Objective To compare neurodevelopmental outcomes of extremely preterm infants conceived after assisted conception (AC) compared with infants conceived spontaneously (non-AC).
Design Population-based retrospective cohort study.
Setting Geographically defined area in New South Wales and the Australian Capital Territory, Australia served by a network of 10 neonatal intensive care units.
Patients Infants <29 weeks’ gestation born between 1998 and 2004.
Intervention At 2–3 years corrected age, 1473 children were assessed with either the Griffiths Mental Developmental Scales or the Bayley Scales of Infant Development.
Main outcome measure Moderate/severe functional disability defined as developmental delay (Griffiths General Quotient or Bayley Mental Developmental Index >2 SD below the mean), cerebral palsy (unable to walk without aids), deafness (bilateral hearing aids or cochlear implant) or blindness (visual acuity <6/60 in the better eye).
Results Mortality and age at follow-up were comparable between the AC and non-AC groups. Developmental outcome was evaluated in 217 (86.5%) AC and 1256 (71.7%) non-AC infants. Using multivariate adjusted analysis, infants born after in-vitro fertilisation at 22–26 weeks’ gestation (adjusted OR 1.79, 95% CI 1.05 to 3.05, p=0.03) but not at 27–28 weeks’ gestation (adjusted OR 0.81, 95% CI 0.37 to 1.77; p=0.59) had higher rate of functional disability than those born after spontaneous conception.
Conclusions AC is associated with adverse neurodevelopmental outcome among high risk infants born at 22–26 weeks’ gestation. This finding warrants additional exploration.
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What is already known on this topic
Infants born after assisted conception have poorer short term neonatal outcome and greater resource utilisation when compared with infants conceived spontaneously.
Long term neurodevelopmental sequelae of these infants remains a controversial issue.
What this study adds
Assisted conception is associated with adverse neurodevelopmental outcome among high risk infants born at 22–26 weeks’ gestation independent of prematurity, multiple pregnancy and gender.
Additional exploration and work is needed to understand the assisted conception-functional disability pathway.
Previous reports suggest that infants born after assisted conception (AC) have a higher risk of perinatal morbidity, higher rates of admission to neonatal intensive care, increased length of stay and greater resource utilisation when compared with infants conceived spontaneously.1–8 The causes of these poorer outcomes have been the subject of much controversy.5 ,8 ,9 Some of the contributory factors include higher frequency of preterm birth, multiple births or vanishing embryo and determinants of low fecundity.8–16
However, short term problems are not the only controversy surrounding AC.15 Some studies suggested that infants born after AC may be burdened by significant long term neurodevelopmental sequelae.7 ,11–13 ,16 ,17 However, data on the long term effect of AC are sparse.17 ,18 With in-vitro fertilisation continuing to rise in the population, addressing long term sequelae becomes an important area of research.8 ,17 ,19
The aim of this study is to compare the neurodevelopmental outcomes at 2–3 years of age (corrected for prematurity) for very high-risk survivors of less than 29 weeks’ gestational age conceived after AC (including in-vitro fertilisation and hyperovulation) compared with infants conceived spontaneously. We hypothesised that infants conceived after AC have comparable neurodevelopmental outcomes to infants conceived spontaneously.
This study was part of a geographically-defined, prospective, longitudinal follow-up of neurodevelopmental outcomes among premature infants who were treated in 10 neonatal intensive care units (NICUs) (eight perinatal centres and two children's hospitals) in New South Wales (NSW) or the Australian Capital Territory (ACT) and born between 1st January 1998 and 31st December 2004. A full description of the NSW and ACT neonatal service organisation and networking, medical and nursing staffing and roster structures of the collaborating NICUs is available elsewhere.20–23 Ethics approval was granted by the ACT Health Human Research Ethics Committee (No ETHLR.10/348).
Data were obtained from the following sources: (i) The NICUS Data Collection, an ongoing prospective statewide audit of infants admitted to the 10 NICUs in NSW and the ACT during the neonatal period for one of the following reasons: gestational age less than 32 weeks, birth weight less than or equal to 1500 grams, assisted ventilation (mechanical ventilation or continuous positive airways pressure), or major surgery (opening of a body cavity). Definitions and accuracy of the data have been documented elsewhere.24 (ii) NICUs’ Follow-up Data Collection, an ongoing statewide audit at 2–3 years of age, corrected for prematurity, of infants born less than 29 weeks’ gestation.
Follow-up assessment and tools
All surviving children were offered an assessment at 2–3 years of age, corrected for prematurity (conducted between 2001 and 2008). Children were assessed by the developmental assessment team at the tertiary hospitals (90%). If the parents were unable to travel to a tertiary hospital then the local paediatrician or family physician examined the child (10%) and the child was then referred for a detailed developmental assessment by a local developmental assessment service or at a tertiary hospital if indicated.
Each formal developmental assessment included a hearing examination by an audiologist, a vision test by an ophthalmologist or optometrist, a neurological examination by a developmental paediatrician or paediatric physiotherapist and a developmental assessment using the Griffiths Mental Developmental Scales (GMDS)25 (85%) or Bayley Scales of Infant Development-II (BSID-II)26 (15%) performed by a clinical psychologist or a developmental paediatrician. The mean for the general quotient (GQ) of the GMDS is 100.2 with a SD of 12.8. The mean for the mental developmental index (MDI) of the BSID-II is 100 with SD of 15. Each child's height, weight and head circumference were also measured at assessment. Cerebral palsy (CP) was diagnosed if the child had non-progressive motor impairment characterised by abnormal muscle tone and a decreased range or decreased control of movements, accompanied by neurological signs.27
NICUS Database defines AC as any type of infertility treatment, used during the conception or used to conceive this pregnancy. These include in vitro fertilisation techniques (gamete intrafallopian transfer, zygote intrafallopian transfer and intracytoplasmic sperm injection) (n=162) and hyperovulation (hormone therapy used to stimulate ovulation) (n=46) and donor insemination techniques (n=9).24 The NSW population-based birth weight charts28 were used at birth and the USA National Centre for Health Statistics growth curves29 were used at 2–3 years of age, corrected for prematurity. Large for gestational age and small for gestational age were defined as weight for gestation greater than 90th and less than 10th percentile, respectively.
The primary outcome measure for this study was moderate/severe functional disability (FD)30–33 at 2–3 years of age, corrected for prematurity, defined as: (i) Moderate FD: developmental delay (GMDS-GQ or BSIDII-MDI between 2 and 3 SD below the mean), moderate CP (able to walk with the assistance of aids), sensorineural or conductive deafness (requiring amplification with bilateral hearing aids or unilateral/bilateral cochlear implant); (ii) Severe FD: developmental delay (GMDS-GQ or BSIDII-MDI 3 or more SD below the mean), bilateral blindness (visual acuity of less than 6/60 in the better eye), or severe CP (unable to walk with the assistance of aids).
Statistical analyses were performed using Predictive Analytics SoftWare Statistics V.18.0.2 (SPSS: An IBM Company, Chicago, Illinois, USA, 2010). Data are presented as number (%) with OR and 95% CI or median and IQR. The clinical and demographic characteristics were compared by X2-test with continuity correction and the Mann-Whitney test where appropriate.
We performed stepwise multiple logistic regression elimination analysis34 to establish the independent influence of AC on adverse neurodevelopmental outcomes, after controlling for significant confounding factors (maternal age and multiple pregnancy) in addition to other predictors (outborn, gender, gestational age and birth weight) identified in other studies.35 In this multivariate model we controlled for the antenatal and perinatal but not intermediate variables intraventricular haemorrhage, retinopathy of prematurity (ROP), necrotising enterocolitis and chronic lung disease (CLD) as these may be related, directly or indirectly, to AC and thus might act as intermediate co-morbidities through which the effect of AC is mediated. Entry and removal from the stepwise logistic regression model occurred if p<0.1 and p>0.05 respectively. All analyses were pre-specified. All p values were two-sided and the significance level was not changed when multiple comparisons were performed.36
Figure 1 shows the profile of the study group from birth to follow-up. Total of 343 (12.7%) infants were born after AC and admitted to one of the collaborating NICU during the study period.
Of the 2103 infants discharged home, 33 infants died after hospital discharge and 497 infants were lost to follow-up. Assessments were completed at 2–3 years of age, corrected for prematurity, for 217 (86.5%) of the 251 children eligible for follow-up in the AC group compared with 1256 (73.1%) of the 1719 children eligible for follow-up in the non-AC (conceived spontaneously) group. Among the AC group who were followed up (n=217), there were 162 (74.7%) who conceived after in vitro fertilisation (gamete intrafallopian transfer or zygote intrafallopian transfer), 46 (21.2%) after hyperovulation and 9 (4.1%) after donor insemination techniques.
Profile of infants who were lost to follow-up
The 497 children who were lost to follow-up had a higher birth weight but not gestational age when compared with those who attended the follow-up assessments (table 1). Significantly more infants in the lost to follow-up group were outborn (16.5% vs 7.4%) and of aboriginal ethnicity (7.3% vs 1.4%) when compared with those who were followed-up. Furthermore, infants lost to follow-up were less likely to require mechanical ventilation (77.3% vs 87.3%) and if they did, were ventilated for a shorter duration. Infants lost to follow-up were also less likely to have severe ROP, CLD or treatment with post-natal steroids (table 1).
Perinatal and neonatal outcome
The perinatal characteristics of AC and non-AC infants who were followed-up are shown in table 2. AC mothers were significantly older compared with non-AC group, 38.2% were aged greater than 35 years at the time of delivery compared with 22.1% among the non-AC group. None of the AC group were of aboriginal ethnicity. Primiparous and multiple pregnancies were by far more common among AC group. More AC mothers (31.8%) had a caesarean section in labour compared with non-AC (21.5%) mothers.
The rates of early neonatal morbidities and risk factors known to influence neurodevelopmental outcome (intraventricular haemorrhage, necrotising enterocolitis, ROP, CLD and proven systemic sepsis) were not significantly different between the two study groups with the exception of post-natal steroid for CLD which was higher in non-AC group (28.7% vs 22.1%, p=0.06) and major surgery which was higher among AC group (25.3% vs 19.8%, p=0.08).
The hospital mortality was comparable between AC and non-AC group (21.9% vs 22.2%, p=0.96) even after stratifying by gestational age (figure 2, panel A).
The relationship between AC and moderate to severe FD and growth at 2–3 years of age is summarised in table 3. The post-natal age at assessment was comparable between the two groups. Overall AC children had comparable rate of FD to non-AC (18.9% v 15.9%, unadjusted OR 1.24, 95% CI 0.85 to 1.80, p=0.31). The rate of individual disabilities (GQ/MDI<−2 SD, CP, bilateral blindness or bilateral deafness) was also comparable (table 3). When FD was stratified by gestational age groups, the disability rate was significantly higher in AC infants of 22–26 weeks’ gestational age (31.6% vs 21.0%, unadjusted OR 1.57, 95% CI 1.02 to 2.24, p=0.03) but not in the 27–28 weeks group (table 3). Figure 2, panel B illustrates the gestational age-specific FD. There is apparent high FD rate in lower gestation with apparent convergence at 26 weeks’ gestation (figure 2, panel B).
After controlling for confounding factors by stepwise multivariate analysis, the adjusted risk of FD was comparable after in vitro fertilisation (OR 1.30, 95% CI 0.82 to 2.08, p=0.27) and hyperovulation (OR 1.02, 95% CI 0.43 to 2.41; p=0.97) to those born after spontaneous conception. Significant factors associated with FD were gestational age, small for gestational age and male gender (table 4).
In vitro fertilisation and hyperovulation subgroups
In subgroup adjusted analysis, the risk of FD was higher for infants born after in vitro fertilisation at 22–26 gestational week (adjusted OR 1.79, 95% CI 1.05 to 3.05; p=0.03) but not for those born at 27–28 gestational week (adjusted OR 0.81, 95% CI 0.37 to 1.77; p=0.59) or those born after hyperovulation (adjusted OR 1.60 (95% CI 0.54 to 4.75; p=0.40) for 22–26 weeks subgroup and adjusted OR 0.55 (95% CI 0.13 to 2.40; p=0.43) for 27–28 weeks subgroup) (table 4).
In this cohort of prospectively followed children, we found a significant association between in vitro fertilisation and the risk of FD in high-risk infants born at 22–26 weeks when compared with children conceived spontaneously. Proposed pathway for CP and FD in AC includes prematurity and its causes such as multiplicity, subfecundity and vanishing embryo syndrome.11 ,15 ,17 ,37–39
Our follow-up rate of 74.8% of 1970 infants eligible for follow-up is comparable with other published studies.40–42 Furthermore, the rate of FD in our study is similar to disability rates previously reported among children of very low and extremely low birth weights.32 ,42–45
We found that the children who were followed-up were sicker and required more intensive care support than those who were lost to follow-up (table 1). This is consistent with a recent American study40 which found that children who were lost to follow-up were generally healthier and had fewer potential risk factors for adverse neurodevelopmental outcome than those who attended follow-up in contrast to other previous European41 ,46 studies and an earlier Australian study.47 Indeed, Castro et al40 speculated that follow-up studies based on infants who are compliant with follow-up may lead to an overestimation of adverse outcomes in survivors.
Our findings concur with Zhu et al and Lidegaard et al.15 ,48 Zhu et al15 found increased risk of CP even after adjusting for subfecundity, prematurity and multiplicity. Similarly, Lidegaard et al48 found a statistically significant increased risk of CP for singletons, but they did not adjust for preterm delivery. In other studies, the risk attributable to AC was not significant after adjusting for confounding factors such as multiplicity and prematurity.11 ,17 In our study, the risk of FD was less after adjusting for confounding factors but nevertheless it was still a significant risk. This may underscore an alternative AC-FD pathway not explained by multiplicity, prematurity and gender effect. This finding warrants additional exploration and work to understand the AC-FD pathway.
Our data is not without shortcomings. We lack other information that maybe relevant to neurodevelopmental outcome in our cohort such as causes and duration of subfecundity,15 vanishing embryo syndrome,37 type of zygoticity11 or post-discharge factors such as socioeconomic status and maternal education,49–51 all of which may have a significant association with later neurodevelopmental outcomes. As this study cohort was drawn from an entire population in NSW and ACT, it is unlikely to be biased by centre-based information.
The authors thank the directors, the NICUS members and the audit officers of all tertiary units in supporting this collaborative study: NICUS, Dr Jennifer Bowen (Chairperson), Barbara Bajuk (Coordinator), Trina Vincent (Research Officer); Canberra Hospital, A/Prof Zsuzsoka Kecskés (Director), Dr Hazel Carlisle, John Edwards; John Hunter Children's Hospital, Dr Chris Wake (Director), Dr Anne Vimpani, Lynne Cruden; Royal Prince Alfred Hospital, A/Prof Nick Evans (Director), Dr Phil Beeby, A/Prof David Osborn, Dr Ingrid Rieger, Shelley Reid; Liverpool Hospital, Dr Robert Guaran (Director), Dr Ian Callander, Dr Jacqueline Stack, Kathryn Medlin, Sara Wilson; Nepean Hospital, Dr Lyn Downe (Director), Dr Basiliki Lampropoulos, Mee Fong Chin; The Children's Hospital at Westmead, Prof Nadia Badawi (Director), Dr Alison Loughran-Fowlds, Caroline Karskens; Royal North Shore Hospital, Dr Mary Paradisis, A/Prof Martin Kluckow, Sara Sedgley; Sydney Children's Hospital, Dr Andrew Numa (Director), Dr Gary Williams, Janelle Young; Westmead Hospital, Dr Mark Tracy (Director), Dr Melissa Luig, Jane Baird; and Royal Hospital for Women, A/Prof Kei Lui (Director), Dr Lee Sutton, Diane Cameron. We also thank the babies and their families, the nursing and midwifery, obstetric and medical records staff of the obstetric and children's hospitals in NSW and the ACT.
Contributors NB and MW conceived the study; AM and BB designed the study; BB retrieved and cleaned the data; AM undertook the statistical analyses and led the writing of this paper. All five authors interpreted the results and contributed to the final manuscript.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
Ethics approval Ethics approval was granted by the ACT Health Human Research Ethics Committee (No ETHLR.10/348).