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In vitro fertilization and late preterm preschoolers' neuropsychological outcomes: the PETIT study

      Objective

      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.

      Key words

      For Editors' Commentary, see Contents
      Following the first successful in vitro fertilization (IVF) birth in 1978,
      • 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.
      the incidence of IVF birth has increased to 1% of all births in the United States.
      • Mains L.
      • Zimmerman M.
      • Blaine J.
      • et al.
      Achievement test performance in children conceived by IVF.
      Successful live birth rates have risen to 41.7% for women under age 35 years and 12.5% for women over age 42 years.

      Society for Assisted Reproductive Technology. IVF Live Birth Rates Clinic Summary Report 2012. Society for Assisted Reproductive Technology.

      IVF is a viable option in cases of infertility caused by endometriosis, fallopian tube damage, partner sterility, or advanced maternal age,
      • Hammarberg K.
      • Astbury J.
      • Baker H.W.G.
      Women's experience of IVF: a follow-up study.
      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.
      • Mains L.
      • Zimmerman M.
      • Blaine J.
      • et al.
      Achievement test performance in children conceived by IVF.
      • Ceelen M.
      • van Weissenbruch M.M.
      • Vermeiden J.P.W.
      • van Leeuwen F.E.
      • Delemarre-van de Waal H.
      Cardiometabolic differences in children born after in vitro fertilization: follow-up study.
      • Koivurova S.
      • Hartikainen A.-L.
      • Sovio U.
      • Gissler M.
      • Hemminki E.
      • Jarvelin M.-R.
      Growth, psychomotor development, and morbidity up to 3 years of age in children born after IVF.
      • Middleburg K.J.
      • Heineman M.J.
      • Bos A.F.
      • Hadders-Algra M.
      Neuromotor, cognitive, language, and behavioural outcome in children born following IVF or ICSI—a systematic review.
      A 14% prevalence rate of preterm birth (<37 weeks) has also been reported in IVF children compared with children spontaneously conceived.
      • 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.
      • Koivurova S.
      • Hartikainen A.-L.
      • Sovio U.
      • Gissler M.
      • Hemminki E.
      • Jarvelin M.-R.
      Growth, psychomotor development, and morbidity up to 3 years of age in children born after 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.
      The literature regarding neuropsychological and behavioral outcomes of children born following IVF has been inconsistent. Outcomes are either reported to be advantageous,
      • Mains L.
      • Zimmerman M.
      • Blaine J.
      • et al.
      Achievement test performance in children conceived by IVF.
      • Sutcliffe A.G.
      • Edwards P.E.
      • Beeson C.
      • Barnes J.
      Comparing parents' perceptions of IVF conceived children's behavior with naturally conceived children.
      adverse,
      • Ludwig A.K.
      • Sutcliffe A.G.
      • Diedrich K.
      • Ludwig M.
      Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies.
      • Wagenaar K.
      • Huisman J.
      • Cohen-Kettenis P.
      • Sdelemarre-van De Waal H.
      Overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization.
      or neither.
      • Koivurova S.
      • Hartikainen A.-L.
      • Sovio U.
      • Gissler M.
      • Hemminki E.
      • Jarvelin M.-R.
      Growth, psychomotor development, and morbidity up to 3 years of age in children born after IVF.
      • Middleburg K.J.
      • Heineman M.J.
      • Bos A.F.
      • Hadders-Algra M.
      Neuromotor, cognitive, language, and behavioural outcome in children born following IVF or ICSI—a systematic review.
      • Wagenaar K.
      • Huisman J.
      • Cohen-Kettenis P.
      • Sdelemarre-van De Waal H.
      Overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization.
      • Jongbloed-Pereboom M.
      • Middleburg K.J.
      • Heineman M.J.
      • Bos A.F.
      • Hadders-Algra M.
      The Groningen assisted reproductive technologies cohort study: developmental status and behavior at 2 years.
      • Leunens L.
      • Celestin-Westreich S.
      • Bonduelle M.
      • Liebaers L.
      • Ponjaert-Kristoffersen I.
      Cognitive and motor development of 8-year-old children born after ICSI compared to spontaneously conceived children.
      • Knoester M.
      • Vandenbrouck J.P.
      • Helmerhorst F.M.
      • van der Westerlaken L.
      • Walther F.J.
      • Veen S.
      Matched follow-up study of 5- to 8-year-old ICSI singletons: a comparison of their neuromotor development to IVF and naturally conceived singletons.
      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.
      • Mains L.
      • Zimmerman M.
      • Blaine J.
      • et al.
      Achievement test performance in children conceived by IVF.
      • Sutcliffe A.G.
      • Edwards P.E.
      • Beeson C.
      • Barnes J.
      Comparing parents' perceptions of IVF conceived children's behavior with naturally conceived children.
      Some studies found IVF to be associated with an increased risk of neurological problems and worse behavioral outcomes in the first year of life,
      • Ludwig A.K.
      • Sutcliffe A.G.
      • Diedrich K.
      • Ludwig M.
      Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies.
      • Wagenaar K.
      • Huisman J.
      • Cohen-Kettenis P.
      • Sdelemarre-van De Waal H.
      Overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization.
      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.
      • Koivurova S.
      • Hartikainen A.-L.
      • Sovio U.
      • Gissler M.
      • Hemminki E.
      • Jarvelin M.-R.
      Growth, psychomotor development, and morbidity up to 3 years of age in children born after IVF.
      • Middleburg K.J.
      • Heineman M.J.
      • Bos A.F.
      • Hadders-Algra M.
      Neuromotor, cognitive, language, and behavioural outcome in children born following IVF or ICSI—a systematic review.
      IVF and non-IVF adolescents did not differ on neuropsychological measures of information processing, attention, or visual-motor integration.
      • Wagenaar K.
      • Huisman J.
      • Cohen-Kettenis P.
      • Sdelemarre-van De Waal H.
      Overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization.
      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.
      • Peacock J.L.
      • Marston L.
      • Marlow N.
      • Calvert S.A.
      • Greenough A.
      Neonatal and infant outcome in boys and girls born very prematurely.
      • Smith G.C.
      Sex, birth weight, and the risk of stillbirth in Scotland, 1980-1996.
      • Stevenson D.K.
      • Verter J.
      • Fanaroff A.A.
      • et al.
      Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage.
      • Zeitlin J.
      • Saurel-Cubizolles M.J.
      • de Mouzon J.
      • Rivera L.
      • Ancel P.
      • Blondel B.
      • Kaminski M.
      Fetal sex and preterm birth: are males at greater risk?.
      An additional study
      • Cserjesi R.
      • Van Braeckel K.N.J.A.
      • Butcher P.R.
      • et al.
      Functioning of 7-year-old children born at 32 to 35 weeks' gestational age.
      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.
      • Baron I.S.
      • Erickson K.
      • Ahronovich M.D.
      • Baker R.
      • Litman F.
      Cognitive deficit in preschoolers born late-preterm.
      • Linnet K.M.
      • Wisborg K.
      • Agerbo E.
      • Secher N.J.
      • Thomsen P.H.
      • Henriksen T.B.
      Gestational age, birth weight, and the risk of 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
      IVF (n = 105)Non-IVF ( n = 292)dTotal (n = 397)tP value
      Participant characteristicsMeanSDMeanSDMeanSD
      Gestational age, wks34.820.7635.030.800.2734.980.79—2.39.020
      Age at testing, y3.090.283.020.150.333.040.202.80.010
      Birthweight, g2322.40384.352535.74537.310.462479.22508.50—3.74< .001
      P < .01.
      Length of hospital stay, d10.656.259.266.690.219.616.591.86.060
      Maternal education, y16.912.0516.022.160.4216.242.173.70< .001
      P < .01.
      Maternal age, y37.734.7233.225.040.9234.405.338.00< .001
      P < .01.
      IVF, in vitro fertilization; LPT, late preterm; Non-IVF, conceived without IVF.
      Berry. Neuropsychological outcome of IVF and late preterm birth. Am J Obstet Gynecol 2013.
      a P < .01.
      Table 2LPT IVF and non-IVF group demographic and medical characteristics
      Participant characteristicsIVF (n = 105)Non-IVF (n = 292)Total (n = 397)
      n%n%n%
      Cesarean delivery9387.619563.428869.7
      Twin delivery5451.44214.49624.2
      Male sex5249.516254.821453.6
      Right-handedness8479.022777.731177.9
      Race/ethnicity
       African American00.0196.2194.8
       White8480.018864.427268.2
       Hispanic43.8258.6297.3
       Other1716.06421.28119.8
      English as second language1716.08729.810426.3
      IVF, in vitro fertilization; LPT, late preterm; Non-IVF, conceived without IVF.
      Berry. Neuropsychological outcome of IVF and late preterm birth. Am J Obstet Gynecol 2013.

      Test instruments

      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.

      Differential Ability Scales, second edition

      This multisubtest
      • Elliott C.D.
      Differential Ability Scales–II.
      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

      This is an untimed paper-and-pencil test
      • Beery K.E.
      • Beery N.A.
      The Beery-Buktenica Developmental Test of Visual-Motor Integration: administration, scoring, and teaching manual.
      of graphomotor proficiency requiring copying of increasingly complex geometric designs. Standardized scores have a mean of 100 and SD of 15.

      Modified-Hopkins Board

      This is a task
      • Baron I.S.
      • Erickson K.
      • Ahronovich M.D.
      • Litman F.R.
      • Brandt J.
      Spatial location memory test performance discriminates children born at extremely low birth weight and late-preterm at age three.
      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).

      Purdue pegboard Test of Manual Dexterity

      This is a timed test
      • Gardner R.A.
      • Broman M.
      The Purdue pegboard: normative data on 1334 school children.
      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.

      Noun fluency

      This is a measure of verbal word retrieval
      • Baron I.S.
      Neuropsychological evaluation of the child.
      • Gaddes W.H.
      • Crockett D.J.
      The Spreen-Benton aphasia tests: normative data as a measure of normal language development.
      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)

      This parental questionnaire
      • Gioia G.
      • Espy K.
      • Isquith P.
      Behavior Rating Inventory of Executive Function Preschool Version.
      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

      The parental questionnaire
      • Reynolds C.R.
      • Kamphaus R.W.
      Behavior Assessment System for Children.
      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.
      • Cohen J.
      Statistical power analysis for the behavioral sciences.
      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.
      Table 3Main effects for gender differences
      Name of testMeanSDMeanSDdf1df2FP valued
      Copying51.020.8745.970.85139317.67< .0015.87
      Picture similarities54.770.8150.910.80139611.67.0014.80
      Purdue pegboard
      • Gardner R.A.
      • Broman M.
      The Purdue pegboard: normative data on 1334 school children.
      both hands
      3.640.133.020.13137111.79.0014.77
      BRIEF inhibit49.590.8746.240.8513927.76.0063.89
      Covariates were constant at mean values for birthweight of 2486.1 g, maternal education of 16.25 years, and age of the mothers at 34.41 years.
      BRIEF, Behavior Rating Inventory of Executive Function.
      Berry. Neuropsychological outcome of IVF and late preterm birth. Am J Obstet Gynecol 2013.

      Comment

      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.
      • Krey L.
      • Liu H.
      • Zhang J.
      • Grifo J.
      Fertility and maternal age: strategies to improve pregnancy outcome.
      However, significant differences in birthweight may be spurious because both groups fell within the normal range (Figure) .
      • Fenton T.R.
      A new growth chart for preterm babies: Babson and Benda's chart updated with recent data and a new format.
      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.
      Figure thumbnail gr1
      FigureFrequency distribution of birthweight
      Frequency distribution of birthweight (g) for IVF and non-IVF LPT 3 year olds falling within a normal range.
      IVF, in vitro fertilization; LPT, late preterm; non-IVF, conceived without IVF.
      Berry. Neuropsychological outcome of IVF and late preterm birth. Am J Obstet Gynecol 2013.
      These findings are in accordance with literature reporting no adverse outcomes in children born at term following IVF,
      • Koivurova S.
      • Hartikainen A.-L.
      • Sovio U.
      • Gissler M.
      • Hemminki E.
      • Jarvelin M.-R.
      Growth, psychomotor development, and morbidity up to 3 years of age in children born after IVF.
      • Middleburg K.J.
      • Heineman M.J.
      • Bos A.F.
      • Hadders-Algra M.
      Neuromotor, cognitive, language, and behavioural outcome in children born following IVF or ICSI—a systematic review.
      • Jongbloed-Pereboom M.
      • Middleburg K.J.
      • Heineman M.J.
      • Bos A.F.
      • Hadders-Algra M.
      The Groningen assisted reproductive technologies cohort study: developmental status and behavior at 2 years.
      • Knoester M.
      • Vandenbrouck J.P.
      • Helmerhorst F.M.
      • van der Westerlaken L.
      • Walther F.J.
      • Veen S.
      Matched follow-up study of 5- to 8-year-old ICSI singletons: a comparison of their neuromotor development to IVF and naturally conceived singletons.
      • Wagenaar K.
      • van Weissenbruch M.M.
      • Knol D.L.
      • Cohen-Kettenis P.T.
      • Delemarre-va de Waal H.A.
      • Huisman J.
      Information processing, attention and visual-motor function of adolescents born after in vitro fertilization compared with spontaneous conception.
      studies that did not report outcomes following LPT birth. Two studies
      • Ludwig A.K.
      • Sutcliffe A.G.
      • Diedrich K.
      • Ludwig M.
      Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies.
      • Wagenaar K.
      • Huisman J.
      • Cohen-Kettenis P.
      • Sdelemarre-van De Waal H.
      Overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization.
      reporting adverse outcomes for children conceived after IVF presented only slight indications of differences between the IVF and non-IVF groups. Ludwig et al
      • Ludwig A.K.
      • Sutcliffe A.G.
      • Diedrich K.
      • Ludwig M.
      Post-neonatal health and development of children born after assisted reproduction: a systematic review of controlled studies.
      merely specified that neurological problems in IVF children could not be excluded, and Wagenaar et al
      • Wagenaar K.
      • Huisman J.
      • Cohen-Kettenis P.
      • Sdelemarre-van De Waal H.
      Overview of studies on early development, cognition, and psychosocial well-being in children born after in vitro fertilization.
      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.
      • Peacock J.L.
      • Marston L.
      • Marlow N.
      • Calvert S.A.
      • Greenough A.
      Neonatal and infant outcome in boys and girls born very prematurely.
      • Smith G.C.
      Sex, birth weight, and the risk of stillbirth in Scotland, 1980-1996.
      • Stevenson D.K.
      • Verter J.
      • Fanaroff A.A.
      • et al.
      Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage.
      • Zeitlin J.
      • Saurel-Cubizolles M.J.
      • de Mouzon J.
      • Rivera L.
      • Ancel P.
      • Blondel B.
      • Kaminski M.
      Fetal sex and preterm birth: are males at greater risk?.
      • Hintz S.R.
      • Kendrick D.E.
      • Vohr B.R.
      • Poole W.K.
      • Higgins R.D.
      Gender differences in neurodevelopmental outcomes among extremely preterm, extremely-low-birthweight infants.
      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.
      • Baron I.S.
      • Litman F.R.
      • Ahronovich M.D.
      • Baker R.
      Late preterm birth: a review of medical and neuropsychological childhood outcomes.
      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,
      • Mains L.
      • Zimmerman M.
      • Blaine J.
      • et al.
      Achievement test performance in children conceived by IVF.
      • Koivurova S.
      • Hartikainen A.-L.
      • Sovio U.
      • Gissler M.
      • Hemminki E.
      • Jarvelin M.-R.
      Growth, psychomotor development, and morbidity up to 3 years of age in children born after IVF.
      • Sutcliffe A.G.
      • Edwards P.E.
      • Beeson C.
      • Barnes J.
      Comparing parents' perceptions of IVF conceived children's behavior with naturally conceived children.
      • Leunens L.
      • Celestin-Westreich S.
      • Bonduelle M.
      • Liebaers L.
      • Ponjaert-Kristoffersen I.
      Cognitive and motor development of 8-year-old children born after ICSI compared to spontaneously conceived children.
      • Knoester M.
      • Vandenbrouck J.P.
      • Helmerhorst F.M.
      • van der Westerlaken L.
      • Walther F.J.
      • Veen S.
      Matched follow-up study of 5- to 8-year-old ICSI singletons: a comparison of their neuromotor development to IVF and naturally conceived singletons.
      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.

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