outcome between ART and spontaneously conceived children aged 5–8 years [33], [55], [71], [72]. The largest of these studies compared cohorts of 540 ICSI, 437 IVF, and 538 naturally conceived children aged 5 years, across five European countries [33]. However, cerebral palsy and epilepsy are rare, and in order for studies to have the necessary statistical power to be able to identify differences in the risk of these conditions, sample sizes of several thousand children are required. Such cohorts can only be obtained in registry-based studies. Furthermore, most of the prospective studies excluded children born following multiple pregnancies or born <32 weeks of gestation, thus excluding many children at higher risk of neurological morbidity.

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6. Growth and physical health 

The vast majority of studies investigating growth beyond the neonatal period have not found any difference between ART and spontaneously conceived (SC) children. The weight, height, and head circumference of IVF and ICSI children at the ages of 6–12 months [73], 1–3 years [46], 5 years [33], [74], [75], 8 years [71], [76], and 6–12 years [77] have been reported to be normal. Recently, similarly reassuring findings have been reported in a cohort of children aged 3 months to 4 years conceived after preimplantation genetic diagnosis [58]. Studies involving detailed physical examinations have not revealed any significant differences between ART and SC children [33], [71], [74], [75].

Contrary to these findings, two studies have reported differences in growth parameters between IVF children and SC controls [50], [78]. Koivurova and colleagues found IVF singletons to be significantly lighter in weight than SC controls up until the age of 3 [50]. Recently, a group from New Zealand reported that their cohort of 69 IVF/ICSI children aged 5–6 years were significantly taller than SC controls, following adjustment for age and parental height [78]. They also found higher serum levels of insulin-like growth factors I and II in the ART children.

Evidence regarding the incidence of childhood illnesses and healthcare utilisation amongst ART children is not consistent. Bonduelle et al. conducted structured interviews with parents and found that IVF and ICSI children were more likely than SC controls to have experienced a significant childhood illness by the age of 5 years [33]. Another study reported that significantly more IVF children had been diagnosed with at least one illness by the age of 3, in particular regarding respiratory diseases and diarrhoea [50]. However, most studies have not found any difference between ART and SC children regarding childhood or chronic illnesses up to the age of 8 years [54], [71], [73], [74], [75], [76].

Various reports have suggested that ART children are more likely than SC children to use hospital services, up to the age of 6 years [33], [64], [69], [75]. Bonduelle and colleagues found that ICSI children were more likely than SC controls to use various types of therapy, including physiotherapy, dietary, and orthoptic therapy [74]. In Finland, Koivurova et al. showed that children up to the age of 7 born following IVF were more frequently admitted to hospital than SC controls, and that post-neonatal hospital care costs per IVF child were 2.6-fold greater than SC controls [79]. Other studies did not show any difference between ART and SC children regarding medical care utilisation [71], [76], [80]. When interpreting reports of increased healthcare utilisation by ART children, a number of factors should be considered. The increased risk of cerebral palsy in these children (largely related to greater multiple pregnancy and prematurity rates) is likely to account, in part, for such findings. It is also possible that they may represent heightened concern amongst parents of ART children regarding the health of their children.

A number of studies have observed an increase in surgical interventions in singletons born after IVF or ICSI [33], [74], [75], whilst others reported no difference when compared to SC controls [54], [71]. Bonduelle et al. noted a higher incidence of minor ear surgery (tympanic drains±adenoidectomy) in ICSI children up to the age of 5 [74]. A multicentre European study reported that a higher proportion of ICSI and IVF children required genitourinary surgery (other than circumcision), corresponding with an observation of a higher rate of genitourinary defects in boys conceived by ICSI [33]. A recent German study also reported that ICSI boys underwent more urogenital surgery than SC controls (19.2% vs. 8.9%, p=0.013), corresponding with a higher incidence of undescended testes in the ICSI boys [75]. An increased risk of genitourinary defects in ICSI boys could relate to the underlying paternal subfertility [81].

In summary, the majority of available evidence suggests that children conceived following assisted reproduction grow no differently to naturally conceived children. Although there is conflicting information regarding incidence of childhood illnesses and utilization of medical services, the available evidence regarding the physical health of ART children up to the age of 8 years is generally reassuring.

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7. Risk of cancer 

A limited number of studies have addressed the issue of childhood cancer among children conceived by assisted reproduction. A report from the Netherlands identified five cases of retinoblastoma in IVF children between November 2000 and February 2002, significantly more than would be expected [82]. A Swedish registry-based study identified five cases of Langerhan's histiocytosis among 16,280 IVF-conceived infants born between 1982 and 2001, in comparison to 0.9 expected cases based upon incidence in the general population (relative risk=5.6, 95% CI 1.8–13.0) [69]. However, the overall risk of cancer, and the individual incidence of all other recorded cancers, was not greater than that expected from rates in the general population.

The concerns reported by these two studies have not been verified by any other investigations. A number of cohort studies have been published which have not identified any increased risk of childhood cancer in ART children when compared to rates in the general population [64], [83], [84], [85]. However, because childhood cancers are rare, larger studies are required to reliably observe any increase in their risk amongst ART children.

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8. Psychosocial outcome and family dynamics 

There are a various theoretical concerns regarding the implications of conception by assisted reproductive techniques upon the social and emotional welfares of children. Couples who conceive using ART may experience periods of significant stress and anxiety, relating to the period of infertility preceding treatment or to the treatment procedures themselves. This could affect adaptation to the parent role, influencing how parents view their children, which could in turn affect child–parent relationships and influence children's behaviour and emotional development. For example, if ART children were seen to be more vulnerable by their parents, this could lead to overprotective parenting. A number of studies have been conducted to investigate these concerns.

Golombok and colleagues studied a cohort of 116 IVF children from four European countries, comparing them to similar numbers of naturally conceived controls and adopted children [86], [87]. They initially studied the children when they were aged between 4 and 8 years, and followed them up at the beginning of adolescence (age 12). The incidence of psychiatric disorders and behavioural problems in the children and measures of their social functioning were similar between the groups. Mothers of IVF children reported significantly less stress than those of NC controls. The IVF parents were found to have positive relationships with their children, characterised by a combination of affection and appropriate control.

A larger multi-national European study compared 436 IVF and 540 ICSI children aged 4–5 years with 542 NC controls [88]. No differences were reported between ART and NC families regarding parental mental health problems, parental stress, marital discord, or emotional and behavioural problems in the children. Mothers who had conceived using ICSI reported fewer negative, rejecting, or aggressive feelings towards their children than mothers in the control group. When children's own views towards their parents were assessed, there was no difference between the feelings of ART and NC children towards their mothers. However, ICSI children expressed more positive feelings about their fathers than controls.

Ponjaert-Kristoffersen et al. reported fewer behaviour problems in a cohort of 300 ICSI children aged 5 years, and reduced stress in their parents, when compared to naturally conceived controls [53]. In a smaller study, a Dutch group observed fewer behaviour problems amongst IVF children aged 5–8 years compared to NC controls, but no difference when comparing ICSI children with controls [89]. They also reported that ICSI parents experienced more stress than NC parents, but postulated that this may have resulted from selection bias. Banerjee et al. recently published the first study investigating the psychosocial well being of children conceived following preimplantation genetic diagnosis [58]. They revealed no difference in parental stress in the two groups. The PGD parents exhibited more warmth, and less aggression and rejection towards their children than the controls.

In summary, the evidence suggests that ART children up to 12 years of age do not experience negative psychosocial outcomes in respect to family functioning, child–parent relationships or behavioural problems, when compared to naturally conceived children. In fact, the opposite may be the case, with a number of studies reporting more positive relationships between parents and ART children. This may, in part, be due to the presence in control groups of families that had not planned their child. However, as ART children grow older other factors may influence their psychological well being. Although maintenance of family secrets is known to present a risk to family functioning [90], a significant proportion of parents who have conceived using ART do not tell their children about the nature of their conception [91].

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9. Areas for future research 

It is essential that further studies continue to follow up ART children. Assisted reproductive technologies are rapidly advancing, and becoming progressively more ‘invasive’. Researchers must continue to assess the outcomes of the changing techniques. Although the oldest children to be conceived by IVF are now in early adult life, studies to date have only followed up ART children into early teenage years. Certain illnesses, such as various cancers, do not manifest until later in life, and longer-term follow-up studies are required to assess the impact of ART on children through puberty into adult life. Low birth weight is associated with increased incidence of hypertension, diabetes mellitus and cardiovascular disease in adult life [92], [93], [94]. Given the increased risk of low birth weight in ART babies, these children may be at increased cardiovascular risk as they enter adulthood. Another unexplored area of concern for ART children entering adult life is the risk of infertility. Boys conceived to infertile fathers with the help of ICSI could inherit genetic defects, such as certain Y-chromosome abnormalities, that render them subfertile. Further follow-up studies of ART children must be undertaken to explore these concerns.

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10. Conclusions 

In recent years an increasing number of well-designed studies have improved our understanding of the well being of children born following assisted reproductive technologies. The main risks for the health of these children remain multiple pregnancies and low birth weight, which increase the risk of long-term neurological problems such as cerebral palsy. Such risks need to be explained when counselling couples considering fertility treatment. The available evidence regarding the longer-term outcome of singletons born at term following ART is generally reassuring, although there remains an increased risk of adverse perinatal outcomes in these children when compared to singleton controls. Various factors are likely to contribute to these risks, including underlying parental subfertility, procedural factors, and higher maternal age, although the relative contributions of these have yet to be established. With an increasing tendency towards single-embryo transfer, multiple pregnancy rates should fall, with subsequent benefit for the long-term well being of ART children.

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11. Conflict of interest 

The authors declare no conflicts of interest.

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PII: S0143-4004(08)00259-2

doi:10.1016/j.placenta.2008.08.013

Placenta
Volume 29, Supplement 2 , Pages 135-140, October 2008

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