Strömberg, B., Dahlquist, G., Ericson, A., Finnström, O., Köster, M., & Stjernqvist, K. (2002). Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet (London, England), 359(9305), 461-465. https://doi.org/10.1016/S0140-6736(02)07674-2
Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet. 2002;359(9305):461-465. doi:10.1016/S0140-6736(02)07674-2
Strömberg, Bo, et al. "Neurological sequelae in children born after in-vitro fertilisation: a population-based study." Lancet (London, England), vol. 359, no. 9305, 2002, pp. 461-465.
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There is an absence of population-based long-term studies on the risk of neurological sequelae in children born after in-vitro fertilisation (IVF). Our aim was to compare the frequency of such problems between IVF-born children and controls.
Methods
We did a population-based retrospective cohort study in which we compared development of neurological problems in 5680 children born after IVF, with 11360 matched controls. For 2060 twins born after IVF, a second set of controls (n=4120), all twins, were selected. We obtained data on neurological problems from the records of the Swedish habilitation centres.
Findings
Children born after IVF are more likely to need habilitation services than controls (odds ratio 1.7, 95% CI 1.3-2.2). For singletons, the risk was 1.4 (1.0-2.1). The most common neurological diagnosis was cerebral palsy, for which children born after IVF had an increased risk of 3.7(2.0-6.6), and IVF singletons of 2.8 (1.3-5.8). Suspected developmental delay was increased four-fold (1.9-8.3) in children born after IVF. Twins born after IVF did not differ from control twins with respect to risk of neurological sequelae. Low-birthweight and premature infants were more likely to need habilitation than fullterm babies. Maternal age did not affect risk.
Interpretation
Our study suggests that children born after IVF have an increased risk of developing neurological problems, especially cerebral palsy. These risks are largely due to the high frequency of twin pregnancies, low birthweight, and prematurity among babies born after IVF. To limit these risks, we recommend that only one embryo should be transferred during IVF.
Källén B et al., 2013·Archives of disease in childhood
To investigate a proposed association between in vitro fertilisation (IVF) and child asthma. The risk for asthma after IVF was estimated as ORs using Mantel-Haenszel analysis. The Swedish Medical Birth Register. Of the 2 628 728 children born in 1982-2007 and surviving the perinatal period, 31 918 were conceived by IVF. Presence of asthma was defined as at least five prescriptions of antiasthmatic drugs during the period 1 July 2005-31 December 2009 according to the Swedish Prescribed Drug Register (115 767 children, 2323 of whom were born after IVF). A significantly increased risk for asthma, albeit small, was found in children conceived by IVF (aOR 1.28, 95% CI 1.23 to 1.34), increasing the absolute risk from 4.4% to 5.6%. The risk increase for asthma was the same in boys and girls, in singletons and twins, and after caesarean section and vaginal delivery. The risk was higher for preterm than term singletons. For children with a low Apgar score, respiratory diagnoses, mechanical ventilation, continuous positive airway pressure or neonatal sepsis, the effect of IVF on asthma risk was low and statistically non-significant. Adjustment for length of involuntary childlessness eliminated the effect, and removal of infants whose mothers had used antiasthmatics in early pregnancy reduced the risk. This study verifies an association between IVF and asthma in children. This can be partly explained by neonatal morbidity and by maternal asthma acting as mediators, but the main risk factor is parental subfertility. The mechanism for this is unclear.
Källén B et al., 2005·BJOG : an international journal of obstetrics and gynaecology
To investigate obstetric characteristics, maternal morbidity and mortality among Swedish women giving birth after in vitro fertilisation (IVF) treatment. Register study. Nationwide study in Sweden. All women known to have had IVF in Sweden 1982-2001. Using Swedish health registers, women who had given birth after IVF were identified from all Swedish IVF clinics and compared with all women who gave birth. Analysis was performed with the Mantel-Haenszel technique. Diagnoses during pregnancy, at delivery and at re-admission within 60 days after delivery and risk of cancer. IVF women had an increased risk of bleeding in early pregnancy [odds ratio (OR) = 4.59, 95% confidence interval (95% CI) 4.08-5.15] and of ovarian torsion during pregnancy (OR = 10.6, 5.69-10.7). They were also more likely to encounter pre-eclampsia (OR = 1.63, 1.53-1.74), placental abruption (2.17, 1.74-2.72), placenta praevia (3.65, 3.15-4.23), bleeding in association with vaginal delivery (1.40, 1.38-1.50) and premature rupture of membranes (PROM) (2.54, 2.34-2.76). Interventions including caesarean sections (1.38, 1.32-1.43) and induction of labour (1.37, 1.29-1.46) in singleton pregnancies was more frequent. The type of IVF method had little effect on these results, but there was a tendency for women who had received intra-cytoplasmatic sperm injection (ICSI) to have slightly fewer complications than women having standard IVF. There was a significant decrease in cancer risk after IVF (0.79, 0.69-0.91) but a suggested increase in the risk of ovarian cancer both before (2.70, 1.49-4.91) and after (2.08, 1.15-3.76) IVF. No change in mortality was observed. Women treated with IVF had an increased obstetric morbidity. This seems to contribute little to the well-known increased risk of preterm delivery.
Goldsmith S et al., 2018·Developmental medicine and child neurology
To calculate the birth prevalence of cerebral palsy (CP) after assisted reproductive technology (ART) and compare the clinical outcomes of children with CP after ART or natural conception. This cohort study used linked CP and ART register data from live births in Western Australia (1994-2002). Birth prevalence was calculated and data analysed using descriptive statistics and logistic regression. It was adjusted for confounding variables and stratified by plurality and gestational age. In total, 211 660 live births were included; prevalence of CP was increased in children born after ART (7.2/1000 live births compared with naturally conceived births, 2.5/1000). Odds of CP were doubled for singletons; when stratified by gestational age odds were only increased in the under 32-week group. Prevalence of CP was increased in ART (9.9/1000 live births) and naturally conceived twins (8.4/1000 live births). Clinical outcomes were similar between ART and naturally conceived children. The birth prevalence of CP is increased two-fold after ART. After stratification for gestational age and plurality, residual risk remains in singletons born very preterm. Birth prevalence of CP will be tracked over time to identify any impact of changes to clinical practice. In Western Australia, assisted reproductive technology (ART) increases birth prevalence of cerebral palsy (CP), mediated mostly by preterm and multiple births. Preterm birth alone does not account for the doubled odds of CP for ART singletons born very preterm. Clinical outcomes are similar between ART and naturally conceived children with CP.
Treatment for infertility using assisted reproductive technologies (ART) is highly successful and has been used to help a steadily growing number of couples worldwide. In 1999, in the United States, more than 86,000 treatment cycles were performed resulting in the birth of more than 30,000 babies. Despite this widespread application, few follow-up studies of children conceived through ART have been performed, and more rigorous investigation of this important issue has clearly been needed. In recent months, three studies linking ART with several complications have been published in high profile and widely read general medical journals: Schieve et al. (1) reported that singletons conceived using ART were at an increased risk for low birth weight, whereas Hansen et al. (2) suggested an increased risk of major birth defects. Finally, Stromberg et al. (3) concluded that children conceived through IVF have an increased risk of neurological problems, especially cerebral palsy.
The importance of these studies is obvious as they provide clues of possible risks associated with ART. However, they are all retrospective analyses of data collected through registries and therefore are vulnerable to biases inherent to such study design. We must be careful not to overinterpret the data by concluding that the use of ART, whether from gamete or embryo manipulation or use of medications, is the direct cause of the complications—the observed associations may simply be explained by one or more confounders, such as an underlying infertility-related condition in the treated women. This short communication is an attempt to place these three articles in proper perspective for the clinician and to provide the impetus for conducting further studies to determine the true nature of the described associations.
At the outset, it should be stated that a major weakness of all three studies is the lack of proper controls. If the aim of a study is to determine whether a cause and effect relationship exists between the process of IVF and a specific outcome (i.e., low birth weight, major birth defects, neurological problems), the appropriate control population is that of babies born to infertile women achieving pregnancies by methods other than IVF. None of the three studies specifically included such a control population.
Davies MJ et al., 2012·The New England journal of medicine
The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain. We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child's fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility. Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07 (95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects. The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.).
Sargisian N et al., 2024·European heart journal·Free full text on PubMed Central
Children born after assisted reproductive technology (ART) have worse perinatal outcomes compared with spontaneously conceived children. This study investigates whether children conceived after ART have a higher risk of congenital heart defects (CHDs) compared with children born after spontaneous conception (SC). All 7 747 637 liveborn children in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1987-2015), where 171 735 children were conceived after ART, were included. National ART and medical birth registry data were cross-linked with data from other health and population registries. Outcomes were major CHDs, severe CHDs, 6 hierarchical CHD lesion groups, and 10 selected major CHDs, diagnosed prenatally or up to 1 year of age (Denmark, Finland, and Sweden) and prenatally or at birth (Norway). The association between ART and CHDs was assessed with multivariable logistic regression analysis, with adjustment for available confounders. Major CHDs were detected in 3159 children born after ART (1.84%) and in 86 824 children born after SC [1.15%; adjusted odds ratio (AOR) 1.36; 95% confidence interval (CI) 1.31-1.41]. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 594 children born after ART (0.35%) and in 19 375 children born after SC (0.26%; AOR 1.30; 95% CI 1.20-1.42). Risk was similar between ICSI and IVF and between frozen and fresh embryo transfer. Assisted reproductive technology-conceived children have a higher prevalence of major CHDs, being rare, but severe conditions. The absolute risks are, however, modest and partly associated with multiple pregnancies, more prevalent in ART.
Assisted Reproduction › Safety and Risks › Long Term Child Outcomes
PMID 11853790 11853790 DOI 10.1016/S0140-6736(02)07674-2 10.1016/S0140-6736(02)07674-2 Strömberg et al. 2002, Strömberg 2002
Cite this article
Strömberg, B., Dahlquist, G., Ericson, A., Finnström, O., Köster, M., & Stjernqvist, K. (2002). Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet (London, England), 359(9305), 461-465. https://doi.org/10.1016/S0140-6736(02)07674-2
Strömberg B, Dahlquist G, Ericson A, Finnström O, Köster M, Stjernqvist K. Neurological sequelae in children born after in-vitro fertilisation: a population-based study. Lancet. 2002;359(9305):461-465. doi:10.1016/S0140-6736(02)07674-2
Strömberg, Bo, et al. "Neurological sequelae in children born after in-vitro fertilisation: a population-based study." Lancet (London, England), vol. 359, no. 9305, 2002, pp. 461-465.
Keywords
Adolescent, Adult, Age Distribution, Cerebral Palsy/epidemiology/etiology, Child, Child, Preschool, Female, Fertilization in Vitro/adverse Effects, Humans, Infant, Male, Maternal Age, Population Surveillance, Registries, Retrospective Studies, Risk Factors, Sex Distribution, Sweden/epidemiology, Twins
