Journal of Perinatology (2014) 34, 677–682 © 2014 Nature America, Inc. All rights reserved 0743-8346/14 www.nature.com/jp
ORIGINAL ARTICLE
Congenital heart defects and maternal fever: systematic review and meta-analysis QY Shi1,8, JB Zhang2,8, YQ Mi3, Y Song4, J Ma5,9 and YL Zhang6,7,9 OBJECTIVE: To systematically review and meta-analyze the relation between maternal fever in the first trimester and congenital heart defect (CHD) in offspring. STUDY DESIGN: We searched PubMed (1977–2012), Embase (1974–2012) and the Cochrane Library (2012) databases to identify relevant articles. Random effects model were performed, with the conduction of subgroup analysis. RESULT: Meta-analysis yielded a pooled odds ratio of 1.53 (95% confidence interval = 1.36 to 1.73) for the magnitude of the relation between maternal fever in the first trimester and CHD in offspring. As to subgroup analysis, it is associated with ventricular septal defects (VSDs) and right obstructive defects. CONCLUSION: Our analysis suggests that maternal fever in the first trimester is the risk factor of congenital heart diseases in offspring. Through the subgroup analysis, we find that exposure to maternal fever is the risk factor of VSD and right obstructive defects. Journal of Perinatology (2014) 34, 677–682; doi:10.1038/jp.2014.76; published online 8 May 2014
INTRODUCTION Congenital heart defects (CHDs) are one of the most prevalent and serious birth defects, and they are the leading causes of death from congenital malformations.1–2 Many genetic and environmental factors that may relate to CHDs have been studied, but the causes of CHD are still unclear. Some reports have shown that increased maternal age at conception was associated with increased risk for CHD.3 About 1% of cardiovascular malformations can be attributed to maternal diseases, such as type 1 diabetes, phenylketonuria, epilepsy.4–6 Another 1% of cardiovascular malformations are caused by teratogen exposure.7 Among these teratogens, maternal fever has been an important one. Maternal fever has been proved to associate with many birth defects, especially defects of the central nervous system.8–10 More recently, a number of studies have sought to explore the association between maternal fever and CHD. Nonetheless, the results of individual studies were different. For example, Botto et al.11 reported positive association between maternal fever in the first trimester and CHD (odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.4–2.4), whereas Oster et al.12 showed insignificant association (OR = 1.1, 95% CI = 0.9–1.4). In addition, the relation of maternal fever and the subtypes of CHD were also variable. For instance, Botto et al.11 indicated a significant association between maternal fever and ventricular septal defect (VSD; OR = 1.8, 95% CI = 1.1–2.9), whereas Oster et al.12 held different opinion (OR = 1.12, 95% CI = 0.77–1.64). The results might be unreliable owing to the small sample size of subtypes of each study, thus it is necessary to synthesize them to obtain a summary
point estimate. For above reasons, we systematically reviewed and meta-analyzed the relation between maternal fever in the first trimester and CHD in offspring. METHODS Identification of studies We searched PubMed (1977–2012), Embase (1974–2012) and the Cochrane Library (2012) databases to identify relevant articles. We examined the reference lists of all known primary and review articles to identify cited articles not captured by the electronic searches. Language restrictions were not applied. A variable of the following search terms was used: (CHDs OR congenital heart disease OR congenital heart malformation OR congenital heart block) AND (maternal fever OR maternal febrile OR maternal hyperthermia OR maternal pyrexia OR (fever AND pregnancy) OR (febrile AND pregnancy) OR (hyperthermia AND pregnancy) OR (pyrexia AND pregnancy)). Besides, we also searched terms of (birth defects) AND (risk factors).
Inclusion and exclusion criteria Studies were included in the meta-analysis when they met the following inclusion criteria. Subject: Studies were included if they reported the associations between maternal fever in the first trimester and CHDs in offspring. Study design: Studies were included if they were case–control studies or cohort studies. Exposure: Studies were included if exposure related to fever or febrile illness with fever were clear and similar. Exposure window: Studies were included if exposure window was approximately in the first trimester during pregnancy. Outcome: Studies were included if the diagnosis of CHDs in offspring were clearly presented and the diagnostic
1 Tianjin Second People’s Hospital, School of Graduate, Tianjin Medical University, Tianjin, China; 2Tianjin Teda International Cardiovascular Disease Hospital, Clinical College of Cardiovascular, Tianjin Medical University, Tianjin, China; 3Depanment of Chinese Integrative Medicine, Tianjin Second People’s Hospital, Tianjin Medical University, Tianjin, China; 4 Coronary Care Unit, Tianjin Teda International Cardiovascular Disease Hospital, Clinical College of Cardiovascular, Tianjin Medical University, Tianjin, China; 5Department of Health Statistics, College of Public Health, Tianjin Medical University, Tianjin, China; 6Institute of Reproductive and Child Health/Ministry of Health Key Laboratory of Reproductive Health, School of Public Health, Peking University Health Science Center, Beijing, China and 7Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China. Correspondence: Dr Jun Ma, Department of Health Statistics, College of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Tianjin 300070, China or Dr YL Zhang, Institute of Reproductive and Child Health/Ministry of Health Key Laboratory of Reproductive Health, School of Public Health, Peking University Health Science Center, Beijing 100191, China. E-mail: [email protected] or [email protected] 8 These authors contributed equally to this work. 9 These authors contributed equally to this work. Received 5 November 2013; revised 27 February 2014; accepted 13 March 2014; published online 8 May 2014
Congenital heart defects and maternal fever QY Shi et al
678 approach of cases and control groups were identical. Data: Studies were included if we could get the information of OR and 95% CI. The electronic searches were scrutinized and two independent reviewers (YL Zhang and QY Shi) examined titles and abstracts to decide if the full-text articles should be obtained (n = 75). We decided to get full 35 reports of the 75 studies after looking through titles, abstracts and references. The decision to exclude any of these studies was made by the consensus of two authors. Finally, four studies were excluded for the duplicate data from the same study programs. Sixteen studies reporting influenza, infection, medication, sauna bathing and working temperature without the clear information of fever were excluded. Eight studies were excluded as they reported exposure window as the entire pregnancy period (Figure 1).
Quality assessment Study quality was assessed by two researchers (QY Shi and JB Zhang) using Newcastle-Ottawa Scale on case–control studies.13 Three major components, that is, selection of case and controls (Selection), comparability of case and controls (Comparability) and ascertainment of exposure (Exposure), comprized the scale, including eight small items (four on Selection, one on Comparability and three for Exposure). A study can be awarded a maximum of one * for each numbered item within the Selection and Exposure categories. A maximum of two * can be given for Comparability. Where reviewers disagreed, specific criteria were discussed with a third reviewer until consensus was reached.
Data extraction procedures Two reviewers (QY Shi and JB Zhang) independently extracted basic information in a standardized manner: first author, year, data acquisition
(period), CHD infants/fever mothers, CHD infants/non-fever mothers and interview time. Data on information of exposure, diagnosis of outcomes and detailed information of subtypes of CHD were collected.
Statistical analysis The main outcome in this analysis was the OR and its 95% CI. We pooled the ORs depending on the heterogeneity. Heterogeneity was evaluated graphically with forest plots and statistically with χ2 and I2 tests. I2 is an estimate of the proportion of total variation in study estimates that is due to heterogeneity. I2>25% indicate significant heterogeneity. The fixed effects model was used to estimate the variance of the summary OR when study heterogeneity was low and the random effects model when study heterogeneity was moderate to high. We also count the weight of each study according to the formula: wi = (1/ai+1/bi+1/ci+1/di)-1. All analyses were conducted with Stata statistical software (version 11; Stata Corp LD, College Station, TX, USA).
RESULTS Studies included in meta-analysis In this analysis, seven studies involving 12 030 cases and 51 729 controls were included.11–12,14–18 All the seven studies were retrospective studies, and they were published from 1989 to 2011. Four of seven studies were conducted in America.11–12,14,18 The rest of the three were, respectively, conducted in Hungary,17 Finland15 and China.16 Four of seven had reported different kinds of CHDs in detail.11,12,15,18 All had reported diagnostic methods of CHD and five had declared diagnostic time around 1year old.11–12,14–15,17 The information of exposure, diagnostic information and subtypes of CHD are shown in Tables 1,2 and Supplementary Table 1, respectively. The assessment of the study quality was available in Table 3. The association between CHD and maternal fever Table 4 shows the pooled estimate of the association between non-classified CHD and maternal fever in the first trimester generated by meta-analysis for all the seven studies combined. The pooled estimate for all seven studies combined was 1.53 (95% CI = 1.36–1.73). There was unobvious heterogeneity in women with maternal fever (I2 = 35.4%). There was no significant heterogeneity among the studies (P = 0.158).
Figure 1.
Table 1.
Flow chart of meta-analysis
Influence of individual studies We observed the shift of point estimate and 95% CI from the middle line through removing individual studies to analyze the influence of each study (Supplementary Figure 1). The pooled OR changed more or less when excluding any study from our metaanalysis. The results indicated that study by Oster et al. moved the farthest from the middle line, thus proving to be the most influential study of pooled size effect.
Exposure and exposure window of seven studies
Study 14
Adams et al. Tikkanen et al.15 Zhang and Cai16 Botto et al.11 Acs et al.17 Cleves et al.18 Oster et al.12
Exposure
Exposure window
Fever Fever exceeding 38°C Cold with fever Any source of fever and specific source of fever Flu with fever during epidemic months (between December and April) in epidemic and nonepidemic years Urinary tract infection with fever (above 101°F) Fever of 101°F or higher (⩾38.3°C)
From the month before conception to the third month of gestation During the first trimester of pregnancy During the first trimester of pregnancy From 1 month before conception to the third month of pregnancy During the second and third month of pregnancy
Journal of Perinatology (2014), 677 – 682
During the first trimester of pregnancy From 3 months before pregnancy to the end of the first trimester of pregnancy
© 2014 Nature America, Inc.
Congenital heart defects and maternal fever QY Shi et al
679 Table 2.
Diagnostic characteristics of seven studies
Study Adams et al.14 Tikkanen et al.
15
Zhang and Cai16 Botto et al.
11
Acs et al.17 Cleves et al.18
Oster et al.12
Congenital heart defects
Diagnostic time
Diagnostic methods
Conotruncal defects
During their first year of life
VSD, ASD, CAS, LHHS, ECD, other defects
Before 1 year of age
All defects and VSD
Before 8 days after birth
Outflow tract defects, VSD, ASD, AVSD, Ebstein anomaly, anomalous pulmonary venous return, all right obstructive defectgs, all left obstructive defects All defects
During the first year of life
By the Metropolitan Atlanta Congenital Defects Program Cardiac catheterization, ultrasound, sugery or autopsy By pediatricians or pathologist who had no knowledge of maternal cold history An anatomic diagnosis and an overall clinical diagnosis
From the second trimester of pregnancy to the end of the first postnatal year Not mention
Conotruncal defects, VSD, ASD, AVSD, right-sided obstructive defects, left-sided obstructive defects, anomalous pulmonary venous return VSD, ASD, AVSD, Ebstein anomaly, right-sided By 1 year of age obstructive defects, left-sided obstructive defects, total anomalous pulmonary venous return
Be identified in the Hungarian Congential Abnormality Registry (HCAR) Echocardiogram, heart catheterization, or surgical or autopsy report Echocardiography, catheterization, surgery, or autopsy
Abbreviations: ASD, atrial septal defect; AVSD, atrioventricular septal defect; CAS, conus arterious; ECD, endocardial cushion defect; LHHS, left heart hypoplastic syndrome; VSD, ventricular septal defect.
Table 3.
Quality ratings of seven studies
Study 14
Adams et al. Tikkanen et al.15 Zhang and Cai16 Botto et al.11 Acs et al.17 Cleves et al.18 Oster et al.12
Selection
Comparability
Exposure
★★★★ ★★★ ★★★ ★★★★ ★★★★ ★★★★ ★★★★
★★ ★ ★ ★★ ★★ ★★ ★★
★★★ ★★ ★★ ★★★ ★★★ ★★★ ★★★
Subgroup analysis Although the heterogeneity of the seven studies was low, we could not rule out the possibility that they canceled out with each other. And considering etiological difference of various CHD, we conducted subgroup analysis of CHD. The common classification of CHD include VSD, atrial septal defect (ASD), atrioventricular septal defect, conotruncal defects, Ebstein anomaly, anomalous pulmonary venous return, right obstructive defects, left obstructive defects and so on. Supplementary Table 1 shows the phenotypes of CHD in each study. We confirmed any sort of CHD above as a subgroup if at least three studies reported the association between it and maternal fever and in each study at least three cases were reported for this disease. Finally, we defined five subgroups: VSD, ASD, conotruncal defects, right obstructive defects and left obstructive. The associations of fever with cardiac phenotypes are outlined in Tables 5, 6, Supplementary Tables 2, 3 and 4. The aggregated OR associated with maternal fever in the first trimester for VSD in offspring was 1.34 (95% CI = 1.02–1.76), 1.46 (95% CI = 0.95–2.23) for ASD, 1.22 (95% CI = 0.91–1.63) for conotruncal defects, 2.05 (95%CI = 1.47–2.87) for right obstructive defects and 1.32 (95% CI = 0.88–1.96) for left obstructive defects. There was significant unexplained heterogeneity for studies for children with ASD (I2 = 61.7%, P = 0.050) and left obstructive defects (I2 = 82.4%, P = 0.003). There was no evidence of heterogeneity for studies in children with VSD, conotruncal defects and right obstructive defects (I2 = 0%). © 2014 Nature America, Inc.
Publication bias analysis We conducted Begg’s funnel plot and Egger’s corresponding asymmetry test for the eight studies. Egger’s test provided little evidence of publication bias (P = 0.914). DISCUSSION This is the first meta-analysis review of association between maternal fever in the first trimester and CHD in offspring. The studies of the association between maternal fever and birth defects in offspring date back to the beginning of last century. An obstetrician found that the number of neonates with birth defects increased significantly after global pandemic influenza in 1918, and almost all women delivering those babies had had the flu.19 In those studies of the association between maternal fever and birth defects in offspring, neural tube defects are the most studied about birth defects.8–10 A systematic review and meta-analysis about published literature from 1980 to 2003 regarding maternal fever and neural tube defects suggested that the odds of children with neural tube defects when their mother had maternal influenza or fever during pregnancy was 1.92 (95% CI = 1.61–2.29).8 However, the studies on association between maternal fever in the first trimester and CHD in offspring are far less than the neural tube defects. Our systematic review and meta-analysis of the published literature showed that in women who had experienced fever in the first trimester of their pregnancy, there was a significant association between maternal fever and CHD in aggregate (OR = 1.53, 95% CI = 1.36–1.73; Table 4). In addition, for specific heart defects, significant relations were detected between maternal reports of fever and VSD (OR = 1.34, 95% CI = 1.02–1.76; Table 5) and right-sided obstructive defects (OR = 2.05, 95% CI = 1.47–2.87; Table 6). Because all of the seven studies were retrospective, it is necessary to evaluate their potential recall bias. Generally, there were several means to control recall bias, such as elaborated protocols or objective indicators. In seven studies, Adams et al.14 conducted interviews for more than 3 years after conception, so respondents might have failed to recall whether they had experienced fever or which medications they had used, the same as Botto et al.11 (2–12 years ) and Cleves et al.18 (6 weeks to 24 months). Zhang et al.16 (soon after delivery), Tikkanen et al.15 Journal of Perinatology (2014), 677 – 682
Congenital heart defects and maternal fever QY Shi et al
680 Table 4.
OR and 95% CI of CHD associated with maternal fever in the first trimester Study Adams et al.14
CHD infants /Fever mothers
CHD infants /Non-fever mothers
Weight(%)
Odds ratio(fixed) 95% CI
8/83
83/1290
2.37
1.55 (0.72,3.32)
Tikkanen et al.15
57/573
63/1055
10.45
1.74 (1.20,2.53)
Zhang and Cai16
10/19
62/153
1.70
1.63 (0.63,4.24)
Botto et al.11
93/829
186/2890
19.26
1.84 (1.41,2.39)
Acs et al.17
105/4480
535/38151
28.73
1.69 (1.37,2.08)
Cleves et al.18
33/3685
27/4755
6.11
1.58 (0.95,2.64)
Oster et al.12
119/2361
155/3435
31.37
1.12 (0.88,1.43)
Overall
425/12030
1111/51729
100.00
1.53 (1.36,1.73)
Abbreviations: CHD, congenital heart defect; CI, confidence interval; OR, odds ratio. I2 = 35.4%, P = 0.158.
Table 5.
Subgroup analysis of VSD associated with maternal fever in the first trimester Study
CHD infants /Fever mothers
CHD infants /Non-fever mothers
Weight(%)
Odds ratio(fixed) 95% CI
Tikkanen, et al.15
17/216
63/1055
23.93
1.35 (0.77,2.35)
Botto, et al.11
22/194
186/2890
25.17
1.88 (1.18,2.97)
Cleves, et al.18
4/703
20/4086
7.08
1.18 (0.40,3.41)
Oster, et al.12
23/479
155/3435
43.81
1.07 (0.88,1.87)
Overall
66/1592
424/11466
100.00
1.34 (1.02,1.76)
Abbreviations: CHD, congenital heart defect; CI, confidence interval; VSD, ventricular septal defect. I2 = 0.0%, P = 0.402.
(average 92 days for cases and 96 days for controls), ACS et al.17 (3.5 ± 1.2 months for cases and 5.2 ± 2.9 months for controls) and Oster et al.12 (7 months for 80% of case mothers and 74% of control mothers, 12 months after birth for less than 10% of each group) gathered information in a relatively short time, which might to some extent control recall bias. Beyond that, because the birth of an infant with CHD is a serious traumatic event for most mothers, they try to find a causal explanation and are more inclined to report fever during pregnancy. Meanwhile, pregnant women might ignore a fever without obvious symptoms or misinterpret tactile hyperthemia as true fever during gestation time as Adams et al.,14 Zhang et al.,16 Botto et al.11 and Acs et al.17 did not give a strict definition and detailed information of fever Journal of Perinatology (2014), 677 – 682
including timing, magnitude and duration of the temperature evaluation. These epidemiologic studies indeed have limitations; however, the relatively consistent findings might suggest similar recall bias. As to specific phenotypes, significant relations were detected between maternal reports of fever and VSD (1.34, 95% CI = 1.02 –1.76; Table 5) and right-sided obstructive defects (2.05, 95% CI = 1.47–2.87; Table 6). Among four studies exploring VSD, Cleves et al.18 and Oster et al.12 excluded case infants with isolated muscular VSDs. Tikkanen et al.15 and Botto et al.11 did not mention anything about muscular VSD (Supplementary Table 1). Smaller muscular defects are very likely to close over time and may only require © 2014 Nature America, Inc.
Congenital heart defects and maternal fever QY Shi et al
681 Table 6.
Subgroup analysis of right obstructive defects associated with maternal fever in the first trimester
CHD infants /Fever mothers
CHD infants /Non-fever mothers
Weight(%)
Odds ratio(fixed) 95% CI
Botto et al.11
12/91
186/2890
26.49
2.21 (1.18,4.13)
Cleves et al.18
9/673
27/4755
17.75
2.37 (1.11,5.07)
Oster et al.12
22/270
155/3435
55.76
1.88 (1.18,2.99)
Overall
43/1034
369/11080
100
2.05 (1.47,2.87)
Study
Abbreviations: CHD, congenital heart defect; CI, confidence interval. I2 = 0.0%, P = 0.846.
observation in the first year of life. Some studies reported spontaneous closure of muscular VSDs was 84%.20 When analyzing right obstructive defects, Cleves et al.18 did not involve tricuspid atresia, whereas the other two studies included it. Besides, Cleves et al.18 deemed Ebstein anomaly as right a kind of obstructive defect, whereas the other two studies regarded it as an isolated CHD. Botto et al.11 and Cleves et al.18 included pulmonary atresia but Oster et al.12 did not. There was significant unexplained heterogeneity when we analysis the occurrence of fever and ASD (I2 = 61.7%, P = 0.050; Supplementary Table 2). The high heterogeneity might come from the definition of ASD and fever. Cleves et al.18 included ASD secundum, sinus venosus ASDs and ASD (not otherwise specified), whereas Tikkanen et al.,15 Botto et al.11 and Oster et al.12 did not state anything special on it (Supplementary Table 1). And Tikkanen et al.15 defined fever as exceeding 38 °C (100.4 °F), lower than defined by Cleves et al.18 and Oster et al.,12 38.3 ℃ (101 °F), which might contribute to the greater point estimate than Cleves et al.18 and Oster et al.12 There was also significant high heterogeneity for infants with left obstructive defects (I2 = 82.4%, P = 0.003; Supplementary Table 4). Among the three studies, Botto et al.11 did not give a rigorous definition of fever, which might cause the misclassification of exposure and non-exposure groups and showed a higher increased risk than Cleves et al.18 and Oster et al.12 With respect to fever, two factors might potentially account for the inconsisitent findings on our study. First, only Tikkanen et al.,15 Cleves et al.18 and Oster et al.12 have rigorously defined maternal fever. Among them, Cleves et al.18 and Oster et al.12 defined exposure as a report of temperature of ⩾ 38.3 ℃ (101 °F), whereas Tikkanen et al.15 encompassed a broader temperature range of exceeding 38 ℃ (100.4 °F). Interestingly, Tikkanen et al.15 found almost a twofold increase in the risk of CHD in association with maternal fever (OR = 1.74, 95% CI = 1.20–2.53), whereas Cleves et al.18 and Oster et al.12 reported a modestly increased risk of CHD (OR = 1.58, 95% CI = 0.95–2.64 and OR = 1.12, 95% CI = 0.88–1.43, respectively; Table 4). The lower definition of fever in study by Tikkanen et al. might cause an overestimation of the association between maternal fever and CHD.15 For Adams et al.,14 Zhang et al.,16 Botto et al.11 and Acs et al.17 who did not give a strict definition of fever, it might result in misclassification of exposure and non-exposure groups. Meanwhile, it is necessary to take the underlyling disease into account because fever is only a clinical symptom. Among the © 2014 Nature America, Inc.
possible etiologies, infection is the most common pathogenesis, which is often caused by viral, bacterial and fungal organisms. Disentangle the teratogen effects of fever and underlying infection remains difficult because of a high level of concordance in reports of such exposures. The role of fever in the origin of CHD is currently being controversial. Edwards et al.21 in 1986 have proven maternal hyperthermia to be teratogenic in several animal species. Nevertheless, Lynberg et al.19 have demonstrated common infections were associated with an increased risk for congenital anomalies even without fever. In addition, among the seven studies, Adams et al.,14 Tikkanen et al.,15 Botto et al.11 and Oster et al.12 all had problems on the illness or attendant fever actually caused the defects remaining to be solved. Zhang et al. reported similar risk of birth defects in offspring between pregnant women having cold with and without fever (OR = 1.4, 95% CI = 0.7–2.9 and OR = 0.9, 95% CI = 0.4–1.8), thus he did not regard fever as a teratogenic factor of CHD. However, Zhang et al. excluded gravidas having fever without cold, and it might underestimate the association between maternal fever and CHD. In addition, it should be noted that Zhang et al. did not set a rigorous definition of fever, which might cause the misclassification of exposure and non-exposure groups and further generate similar ORs between women with and without fever mentioned above.16 Acs et al. showed that among mothers with flu, approximately 91.5% of them reported fever. He suggested fever itself were teratogenic, because significant association between maternal flu and CHD was not found in women who had received anti-fever treatment.17 Cleves et al. concluded that estimated ORs within specific phenotypes of CHD were greater among women reporting a fever-associated urinary tract infections than among women without fever, except hypoplastic left heart syndrome. In addition, they observed the significant relation between urinary tract infections and right ventricular outflow tract obstructive defects (OR = 2.47, 95% CI = 1.05–5.80) and pulmonary valve stenosis (OR = 3.03, 95% CI = 1.20–7.62) only when with fever.18 The possible mechanisms underlying the associations between maternal fever and specific types of CHD are unclear. Numerous studies have suggested that hyperthermia may lead to cell death.22–24 Specifically, hyperthermia has been shown to lead to vascular abnormalities in chick embryos.25 The role of maternal antipyretic use in the development of CHD remains controversial. Among the seven studies, Acs et al. found Journal of Perinatology (2014), 677 – 682
Congenital heart defects and maternal fever QY Shi et al
682 the proportion of anti-fever drugs used by the control mothers with flu was greater in the second and/or third month of gestation than in the case of mothers with flu. The OR of having infants with CHD for mothers taking anti-fever drugs when flu was 1.4 (95% CI = 0.9–2.1), compared with the mothers with fever taking no anti-fever drug (OR = 1.7, 95% CI = 1.3–2.2). Therefore, Acs et al. indicated the protective effect of anti-fever drugs. However, feverreducing medications was not always used for fever, and they might provide a protective effect by reducing other symptoms as well.17 Cleves et al. found no significant difference on the risk of CHD infants between maternal urinary tract infection with and without taking sulfonamide.18 The study also has some limitations. First, because few studies have examined the relation between maternal fever and CHD, only seven studies could be included. As a result, we need more prospective studies to corroborate the association between maternal fever and CHD. Second, this meta-analysis only addresses the criterion of consistency of findings across studies. Other criteria for causality remain to be addressed, including temporal relationship, dose-response, biologic plausibility and animal experiments. Last, there might be publication bias owing to the studies with negative results were not publised. As a consequence, we need more rigorously designed and highqualified epidemiologic studies. CONCLUSION Our analysis suggests that maternal fever in the first trimester is the risk factor of congenital heart diseases in offspring. Through the subgroup analysis, we find that exposure to maternal fever is the risk factor of VSD and right obstructive defects. Considering that maternal fever in the first trimester is common in pregnant women, our findings are pervasiveness in individual and population level. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This work was supported by the grants from National Natural Science Foundation of China (No. 21003077), the Open Project of Key Laboratory of Advanced Energy Materials Chemistry (No. KLAEMC-OP201101)
AUTHOR CONTRIBUTIONS YL Zhang, QY Shi and JB Zhang were involved in the conceptualization, research design, execution and write-up of the first draft of the manuscript. YQ Mi, Y Song and J Ma advised on the design of the study, and the analysis and interpretation of the results. All authors were involved in the preparation of the manuscript.
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2 Zhang YL, Riehle-Colarusso T, Correa A, Li S, Feng X, Gindler J et al. Observed prevalence of congenital heart defects from a surveillance study in china. J Ultrasound Med 2011; 30(7): 989–995. 3 Tikkanen J, Heinonen OP. Risk factors for cardiovascular malformations in Finland. Eur J Epidemiol 1990; 6(4): 348–356. 4 Shaw GM, Malcoe LH, Swan SH, Cummins SK, Schulman J. Congenital cardiac anomalies relative to selected maternal exposures and conditions during early pregnancy. Eur J Epidemiol 1992; 8(5): 757–760. 5 Frohn-Mulder IM, Meilof JF, Szatmari A, Stewart PA, Swaak TJ, Hess J. Clinical significance of maternal Anti-Ro/SS-A antibodies in children with isolated heart block. J Am College Cardiol 1994; 23(7): 1677–1681. 6 Jenkins KJ, Correa A, Feinstein JA, Botto L, Britt AE, Daniels SR et al. Non-inherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics. Circulation 2007; 115(23): 2995–3014. 7 Nora JJ, Nora AH. The evolution of specific genetic and environmental counseling in congenital heart diseases. Circulation 1987; 57(2): 205–213. 8 Moretti ME, Bar-Oz B, Fried S, Koren G. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiol 2005; 16(2): 216–229. 9 Edwards MJ. Review: hyperthermia and fever during pregnancy. Birth Defects Res A Clin Mol Teratol 2006; 76(7): 507–516. 10 Shahrukh Hashmi S, Gallaway MS, Waller DK, Langlois PH, Hecht JT. Maternal fever during early pregnancy and the risk of oral clefts. Birth Defects Res A Clin Mol Teratol 2010; 88(3): 186–194. 11 Botto LD, Lynberg MC, Erickson JD. Congenital heart defects, maternal febrile illness, and multivitamin use: a population-based study. Epidemiol 2001; 12(5): 485–490. 12 Oster ME, Riehle-Colarusso Tiffany, Alverson CJ, Correa A. Associations between maternal fever and influenza and congenital heart defects. J Pediatr 2011; 158(6): 990–995. 13 Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M et al. The NewcastleOttawa Scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses http://www.lri.ca 2000. 14 Adams MM, Mulinare J, Dooley K. Risk factors for conotruncal cardiac defects in Atlanta. J Am Coll Cardiol 1989; 14(2): 432–442. 15 Tikkanen J, Heinonen OP. Maternal hyperthermia during pregnancy and cardiovascular malformations in the offspring. Eur J Epidemiol 1991; 7(6): 628–635. 16 Zhang J, Cai WW. Association of the common cold in the first trimester of pregnancy with birth defects. Pediatrics 1993; 92(4): 559–563. 17 Acs N, Banhidy F, Puho E, Czeizel AE. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol 2005; 73(12): 989–996. 18 Cleves MA, Malik S, Yang S, Carter TC, Hobbs CA. Maternal urinary tract infections and selected cardiovascular malformations. Birth Defects Res A Clin Mol Teratol 2008; 82(6): 464–473. 19 Lynberg M C, Khoury MJ, Lu X, Cocian T. Maternal flu, fever, and the risk of neural tube defects: A population based case-control study. Am J Epidemiol 1994; 140(3): 244–255. 20 Miyake T, Shinohara T, Inoue T, Marutani S, Takemura T. Spontaneous closure of muscular trabecular ventricular septal defect: comparison of defect position. Acta Paediatr 2011; 100(10): e158–e162. 21 Edwards MJ. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance. Teratogenesis Carcinog Mutagen 1986; 6(6): 563–582. 22 Mirkes PE, Cornel LM, Park HW, Cunningham ML. Induction of thermotolerance in early postimplantation rat embryos is associated with increased resistance to hyperthermia-induced apoptosis. Teratol 1997; 56(3): 210–219. 23 Edwards MJ. Apoptosis, the heat shock response, hyperthermia, birth defects, disease and cancer: where are the common links? Cell Stress Chaperones 1998; 3 (4): 213–220. 24 Roulston A, Marcellus RC, Branton PE. Viruses and apoptosis. Annu Rev Microbiol 1999; 53: 577–628. 25 Nilsen NO. Vascular abnormalities due to hyperthermia in chick embryos. Teratol 1984; 30(2): 237–251.
Supplementary Information accompanies the paper on the Journal of Perinatology website (http://www.nature.com/jp)
Journal of Perinatology (2014), 677 – 682
© 2014 Nature America, Inc.
ORIGINAL ARTICLE
Congenital heart defects and maternal fever: systematic review and meta-analysis QY Shi1,8, JB Zhang2,8, YQ Mi3, Y Song4, J Ma5,9 and YL Zhang6,7,9 OBJECTIVE: To systematically review and meta-analyze the relation between maternal fever in the first trimester and congenital heart defect (CHD) in offspring. STUDY DESIGN: We searched PubMed (1977–2012), Embase (1974–2012) and the Cochrane Library (2012) databases to identify relevant articles. Random effects model were performed, with the conduction of subgroup analysis. RESULT: Meta-analysis yielded a pooled odds ratio of 1.53 (95% confidence interval = 1.36 to 1.73) for the magnitude of the relation between maternal fever in the first trimester and CHD in offspring. As to subgroup analysis, it is associated with ventricular septal defects (VSDs) and right obstructive defects. CONCLUSION: Our analysis suggests that maternal fever in the first trimester is the risk factor of congenital heart diseases in offspring. Through the subgroup analysis, we find that exposure to maternal fever is the risk factor of VSD and right obstructive defects. Journal of Perinatology (2014) 34, 677–682; doi:10.1038/jp.2014.76; published online 8 May 2014
INTRODUCTION Congenital heart defects (CHDs) are one of the most prevalent and serious birth defects, and they are the leading causes of death from congenital malformations.1–2 Many genetic and environmental factors that may relate to CHDs have been studied, but the causes of CHD are still unclear. Some reports have shown that increased maternal age at conception was associated with increased risk for CHD.3 About 1% of cardiovascular malformations can be attributed to maternal diseases, such as type 1 diabetes, phenylketonuria, epilepsy.4–6 Another 1% of cardiovascular malformations are caused by teratogen exposure.7 Among these teratogens, maternal fever has been an important one. Maternal fever has been proved to associate with many birth defects, especially defects of the central nervous system.8–10 More recently, a number of studies have sought to explore the association between maternal fever and CHD. Nonetheless, the results of individual studies were different. For example, Botto et al.11 reported positive association between maternal fever in the first trimester and CHD (odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.4–2.4), whereas Oster et al.12 showed insignificant association (OR = 1.1, 95% CI = 0.9–1.4). In addition, the relation of maternal fever and the subtypes of CHD were also variable. For instance, Botto et al.11 indicated a significant association between maternal fever and ventricular septal defect (VSD; OR = 1.8, 95% CI = 1.1–2.9), whereas Oster et al.12 held different opinion (OR = 1.12, 95% CI = 0.77–1.64). The results might be unreliable owing to the small sample size of subtypes of each study, thus it is necessary to synthesize them to obtain a summary
point estimate. For above reasons, we systematically reviewed and meta-analyzed the relation between maternal fever in the first trimester and CHD in offspring. METHODS Identification of studies We searched PubMed (1977–2012), Embase (1974–2012) and the Cochrane Library (2012) databases to identify relevant articles. We examined the reference lists of all known primary and review articles to identify cited articles not captured by the electronic searches. Language restrictions were not applied. A variable of the following search terms was used: (CHDs OR congenital heart disease OR congenital heart malformation OR congenital heart block) AND (maternal fever OR maternal febrile OR maternal hyperthermia OR maternal pyrexia OR (fever AND pregnancy) OR (febrile AND pregnancy) OR (hyperthermia AND pregnancy) OR (pyrexia AND pregnancy)). Besides, we also searched terms of (birth defects) AND (risk factors).
Inclusion and exclusion criteria Studies were included in the meta-analysis when they met the following inclusion criteria. Subject: Studies were included if they reported the associations between maternal fever in the first trimester and CHDs in offspring. Study design: Studies were included if they were case–control studies or cohort studies. Exposure: Studies were included if exposure related to fever or febrile illness with fever were clear and similar. Exposure window: Studies were included if exposure window was approximately in the first trimester during pregnancy. Outcome: Studies were included if the diagnosis of CHDs in offspring were clearly presented and the diagnostic
1 Tianjin Second People’s Hospital, School of Graduate, Tianjin Medical University, Tianjin, China; 2Tianjin Teda International Cardiovascular Disease Hospital, Clinical College of Cardiovascular, Tianjin Medical University, Tianjin, China; 3Depanment of Chinese Integrative Medicine, Tianjin Second People’s Hospital, Tianjin Medical University, Tianjin, China; 4 Coronary Care Unit, Tianjin Teda International Cardiovascular Disease Hospital, Clinical College of Cardiovascular, Tianjin Medical University, Tianjin, China; 5Department of Health Statistics, College of Public Health, Tianjin Medical University, Tianjin, China; 6Institute of Reproductive and Child Health/Ministry of Health Key Laboratory of Reproductive Health, School of Public Health, Peking University Health Science Center, Beijing, China and 7Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China. Correspondence: Dr Jun Ma, Department of Health Statistics, College of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Tianjin 300070, China or Dr YL Zhang, Institute of Reproductive and Child Health/Ministry of Health Key Laboratory of Reproductive Health, School of Public Health, Peking University Health Science Center, Beijing 100191, China. E-mail: [email protected] or [email protected] 8 These authors contributed equally to this work. 9 These authors contributed equally to this work. Received 5 November 2013; revised 27 February 2014; accepted 13 March 2014; published online 8 May 2014
Congenital heart defects and maternal fever QY Shi et al
678 approach of cases and control groups were identical. Data: Studies were included if we could get the information of OR and 95% CI. The electronic searches were scrutinized and two independent reviewers (YL Zhang and QY Shi) examined titles and abstracts to decide if the full-text articles should be obtained (n = 75). We decided to get full 35 reports of the 75 studies after looking through titles, abstracts and references. The decision to exclude any of these studies was made by the consensus of two authors. Finally, four studies were excluded for the duplicate data from the same study programs. Sixteen studies reporting influenza, infection, medication, sauna bathing and working temperature without the clear information of fever were excluded. Eight studies were excluded as they reported exposure window as the entire pregnancy period (Figure 1).
Quality assessment Study quality was assessed by two researchers (QY Shi and JB Zhang) using Newcastle-Ottawa Scale on case–control studies.13 Three major components, that is, selection of case and controls (Selection), comparability of case and controls (Comparability) and ascertainment of exposure (Exposure), comprized the scale, including eight small items (four on Selection, one on Comparability and three for Exposure). A study can be awarded a maximum of one * for each numbered item within the Selection and Exposure categories. A maximum of two * can be given for Comparability. Where reviewers disagreed, specific criteria were discussed with a third reviewer until consensus was reached.
Data extraction procedures Two reviewers (QY Shi and JB Zhang) independently extracted basic information in a standardized manner: first author, year, data acquisition
(period), CHD infants/fever mothers, CHD infants/non-fever mothers and interview time. Data on information of exposure, diagnosis of outcomes and detailed information of subtypes of CHD were collected.
Statistical analysis The main outcome in this analysis was the OR and its 95% CI. We pooled the ORs depending on the heterogeneity. Heterogeneity was evaluated graphically with forest plots and statistically with χ2 and I2 tests. I2 is an estimate of the proportion of total variation in study estimates that is due to heterogeneity. I2>25% indicate significant heterogeneity. The fixed effects model was used to estimate the variance of the summary OR when study heterogeneity was low and the random effects model when study heterogeneity was moderate to high. We also count the weight of each study according to the formula: wi = (1/ai+1/bi+1/ci+1/di)-1. All analyses were conducted with Stata statistical software (version 11; Stata Corp LD, College Station, TX, USA).
RESULTS Studies included in meta-analysis In this analysis, seven studies involving 12 030 cases and 51 729 controls were included.11–12,14–18 All the seven studies were retrospective studies, and they were published from 1989 to 2011. Four of seven studies were conducted in America.11–12,14,18 The rest of the three were, respectively, conducted in Hungary,17 Finland15 and China.16 Four of seven had reported different kinds of CHDs in detail.11,12,15,18 All had reported diagnostic methods of CHD and five had declared diagnostic time around 1year old.11–12,14–15,17 The information of exposure, diagnostic information and subtypes of CHD are shown in Tables 1,2 and Supplementary Table 1, respectively. The assessment of the study quality was available in Table 3. The association between CHD and maternal fever Table 4 shows the pooled estimate of the association between non-classified CHD and maternal fever in the first trimester generated by meta-analysis for all the seven studies combined. The pooled estimate for all seven studies combined was 1.53 (95% CI = 1.36–1.73). There was unobvious heterogeneity in women with maternal fever (I2 = 35.4%). There was no significant heterogeneity among the studies (P = 0.158).
Figure 1.
Table 1.
Flow chart of meta-analysis
Influence of individual studies We observed the shift of point estimate and 95% CI from the middle line through removing individual studies to analyze the influence of each study (Supplementary Figure 1). The pooled OR changed more or less when excluding any study from our metaanalysis. The results indicated that study by Oster et al. moved the farthest from the middle line, thus proving to be the most influential study of pooled size effect.
Exposure and exposure window of seven studies
Study 14
Adams et al. Tikkanen et al.15 Zhang and Cai16 Botto et al.11 Acs et al.17 Cleves et al.18 Oster et al.12
Exposure
Exposure window
Fever Fever exceeding 38°C Cold with fever Any source of fever and specific source of fever Flu with fever during epidemic months (between December and April) in epidemic and nonepidemic years Urinary tract infection with fever (above 101°F) Fever of 101°F or higher (⩾38.3°C)
From the month before conception to the third month of gestation During the first trimester of pregnancy During the first trimester of pregnancy From 1 month before conception to the third month of pregnancy During the second and third month of pregnancy
Journal of Perinatology (2014), 677 – 682
During the first trimester of pregnancy From 3 months before pregnancy to the end of the first trimester of pregnancy
© 2014 Nature America, Inc.
Congenital heart defects and maternal fever QY Shi et al
679 Table 2.
Diagnostic characteristics of seven studies
Study Adams et al.14 Tikkanen et al.
15
Zhang and Cai16 Botto et al.
11
Acs et al.17 Cleves et al.18
Oster et al.12
Congenital heart defects
Diagnostic time
Diagnostic methods
Conotruncal defects
During their first year of life
VSD, ASD, CAS, LHHS, ECD, other defects
Before 1 year of age
All defects and VSD
Before 8 days after birth
Outflow tract defects, VSD, ASD, AVSD, Ebstein anomaly, anomalous pulmonary venous return, all right obstructive defectgs, all left obstructive defects All defects
During the first year of life
By the Metropolitan Atlanta Congenital Defects Program Cardiac catheterization, ultrasound, sugery or autopsy By pediatricians or pathologist who had no knowledge of maternal cold history An anatomic diagnosis and an overall clinical diagnosis
From the second trimester of pregnancy to the end of the first postnatal year Not mention
Conotruncal defects, VSD, ASD, AVSD, right-sided obstructive defects, left-sided obstructive defects, anomalous pulmonary venous return VSD, ASD, AVSD, Ebstein anomaly, right-sided By 1 year of age obstructive defects, left-sided obstructive defects, total anomalous pulmonary venous return
Be identified in the Hungarian Congential Abnormality Registry (HCAR) Echocardiogram, heart catheterization, or surgical or autopsy report Echocardiography, catheterization, surgery, or autopsy
Abbreviations: ASD, atrial septal defect; AVSD, atrioventricular septal defect; CAS, conus arterious; ECD, endocardial cushion defect; LHHS, left heart hypoplastic syndrome; VSD, ventricular septal defect.
Table 3.
Quality ratings of seven studies
Study 14
Adams et al. Tikkanen et al.15 Zhang and Cai16 Botto et al.11 Acs et al.17 Cleves et al.18 Oster et al.12
Selection
Comparability
Exposure
★★★★ ★★★ ★★★ ★★★★ ★★★★ ★★★★ ★★★★
★★ ★ ★ ★★ ★★ ★★ ★★
★★★ ★★ ★★ ★★★ ★★★ ★★★ ★★★
Subgroup analysis Although the heterogeneity of the seven studies was low, we could not rule out the possibility that they canceled out with each other. And considering etiological difference of various CHD, we conducted subgroup analysis of CHD. The common classification of CHD include VSD, atrial septal defect (ASD), atrioventricular septal defect, conotruncal defects, Ebstein anomaly, anomalous pulmonary venous return, right obstructive defects, left obstructive defects and so on. Supplementary Table 1 shows the phenotypes of CHD in each study. We confirmed any sort of CHD above as a subgroup if at least three studies reported the association between it and maternal fever and in each study at least three cases were reported for this disease. Finally, we defined five subgroups: VSD, ASD, conotruncal defects, right obstructive defects and left obstructive. The associations of fever with cardiac phenotypes are outlined in Tables 5, 6, Supplementary Tables 2, 3 and 4. The aggregated OR associated with maternal fever in the first trimester for VSD in offspring was 1.34 (95% CI = 1.02–1.76), 1.46 (95% CI = 0.95–2.23) for ASD, 1.22 (95% CI = 0.91–1.63) for conotruncal defects, 2.05 (95%CI = 1.47–2.87) for right obstructive defects and 1.32 (95% CI = 0.88–1.96) for left obstructive defects. There was significant unexplained heterogeneity for studies for children with ASD (I2 = 61.7%, P = 0.050) and left obstructive defects (I2 = 82.4%, P = 0.003). There was no evidence of heterogeneity for studies in children with VSD, conotruncal defects and right obstructive defects (I2 = 0%). © 2014 Nature America, Inc.
Publication bias analysis We conducted Begg’s funnel plot and Egger’s corresponding asymmetry test for the eight studies. Egger’s test provided little evidence of publication bias (P = 0.914). DISCUSSION This is the first meta-analysis review of association between maternal fever in the first trimester and CHD in offspring. The studies of the association between maternal fever and birth defects in offspring date back to the beginning of last century. An obstetrician found that the number of neonates with birth defects increased significantly after global pandemic influenza in 1918, and almost all women delivering those babies had had the flu.19 In those studies of the association between maternal fever and birth defects in offspring, neural tube defects are the most studied about birth defects.8–10 A systematic review and meta-analysis about published literature from 1980 to 2003 regarding maternal fever and neural tube defects suggested that the odds of children with neural tube defects when their mother had maternal influenza or fever during pregnancy was 1.92 (95% CI = 1.61–2.29).8 However, the studies on association between maternal fever in the first trimester and CHD in offspring are far less than the neural tube defects. Our systematic review and meta-analysis of the published literature showed that in women who had experienced fever in the first trimester of their pregnancy, there was a significant association between maternal fever and CHD in aggregate (OR = 1.53, 95% CI = 1.36–1.73; Table 4). In addition, for specific heart defects, significant relations were detected between maternal reports of fever and VSD (OR = 1.34, 95% CI = 1.02–1.76; Table 5) and right-sided obstructive defects (OR = 2.05, 95% CI = 1.47–2.87; Table 6). Because all of the seven studies were retrospective, it is necessary to evaluate their potential recall bias. Generally, there were several means to control recall bias, such as elaborated protocols or objective indicators. In seven studies, Adams et al.14 conducted interviews for more than 3 years after conception, so respondents might have failed to recall whether they had experienced fever or which medications they had used, the same as Botto et al.11 (2–12 years ) and Cleves et al.18 (6 weeks to 24 months). Zhang et al.16 (soon after delivery), Tikkanen et al.15 Journal of Perinatology (2014), 677 – 682
Congenital heart defects and maternal fever QY Shi et al
680 Table 4.
OR and 95% CI of CHD associated with maternal fever in the first trimester Study Adams et al.14
CHD infants /Fever mothers
CHD infants /Non-fever mothers
Weight(%)
Odds ratio(fixed) 95% CI
8/83
83/1290
2.37
1.55 (0.72,3.32)
Tikkanen et al.15
57/573
63/1055
10.45
1.74 (1.20,2.53)
Zhang and Cai16
10/19
62/153
1.70
1.63 (0.63,4.24)
Botto et al.11
93/829
186/2890
19.26
1.84 (1.41,2.39)
Acs et al.17
105/4480
535/38151
28.73
1.69 (1.37,2.08)
Cleves et al.18
33/3685
27/4755
6.11
1.58 (0.95,2.64)
Oster et al.12
119/2361
155/3435
31.37
1.12 (0.88,1.43)
Overall
425/12030
1111/51729
100.00
1.53 (1.36,1.73)
Abbreviations: CHD, congenital heart defect; CI, confidence interval; OR, odds ratio. I2 = 35.4%, P = 0.158.
Table 5.
Subgroup analysis of VSD associated with maternal fever in the first trimester Study
CHD infants /Fever mothers
CHD infants /Non-fever mothers
Weight(%)
Odds ratio(fixed) 95% CI
Tikkanen, et al.15
17/216
63/1055
23.93
1.35 (0.77,2.35)
Botto, et al.11
22/194
186/2890
25.17
1.88 (1.18,2.97)
Cleves, et al.18
4/703
20/4086
7.08
1.18 (0.40,3.41)
Oster, et al.12
23/479
155/3435
43.81
1.07 (0.88,1.87)
Overall
66/1592
424/11466
100.00
1.34 (1.02,1.76)
Abbreviations: CHD, congenital heart defect; CI, confidence interval; VSD, ventricular septal defect. I2 = 0.0%, P = 0.402.
(average 92 days for cases and 96 days for controls), ACS et al.17 (3.5 ± 1.2 months for cases and 5.2 ± 2.9 months for controls) and Oster et al.12 (7 months for 80% of case mothers and 74% of control mothers, 12 months after birth for less than 10% of each group) gathered information in a relatively short time, which might to some extent control recall bias. Beyond that, because the birth of an infant with CHD is a serious traumatic event for most mothers, they try to find a causal explanation and are more inclined to report fever during pregnancy. Meanwhile, pregnant women might ignore a fever without obvious symptoms or misinterpret tactile hyperthemia as true fever during gestation time as Adams et al.,14 Zhang et al.,16 Botto et al.11 and Acs et al.17 did not give a strict definition and detailed information of fever Journal of Perinatology (2014), 677 – 682
including timing, magnitude and duration of the temperature evaluation. These epidemiologic studies indeed have limitations; however, the relatively consistent findings might suggest similar recall bias. As to specific phenotypes, significant relations were detected between maternal reports of fever and VSD (1.34, 95% CI = 1.02 –1.76; Table 5) and right-sided obstructive defects (2.05, 95% CI = 1.47–2.87; Table 6). Among four studies exploring VSD, Cleves et al.18 and Oster et al.12 excluded case infants with isolated muscular VSDs. Tikkanen et al.15 and Botto et al.11 did not mention anything about muscular VSD (Supplementary Table 1). Smaller muscular defects are very likely to close over time and may only require © 2014 Nature America, Inc.
Congenital heart defects and maternal fever QY Shi et al
681 Table 6.
Subgroup analysis of right obstructive defects associated with maternal fever in the first trimester
CHD infants /Fever mothers
CHD infants /Non-fever mothers
Weight(%)
Odds ratio(fixed) 95% CI
Botto et al.11
12/91
186/2890
26.49
2.21 (1.18,4.13)
Cleves et al.18
9/673
27/4755
17.75
2.37 (1.11,5.07)
Oster et al.12
22/270
155/3435
55.76
1.88 (1.18,2.99)
Overall
43/1034
369/11080
100
2.05 (1.47,2.87)
Study
Abbreviations: CHD, congenital heart defect; CI, confidence interval. I2 = 0.0%, P = 0.846.
observation in the first year of life. Some studies reported spontaneous closure of muscular VSDs was 84%.20 When analyzing right obstructive defects, Cleves et al.18 did not involve tricuspid atresia, whereas the other two studies included it. Besides, Cleves et al.18 deemed Ebstein anomaly as right a kind of obstructive defect, whereas the other two studies regarded it as an isolated CHD. Botto et al.11 and Cleves et al.18 included pulmonary atresia but Oster et al.12 did not. There was significant unexplained heterogeneity when we analysis the occurrence of fever and ASD (I2 = 61.7%, P = 0.050; Supplementary Table 2). The high heterogeneity might come from the definition of ASD and fever. Cleves et al.18 included ASD secundum, sinus venosus ASDs and ASD (not otherwise specified), whereas Tikkanen et al.,15 Botto et al.11 and Oster et al.12 did not state anything special on it (Supplementary Table 1). And Tikkanen et al.15 defined fever as exceeding 38 °C (100.4 °F), lower than defined by Cleves et al.18 and Oster et al.,12 38.3 ℃ (101 °F), which might contribute to the greater point estimate than Cleves et al.18 and Oster et al.12 There was also significant high heterogeneity for infants with left obstructive defects (I2 = 82.4%, P = 0.003; Supplementary Table 4). Among the three studies, Botto et al.11 did not give a rigorous definition of fever, which might cause the misclassification of exposure and non-exposure groups and showed a higher increased risk than Cleves et al.18 and Oster et al.12 With respect to fever, two factors might potentially account for the inconsisitent findings on our study. First, only Tikkanen et al.,15 Cleves et al.18 and Oster et al.12 have rigorously defined maternal fever. Among them, Cleves et al.18 and Oster et al.12 defined exposure as a report of temperature of ⩾ 38.3 ℃ (101 °F), whereas Tikkanen et al.15 encompassed a broader temperature range of exceeding 38 ℃ (100.4 °F). Interestingly, Tikkanen et al.15 found almost a twofold increase in the risk of CHD in association with maternal fever (OR = 1.74, 95% CI = 1.20–2.53), whereas Cleves et al.18 and Oster et al.12 reported a modestly increased risk of CHD (OR = 1.58, 95% CI = 0.95–2.64 and OR = 1.12, 95% CI = 0.88–1.43, respectively; Table 4). The lower definition of fever in study by Tikkanen et al. might cause an overestimation of the association between maternal fever and CHD.15 For Adams et al.,14 Zhang et al.,16 Botto et al.11 and Acs et al.17 who did not give a strict definition of fever, it might result in misclassification of exposure and non-exposure groups. Meanwhile, it is necessary to take the underlyling disease into account because fever is only a clinical symptom. Among the © 2014 Nature America, Inc.
possible etiologies, infection is the most common pathogenesis, which is often caused by viral, bacterial and fungal organisms. Disentangle the teratogen effects of fever and underlying infection remains difficult because of a high level of concordance in reports of such exposures. The role of fever in the origin of CHD is currently being controversial. Edwards et al.21 in 1986 have proven maternal hyperthermia to be teratogenic in several animal species. Nevertheless, Lynberg et al.19 have demonstrated common infections were associated with an increased risk for congenital anomalies even without fever. In addition, among the seven studies, Adams et al.,14 Tikkanen et al.,15 Botto et al.11 and Oster et al.12 all had problems on the illness or attendant fever actually caused the defects remaining to be solved. Zhang et al. reported similar risk of birth defects in offspring between pregnant women having cold with and without fever (OR = 1.4, 95% CI = 0.7–2.9 and OR = 0.9, 95% CI = 0.4–1.8), thus he did not regard fever as a teratogenic factor of CHD. However, Zhang et al. excluded gravidas having fever without cold, and it might underestimate the association between maternal fever and CHD. In addition, it should be noted that Zhang et al. did not set a rigorous definition of fever, which might cause the misclassification of exposure and non-exposure groups and further generate similar ORs between women with and without fever mentioned above.16 Acs et al. showed that among mothers with flu, approximately 91.5% of them reported fever. He suggested fever itself were teratogenic, because significant association between maternal flu and CHD was not found in women who had received anti-fever treatment.17 Cleves et al. concluded that estimated ORs within specific phenotypes of CHD were greater among women reporting a fever-associated urinary tract infections than among women without fever, except hypoplastic left heart syndrome. In addition, they observed the significant relation between urinary tract infections and right ventricular outflow tract obstructive defects (OR = 2.47, 95% CI = 1.05–5.80) and pulmonary valve stenosis (OR = 3.03, 95% CI = 1.20–7.62) only when with fever.18 The possible mechanisms underlying the associations between maternal fever and specific types of CHD are unclear. Numerous studies have suggested that hyperthermia may lead to cell death.22–24 Specifically, hyperthermia has been shown to lead to vascular abnormalities in chick embryos.25 The role of maternal antipyretic use in the development of CHD remains controversial. Among the seven studies, Acs et al. found Journal of Perinatology (2014), 677 – 682
Congenital heart defects and maternal fever QY Shi et al
682 the proportion of anti-fever drugs used by the control mothers with flu was greater in the second and/or third month of gestation than in the case of mothers with flu. The OR of having infants with CHD for mothers taking anti-fever drugs when flu was 1.4 (95% CI = 0.9–2.1), compared with the mothers with fever taking no anti-fever drug (OR = 1.7, 95% CI = 1.3–2.2). Therefore, Acs et al. indicated the protective effect of anti-fever drugs. However, feverreducing medications was not always used for fever, and they might provide a protective effect by reducing other symptoms as well.17 Cleves et al. found no significant difference on the risk of CHD infants between maternal urinary tract infection with and without taking sulfonamide.18 The study also has some limitations. First, because few studies have examined the relation between maternal fever and CHD, only seven studies could be included. As a result, we need more prospective studies to corroborate the association between maternal fever and CHD. Second, this meta-analysis only addresses the criterion of consistency of findings across studies. Other criteria for causality remain to be addressed, including temporal relationship, dose-response, biologic plausibility and animal experiments. Last, there might be publication bias owing to the studies with negative results were not publised. As a consequence, we need more rigorously designed and highqualified epidemiologic studies. CONCLUSION Our analysis suggests that maternal fever in the first trimester is the risk factor of congenital heart diseases in offspring. Through the subgroup analysis, we find that exposure to maternal fever is the risk factor of VSD and right obstructive defects. Considering that maternal fever in the first trimester is common in pregnant women, our findings are pervasiveness in individual and population level. CONFLICT OF INTEREST The authors declare no conflict of interest.
ACKNOWLEDGEMENTS This work was supported by the grants from National Natural Science Foundation of China (No. 21003077), the Open Project of Key Laboratory of Advanced Energy Materials Chemistry (No. KLAEMC-OP201101)
AUTHOR CONTRIBUTIONS YL Zhang, QY Shi and JB Zhang were involved in the conceptualization, research design, execution and write-up of the first draft of the manuscript. YQ Mi, Y Song and J Ma advised on the design of the study, and the analysis and interpretation of the results. All authors were involved in the preparation of the manuscript.
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Journal of Perinatology (2014), 677 – 682
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