Summary
Behavioral pattern in children of infertile couples may be influenced by both the underlying causes of infertility and stress in the couples. Treatment procedures, such as, culture media and manipulation of gametes and embryos, may also result in developmental problems. We examined behavioral problems in children as a function of infertility and infertility treatment, using data from three population-based birth cohorts in Denmark (Aalborg-Odense Birth Cohort, Aarhus Birth Cohort, and Danish National Birth Cohort). Information on time to pregnancy and infertility treatment was collected during pregnancy. Children aged between 7 and 21 years were assessed through the Strengths and Difficulties Questionnaire (SDQ). The SDQ was completed by mothers in all cohorts and, in addition, by teachers in the Aarhus cohort and by children themselves in the Aalborg-Odense cohort. Children born after a time to pregnancy of more than 12 months and no infertility treatment had a behavioral pattern similar to children of fertile parents. Teachers reported a higher total difficulties score for children born after infertility treatment, but no significant differences were seen on any subscales of the teachers’ report, and both mothers and the children did not report any difference on the total difficulties score and the prosocial behavior score. Our results are thus overall reassuring regarding behavioral problems in children born to infertile couples, regardless of infertility treatment.
Keywords: behavioral problems, child development, infertility, infertility treatment, Strengths and Difficulties Questionnaire (SDQ)
Introduction
Infertility, defined as a couple’s inability to conceive after one year of unprotected sexual intercourse, affects about 10-20% of couples worldwide and, currently, about 1-3% of all children in many industrialized countries are born after assisted reproductive technologies (ART).1–3 Couples who have tried to conceive for a long time may experience significant stress and anxiety related to the waiting time and the treatment, which could affect their ability to adapt to parenting and, as a consequence, influence their children’s emotional and behavioral development.4–6 Studies among these parents suggested that early parenting difficulties appear to be higher and postnatal self-confidence is lower.7 Both overprotection and unrealistic expectations may play a role, although these families seem to function well overall.8,9 Furthermore, causes of infertility may persist during pregnancy and beyond and, potentially, affect child health. It has also been hypothesized that several ART procedures, such as culture media, in vitro manipulation of gametes and embryos, may result in behavioral and developmental problems in the offspring, perhaps through epigenetic changes.10,11 Modifications of gene expression during gametogenesis and embryogenesis may further interact with the early family environment.11
Psychiatric disorders in children and adolescents are common, with a prevalence of about 10%.12,13 Prevention, detection, and treatment of these problems are very important not only to relieve the public health burden, but also to prevent perpetuation of these problems into the next generation. While little is known about the behavioral problems in children who are conceived naturally after a long waiting time,14,15 a number of studies among children born after ART suggest that ART children do not have more behavioral problems than naturally conceived children.8,14–20 Some studies even suggested a more positive relationship between these children and their parents.21–23 This may be due to different parenting style for a highly-desired child, to other characteristics of the family, or to the fact that unplanned children were included in the reference population. Although a few small studies included children up to 18 years of age,14,15 most studies have included pre-puberty children. Subtle differences may not be detectable in these young children, since mental disorders increase with age in childhood and early adulthood.13,24
In this study, we used three Danish birth cohorts to examine whether parental infertility and infertility treatment were associated with behavioral problems in children and adolescents.
Methods
Study population
We used data from three population-based birth cohorts in Denmark: the Danish National Birth Cohort (1996-2002),25 the Aarhus Birth Cohort (1990-1992),26 and the Aalborg-Odense Birth Cohort (1984-1987).27 All birth cohorts were initiated during pregnancy, and information on time to pregnancy, as well as socio-demographic, environmental, and lifestyle factors, was collected through questionnaires prior to the birth of the child. The children were followed up to the ages of 7, 10-12, and 18-21 years in the three cohorts, respectively.
The Danish National Birth Cohort was established to explore the potential importance of social, environmental, and lifestyle factors during pregnancy and early childhood on subsequent health and development.25 Women were recruited early in pregnancy by general practitioners between 1996 and 2002. Participants were administered four computer-assisted telephone interviews. When the child was 7 years old, a follow-up questionnaire about child health and development, including the Strengths and Difficulties Questionnaire (SDQ), was filled out by the primary caregiver, either through the internet or on paper. A total of 31508 caregivers, usually the mother, responded between July 2005 and February 2008 (about 60% of the eligible). We linked the 7-year follow-up data with the first interview data and excluded twins, triplets, and those with no data from the first interview (N=703, 12, and 1140, respectively). We also excluded those with no or incomplete answer to the parent SDQ (N=152 and 917, respectively) and those with no or possibly wrong date for completion of the questionnaire (N=9), as well as those with incomplete information on pregnancy planning, time to pregnancy or treatment and those with “partly planned” pregnancies (N=215 and 3630, respectively), thus leaving 24730 singletons in the National Birth Cohort available for analysis.
The Aarhus Birth Cohort, started in 1989, is an ongoing pregnancy cohort that invites all women who give birth at Aarhus University Hospital. The cohort is based on consecutive recruitment through the antenatal health care service. The present study was based on children born between January 1990 and June 1992. In 2001 (when the children were between 9 and 11 years old), parents of 8244 children who were alive and could be traced by means of the civil registration system were asked to fill in a questionnaire concerning child health and development. A total of 5974 parents responded (72%). Of these, 5045 parents also allowed us to contact their child’s teacher. In 2002 (when the children were between 10 and 12 years old), the SDQ was sent to the parents and teachers. Overall, 5266 parents and 4350 teachers returned the questionnaire (The response rates among those who received the SDQ questionnaires were 88% and 86%, respectively; the response rates based on the 8244 children traced at an age between 9 and 11 years were 64% and 53%, respectively). We excluded the responses concerning twins and triplets (N=117 returned by parents and 105 returned by teachers). We also excluded 702 singletons with incomplete answer to the parent-reported SDQ and 261 singletons with incomplete answer to the teacher-reported SDQ, as well as those with incomplete information on pregnancy planning, time to pregnancy or treatment (N=228 for parent-reported SDQ and 195 for teacher-reported SDQ). Consequently, 4219 parent-reported SDQ and 3789 teacher-reported SDQ for singletons in the Aarhus cohort were available for analysis.
In the Aalborg-Odense Birth Cohort, all pregnant women in Aalborg and Odense were invited to participate in the “Healthy Habits for Two” cohort study between April 1984 and April 1987, and 11980 pregnant women agreed. In 2002 (when the children were between 15 and 18 years old), a follow-up questionnaire on the child’s health and development, including a modified version of the SDQ (see below), was mailed to the 10636 mother-child (singletons only) pairs who could be traced by means of the civil registration system. A total of 7841 parents responded (74%). In 2005 (when the children were between 18 and 21 years old), a follow-up questionnaire on health and lifestyle, including the self-reported SDQ, was provided to 9811 youths who were alive and living in the country. A total of 6195 (63%) responded through the internet or ordinary mail. We excluded children having no or incomplete answer to the parent-reported SDQ (N=14 and 501, respectively) and children providing no or incomplete answer to the self-reported SDQ (N=13 and 445, respectively), as well as those with incomplete information on pregnancy planning, time to pregnancy or treatment (N=324 for parent-reported SDQ and 254 for self-reported SDQ), thus leaving 7002 children with parent-reported SDQ and 5483 children with self-reported SDQ available for analysis.
Infertility and infertility treatment
In all three cohorts the questionnaires administered during pregnancy asked if the pregnancy had been planned, how long the women had tried to become pregnant before succeeding (time to pregnancy), and whether they or their partner had been treated for infertility. The question about infertility treatment was broader in the Aalborg-Odense cohort and included those having been examined for infertility. Time to pregnancy was reported in four categories (0-2, 3-5, 6-12, and more than 12 months) in the National Birth Cohort, the exact number of months in the Aarhus cohort, and three categories (0-6, 7-12, and more than 12 months) in the Aalborg-Odense cohort.
We defined couples as “fertile” if they had planned their pregnancy and conceived within 12 months without receiving infertility treatment. Couples who planned their pregnancy but took longer than 12 months to conceive without being treated for infertility were classified as “untreated infertile”, while couples who reported being treated (or examined) for infertility were considered as “treated infertile”. Couples who did not plan their pregnancy and who had not been treated for infertility were classified as having an unplanned pregnancy. In all three cohorts, we excluded couples with incomplete information on pregnancy planning, time to pregnancy or treatment, including couples who (i) did not provide information on pregnancy planning; (ii) reported having planned the pregnancy while using contraception; (iii) reported having planned the pregnancy but provided no information on time to pregnancy; and (iv) did not provide information on treatment. In the National Birth Cohort, we also excluded couples with a “partly planned” pregnancy (an additional response category besides planned and unplanned pregnancies: see exclusions details in the previous section “Study population”), as we had limited confidence in the accuracy of the reported TTP for this group.
In the National Birth Cohort, women reporting that she or her male partner had received infertility treatment were further asked “What kind of infertility treatment did you or your male partner receive?” Specified response categories included intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF), intrauterine insemination (IUI)(the large majority of cases using partner’s sperm), and ovulation induction (OI).
Strengths and Difficulties Questionnaire (SDQ)
The SDQ is a measure of emotional, behavioral and social functioning in children and adolescents from 3 to 16 years of age (http://www.sdqinfo.com). The questionnaire includes 25 questions and is available as a parent-, teacher-, or self-reported version. For example, one question on emotional symptoms is phrased: “Often complains of headaches, stomach-aches or sickness” in the parent- and teacher-reported version, and “I get a lot of headaches, stomach-aches or sickness” in the self-reported version. All questions refer to the past 6 months. Each question could be answered as 0 (not true), 1 (somewhat true) or 2 (certainly true). Five subscale scores (emotional symptoms, conduct problems, hyperactivity, peer problems, and prosocial behavior) can be calculated based on five questions for each. The total difficulties score consists of the sum of all subscales except prosocial behavior (details of the calculations are available on the SDQ website). Studies have shown that the psychometric properties of the SDQ, as well as its validity and reliability, are satisfactory,28–31 and that the SDQ is better than the Child Behavior Checklist at detecting inattention and hyperactivity disorders, and at least as good at detecting internalising and externalising problems.32 Nordic language versions of SDQ have been validated,33,34 and the distributions of the SDQ scores are very similar across Nordic countries.35
In this study, all three cohorts included the parent version of the SDQ, with a modification in the Aalborg-Odense cohort to cover the full period of school age (7-14 years old) instead of the past 6 months. The Aarhus cohort also included the teacher version, and the Aalborg-Odense cohort the self-reported version. The self-reported version was originally designed for children aged 11-16 years, but studies suggest that the results are acceptable among adolescents aged 17-19 years.36,37 In our study, the self-reported version had an error, i.e., the question “I fight a lot. I can make other people do what I want” was split into two questions. We only used the question including the first part, as we considered this to be the core of the original question.
In this study, we a priori applied the cut-off points posted on the SDQ website to the classification of children with abnormal scores for the prosocial behavior and the total difficulties, as well as for the four subscales. We considered these cut-offs more clinically relevant. SDQ scores are extremely left skewed (right skewed for the prosocial behavior score), and using means may hide a clinically relevant difference between the compared groups.
Statistical analysis
Within each cohort, we used logistic regressions to estimate the odds ratios (with 95% confidence intervals) of having an abnormal score for children of untreated infertile couples, children of treated infertile couples, and children who were not planned, compared with children of fertile couples. To reduce the number of main comparisons, we paid more attention to the total difficulties score rather than to the four subscale scores. Within the National Birth Cohort, we also compared children born after different treatment procedures with children of fertile couples. Potential confounders included maternal age at birth of the child (<25, 25-29, 30-34, 35+ years), parity (0, 1+), smoking (yes, no) and alcohol intake (0, 1-4, 5+ units per week) during pregnancy, pre-pregnancy body mass index (<18.5, 18.5-24, 25-29, 30+ kg/m2), and parental education (having or not having high school education in the Aarhus and the Aalborg-Odense cohorts) or occupation (high, medium, or low level, students, or unemployed in the National Birth Cohort).38 The inclusion of these covariates was based on previous studies.39–42 Children’s sex and age at follow-up were also included as covariates.24,42 Since a few (less than 3%) women contributed two children to the cohorts, we used a robust variance estimator to calculate the 95% confidence intervals.43 A p-value of less than 0.05 was considered to be statistically significant. We used Stata/SE 9.1 for all analyses.
Results
In general in all three cohorts, mothers with a long waiting time or who conceived after infertility treatment were older than mothers who conceived within 12 months and without infertility treatment, and their children were more often first-borns (Table 1). These mothers were also more often smokers, overweight or obese, and of low occupational status or education (except for the national cohort where the distributions of smoking and occupational status were similar between the treated infertile mothers and fertile mothers). Overall, pregnant women smoked less in the more recent cohort (24% in the national cohort and 29% in the Aarhus cohort vs. 41% in the Aalborg-Odense cohort), but they were more often overweight or obese (25% in the national cohort vs. 12% in the Aarhus cohort and 11% in the Aalborg-Odense cohort).
Table 1.
Selected characteristics of the children whose parents completed the Strengths and Difficulties Questionnaire (SDQ), according to parents’ fertility status
| Fertile couples | Untreated infertile couples | Treated infertile couples | Couples with unplanned pregnancy | |
|---|---|---|---|---|
| % | % | % | % | |
| Danish National Birth Cohort | N=18173 | N=1894 | N=1567 | N=3096 |
| Maternal age, years | ||||
| <25 | 7.3 | 4.8 | 3.0 | 16.2 |
| 25-29 | 41.4 | 32.5 | 26.2 | 27.7 |
| 30-34 | 39.1 | 42.7 | 43.4 | 33.7 |
| 35+ | 12.1 | 20.1 | 27.4 | 22.4 |
| Parity | ||||
| 0 | 41.7 | 52.3 | 70.0 | 40.9 |
| 1+ | 58.2 | 47.6 | 29.9 | 59.1 |
| Child’s sex | ||||
| Girl | 48.8 | 48.0 | 48.2 | 47.1 |
| Boy | 51.2 | 52.0 | 51.8 | 52.9 |
| Aarhus Birth Cohort | N=2264 | N=281 | N=184 | N=1490 |
| Maternal age, years | ||||
| <25 | 11.8 | 10.7 | 4.3 | 19.6 |
| 2529 | 46.3 | 36.3 | 25.0 | 39.6 |
| 30-34 | 30.8 | 34.9 | 50.5 | 26.0 |
| 35+ | 11.1 | 18.1 | 20.1 | 14.8 |
| Parity | ||||
| 0 | 49.9 | 55.5 | 71.7 | 52.6 |
| 1+ | 50.0 | 44.1 | 27.7 | 47.4 |
| Child’s sex | ||||
| Girl | 48.6 | 53.0 | 51.6 | 49.3 |
| Boy | 51.4 | 47.0 | 48.4 | 50.7 |
| Aalborg-Odense Birth Cohort | N=4622 | N=590 | N=610 | N=1180 |
| Maternal age, years | ||||
| <25 | 27.0 | 24.2 | 9.0 | 38.6 |
| 25-29 | 47.4 | 42.2 | 34.1 | 33.2 |
| 30-34 | 20.7 | 23.1 | 42.0 | 19.1 |
| 35+ | 5.0 | 10.5 | 14.9 | 9.2 |
| Parity | ||||
| 0 | 46.7 | 53.2 | 49.7 | 52.7 |
| 1+ | 53.3 | 46.8 | 50.3 | 47.3 |
| Child’s sex | ||||
| Girl | 47.2 | 53.6 | 50.2 | 51.8 |
| Boy | 52.8 | 46.4 | 49.8 | 48.2 |
Percentages may not add to 100% due to missing values or rounding.
The distributions of the parent-reported SDQ were similar across the three cohorts (Table 2). With respect to the different SDQ versions, the self-reported SDQ had the highest scores on almost all subscales, and the teacher-reported SDQ had the lowest scores.
Table 2.
Mean Strengths and Difficulties Questionnaire (SDQ) scores according to birth cohort and SDQ version
| Danish National Birth Cohort | Aarhus Birth Cohort | Aalborg-Odense Birth Cohort | ||||
|---|---|---|---|---|---|---|
| Mean | SDa | Mean | SDa | Mean | SDa | |
| Parent-reported SDQ | ||||||
| Emotional symptoms | 1.6 | 1.7 | 1.6 | 1.9 | 1.7 | 2.0 |
| Conduct problems | 1.2 | 1.3 | 0.9 | 1.2 | 1.1 | 1.4 |
| Hyperactivity | 2.4 | 2.1 | 2.0 | 2.1 | 2.4 | 2.4 |
| Peer problems | 0.7 | 1.3 | 0.9 | 1.6 | 1.4 | 1.9 |
| Prosocial behavior | 8.3 | 1.6 | 8.5 | 1.5 | 8.0 | 1.8 |
| Total difficulties | 5.8 | 4.4 | 5.4 | 4.8 | 6.6 | 5.6 |
| Teacher-reported SDQ | ||||||
| Emotional symptoms | 1.3 | 1.9 | ||||
| Conduct problems | 0.8 | 1.4 | ||||
| Hyperactivity | 2.1 | 2.6 | ||||
| Peer problems | 1.3 | 1.9 | ||||
| Prosocial behavior | 7.5 | 2.4 | ||||
| Total difficulties | 5.5 | 5.8 | ||||
| Self-reported SDQ | ||||||
| Emotional symptoms | 3.1 | 2.3 | ||||
| Conduct problems | 1.6 | 1.3 | ||||
| Hyperactivity | 3.1 | 2.1 | ||||
| Peer problems | 2.1 | 1.6 | ||||
| Prosocial behavior | 8.1 | 1.6 | ||||
| Total difficulties | 9.8 | 5.0 | ||||
SD: standard deviation.
Children of untreated infertile couples
Compared with children of fertile couples, the mother-, the teacher-, and the self-reported SDQ showed no differences on the total difficulties score or the prosocial behavior score for children whose parents reported an untreated time to pregnancy of more than 12 months (Table 3 and Table 4). There were also no differences on the subscale scores, except that mothers in the Aalborg-Odense cohort reported more emotional symptoms.
Table 3.
Percentages of abnormal Strengths and Difficulties Questionnaire (SDQ) scoresa according to parents’ fertility status in the three birth cohorts
| Fertile couples | Untreated infertile couples | Treated infertile couples | Couples with unplanned pregnancy | |||||
|---|---|---|---|---|---|---|---|---|
| n | % | n | % | n | % | n | % | |
| Danish National Birth Cohort | ||||||||
| Mother’s report, 7 years | ||||||||
| Emotional symptoms | 1238 | 6.8 | 160 | 8.4 | 136 | 8.7 | 253 | 8.2 |
| Conduct problems | 964 | 5.3 | 111 | 5.9 | 75 | 4.8 | 218 | 7.0 |
| Hyperactivity | 893 | 4.9 | 105 | 5.5 | 77 | 4.9 | 202 | 6.5 |
| Peer problems | 700 | 3.9 | 92 | 4.9 | 93 | 5.9 | 189 | 6.1 |
| Prosocial behavior | 392 | 2.2 | 47 | 2.5 | 34 | 2.2 | 73 | 2.4 |
| Total difficulties | 485 | 2.7 | 69 | 3.6 | 54 | 3.4 | 135 | 4.4 |
| Aarhus Birth Cohort | ||||||||
| Mother’s report, 10-12 years | ||||||||
| Emotional symptoms | 187 | 8.3 | 30 | 10.7 | 16 | 8.7 | 129 | 8.7 |
| Conduct problems | 87 | 3.8 | 13 | 4.6 | 6 | 3.3 | 62 | 4.2 |
| Hyperactivity | 87 | 3.8 | 18 | 6.4 | 5 | 2.7 | 65 | 4.4 |
| Peer problems | 162 | 7.2 | 19 | 6.8 | 19 | 10.3 | 123 | 8.3 |
| Prosocial behavior | 52 | 2.3 | 5 | 1.8 | 3 | 1.6 | 31 | 2.1 |
| Total difficulties | 81 | 3.6 | 12 | 4.3 | 9 | 4.9 | 57 | 3.8 |
| Teacher’s report, 10-12 years | ||||||||
| Emotional symptoms | 90 | 4.5 | 8 | 3.3 | 11 | 6.8 | 74 | 5.4 |
| Conduct problems | 117 | 5.8 | 13 | 5.4 | 10 | 6.2 | 92 | 6.7 |
| Hyperactivity | 167 | 8.3 | 22 | 9.1 | 17 | 10.5 | 133 | 9.6 |
| Peer problems | 159 | 7.9 | 16 | 6.6 | 12 | 7.4 | 114 | 8.3 |
| Prosocial behavior | 232 | 11.6 | 26 | 10.8 | 15 | 9.3 | 190 | 13.8 |
| Total difficulties | 135 | 6.7 | 17 | 7.1 | 18 | 11.1 | 111 | 8.0 |
| Aalborg-Odense Birth Cohort | ||||||||
| Mother’s report, 15-18 years | ||||||||
| Emotional symptoms | 438 | 9.5 | 89 | 15.1 | 71 | 11.6 | 158 | 13.4 |
| Conduct problems | 296 | 6.4 | 51 | 8.6 | 40 | 6.6 | 97 | 8.2 |
| Hyperactivity | 338 | 7.3 | 52 | 8.8 | 48 | 7.9 | 108 | 9.2 |
| Peer problems | 551 | 11.9 | 86 | 14.6 | 95 | 15.6 | 170 | 14.4 |
| Prosocial behavior | 191 | 4.1 | 20 | 3.4 | 23 | 3.8 | 61 | 5.2 |
| Total difficulties | 276 | 6.0 | 43 | 7.3 | 42 | 6.9 | 104 | 8.8 |
| Self report, 18-21 years | ||||||||
| Emotional symptoms | 313 | 8.7 | 47 | 10.1 | 42 | 9.2 | 98 | 10.4 |
| Conduct problems | 103 | 2.8 | 14 | 3.0 | 10 | 2.2 | 33 | 3.5 |
| Hyperactivity | 261 | 7.2 | 29 | 6.3 | 22 | 4.8 | 90 | 9.6 |
| Peer problems | 109 | 3.0 | 14 | 3.0 | 7 | 1.5 | 33 | 3.5 |
| Prosocial behavior | 104 | 2.9 | 10 | 2.2 | 10 | 2.2 | 22 | 2.3 |
| Total difficulties | 150 | 4.1 | 21 | 4.5 | 14 | 3.1 | 58 | 6.2 |
The cut-offs for abnormal scores for emotional symptoms, conduct problems, hyperactivity, peer problems, prosocial behavior, and total difficulties were ≥5, ≥4, ≥7, ≥4, <5, and ≥17 for the parent-report, ≥6, ≥4, ≥7, ≥5, <5, and ≥16 for the teacher-report, and ≥7, ≥5, ≥7, ≥6, <5, and ≥20 for the self-report, respectively.
Table 4.
Odds ratios (OR) with 95% confidence intervals [CI] of having an abnormal score according to parents’ fertility status in three birth cohorts
| Untreated infertile couples | Treated infertile couples | Couples with unplanned pregnancy | |||||||
|---|---|---|---|---|---|---|---|---|---|
| Crude OR |
Adjusted ORa |
95% CI | Crude OR |
Adjusted ORa |
95% CI | Crude OR |
Adjusted ORa |
95% CI | |
| Danish National Birth Cohort | |||||||||
| Mother’s report, 7 years | |||||||||
| Emotional symptoms | 1.26 | 1.16 | [0.97, 1.38] | 1.30 | 1.14 | [0.94, 1.39] | 1.22 | 1.08 | [0.93, 1.26] |
| Conduct problems | 1.11 | 1.06 | [0.86, 1.30] | 0.90 | 0.99 | [0.77, 1.27] | 1.35 | 1.12 | [0.95, 1.31] |
| Hyperactivity | 1.14 | 1.09 | [0.88, 1.35] | 1.00 | 1.07 | [0.84, 1.37] | 1.35 | 1.14 | [0.97, 1.35] |
| Peer problems | 1.27 | 1.20 | [0.96, 1.50] | 1.57 | 1.56 | [1.23, 1.96] | 1.62 | 1.28 | [1.07, 1.53] |
| Prosocial behavior | 1.15 | 1.11 | [0.81, 1.52] | 1.01 | 0.97 | [0.68, 1.40] | 1.10 | 1.01 | [0.77, 1.32] |
| Total difficulties | 1.38 | 1.27 | [0.98, 1.65] | 1.30 | 1.32 | [0.98, 1.77] | 1.66 | 1.23 | [0.99, 1.52] |
| Aarhus Birth Cohort | |||||||||
| Mother’s report, 10-12years | |||||||||
| Emotional symptoms | 1.33 | 1.12 | [0.73, 1.72] | 1.06 | 0.88 | [0.52, 1.50] | 1.05 | 0.94 | [0.74, 1.20] |
| Conduct problems | 1.21 | 1.04 | [0.57, 1.92] | 0.84 | 0.79 | [0.34, 1.86] | 1.09 | 0.91 | [0.64, 1.29] |
| Hyperactivity | 1.71 | 1.52 | [0.89, 2.59] | 0.70 | 0.63 | [0.24, 1.62] | 1.14 | 1.03 | [0.73, 1.47] |
| Peer problems | 0.94 | 0.82 | [0.49, 1.36] | 1.49 | 1.27 | [0.76, 2.11] | 1.17 | 1.06 | [0.83, 1.37] |
| Prosocial behavior | 0.77 | 0.76 | [0.29, 2.00] | 0.71 | 0.72 | [0.21, 2.42] | 0.90 | 0.88 | [0.55, 1.41] |
| Total difficulties | 1.20 | 0.97 | [0.52, 1.83] | 1.39 | 1.14 | [0.55, 2.33] | 1.07 | 0.93 | [0.65, 1.33] |
| Teacher’s report, 10-12 years | |||||||||
| Emotional symptoms | 0.73 | 0.61 | [0.29, 1.27] | 1.55 | 1.23 | [0.61, 2.48] | 1.20 | 1.05 | [0.75, 1.47] |
| Conduct problems | 0.92 | 0.88 | [0.46, 1.66] | 1.06 | 1.18 | [0.58, 2.40] | 1.15 | 0.92 | [0.69, 1.24] |
| Hyperactivity | 1.11 | 1.24 | [0.75, 2.05] | 1.29 | 1.52 | [0.85, 2.74] | 1.17 | 1.07 | [0.83, 1.38] |
| Peer problems | 0.83 | 0.70 | [0.40, 1.22] | 0.93 | 0.70 | [0.37, 1.31] | 1.04 | 0.88 | [0.68, 1.14] |
| Prosocial behavior | 0.92 | 0.97 | [0.62, 1.52] | 0.78 | 0.88 | [0.50, 1.57] | 1.22 | 1.14 | [0.92, 1.41] |
| Total difficulties | 1.05 | 1.02 | [0.58, 1.79] | 1.73 | 1.84 | [1.06, 3.19] | 1.21 | 1.04 | [0.79, 1.37] |
| Aalborg-Odense Birth Cohort | |||||||||
| Mother’s report, 15-18 years | |||||||||
| Emotional symptoms | 1.70 | 1.50 | [1.16, 1.92] | 1.26 | 1.20 | [0.91, 1.60] | 1.48 | 1.32 | [1.08, 1.62] |
| Conduct problems | 1.38 | 1.26 | [0.92, 1.73] | 1.03 | 1.15 | [0.81, 1.64] | 1.31 | 1.22 | [0.96, 1.56] |
| Hyperactivity | 1.23 | 1.22 | [0.89, 1.68] | 1.08 | 1.28 | [0.92, 1.78] | 1.28 | 1.25 | [0.98, 1.58] |
| Peer problems | 1.26 | 1.17 | [0.91, 1.50] | 1.36 | 1.35 | [1.05, 1.72] | 1.24 | 1.16 | [0.95, 1.40] |
| Prosocial behavior | 0.81 | 0.81 | [0.50, 1.30] | 0.91 | 0.90 | [0.57, 1.41] | 1.26 | 1.27 | [0.94, 1.71] |
| Total difficulties | 1.24 | 1.13 | [0.80, 1.59] | 1.16 | 1.22 | [0.87, 1.73] | 1.52 | 1.38 | [1.08, 1.76] |
| Self report, 18-21 years | |||||||||
| Emotional symptoms | 1.19 | 1.05 | [0.75, 1.47] | 1.06 | 1.01 | [0.70, 1.45] | 1.23 | 1.08 | [0.84, 1.39] |
| Conduct problems | 1.06 | 1.05 | [0.59, 1.86] | 0.76 | 0.84 | [0.42, 1.65] | 1.24 | 1.17 | [0.79, 1.75] |
| Hyperactivity | 0.86 | 0.84 | [0.56, 1.25] | 0.65 | 0.67 | [0.42, 1.06] | 1.36 | 1.27 | [0.98, 1.64] |
| Peer problems | 1.00 | 0.90 | [0.51, 1.60] | 0.50 | 0.50 | [0.22, 1.10] | 1.17 | 1.06 | [0.72, 1.57] |
| Prosocial behavior | 0.74 | 0.82 | [0.43, 1.58] | 0.75 | 0.94 | [0.46, 1.90] | 0.81 | 0.93 | [0.58, 1.51] |
| Total difficulties | 1.10 | 0.88 | [0.54, 1.41] | 0.73 | 0.68 | [0.38, 1.22] | 1.52 | 1.35 | [0.99, 1.85] |
Reference group: fertile couples.
adjusted for maternal age, parity, smoking and alcohol intake during pregnancy, pre-pregnancy body mass index, parental education (the Aarhus Birth Cohort and the Aalborg-Odense Birth Cohort) or occupation (the Danish National Birth Cohort), and child’s sex and age.
Children of treated infertile couples
Compared with children of fertile couples, the mother- and the self-reported SDQ showed no differences on the total difficulties score or the prosocial behavior score for children born after infertility treatment, while teachers reported a higher total difficulties score in the Aarhus cohort (Table 3 and Table 4). On the subscales, mothers reported more peer problems for children born after infertility treatment in both the National Birth Cohort and the Aalborg-Odense cohort, but teachers reported no differences on any subscales in the Aarhus cohort.
In the National Birth Cohort, no differences on the total difficulties score and the prosocial behavior score were seen for children born after specific treatment procedures. On the subscales, mothers reported more peer problems for children born after IVF or IUI (Table 5).
Table 5.
Odds ratios (OR) with 95% confidence intervals [CI] of having an abnormal score in children born after different treatment proceduresa compared with children of fertile couples, the Danish National Birth Cohort
| ICSI | IVF | IUI | OI | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
|
| ||||||||||||
| Crude | Adjusted | 95% CI | Crude | Adjusted | 95% CI | Crude | Adjusted | 95% CI | Crude | Adjusted | 95% CI | |
| OR | ORb | OR | ORb | OR | ORb | OR | ORb | |||||
| Mother’s report, | ||||||||||||
| 7 years | ||||||||||||
| Emotional symptoms | 1.56 | 1.33 | [0.72, 2.44] | 0.94 | 0.87 | [0.59, 1.27] | 1.20 | 1.06 | [0.74, 1.50] | 1.54 | 1.25 | [0.90, 1.74] |
| Conduct problems | 1.31 | 1.68 | [0.82, 3.44] | 0.86 | 1.06 | [0.67, 1.66] | 0.71 | 0.78 | [0.48, 1.29] | 0.88 | 0.82 | [0.51, 1.31] |
| Hyperactivity | 0.68 | 0.85 | [0.31, 2.36] | 0.93 | 1.15 | [0.74, 1.80] | 0.82 | 0.86 | [0.53, 1.39] | 1.60 | 1.46 | [1.00, 2.14] |
| Peer problems | 1.59 | 1.73 | [0.78, 3.83] | 1.60 | 1.73 | [1.16, 2.58] | 1.74 | 1.77 | [1.18, 2.64] | 1.50 | 1.35 | [0.88, 2.07] |
| Prosocial behavior | 0.39 | 0.38 | [0.05, 2.76] | 1.36 | 1.26 | [0.72, 2.19] | 0.83 | 0.79 | [0.38, 1.61] | 1.03 | 1.03 | [0.52, 2.02] |
| Total difficulties | 1.29 | 1.47 | [0.52, 4.11] | 1.09 | 1.28 | [0.73, 2.23] | 1.01 | 1.01 | [0.57, 1.82] | 1.89 | 1.57 | [0.99, 2.49] |
including intracytoplasmic sperm injection (ICSI), in vitro fertilization (IVF), intrauterine insemination (IUI), and ovulation induction (OI).
adjusted for maternal age, parity, smoking and alcohol intake during pregnancy, pre-pregnancy body mass index, parental occupation, and child’s sex and age.
Children who were not planned
For children born after unplanned pregnancies, mothers reported a higher total difficulties score in the Aalborg-Odense cohort (Table 3 and Table 4). On the subscales, mothers reported more peer problems in the National Birth Cohort and more emotional symptoms in the Aalborg-Odense cohort.
Discussion
In these three large cohorts followed over a long period of time, children born after a long waiting time to pregnancy had no more behavioral problems than children born of more fertile couples. Although children born after infertility treatment had a higher total difficulties score as reported by their teachers, mothers and children themselves reported total difficulties score and prosocial behavior score similar to those of the children of fertile couples. Children who were not planned had more behavioral problems as reported by their mothers.
Children of untreated infertile couples
Children conceived naturally after a long waiting time to pregnancy had a behavioral pattern similar to that of children of fertile couples, which is in line with previous findings.14,15,44,45 These studies included 9-18-year-old children who were conceived naturally by infertile couples as a reference group for IVF children and showed that behavior scores of these children were overall within the normal range, as well as comparable to the IVF children or children born after donor insemination, in particular in late adolescence. Studies also reported good relationships between these parents and children.14 These findings suggest that families where parents have experienced infertility but received no IVF treatment function well. The underlying causes of infertility in the parents are thus unlikely to be related to behavioral problems in children.
Children of treated infertile couples
Children born after infertility treatment had parent- and self-reported total difficulties score and prosocial score similar to those of children born of fertile couples, a finding in line with previous studies, whether the SDQ 8,46 or other instruments 8,14–20 were used as a tool. Although teachers reported a higher total difficulties score for children born after infertility treatment, there was no significant difference on any subscale. On the subscales, mothers did report that children born after infertility treatment had more peer problems, which may reflect a higher degree of concern among parents who underwent treatment, as suggested by the fact that the children themselves failed to report an increased level of difficulties.
ICSI procedure is more radical than IVF, as natural sperm selection is bypassed and spermatozoa with impaired mobility, morphology or genetic abnormalities may be used. In addition, the cause of infertility may be different between patients treated with IVF or ICSI. Nonetheless, we did not find more emotional or behavioral problems among children born following ICSI, a finding in agreement with what had previously been reported.16,23,47
Children who were not planned
Mothers reported more behavioral problems in adolescents who were not planned at the time of conception. This may be due to confounding by social factors, or reflect differences in parental attitude. This finding underscores the importance of how the group of unplanned children is handled in this part of infertility research, and it may also explain why we did not find fewer behavioral problems among children born after ART, as reported in some studies.22,23
Study strengths and limitations
Our study had several strengths. First, it included a large number of children evaluated at different ages and with long follow-up periods. Regardless of exposure and outcome, all children in the birth cohorts were followed up in a similar way from pregnancy to the time of contact, and responders were not aware of the specific aim of this study. Second, we used the SDQs from different responders. When measuring behavioral pattern among children and adolescents, it is important to use several informants (e.g., parents and teachers).48 Parents know their children best but, in contrast to teachers, they may lack comparable information on emotional and behavioral patterns in other children of the same age. Self-reports are generally less strongly associated with clinical psychiatric disorder than parent or teacher reports, except for emotional problems.49 The SDQ has been the most widely used instrument in child behavior research since it was developed a decade ago.48,50 Studies have also shown that the SDQ can serve as a brief and useful screening tool for psychiatric disorders in child mental health clinics.28,32,49–51 Third, we were able to adjust for a number of potential confounders in the analysis.
Our study also had a number of limitations. First, there was moderate loss to follow-up, and non-response may cause selection bias if related to both parental infertility status and behavioral outcomes in children, which could be the case. Second, information on time to pregnancy and infertility treatment was self reported and may have been subject to recall bias.52,53 We believe, however, that short-term recall is rather accurate, and women in our study had to report time to pregnancy about 4-9 months into the pregnancy. The validation study on infertility treatment in the Danish National Birth Cohort yielded a sensitivity of 83% and a specificity of 99% for IVF/ICSI treatment.54 In the Aalborg-Odense cohort, we had to categorize the couples who were treated or examined for infertility as treated, which would result in underestimating the effects of infertility treatment, since some classified as treated would not have been treated. Third, the teacher-reported SDQ was only available for children aged 10-12 years in the Aarhus cohort, and the self-reported SDQ was only available for children aged 18-21 years in the Aalborg-Odense cohort. In addition, the mother-reported SDQ in the Aalborg-Odense cohort was modified to assess the full period of school ages (7-14 years of age) instead of the past six months, which may increase measurement error and affect its reliability. The proportion of children with abnormal scores was low in this study, especially in the National Birth Cohort. The a priori defined cut-offs are based on the UK population and the lower rates above the cut-offs are a more general phenomenon in the Nordic cohorts,35 probably because of cultural differences, but also in part because participants in these cohorts are more likely to be from well-functioning families compared with the general population. Fourth, we lacked information on father, family structure, parenting, and parent-child relationship, and all of these could have an effect on child behavior. If more single-parent families are included in our reference category (i.e., families with fertile parents), this would tend to bias results towards the null. However, our reference category, as well as the groups born of infertile couples, included only children who were planned, and this likely involves the presence of the father. It is possible that part of the problems we saw in the unplanned children depended on this issue. Finally, we had a few discordant findings among the three cohorts, which may be due to the different ages of the children assessed. Some of the differences we found could be due to chance (as we made numerous comparisons), and more attention should as always be paid to the overall pattern and consistency of the results rather than to specific significant associations.
Because teachers reported a higher total difficulties score and mothers reported more peer problems for children born after infertility treatment, future studies should focus on these aspects. Further evaluation should also include the potential effects of specific causes of infertility and new treatment procedures on behavioral problems, as well as other aspects, especially fertility, in the children.
Our findings suggest that the mental development of children born after a long waiting time with or without infertility treatment is, overall, similar to that of children born of fertile couples.
Acknowledgements
The authors thank Matthew P Longnecker and two anonymous reviewers for providing valuable comments on an earlier version of this manuscript. This work was supported by grants from the Danish Medical Research Council (271-05-0115, 27107-0402 and 09-063477) and, in part, by the Intramural program of the NIH, National Institute of Environmental Health Sciences (Z01 ES044003). The Danish National Research Foundation has established the Danish Epidemiology Science Centre that initiated and created the Danish National Birth Cohort. The cohort is furthermore a result of a major grant from this Foundation. Additional support for the Danish National Birth Cohort is obtained from the Pharmacy Foundation, the Egmont Foundation, the March of Dimes Birth Defects Foundation, the Augustinus Foundation, and the Health Foundation.
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