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In vitro fertilization (IVF) is considered a generally safe procedure, although associated with a higher incidence of preterm birth. The literature is inconsistent about the psychological impact of IVF, and we found no reports about outcome in late preterm (LPT) children. Our objective was to study neuropsychological and behavioral outcomes in a cohort of preschoolers born LPT between 2004 and 2007.
Study Design
Participants were 397 LPT children (mean age, 3.8 years) conceived assisted by IVF (n = 105) or non-IVF (n = 292). Standardized performance-based tests of general conceptual ability (intelligence quotient), executive function, focused/selective attention, visual-spatial perception, visual-motor skill, manual dexterity, learning, and memory were administered. Parents completed behavioral and executive function questionnaires.
Results
IVF group characteristics included older maternal age (P < .001), lower birthweight (P < .001), and higher maternal education (P < .001). No main-effect significant group differences were found for any variable after controlling for these variables. However, sex differences were demonstrated for the neuropsychological variables in copying (P > .001), nonverbal reasoning (P = .001), manual dexterity (P = .001), and inhibitory capacity (P = .006), all favoring girls.
Conclusion
Birth following IVF-assisted conception did not increase the risk of intellectual, neuropsychological, or behavioral deficit in LPT preschoolers. As shown in earlier gestational-age participants, girls have selective advantages. These findings should be reassuring for parents who conceive through IVF and deliver infants 1-3 weeks before term gestational age. Future study of these children at elementary school age may detect subtle impairments not yet apparent at age 3 years.
and when other less expensive methods of assisted reproductive technology have failed. Although generally considered to be a safe procedure, potential birth defects, adverse perinatal health outcomes, low birthweight, and preterm birth have been associated with children conceived by IVF.
Centers for Disease Control and Prevention, American Society for Reproductive Medicine, and Society for Assisted Reproductive Technology 2009 assisted reproductive technology success rates: national summary and fertility clinic reports.
US Department of Health and Human Services,
Atlanta2011
The literature regarding neuropsychological and behavioral outcomes of children born following IVF has been inconsistent. Outcomes are either reported to be advantageous,
Some investigators have reported good outcomes as demonstrated by higher scores on standardized achievement tests and by maternal perceptions of fewer behavior problems in children conceived by IVF compared with those born following non-IVF, spontaneous conception.
whereas others found no significant differences in development between IVF and non-IVF groups.
Two studies included 2 additional infertile control groups and found that children born after IVF were at no greater risk of psychomotor, neurodevelopmental, neuromotor, cognitive, language, or behavioral impairments at age 3 years than children born after ovarian hyperstimulation, to subfertile naturally conceiving parents, or spontaneously.
However, none of these studies confined their cohort to children born at late preterm (LPT: 34-36 weeks) gestational age, a population at higher risk compared with those born at term.
The research concerning outcomes of preterm birth by sex indicates that very preterm boys (<25 weeks) are more vulnerable to long-term neurological and motor impairments than girls born at the same gestation.
found that school-aged boys born LPT demonstrated worse visuospatial reasoning, attentional control, and executive functioning than LPT girls. Although these studies support the likelihood of a neuropsychological sex differential, none addressed sex differences for preterm children born after IVF.
Thus, contradictory results characterize the literature on IVF and psychological outcome in children born at term gestational age, sparse data exist about the effects of IVF and sex on children born preterm after IVF, and we found no reported study of IVF in children born late preterm (LPT). Notably, some born LPT will experience associated subtle neuropsychological and behavioral deficits, such as as hyperkinetic disorder.
This study's objective was to study how IVF conception influences the cognitive, neuropsychological, and behavioral outcomes of preschool-aged children born LPT. We hypothesized that preschoolers conceived by IVF and born LPT would have worse cognitive, neuropsychological, and behavioral outcomes compared with LPT preschoolers conceived non-IVF. We also included sex as a supplemental area of inquiry and hypothesized that girls would perform more favorably than boys on all variables.
Materials and Methods
Participants
The Institutional Review Board of Inova Children's Hospital (Falls Church, VA) approved the protocol and procedures described in the following text for this observational, single-center, cohort study, part of the ongoing Prematurity's Effects on Toddlers, Infants, and Teens (PETIT) Study. Parents provided written informed consent prior to their child's participation, which was conducted by well-trained research examiners blind to participant group and preterm status.
The 3 year old study group included 397 LPT participants born between 2004 and 2007: 105 born assisted by IVF (52 male/53 female) and 292 non-IVF (160 male/132 female). LPT participants were recruited through mailing of institutional review board–approved letters to the last known addresses of randomly selected eligible children born at our hospital, through flyers posted in local pediatricians' offices, and through parent community groups. A priori exclusion criteria were genetic disorder, severe sensorineural impairment, brain tumor, or the child not speaking English. Tables 1 and 2 describe participant sociodemographic and medical characteristics by group, obtained from medical records. Participant chronological age at testing ranged from 3 years 6 months to 3 years 11 months.
Table 1LPT IVF and non-IVF groups′ continuous demographic and medical characteristics
Selected tests were developmentally appropriate measures of general conceptual ability (GCA), executive function, attention, memory, language, motor and visual-motor skill, and behavioral symptoms. These domains were chosen to provide a broad representation of emergent neuropsychological and behavioral functioning at age 3 years. Test instruments and parental behavioral report questionnaires included the following parameters.
battery provides GCA, verbal cluster, nonverbal reasoning, and spatial cluster standard scores, each with a mean of 100 and SD of 15 and subtest scores with a mean of 10 and SD of 3. Two core subtests (verbal comprehension and naming vocabulary) comprise the verbal cluster, the nonverbal cluster (picture similarities and matrices), and the spatial cluster (pattern construction and copying). Three additional diagnostic subtests were administered (recognition of pictures, recall of digits forward, and early number concepts).
Developmental Test of Visual-Motor Integration, fifth edition
that requires naming line drawings (initial naming score) printed on individual cards, placement of the card in their correct respective locations over learning trials (trials-to-criterion and errors-to-criterion scores), and delayed recall of the picture names (delayed item naming score) and spatial locations (delayed location recall score).
of motor dexterity requiring unilateral and bilateral placement of keyhole shaped pegs into a form board, yielding 3 raw scores: number of pegs placed by the dominant hand, nondominant hand, and both hands working simultaneously.
of animal exemplars within 60 seconds, providing raw scores for a total number of correct words generated.
Action-verb fluency
The nonstandardized task (Baron, personal communication) requires verbal retrieval of words describing things people do within a 60 second time span, providing raw scores for a total number of correct words generated.
Behavior Rating Inventory of Executive Function: Preschool Parent Form (BRIEF-P)
provides 5 subscale T scores (inhibit, shift, emotional control, working memory, and plan/organize), composite T scores for inhibitory self-control, flexibility, and emergent metacognition, and an overall global executive composite.
Behavioral Assessment Scales for Children-2: Preschool Parent Form
provides 12 subscale T scores (hyperactivity, aggression, anxiety, depression, somatization, attention problems, atypicality, withdrawal, adaptability, social skills, activities of daily living, and functional communication) and index T scores for externalizing problems, internalizing problems, behavioral symptoms, and adaptive skills.
Analysis
Group differences (LPT/IVF vs LPT/non-IVF) on cognitive, neuropsychological, and behavioral variables were examined by conducting Student t tests. Analysis of covariance was conducted to examine differences between sexes (boy vs girl) and group (IVF vs non-IVF) for all variables while controlling for birthweight, maternal education, and maternal age. Effect sizes were calculated using Cohen's d, with a small effect size defined as 0.2, moderate as 0.5, and large as 0.8.
A conservative alpha of .01 was set to control for type I error. The following assumptions were tested: independence of observations, homogeneity of variance, normality of the distribution of the dependent variable, and homogeneity of slopes.
Results
Participant characteristics
Table 1 shows the means, SDs, effect sizes, and t values for the participant characteristics in the LPT IVF and LPT non-IVF groups. Significant differences between the groups were found with moderate effect sizes for birthweight (d = 0.46) and maternal education (d = 0.42) and a large effect size (d = 0.92) for maternal age. The LPT IVF group had significantly lower birthweight than LPT non-IVF (t[395] = –3.74, P > .001, d = 0.46, 99% confidence interval [CI], –325.55 to –101.13). Mothers who conceived by IVF had a higher educational level (t[395] = 3.70, P > .001, d = 0.42, 99% CI, 0.42–1.37) and were older (t[395] = 8.00, P > .001, d = 0.92, 99% CI, 3.40–5.62) than mothers of non-IVF LPT. As indicated in Table 2, the groups did not differ significantly on any categorical demographic or medical variable.
Independent Student t test results indicated that no statistically significant differences were found on any intellectual, neuropsychological, or behavioral variable for the 2 groups. Cohen's d was calculated to measure practical significance; all variables yielded small effect sizes (d < 0.1).
To ascertain whether there were any differences between IVF/non-IVF and sex, analysis of covariance was performed while controlling for the 3 demographic variables that were statistically significantly different: birthweight, maternal age, and maternal education. No significant interaction effects were found between IVF/non-IVF and sex on any variable. Thus, main effects were interpreted; statistically significant main effect differences were found for sex but not for IVF.
As shown in Table 3, girls had statistically significantly more favorable performances than boys on copying (F[1393] = 17.67, P > .001, d = 5.87), picture similarities (F[1,403] = 11.67, P = .001, d = 4.80), Purdue pegboard bilateral trial (F[1,371] = 11.79, P = .001, d = 4.77), and the BRIEF inhibit subscale (F[1,392] = 7.76, P = .006, d = 3.89) after controlling for IVF/non-IVF, birthweight, maternal age, and maternal education.
We studied a LPT cohort recruited from a single tertiary care center at age 3 years, comparing those born following IVF with those conceived non-IVF. We found moderate to large effect sizes between the groups for birthweight, maternal education, and maternal age, consistent with reports that older and more educated women are more likely to use IVF to overcome causes of infertility than younger and less educated women.
Contrary to our hypothesis, risk of intellectual, neuropsychological, or behavioral impairment was not greater in the LPT-IVF group compared with the LPT–non-IVF group at age 3 years.
reporting adverse outcomes for children conceived after IVF presented only slight indications of differences between the IVF and non-IVF groups. Ludwig et al
cited 2 studies in their literature review of IVF in which mothers reported more difficulty with their children and only in the first year.
In agreement with our second hypothesis, we found that girls, regardless of IVF status, performed more favorably than boys on 4 neuropsychological and behavioral variables, whereas boys were not advantaged on any measure. We found very large effect sizes (>3 SD difference) on measures of visual-motor copying, picture matching (reasoning), fine-motor dexterity, and a parental report about inhibitory capacity, consistent with well-described disadvantages in psychological outcomes reported in very preterm boys.
We did not find differences on the other 40 variables, suggesting that these differences were subtle and male sex following IVF was not as great a risk factor as was the LPT birth.
Our study's strengths included that we recruited a large LPT sample size (n = 397), our cohort's very young age (3 years), and recent birth (2004-2007); multidomain measurement using developmentally sensitive tests of intellectual, neuropsychological, and behavioral functioning; and comparisons made between LPT IVF with LPT non-IVF participants born at the same hospital and with similar sociodemographic characteristics, except for birthweight, maternal age, and education.
Limitations were that our retrospective single-center study had a much larger number of LPT non-IVF (n = 292) than LPT IVF participants (n = 105); however, homogeneity of variances tests limited concern about this disparity. Participants' mean maternal age was high, which may limit generalizability of this study's findings to regions with lower socioeconomic and maternal education status. As for the majority of prior literature,
it was not feasible for us to identify a non–IVF-treated infertile control group.
In conclusion, we found no unfavorable intellectual, neuropsychological, or behavioral effects associated with birth LPT following IVF conception in preschool participants. These results should reassure parents who conceive through IVF and deliver infants 1-3 weeks before term gestational age. Inclusion of a second control group of children conceived by non-IVF infertility treatments should be considered in subsequent studies.
Future study of LPT IVF and LPT non-IVF children at elementary school age should help determine whether any subtle impairment will emerge with advancing maturity, and these data are being collected in our PETIT study. Because this study's results cannot be generalized to preterm children born following IVF and less than 34 weeks, future study of children born at earlier gestational ages should be considered. Such research could further enhance our understanding of whether IVF exerts a direct influence on aspects of neuropsychological functioning in the preterm population.
References
McDonald S.D.
Han Z.
Mulla S.
Murphy K.E.
Beyene J.
Ohlsson A.
Preterm birth and low birth weight among in fertilization singletons: a systematic review and meta analyses.
Supported by the Maggie Snyder Foundation for the Premature and Pediatric Pulmonary Patient of Falls Church, VA and by the Inova Health Foundation , Falls Church, VA.
The authors report no conflict of interest.
Reprints not available from the authors.
Cite this article as: Berry KA, Baron IS, Weiss BA, et al. In vitro fertilization and late preterm preschoolers' neuropsychological outcomes: the PETIT study. Am J Obstet Gynecol 2013;209:356.e1-6.
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