Fever during pregnancy and motor development in children: a study within the Danish National Birth Cohort
Abstract
Aim
The aim of this study was to examine how fever during pregnancy is associated with motor development in the child.
Method
This cohort study was based on data from females and their children, from the Danish National Birth Cohort, who took part in an 18-month and/or 7-year follow-up study. Information regarding fever (number of episodes, temperature, duration, and pregnancy week) was obtained around gestation week 12 and at the end of pregnancy. Assessments of motor development in early childhood were based on the ages at which the motor milestones ‘sitting unsupported’ (n=44 256) and ‘walking unassisted’ (n=53 959) were attained. The Developmental Coordination Disorder Questionnaire 2007 (DCDQ’07) was used to identify children with indication of developmental coordination disorder (DCD) at age 7 years (n=29 401). Any associations between the exposure to fever during pregnancy and motor development were estimated using Cox regression and logistic regression analyses.
Results
Fever during pregnancy was reported by 15 234 (28.0%) participants in the 18-month follow-up and by 7965 (26.9%) participants in the 7-year follow-up. Adjusted analyses showed no association between prenatal exposure to fever and either ‘sitting unsupported’ or ‘walking unassisted’. The proportion of children with indication of DCD was 3.1%. The odds ratio of indication of DCD if children were exposed to fever in utero was 1.29 (95% CI 1.12–1.49). However, no dose-response association was found.
Interpretation
We found a significant association between maternal fever during pregnancy and DCD in children at age 7 years. The lack of a dose–response association might suggest that this association is explained by the underlying causes of the fever.
What this paper adds
- First study to investigate maternal fever during pregnancy in relation to motor development in the child.
- Demonstrates that maternal fever during pregnancy is associated with developmental coordination disorder at 7 years of age.
- The lack of a dose–response relationship suggests that this association is caused by the underlying causes of the fever.
This article is commented on by Hashmi on pages 698–699 of this issue.
Abbreviations
-
- DCD
-
- Developmental coordination disorder
-
- DCDQ'07
-
- Developmental Coordination Disorder Questionnaire 2007
Fever during pregnancy is suspected to increase the risk of several adverse outcomes in the developing fetus.1 In human studies, associations have been reported between prenatal fever exposure and neural tube defects,1, 2 congenital malformations including oral clefts,3 and heart defects.4 A recent systematic review provides support for an adverse health impact on children after exposure to fever in utero; however, the authors conclude that the evidence of associations is insufficient for several of the outcomes addressed, and more cohort studies are needed.5 In addition, results from animal studies have shown that exposure to hyperthermia in utero produces adverse outcomes in offspring. In 1967, Edwards6 reported an increased incidence of fetal resorption and congenital malformations in guinea pigs exposed to hyperthermia during fetal life. Since then, animal studies have shown that hyperthermia is associated with fetal death, cardiovascular malformations, and a delayed myogenesis.7-9 The development of the central nervous system appears to be particularly sensitive to elevated body temperatures,7, 10, 11 and hyperthermia has been associated with the disruption of the production and migration of neuronal precursor cells and, thus, may result in abnormal brain development.10
A child's motor abilities are associated with the development of cognitive, emotional, and social skills, and are therefore essential for the overall well-being and development of a child.12 Most infants follow the same sequence of attainment of the motor milestones, but the ages at which they are attained vary. A pronounced delay or failure in achieving motor milestones may be a sign of a disturbance in a child's motor development.13 Non-age-appropriate motor development in children which is not caused by a general medical condition is often referred to as developmental coordination disorder (DCD).14 The mechanisms underlying mild motor disorders are still unknown;15, 16 however, intrauterine growth restriction, stress during pregnancy,17 and smoking during pregnancy18 are all prenatal factors which have been associated with impaired motor development in children. The aim of this study was to examine the relationship between prenatal fever exposure and motor development during childhood.
Method
Study participants
Study participants were recruited from the Danish National Birth Cohort, which is an ongoing nationwide cohort of pregnant females and their children. Between 1996 and 2002, 100 418 participants were recruited into the Danish National Birth Cohort. Recruitment took place at the first prenatal visit to the general practitioner, an examination in the first trimester that is offered to all pregnant females in Denmark. Sixty-four per cent of all general practitioners participated in the recruitment process. Inclusion criteria for the cohort were desire to carry the pregnancy to term and ability to speak Danish well enough to take part in telephone interviews. Approximately 60% of all eligible pregnant females chose to participate in the cohort, corresponding to approximately 30% of all births in Denmark during the enrolment period. Information on parental lifestyle and health was collected through four standardized computer-assisted telephone interviews around gestation week 12, at the end of the pregnancy, and approximately 6 months and 18 months after delivery. When the children were 7 years old, the primary caregiver completed a follow-up questionnaire about the health and development of the child.
In this study, participants were restricted to those who gave birth to live singletons and who had answered the questions related to the occurrence of fever in both interviews conducted during the pregnancy (n=73 657). Furthermore, only the first enrolled pregnancy from each participant was included (Figure S1, supporting information online).
Measurements
Information about fever exposure was obtained from two computer-assisted telephone interviews conducted during pregnancy. The participants were asked about the occurrence of fever during pregnancy and, for each fever episode, they were asked about its duration, their maximum body temperature, and the pregnancy week in which the fever occurred. Participants who reported fever in at least one interview were categorized as ‘exposed’. The number of fever episodes (0, 1, ≥2, or unknown) was based on the maximum number of incidents reported in the first and second interviews. The highest reported temperature was categorized as below 39.0°C, 39.0°C or more, or unknown. The duration of the fever (1d, 2d, 3d, ≥4d, or unknown) was based on the longest episode reported. Furthermore, the total duration of all reported febrile episodes was calculated and categorized into similar groups. Information about pregnancy week for each reported fever episode was obtained from the first pregnancy interview, if the fever episode occurred before the first interview, or from the second interview, if the fever episode occurred after the first interview. The timing of each fever episode was categorized into one of seven gestational periods: pregnancy weeks 1 to 4, 5 to 8, 9 to 12, 13 to 18, 19 to 24, 25 to 30, or 31 to 40. All fever episodes were categorized according to this timing variable.
Information about a child's motor development was obtained by interview approximately 18 months after birth, and from the 7-year questionnaire.
At the 18-month postpartum interview, caregivers were asked to report the ages (in months and weeks) at which the child could first sit unsupported and walk unassisted. Complete data about the motor milestone ‘sitting unsupported’ and relevant covariates were available for 50 680 respondents. A total of 53 959 respondents had information about the age at ‘walking unassisted’ and relevant covariates.
Information about the child's motor development at 7 years of age was based on answers to the Developmental Coordination Disorder Questionnaire 2007 (DCDQ'07). The DCDQ'07 was included in the 7-year questionnaire of the Danish National Birth Cohort in February 2007; thus, questionnaires completed before this date did not include the answers to the DCDQ'07. The DCDQ'07 is a parent-administered questionnaire designed to screen for indication of DCD. The questionnaire consists of 15 items concerning control during movement, fine motor skills/handwriting, and general coordination. Caregivers are asked to compare the child's motor development to peers of the same sex using a 5-point Likert scale with the following answer categories: ‘Not true’, ‘A little true’, ‘Fairly true’, ‘True’, or ‘Very true’. The scores for each item (1–5 points) are summed to give a total score (15–75 points). According to the DCDQ'07 manual, children aged 5 to 7 with a total score of 46 or below are classified as ‘indication of possible, or suspect for DCD’, versus ‘probably not DCD’.19 A total of 29 401 respondents completed all items in the DCDQ'07 and had information about relevant confounding factors.
Confounders
Confounders were identified in two steps. Potential confounding factors were identified a priori based on literature and included maternal age, smoking status during pregnancy, occupational status, and number of older children in the household. Furthermore, we used the ‘change in estimate’ method to investigate the possible confounding effect of factors where the evidence was less solid. We considered a change of at least 10% as a basis for inclusion. Potential confounding factors that were investigated by the ‘change in estimate’ method were stress during pregnancy and age compared with older children in the household. None of these variables changed the effect estimates by 10% or more. Based on the above considerations, the associations were adjusted for maternal age at birth, maternal smoking status during pregnancy, number of older children in the household, and occupational status. Occupational status was based on information from the first interview, at which females were asked about their current or most recent occupation (within the last 6mo) and about the occupation of the child's father. This information was coded according to the Danish version of the International Standard Classification of Occupation, which contains 372 job titles.20 Based on job titles, parents were both categorized as either ‘higher non-manual worker’, ‘lower non-manual worker’, ‘skilled manual worker’, ‘student’, ‘unskilled manual-worker’, ‘not working’, or ‘occupation unknown’. The child's socioeconomic status was categorized according to the highest ranking parent. The analyses between fever in a given pregnancy period and motor development were adjusted for the occurrence of fever in other pregnancy periods.
Statistical analysis
Stratified Cox regression analysis was used to compare the ages at which the developmental milestones ‘sitting unsupported’ and ‘walking unassisted’ were achieved in children exposed to fever prenatally and children not exposed to fever. The time from birth to the age at which the child achieved these two milestones represented the ‘time to event’. Children who were not able to sit without support (n=49) or walk unassisted (n=606) at the time of the interview were censored at the time of the interview in the analysis.
By testing for interaction between each independent variable and the log of survival time, the assumption of proportional hazard was evaluated. In the analysis of the milestone ‘sitting unsupported’, the assumption of proportional hazards was met for the number of febrile episodes, temperature, duration, and timing. However, the assumption was not met for the occurrence of fever. Upon closer examination of the data, we found that the hazard functions were proportional in the time period from the age of 5 months and onwards. Children with an age of less than 5 months at attainment of sitting unsupported were, therefore, not included in the analysis of the association between prenatal fever exposure and the age of attaining this milestone. This reduced the study population to 44 256. In addition, analyses were stratified with respect to confounders in a Cox regression analysis, as these did not meet the assumption of proportional hazards either.
For analysis of age at ‘walking unassisted’, the assumption of proportional hazards was satisfied for all exposures, but not for the selected confounders. These analyses were, therefore, also stratified with respect to the confounders in a Cox regression analysis. To estimate the proportion of children sitting and walking unsupported at a given age, the Kaplan–Meier estimator was used.
Multiple logistic regression analysis was used to compare the risk of DCD among children prenatally exposed to fever with unexposed children. Analyses were adjusted for the confounders mentioned above.
The significance level was set at a p value of 0.05. Analyses were performed using sas software version 9.3 (SAS Institute Inc., Cary, NC, USA). All study participants gave their informed consent to the research, and the study and the publication of its results were approved by the Danish Data Protection Agency.
Results
In total, 15 234 (28.0%) of those who participated in the 18-month interview reported at least one episode of fever during pregnancy and, among these respondents, 11.3% reported two or more episodes of fever. Of the participants who reported at least one fever episode, 7918 (52.0%) gave specific information about their temperature, 13 559 (89.0%) specified the duration of the fever episode, and 12 599 (82.7%) reported the pregnancy week of at least one fever episode. In total, 7965 (26.9%) of those who participated in the 7-year interview reported fever during pregnancy and, of these participants, 860 (10.8%) had at least two episodes of fever, 4085 (51.3%) reported their specific temperature, while 7125 (89.5%) respondents provided information about the duration of the fever episode(s). Information about the timing of at least one fever episode was available for 6659 (83.6%) respondents. Table 1 shows the distributions of selected characteristics of mothers and children, grouped according to their exposure to fever during pregnancy.
| Covariate | Participants in the 18mo interview | Participants in the 7y questionnaire | ||
|---|---|---|---|---|
| Fever (%) (n=15 234) | No fever (%) (n=39 099) | Fever (%) (n=7965) | No fever (%) (n=21 603) | |
| Gestational age at birth, wks | ||||
| ≤31 | 0.1 | 0.2 | 0.2 | 0.1 |
| 32–36 | 3.2 | 3.5 | 3.2 | 3.4 |
| ≥37 | 96.6 | 96.3 | 96.7 | 96.5 |
| Unknown | 0.0 | 0.0 | 0.0 | 0.0 |
| Sex of child | ||||
| Male | 50.7 | 51.1 | 51.2 | 51.1 |
| Female | 49.3 | 48.9 | 48.8 | 48.9 |
| Unknown | 0.0 | 0.0 | 0.0 | 0.0 |
| Congenital malformations | ||||
| 0 malformations | 94.9 | 95.6 | 73.4 | 76.9 |
| ≥1 malformations | 5.1 | 4.4 | 4.6 | 3.6 |
| Unknown | 0.0 | 0.0 | 22.2 | 19.6 |
| Maternal age at birth, y | ||||
| ≤24 | 8.7 | 8.6 | 8.8 | 8.3 |
| 25–29 | 38.3 | 39.2 | 39.4 | 39.6 |
| 30–34 | 38.5 | 36.9 | 36.7 | 36.2 |
| 35–39 | 13.0 | 13.6 | 13.3 | 13.9 |
| ≥40 | 1.5 | 1.7 | 1.8 | 2.0 |
| Unknown | 0.0 | 0.0 | 0.0 | 0.0 |
| Occupational status | ||||
| Higher non-manual worker | 23.8 | 22.6 | 24.2 | 23.7 |
| Lower non-manual worker | 32.3 | 31.1 | 34.3 | 32.4 |
| Skilled manual worker | 26.9 | 28.8 | 25.6 | 27.1 |
| Student | 5.1 | 5.1 | 5.2 | 5.0 |
| Unskilled manual worker | 10.2 | 10.8 | 9.0 | 10.2 |
| Not working | 1.5 | 1.4 | 1.6 | 1.3 |
| Unknown | 0.2 | 0.2 | 0.2 | 0.3 |
| Number of older children in the household | ||||
| 0 | 42.2 | 50.6 | 47.4 | 55.1 |
| 1 | 40.2 | 33.5 | 36.4 | 30.3 |
| 2 | 14.6 | 13.3 | 13.7 | 12.3 |
| ≥3 | 3.0 | 2.5 | 2.3 | 2.2 |
| Unknown | 0.1 | 0.1 | 0.1 | 0.1 |
| Smoking during pregnancy | ||||
| Non-smoker | 72.9 | 75.2 | 74.8 | 77.1 |
| 1–9 cigarettes/d | 14.6 | 13.9 | 14.4 | 13.4 |
| ≥10 cigarettes/d | 12.2 | 10.7 | 10.4 | 9.3 |
| Unknown | 0.3 | 0.3 | 0.4 | 0.2 |
The mean age of the children at completion of the 18-month interview was 19.1 months (range 17.4–34.4mo). The median age at attaining the early motor milestones was 6.5 months (range 4.5–18.0mo) for ‘sitting unsupported’ and 12.5 months (range 1.0–21.0mo) for ‘walking unassisted’. Adjusted analyses showed no association between prenatal fever exposure and sitting unsupported (hazard ratio 0.99, 95% CI 0.97–1.01) or prenatal fever exposure and walking unassisted (hazard ratio 1.01, 95% CI 0.99–1.03), as shown in Table 2.
| Sitting unsupported | Walking unassisted | |||||||
|---|---|---|---|---|---|---|---|---|
| Total (%) (n=44 256) | Adjusted HRa | 95% CI | p | Total (%) (n=53 959) | Adjusted HRa | 95% CI | p | |
| Fever | ||||||||
| No [reference] | 72.3 | 1 | 72.0 | 1 | ||||
| Yes | 27.7 | 0.99 | 0.97–1.01 | 0.49 | 28.0 | 1.02 | 1.00–1.03 | 0.12 |
| Number of episodes | ||||||||
| No fever [reference] | 72.3 | 1 | 72.0 | 1 | ||||
| 1 | 21.6 | 1.00 | 0.98–1.02 | 0.36b | 21.9 | 1.02 | 1.00–1.04 | 0.30b |
| ≥2 | 3.1 | 0.97 | 0.92–1.03 | 3.1 | 0.99 | 0.94–1.04 | ||
| Unknown | 3.0 | 0.96 | 0.90–1.01 | 3.0 | 1.01 | 0.96–1.06 | ||
| Maximum temperature | ||||||||
| No fever [reference] | 72.3 | 1 | 72.0 | 1 | ||||
| <39.0°C | 7.8 | 0.99 | 0.95–1.02 | 0.80b | 7.8 | 0.99 | 0.96–1.02 | 0.04b |
| ≥39.0°C | 6.6 | 0.99 | 0.95–1.03 | 6.8 | 1.04 | 1.00–1.08 | ||
| Unknown | 13.3 | 1.00 | 0.97–1.02 | 13.4 | 1.02 | 0.99–1.05 | ||
| Maximum number of days | ||||||||
| No fever [reference] | 72.3 | 1 | 72.0 | 1 | ||||
| 1d | 6.0 | 0.99 | 0.95–1.03 | 0.30c | 6.1 | 1.03 | 0.99–1.06 | 0.59c |
| 2d | 9.4 | 1.01 | 0.98–1.05 | 9.5 | 1.00 | 0.97–1.03 | ||
| 3d | 4.8 | 1.01 | 0.97–1.06 | 4.9 | 1.02 | 0.98–1.06 | ||
| ≥4d | 4.4 | 0.96 | 0.92–1.01 | 4.5 | 1.03 | 0.99–1.08 | ||
| Unknown | 3.1 | 0.95 | 0.90–1.00 | 3.1 | 1.00 | 0.95–1.05 | ||
| Gestational period, wksd | ||||||||
| 1–4 | 1.6 | 0.98 | 0.91–1.06 | 0.24c | 1.5 | 1.05 | 0.97–1.12 | 0.02c |
| 5–8 | 4.7 | 0.98 | 0.94–1.03 | 4.7 | 1.05 | 1.01–1.09 | ||
| 9–12 | 5.0 | 0.95 | 0.91–1.00 | 4.9 | 0.98 | 0.94–1.02 | ||
| 13–18 | 5.0 | 0.99 | 0.95–1.04 | 5.1 | 1.03 | 0.99–1.07 | ||
| 19–24 | 4.0 | 1.01 | 0.96–1.06 | 4.1 | 1.04 | 0.99–1.08 | ||
| 25–30 | 4.7 | 1.01 | 0.97–1.06 | 4.8 | 0.96 | 0.92–1.00 | ||
| 31–40 | 1.7 | 1.06 | 0.99–1.14 | 1.8 | 1.02 | 0.96–1.09 | ||
- aAdjusted for maternal age, smoking status during pregnancy, occupational status, and number of older children in the household. bTwo-sided p value of the test for homogeneity. ‘Unknown’ and ‘no fever’ are not included in the tests. cTwo-sided p value of the Wald test for trend. dThe comparison group for a particular gestational period consists of participants in the same gestational period without fever. The analyses are adjusted for the occurrence of fever in the other pregnancy weeks. HR, hazard ratio; CI, confidence interval.
Sensitivity analyses were performed in relation to outliers of the outcomes. The exclusion of implausible low values (sitting at age <4mo; walking at age <8mo) did not change the effect estimates. Furthermore, exclusion of children with congenital malformations did not change the hazards ratios for the attainment of the two motor milestones (data not shown).
The mean age at completion of the 7-year interview was 7 years 1 month (range 7y–8y 11mo). The total number of children with indication of DCD was 905, corresponding to 3.1% of the children included in the study. Figure 1a shows the distribution of the DCDQ'07 scores in relation to prenatal fever exposure. The vertical dotted line indicates the intersection of indication and no indication of DCD. Figure 1b shows the range of the DCDQ'07 scale at which indication of DCD is present. The figure indicates that a higher proportion of children exposed to fever prenatally had indication of DCD than children that were not exposed to prenatal fever. Table 3 shows the adjusted odds ratios of DCD according to prenatal fever exposure. Children of mothers who reported fever during pregnancy were significantly more likely to have indication of DCD than non-exposed children, with an odds ratio of 1.29 (95% CI 1.12–1.49). The odds ratio for DCD increased with the number of episodes; however, the difference in the odds ratios between one and two episodes of fever was not significant. Temperature, number of days with fever, and gestational age at fever episode did not significantly change the association. For participants reporting more than one fever episode, the total duration across all fever episodes was also used in the analyses. This did not change the estimates (data not shown). Excluding children with congenital malformations from the analyses did not diminish the observed associations.
| Total (%) (n=29 401) | Number with DCD (n=905) | Adjusted ORa | 95% CI | p | |
|---|---|---|---|---|---|
| Fever | |||||
| No [reference] | 73.1 | 616 | 1 | ||
| Yes | 26.9 | 289 | 1.29 | 1.12–1.49 | 0.0005 |
| Number of episodes | |||||
| No fever [reference] | 73.1 | 616 | 1 | ||
| 1 | 21.3 | 220 | 1.25 | 1.06–1.46 | 0.41b |
| ≥2 | 2.9 | 35 | 1.45 | 1.03–2.06 | |
| Unknown | 2.8 | 34 | 1.48 | 1.03–2.11 | |
| Maximum temperature | |||||
| No fever [reference] | 73.1 | 616 | 1 | ||
| <39.0°C | 7.5 | 74 | 1.20 | 0.93–1.53 | 0.79b |
| ≥39.0°C | 6.3 | 67 | 1.25 | 0.97–1.63 | |
| Unknown | 13.1 | 148 | 1.36 | 1.13–1.64 | |
| Maximum number of days | |||||
| No fever [reference] | 73.1 | 616 | 1 | ||
| 1 | 5.9 | 62 | 1.28 | 0.98–1.67 | 0.75c |
| 2 | 9.4 | 93 | 1.17 | 0.94–1.47 | |
| 3 | 4.7 | 54 | 1.41 | 1.06–1.87 | |
| ≥4 | 4.2 | 46 | 1.34 | 0.99–1.82 | |
| Unknown | 2.8 | 34 | 1.44 | 1.01–2.06 | |
| Gestational period, wksd | |||||
| 1–4 | 1.4 | 16 | 1.31 | 0.79–2.18 | 0.59c |
| 5–8 | 4.4 | 46 | 1.14 | 0.84–1.55 | |
| 9–12 | 4.6 | 52 | 1.27 | 0.95–1.69 | |
| 13–18 | 4.9 | 36 | 1.17 | 0.88–1.56 | |
| 19–24 | 4.0 | 23 | 0.83 | 0.58–1.20 | |
| 25–30 | 4.7 | 46 | 1.32 | 1.00–1.75 | |
| 31–40 | 2.1 | 22 | 1.26 | 0.84–1.91 | |
- aAdjusted for maternal age, smoking status during pregnancy, occupational status, and number of older children in the household. bTwo-sided p value of the test for homogeneity. ‘Unknown’ and ‘no fever’ are not included in the tests. cTwo-sided p value of the Wald test for trend. dThe comparison group for a particular gestational period consists of females in the same gestational period without fever. The analyses are adjusted for the occurrence of fever in the other pregnancy weeks. CI, confidence interval; DCD, developmental coordination disorder; OR, odds ratio.
Among children who attained the milestone ‘sitting unsupported’ at an age above the 95% centile, 11.8% had DCD at age 7 years. Of the children achieving this milestone at an age less than the 95% centile, 2.6% had DCD at age 7 years. Regarding the milestone ‘walking unassisted’, 20% had DCD at age 7 years if they had an age at attainment of this milestone above the 95% centile; only 2.3% of the children with an age at attainment of this milestone below the 95% centile had DCD at the age of 7 years.
Discussion
In this study, we found no significant associations between fever in pregnancy and the age at attainment of two motor milestones in early childhood. However, the analyses did show an increased risk of DCD at 7 years of age among children prenatally exposed to fever compared with unexposed children. Number of fever episodes, temperature, duration, and timing of the fever did not change this association significantly.
Children often attain motor milestones in a fixed sequence; however, the age at attainment varies considerably.21 In most cases, these differences in age at achieving motor milestones do not indicate motor disorders, but are considered to reflect natural variations.13 This large span of ages for what is considered typical for attaining motor milestones complicates the identification of children with mild motor disorders in early childhood. Mild disturbances in motor development may, in fact, manifest only when the child gets older, and motor challenges become more complex. Delayed attainment of a single function rarely has clinical relevance, whereas a more general delay in motor development is likely to be significant.22 In this study, analysis of agreement among the outcome measures showed that the majority of children with an age above the 95% centile at attainment of the two motor milestones in early childhood did not have indication of DCD at 7 years of age. These findings are consistent with results from other studies, which support the hypothesis that children who achieve milestones at a late age often compensate for this motor delay later in childhood.23, 24
The authors did not find any significant differences between the association of prenatal fever exposure and indication of DCD with respect to the number of fever episodes, temperature, duration, or timing of the fever. This may indicate that the association between prenatal fever exposure and DCD is caused not specifically by an increase in the core body temperature, but by the underlying cause of the febrile illness or a factor associated with this. In this study, however, we had no information about the occurrence of infectious diseases in relation to the reported fever episodes.
Furthermore, it might be relevant to consider the use of antipyretic medicine in relation to fever incidents. Antipyretics might act as mediators of the association between fever and motor development or as confounders, possibly by reducing the duration and maximum temperature of the fever. In a recent review and meta-analysis investigating adverse health outcomes in children exposed to fever during pregnancy, the authors showed that antipyretic medication may have a protective effect when used in relation to febrile episodes.5 However, in this study, the participants did not report the use of antipyretic medication in relation to the occurrence of fever. Thus, it was not possible to distinguish between potentially confounding, mediating, or modifying effects of infectious diseases and the use of antipyretic medication.
In the current study, the large study population and the prospective study design contribute to the statistical power and reduce the risk of bias. The results of this study are unlikely to have been subject to selection bias, as neither the physicians’ decision to recruit participants for the Danish National Birth Cohort nor the participants’ decision to take part is likely to be related to fever during pregnancy or the motor development of their children. Furthermore, a study about the risk of bias resulting from low participation rates concluded that although participants in the Danish National Birth Cohort were marginally healthier than the background population, any bias of risk estimates caused by a ‘healthy woman phenomenon’ would be small.25
Information about exposure and outcome was based on self-reporting. Because of the prospective study design, potential misclassification of fever incidence is most likely non-differential and thus might have biased the association towards the null. The reported incidence of fever during pregnancy (28%) corresponds well with results from another study using self-reported fever information.26 Temperature, timing, and duration of the febrile episodes represent information of details and thus might be more difficult for the respondents to recall.
As with any observational study, unmeasured confounding factors are a concern. In the present study, adjustment for several potential confounders influenced results only marginally. Furthermore, sensitivity analysis in relation to different categorizations of the exposure variables and exclusion of children with congenital malformations did not diminish the observed associations.
Motor development was assessed by the age at attainment of two major motor milestones in early childhood, and by indication of DCD at 7 years of age. Information about the acquisition of motor milestones was based solely on parent reports. The timespan between the attainment of the two milestones and the time of the interview (approximately 18mo after birth) may have resulted in inaccurate information and thus resulted in misclassification. However, in the years after the attainment of motor milestones, parents are likely to remember the age of attainment with great precision.27 Furthermore, one study has shown that parental assessment of children's motor development is often consistent with that of professionals.28 The mean ages at attaining the two milestones were consistent with findings in other studies.21, 29 We also performed sensitivity analyses in which participants who reported implausible low values in relation to attaining the motor milestones were excluded, which did not affect the results.
The screening instrument DCDQ'07 was used to assess indication of DCD. This instrument was validated in a Canadian population, and showed high internal validity, sensitivity, and specificity.30 These findings are in concurrence with other validation studies of the DCDQ'07.31, 32
Conclusion
We did not find any evidence for an effect of fever during pregnancy on early motor development, measured as the timing of achieving ‘sitting unsupported’ and ‘walking unassisted’. However, we found a significant association between fever during pregnancy and DCD at age 7 years; thus, it cannot be excluded that fever during pregnancy has a negative effect on motor development. The lack of a dose–response relationship might suggest that the cause of fever, rather than the fever itself, explains this association.
Acknowledgements
The authors have stated that they had no interests which might be perceived as posing a conflict or bias.
