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A systematic review of the risks of a low birthweight (LBW), preterm, and small-for-gestational-age births in relation to paternal factors was performed. Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, and bibliographies of identified articles were searched for English-language studies. Study qualities were assessed according to a predefined checklist. Thirty-six studies of low-to-moderate risk of bias were reviewed for various paternal factors: age, height, weight, birthweight, occupation, education, and alcohol use. Extreme paternal age was associated with higher risk for LBW. Among infants who were born to tall fathers, birthweight was approximately 125-150 g higher compared with infants who were born to short fathers. Paternal LBW was associated with lower birthweight of the offspring. In conclusion, paternal characteristics including age, height, and birthweight are associated with LBW. Paternal occupational exposure and low levels of education may be associated with LBW; however, further studies are needed. Article Outline• Abstract • Criteria for consideration of studies for this review • Search strategy for identification of studies • Assessment of quality of included studies • Heterogeneity and publication bias assessment • Results • Methodologic quality of included studies • Paternal weight and body mass • Comment • Paternal occupational exposure • Appendix Low birthweight (LBW) birth and preterm births (PTBs) are public health issues with significant individual, familial, and societal impact. Familial influence in the cause of LBW/PTB births is suspected; however, the major research attention has been focused on maternal determinants. Paternal factors (such as advanced paternal age1 and chemical exposures) have been linked with congenital malformations. De La Rochebrochard et al,2 in a minireview, concluded that advanced paternal age (>40 years) was associated with miscarriages and fetal deaths. Diseases such as Alpert syndrome, Marfan syndrome, and Waardenberg syndrome are associated with advanced paternal age. Strobino et al3 reviewed the connection between paternal occupational exposure and effect on offspring. They reported that paternal occupation was not associated with spontaneous abortion and that there was a lack of conclusive impact on other birth outcomes. For Editors' Commentary, see Table of Contents See related editorial,page 99 Studies have reported paternal factors that influence birthweight or gestational age. However, no comprehensive review of paternal determinants or factors on LBW, PTB, or small for gestational age (SGA) births has been conducted. The objective of this study was to review systematically the risk of an infant with LBW, PTB, and SGA in relation to various reported paternal factors. Materials and Methods The data were extracted from published articles; therefore, no ethical approval was obtained. Criteria for consideration of studies for this reviewObservational studies that explored the association of any of the paternal factors and the outcomes of LBW, PTB, and SGA births of offspring were included in this review. If the study provided adequate information on the method of ascertainment of the paternal factor and its effects on any of the outcomes of interest, the study was eligible for inclusion in the review. We included only information that was available from the publications and did not contact primary authors. Studies that were published as abstracts were excluded. Types of studiesObservational cohort studies, case control studies, and studies of surveys or interviews were included. Reports of data from national or local vital statistics that were not published as peer-reviewed articles were not included. Types of participantsWomen who had a live birth were included. Data on reports of maternal influence on birth outcomes were not included in this review. Assessment of exposurePrevious knowledge of the subject indicated that paternal age, anthropometry, paternal birthweight, occupation, and educational background would be probable exposures to be included in the review.4 We did not include paternal race as an exposure variable because race has a complex interaction with maternal race. Similarly, we excluded paternal smoking as an exposure because most studies have reported on environmental tobacco exposure, which could have been from partners or other sources, and it was difficult to differentiate. We included studies that reported a collection of ascertainment of exposure data from maternal charts, interview, and direct or indirect assessments. Types of outcome measuresStudies that reported data on any of the following outcomes were included: (1) LBW birth defined as birthweight <2.5 kg; (2) PTB defined as gestational age <37 weeks; (3) birthweight in grams; (4) gestational age in weeks, and (5) SGA birth defined as birthweight <10th percentile for gestational age. Search strategy for identification of studiesElectronic databases (Medline, Embase, and Cumulative Index of Nursing and Allied Health Literature) were searched, with assistance from an experienced librarian, from their inception to March 2009 for all published studies in the English language. The search terms were modified according to database requirements. The reference lists of the identified articles were reviewed to locate additional eligible studies. The articles were scanned initially on the basis of titles and abstracts. The reviewer was not blinded to authors or institution. Selected articles were retrieved in full and were assessed for eligibility. Search terms used were low birthweight; premature birth; preterm birth; small for gestational age; growth, intrauterine; growth restriction, fetal; growth restriction, intrauterine; high risk pregnancy; infant, premature; infant, newborn; pregnancy; familial factors; father, paternal factors, paternal age, paternal birthweight, occupation, education, anthropometry, weight, height, body mass, and body mass index. Methods of the reviewData extractionData from each eligible study were extracted into custom-made data collection forms. Minor modifications (such as combining birthweight means for male and female subjects) and the calculation of raw percentages from available data were done. Confounders that were adjusted for in the analyses in the individual studies were reported. When adjusted data were reported in the primary studies, they were extracted and noted in the results. Assessment of quality of included studiesThe methodologic quality of studies was assessed with a predefined checklist that was based on criteria for the sample selection, exposure assessment, outcome assessment, confounder, and analytical and attrition biases (Appendix). The classifications were applied in each category: cannot tell, no bias, low risk, moderate risk, or high risk of bias. Data synthesisWe expected a significant degree of clinical heterogeneity among studies in each of the paternal factors and planned for a systematic review and not metaanalyses from the outset. Qualitative synthesis of the evidence was planned because of the reasons mentioned earlier. Heterogeneity and publication bias assessmentClinical heterogeneity was assessed and reported in the Tables. ResultsDescription of studiesThirty-eight studies were included in this review.5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42 Some of the included studies reported on >1 paternal factor. Paternal alcohol use was identified as an exposure during the literature review (which was not planned a priori). Eleven studies were excluded after detailed evaluation. Details of included studies and reasons for excluded studies are given in Figure 1.43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53
Methodologic quality of included studiesThe results of the quality assessments of the included studies are reported in TABLE 1, TABLE 2, TABLE 3, TABLE 4, TABLE 5, TABLE 6. The studies had low-to-moderate risk of biases. The major criticism of the included studies was that the assessment of exposure in many reports was indirect (such as maternal history, derived or deduced assessment method for occupational exposure). Adjustment of confounders was variable among studies; however, compared with other reports of determinants of LBW/PTB births, most of the studies in this category have accounted for common confounders. Assessment of outcomes was satisfactory in most studies. Many studies reported only incidence or percentage of outcome data and not odds ratio or relative risk and their associated confidence interval. The data in the Tables reflect what is reported in the articles. If the risk estimates are missing from a Table, the implication is that they were not reported.
Paternal ageThere was variability in age cut-offs that were used in the studies as well as the reference age for comparison of groups. Exploratory analysis of a relationship between paternal age and LBW births was conducted. Figure 2 demonstrates the relationship of paternal age (mid values from all reported age groups and conversion of the 25- to 28-year age group as the reference group for each study) and LBW births in 6 studies that reported the odds of LBW births in various age groups. A “saucer-shaped” association can be inferred with higher odds at both extremes. No association between paternal age and PTB or SGA births was identified in any of the studies. Characteristics of the included studies, assessment of biases, and reported results are outlined in Table 1.
Paternal heightPaternal height showed significant correlation with birthweight of the offspring in most of the studies. On average, there was 125-150 g reduction in birthweight of the offspring of short vs tall fathers. Characteristics of the included studies, assessment of biases, and reported results are given in Table 2. Paternal weight and body massMost of the studies reported a nonsignificant relationship with paternal body weight or mass and birthweight and LBW births. In 1 study, a significant relationship became nonsignificant when maternal body mass was considered. Characteristics of the included studies, assessment of biases, and reported results are given in Table 3. Paternal birthweightThree studies reported that an infant's birthweight increased as paternal birthweight increased. The odds of a LBW birth were higher if the father had a LBW birth. Interestingly, 1 study reported higher rates of PTBs as the father's birthweight increased; however, this might be attributed to maternal characteristic. Characteristics of the included studies, assessment of biases, and reported results are given in Table 4. Paternal occupationHigher and prolonged lead exposures were associated with higher risk of LBW birth and PTB; however, details of timing of exposure in relation to pregnancy were not available in detail to assess direct effect. One large study reported a higher adjusted risk of SGA births among workers who were exposed to benzene, chromium, and other minerals and a higher risk of PTBs among workers who were exposed to x-rays. Other occupations that were assessed were not associated with higher risk of adverse outcomes. Characteristics of the included studies, assessment of biases, and reported results are given in Table 5. Paternal educationOne study reported a higher risk of LBW births and another reported a higher risk of PTBs among fathers who had a high school education only, compared with fathers who had a college education. Characteristics of the included studies, assessment of biases, and reported results are given in Table 6. Paternal alcohol useOne small study reported a 200-g reduction in birthweight with regular alcohol use; other studies reported no difference in the risk of LBW birth or PTBs with different levels of paternal alcohol use.26, 40, 41, 42 Characteristics of the included studies, assessment of biases, and reported results are given in Table 6. CommentIn this systematic review of 36 studies on paternal factors and birth outcomes, certain positive and negative associations were observed. Extreme paternal ages (<20 and >40 years) may be associated with LBW; however, no consistent associations with PTBs and SGA births were identified. Paternal height and paternal occupational exposure to lead were associated with LBW and birthweight of the offspring. The infant's birthweight increased with a higher paternal birthweight. Paternal weight, body mass, and occupational exposures to herbicides, plant work, woodwork and paternal alcohol use were not associated with birth outcomes. A lower level of paternal education was associated with LBW/PTB and SGA births; however, confirmation of data from larger studies is warranted. Paternal ageAdvanced paternal age has been linked with fetal loss,54 congenital malformations,55 single gene disorders,56 lower intelligence, dyslexia,57 and mental disorders58 in children. Studies of the impact of paternal age on LBW, PTB, or SGA outcomes have concluded varied results.5, 6, 10, 14 Biologic rationale behind the influence of paternal age on birth outcomes stems from the identification of greater expression of paternal genes on the placenta59 and higher chances of mutation that involves those genes in immature men compared with mature men60 and in men of advanced age.61 A paternal “weathering” phenomenon (ie, biologic effects of male aging that is hastened by harsh living conditions over years) has been suspected.11 The overall impression from our systematic review of included studies and the plot of paternal age–LBW birth incidence curve suggest that, if there was an effect of paternal age on LBW birth, it would appear to be modest for advanced paternal age. Paternal anthropometryAll 10 reviewed studies reported an increase in birthweight as father's height increased. The magnitude of increase between the lowest group and the highest group was approximately 125-150 g. No studies reported incidences of LBW, PTB, or SGA births. The effect is presumed to be of genetic origin.21 Studies of paternal weight and its influence on birthweight revealed contradictory results. Two studies reported an approximate 75- to 100-g increase in birthweight among the highest weight/body mass index group,22, 25 compared with the lowest weight/body mass index group. Three studies reported no significant influence.9, 19, 21 All of these studies had very small sample sizes, and a large population-based study is warranted. Paternal birthweightLower paternal birthweight was associated with lower infant birthweight. Paternal LBW was associated with higher risk of an infant with LBW, which is an effect that is similar to maternal LBW. PTB rate was lower for fathers in the LBW birth category. However, this information comes from very few and small studies. Ascertainment issues regarding birthweight of the father should not be ignored in the interpretation of these results. Also, studies from different countries were included in this review; therefore, it may have affected the results because there are different norms for birthweight in different ethnic backgrounds. Paternal occupational exposureThere are 2 pathways by which paternal exposure contribute to an effect on birth outcomes: either paternal exposure leads to maternal exposure and the effect is exerted or paternal exposure leads to alteration in the germ cell line that leads to either increased infertility or abnormality in conception.3 Lead, dioxin, and organic solvents are the more commonly studied exposures. Animal experiments reported lower birthweight after male animal exposure to lead.62 Lead exposure has been shown to be associated with infertility, still births, and spontaneous abortions.38 The effect is suspected to be due to effects on the metabolic activity of the sperm.63 Higher and prolonged exposure to lead may be associated with increased risk of LBW births and PTBs; however, ascertainment bias played a major role in included studies. Agent Orange was a widely used herbicide in Vietnam, and contamination of this by dioxin prompted a series of studies that explored the association of paternal exposure with birth outcomes.31 Two studies reported no significant association between exposure to dioxin and LBW birth or PTB.31, 33 Organic solvents can pass the blood-testis barrier and the placenta. Two studies of this association revealed no significant association.29, 30 Several studies of occupational exposure assessment have classified exposure based on interviews, databases, and expected hours of exposure.28, 29, 30, 31, 34 The possibility of misclassification and recall bias cannot be ruled out. Other paternal factorsPaternal alcohol intake was not associated significantly with PTB/SGA births in 1 study,41 but another study reported a 180-g increase in mean birthweight among offspring of the occasional drinker, compared with regular drinkers.48 The biologic rationale for such an effect remains to be understood. Less than a high school education was associated with a higher rate of PTB, and education less than college level was associated with higher odds of LBW births. Paternal low education level may be a marker for other underlying health determinants such as poverty, adverse home environment, and associated stress. There was significant heterogeneity in the reported studies that assessed paternal factors and its association to offspring outcomes. Keeping this in mind, we planned for a systematic review from the onset and not metaanalyses. Major clinical heterogeneities among studies were identified for inclusion of the studies (single institution-based study vs national sample) and for adjustment of confounders (different studies controlled for different confounders). A number of studies identified associations in univariate analyses; however, when confounders such as maternal factors were considered, the association became nonsignificant. The major issues with parental occupational exposure were ascertainment of a bias for exposure and recall bias. Strengths of this systematic review lie in the focused question, comprehensive and extensive literature search, and inclusion of studies from various countries. However, there are limitations of this review. First, there was heterogeneity in studies even within various exposure categories. Second, data on paternal factors are not collected regularly because fathers may not be present at prenatal visits and data are collected from mothers. The information that is collected could be subject to inaccuracies. Additionally, occupational exposure data were obtained from administrative databases or calculated in terms of duration or intensity of exposure. This is subject to ascertainment bias. Additionally, no detailed information regarding the timing of exposure and the protection used by fathers were reported. Third, various studies adjusted for different confounders in their analyses, and some studies did not adjust for confounders. It is important to adjust for various maternal confounders to assess the independent effect of paternal exposure. This limited our ability to conclude anything definitively about any of the factors. Fourth, publication bias should be considered. There is a possibility that, if the studies reported no association for any of the paternal exposures, there may have been less likelihood of publication. Fifth, we restricted our search to English language publications primarily because of the scope of information that may or may not be available in other languages. Literature searchers have found minimal difference with the inclusion of non-English language articles.64 We have not included gray literature, abstracts, and proceedings because the quality of such studies cannot be assessed adequately. Finally, none of the studies used any objective measure to confirm paternity; the data on paternity were obtained from maternal history in all studies. ImplicationsThere are clinically significant and important implications of these results. Pregnancies that were conceived from younger and advanced age fathers, short-statured fathers, fathers who were LBW at birth, and fathers with less than a college education could be considered to be at a greater risk. This information can be used during counseling and education sessions. ConclusionIn this comprehensive systematic review of paternal factors, associations were identified for paternal age, height, and LBW. Higher paternal birthweight resulted in heavier offspring. Heavy and prolonged lead exposure may be associated with LBW. Paternal weight, body mass, and workers with occupational exposures to herbicides, plant work, and wood were not associated with birth outcomes. Low paternal education may be associated with LBW/PTB births; however, further studies are warranted. AcknowledgmentsWe sincerely thank Elizabeth Uleryk, Chief Librarian at the Hospital for Sick Children, Toronto, for her contribution in developing search strategy and running searches on a periodic basis, for which she did not receive any compensation. Contributors: guarantor: Shah PS; grant concept and design: all members of the group; study concept and design: Shah PS; acquisition of data, analysis, and interpretation of data, drafting of the manuscript: Shah PS; critical revision of the manuscript for intellectual content: Shah PS and all members of group. Members of the Knowledge Synthesis Group on determinants of LBW/preterm births: Prakesh S Shah, University of Toronto, Toronto, Ontario, Canada; Arne Ohlsson, University of Toronto, Ontario, Canada; Sarah D McDonald, McMaster University, Hamilton, Ontario, Canada; Eileen Hutton, McMaster University, Hamilton, Ontario, Canada; Vibhuti Shah, University of Toronto, Toronto, Ontario, Canada; Joseph Beyene, University of Toronto, Toronto, Ontario, Canada; Corine Frick, University of Calgary, Calgary, Alberta, Canada; Fran Scott, University of Toronto, Toronto, Ontario, Canada; Kellie E Murphy, University of Toronto, Ontario, Canada; Christine Newburn-Cook, University of Alberta, Edmonton, Alberta, Canada; Victoria Allen, Dalhousie University, Halifax, Nova Scotia, Canada. Appendix
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MEDLINE | CrossRef 60. 60 Semen characteristics as a function of age in 833 fertile men. Fertil Steril. 1983;39:530–535. MEDLINE 61. 61. The origins, patterns and implications of human spontaneous mutation. Nat Rev Genet. 2000;1:40–47. MEDLINE | CrossRef 62. 62. Reproductive ability and progeny of F 1 lead-toxic rats. Fertil Steril. 1971;22:755–760. MEDLINE 63. 63. Sperm nuclear stability and male infertility. Arch Androl. 1990;25:253–259. MEDLINE 64. 64. The inclusion of reports of randomised trials published in languages other than English in systematic reviews. Health Technol Assess. 2003;7:1–90. MEDLINE Department of Pediatrics, Mount Sinai Hospital, and the Departments of Pediatrics and of Health Policy, Management and Evaluations, University of Toronto, Toronto, Ontario, Canada
This study was supported by funding from the Canadian Institute of Health Research (CIHR) Knowledge Synthesis/Translation Grant no. KRS 86242. The CIHR has played no role in the analyses, the writing of the report, the interpretation of data, or the decision to submit the manuscript. PII: S0002-9378(09)00952-1 doi:10.1016/j.ajog.2009.08.026 © 2010 Mosby, Inc. All rights reserved.
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FULL TEXT
Paternal factors and low birthweight, preterm, and small for gestational age births: a systematic review
Do fathers matter? Paternal contributions to birth outcomes and racial disparities
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