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The impact of maternal lifestyle factors on periconception outcomes: a systematic review of observational studies

Published:October 26, 2018DOI:https://doi.org/10.1016/j.rbmo.2018.09.015

      Abstract

      The main risk factors for important reproductive health issues such as subfertility and perinatal mortality largely originate in the periconception period. To evaluate associations between modifiable maternal lifestyle factors and periconception outcomes, a systematic search was conducted for relevant studies published from 1990 to February 2017 on Embase, Medline, Web of Science, Cochrane database, PubMed and Google Scholar. The initial search identified 6166 articles, of which 49 studies were eligible for inclusion. Fecundity (the capacity to have a live birth) showed significant inverse associations with smoking, alcohol use and poor diet. Studies regarding time to pregnancy showed a decline in fecundity ratios (the monthly conception rate among exposed relative to unexposed couples) with increasing body mass index (BMI). Furthermore, risk of first-trimester miscarriage was found to be increased in smokers, alcohol and caffeine consumers, and with increasing BMI. Vitamin supplement use showed a decrease in this risk. This review demonstrates that maternal modifiable lifestyle factors affect periconception outcomes. If couples planning a pregnancy are more aware and supported to adopt healthy lifestyles during the periconceptional ‘window of opportunity’, short-term reproductive health as well as health in later life and even of future generations can be further improved.

      Keywords

      Introduction

      • Ravelli G.P.
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      were one of the first to show increased rates of obesity as a composite determinant of poor lifestyles, in individuals who had been exposed to famine in utero. The link between early-life environment and adult disease was subsequently investigated in women exposed to famine in the Dutch hunger winter during the last winter of the Second World War, showing that offspring exposed to starvation in utero indeed had an increased risk of metabolic and cardiovascular diseases in adulthood (
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      ,
      • Painter R.C.
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      ). In the 1980s, this concept was developed by David Barker, who reported for the first time a negative correlation between low birthweight and the rate of death from ischaemic heart disease (
      • Barker D.J.
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      • Barker D.J.
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      Weight in infancy and death from ischaemic heart disease.
      ). He also postulated that low birthweight in offspring, as a proxy for poor prenatal maternal nutrition, not only increases the risk of coronary heart disease in adulthood, but also of other non-communicable diseases (NCD), such as obesity and certain cancers (
      • Barker D.J.
      • Osmond C.
      Infant mortality, childhood nutrition, and ischaemic heart disease in england and wales.
      ,
      • Barker D.J.
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      Weight in infancy and death from ischaemic heart disease.
      ,
      • Barker D.J.
      • Gluckman P.D.
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      ). To explain these findings, it was suggested that, due to plasticity, fetuses can adapt to the environment they expect to enter into once outside the womb. This has been the basis for the hypothesis of the Developmental Origins of Health and Disease (DOHaD) (
      • Barker D.J.
      The developmental origins of adult disease.
      ).
      The DOHaD paradigm focuses mainly on exposures during pregnancy and outcomes at birth and in later life. However, many adverse pregnancy outcomes, such as subfertility, congenital malformations, low birthweight and preterm birth, originate in the periconception period, a critical window which has been neglected in both research and patient care. Therefore, based on molecular biological processes and epigenetics, we have defined the periconception period as a time span of 14 weeks before to up to 10 weeks after conception (
      • Steegers-Theunissen R.P.
      • Twigt J.
      • Pestinger V.
      • Sinclair K.D.
      The periconceptional period, reproduction and long-term health of offspring: The importance of one-carbon metabolism.
      ). During this critical period, fertilization, implantation and development and growth of the embryo and placenta take place (
      • Macklon N.S.
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      ,

      Steegers-Theunissen, R.P., 2010. Nieuw leven in een veranderende omgeving.

      ). This window is therefore pivotal to human reproduction in general and pregnancy outcome in particular.
      The periconception environment is determined by maternal pre-existing medical conditions and modifiable lifestyles, including smoking, diet and body mass index (BMI) (
      • Steegers-Theunissen R.P.
      • Steegers E.A.
      Embryonic health: New insights, mhealth and personalised patient care.
      ). The prevalence of poor lifestyle behaviours in the reproductive population is comparable to the prevalence in the general population (
      • Hammiche F.
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      • De Cock M.
      • De Vries J.H.
      • Lindemans J.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Tailored preconceptional dietary and lifestyle counselling in a tertiary outpatient clinic in the netherlands.
      ). There is growing evidence about the impact of lifestyle factors on fertility in women of reproductive age (
      • Bunting L.
      • Tsibulsky I.
      • Boivin J.
      Fertility knowledge and beliefs about fertility treatment: Findings from the international fertility decision-making study.
      ,
      • Temel S.
      • Van Voorst S.F.
      • Jack B.W.
      • Denktas S.
      • Steegers E.A.
      Evidence-based preconceptional lifestyle interventions.
      ). Being obese or overweight before conception is thought to exert a negative influence on female fertility due to dysregulation of the hypothalamic-pituitary-ovarian axis leading to ovulatory dysfunction (
      • Broughton D.E.
      • Moley K.H.
      Obesity and female infertility: Potential mediators of obesity’s impact.
      ). Excessive gestational weight gain and obesity during pregnancy are key predictors of childhood obesity and of metabolic complications in adulthood (
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Colaci D.S.
      • Afeiche M.C.
      • Toth T.L.
      • Gillman M.W.
      • Missmer S.A.
      • Chavarro J.E.
      Prepregnancy and early adulthood body mass index and adult weight change in relation to fetal loss.
      ). Children of women who are overweight or obese from the beginning of pregnancy are also at increased risk of cognitive deficits, externalizing problems (particularly attention-deficit/hyperactivity disorder), and internalizing psychopathology in childhood and adolescence (
      • Van Lieshout R.J.
      Role of maternal adiposity prior to and during pregnancy in cognitive and psychiatric problems in offspring.
      ). Besides BMI, smoking is another common lifestyle factor affecting both fecundity (
      • Crawford S.
      • Smith R.A.
      • Kuwabara S.A.
      • Grigorescu V.
      Risks factors and treatment use related to infertility and impaired fecundity among reproductive-aged women.
      ) and embryonic growth during the first six months of life (
      • De Brito M.L.
      • Nunes M.
      • Bernardi J.R.
      • Bosa V.L.
      • Goldani M.Z.
      • Da Silva C.H.
      Somatic growth in the first six months of life of infants exposed to maternal smoking in pregnancy.
      ). These data suggest an extension of the window of opportunity for prevention and intervention in to the earliest moments of life.
      Before the advent of high-resolution ultrasound, and in particular of three-dimensional ultrasound, in-vivo data on embryonic and placental development during the first trimester of pregnancy was limited. These non-invasive techniques have now provided large databases on normal and abnormal feto-placental development, thus enabling a better understanding of the pathophysiology of the early embryonic development and its possible impact during pregnancy and after birth (
      • Rousian M.
      • Koning A.H.
      • Van Oppenraaij R.H.
      • Hop W.C.
      • Verwoerd-Dikkeboom C.M.
      • Van Der Spek P.J.
      • Exalto N.
      • Steegers E.A.
      An innovative virtual reality technique for automated human embryonic volume measurements.
      ,
      • Rousian M.
      • Verwoerd-Dikkeboom C.M.
      • Koning A.H.
      • Hop W.C.
      • Van Der Spek P.J.
      • Steegers E.A.
      • Exalto N.
      First trimester umbilical cord and vitelline duct measurements using virtual reality.
      ,
      • Van Uitert E.M.
      • Exalto N.
      • Burton G.J.
      • Willemsen S.P.
      • Koning A.H.
      • Eilers P.H.
      • Laven J.S.
      • Steegers E.
      • Steegers-Theunissen R.P.
      Human embryonic growth trajectories and associations with fetal growth and birthweight.
      ). This has also stimulated periconceptional prospective research on the influence of maternal lifestyle factors on the risk of first trimester abnormal outcomes, mainly miscarriage, congenital malformations and embryonic growth (
      • Van Uitert E.M.
      • Van Der Elst-Otte N.
      • Wilbers J.J.
      • Exalto N.
      • Willemsen S.P.
      • Eilers P.H.
      • Koning A.H.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Periconception maternal characteristics and embryonic growth trajectories: The rotterdam predict study.
      ,
      • Koning I.V.
      • Baken L.
      • Groenenberg I.A.
      • Husen S.C.
      • Dudink J.
      • Willemsen S.P.
      • Gijtenbeek M.
      • Koning A.H.
      • Reiss I.K.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Growth trajectories of the human embryonic head and periconceptional maternal conditions.
      ,
      • Koning I.V.
      • Dudink J.
      • Groenenberg I.a.L.
      • Willemsen S.P.
      • Reiss I.K.M.
      • Steegers-Theunissen R.P.M.
      Prenatal cerebellar growth trajectories and the impact of periconceptional maternal and fetal factors.
      ).
      The awareness of the importance of the periconception period is rising, resulting in more published research on this topic. The aim of this review was to provide a systematic and detailed analysis of the literature on maternal lifestyle factors during the periconception period and their impact on fecundity and time to pregnancy, as preconception outcomes, and on miscarriage and embryonic growth as first-trimester pregnancy outcomes.

      Materials and methods

      Systematic review information sources and search strategy

      The literature review was conducted using the ‘Meta-analysis of Observational Studies in Epidemiology (MOOSE)’ guidelines (
      • Stroup D.F.
      • Berlin J.A.
      • Morton S.C.
      • Olkin I.
      • Williamson G.D.
      • Rennie D.
      • Moher D.
      • Becker B.J.
      • Sipe T.A.
      • Thacker S.B.
      Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis of observational studies in epidemiology (moose) group.
      ). Searches were carried out using the electronic databases Embase, Medline, PubMed, Web of Science, Google Scholar and Cochrane databases. The search protocol was designed a priori and registered with the PROSPERO registry (PROSPERO 2016: CRD42016046123). The search strategy consisted of MeSH terms and keywords for lifestyle exposures of interest, including diet, smoking, alcohol, folic acid/vitamin supplement use, physical activity and obesity (Supplementary Table 1). These were combined using the Boolean operator ‘or’.

      Systematic review eligibility criteria and used definitions

      The periconception outcomes, as defined in the International glossary on infertility and fertility care, 2017 (
      • Zegers-Hochschild F.
      • Adamson G.D.
      • Dyer S.
      • Racowsky C.
      • De Mouzon J.
      • Sokol R.
      • Rienzi L.
      • Sunde A.
      • Schmidt L.
      • Cooke I.D.
      • Simpson J.L.
      • Van Der Poel S.
      The international glossary on infertility and fertility care, 2017.
      ), were:
      • (i)
        Fertility: the capacity to establish a clinical pregnancy.
      • (ii)
        Fecundity: the capacity to have a live birth.
      • (iii)
        fecundability: The probability of a pregnancy, during a single menstrual cycle in a woman with adequate exposure to spermatozoa and no contraception, culminating in live birth. Frequently measured as the monthly probability.
      • (iv)
        fecundability ratio: the monthly conception rate among exposed relative to unexposed couples.
      • (v)
        Time to pregnancy (TTP): the time taken to establish a pregnancy, measured in months or in numbers of menstrual cycles.
      • (vi)
        Miscarriage: spontaneous loss of a clinical pregnancy before 22 completed weeks of gestational age. In this review; however, only first-trimester miscarriages (until the 12th week of gestation) were taken into account.
      • (vii)
        Embryonic growth: the process by which the embryo forms and develops. In this review only growth, measured by crown-rump length (CRL) was taken into account. For embryo development the Carnegie stages were used.
      • (viii)
        Yolk sac: a membranous sac attached to the embryo, formed by cells of the hypoblast adjacent to the embryonic disk. In this review the size of the yolk sac was taken into account.
      It was found that the terms ‘fertility’, ‘fecundity’ and ‘fecundability’ were used interchangeably in the literature. Therefore, all terms in the literature search were included and papers excluded that only provided data on birth outcomes. We did not expect to find literature on congenital malformations and placental size in the first trimester, and therefore did not include those keywords in the literature search. The results of all the periconception outcome searches were combined with ‘or’. The results of the separate lifestyle factors and periconception outcome searches were then combined with ‘and’.

      Inclusion and exclusion criteria

      Observational studies of any design that investigated the relationship between maternal lifestyle factors and any of the periconception outcomes of interest were eligible for inclusion in the review. The periconception period was defined as the 14 weeks before and 10 weeks after conception (
      • Steegers-Theunissen R.P.
      • Twigt J.
      • Pestinger V.
      • Sinclair K.D.
      The periconceptional period, reproduction and long-term health of offspring: The importance of one-carbon metabolism.
      ). Articles published between 1990 and February 2017 were included and the search was limited to articles published in English. Animal studies and those focused on IVF/intracytoplasmic sperm injection (ICSI)-treatment, male lifestyle factors, semen parameters, congenital anomalies or teratogenicity were excluded. Articles that only reported outcomes in the second or third trimester or later life, editorials and review articles were also excluded.

      Full text review and data extraction

      Title, abstracts and full-text articles were independently assessed for content, data extraction and analysis. References of included studies were also reviewed. ECO reviewed the titles and abstracts and selected papers for full-text review. Full-text review and data extraction was completed by ECO, JH and BG, with all papers reviewed by at least two people. Data were inputted into a template designed specifically for this review. Differences were resolved by discussion between these three authors. Data extracted included the location, year of publication, study design, setting, study population, sample size, exposures of interest, outcome data, exclusion criteria, statistical analysis, potential confounders, results and conclusion.

      Quality of study and risk of bias

      The ErasmusAGE quality score for systematic reviews was used to assess the quality of studies included in this review (see Supplementary Table 2). This tool is based on previously published scoring systems (
      National Collaborating Centre
      Quality assessment tool for quantitative studies.
      ,
      • Carter P.
      • Gray L.J.
      • Troughton J.
      • Khunti K.
      • Davies M.J.
      Fruit and vegetable intake and incidence of type 2 diabetes mellitus: Systematic review and meta-analysis.
      ) and is composed of five items covering study design, study size, method of measuring exposure and outcome, and analysis. The parameters for these items can be adapted, based on literature and discussion with experts, as relevant for each review. The parameters chosen for this review are shown in Supplementary Table 2. Each item was allocated zero, one or two points giving a total score between zero and ten, with ten representing the highest quality.

      Results

      Results of search and description of studies

      Figure 1 summarizes the process of literature identification and selection of studies. The initial search identified 10,696 records of which 4530 were duplicates. Of the remaining 6166 records, a total of 6012 publications were excluded because they did not fulfil the selection criteria. The full text of 154 papers were read, and 105 papers were excluded, leaving 49 articles for analysis.
      Figure 1.
      Figure 1Prisma flowchart of included and excluded studies.
      The characteristics of the included studies are shown in Table 1. Thirty-five studies were identified as prospective (
      • Laurent S.L.
      • Thompson S.J.
      • Addy C.
      • Garrison C.Z.
      • Moore E.E.
      An epidemiologic study of smoking and primary infertility in women.
      ,
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Windham G.C.
      • Von Behren J.
      • Fenster L.
      • Schaefer C.
      • Swan S.H.
      Moderate maternal alcohol consumption and risk of spontaneous abortion.
      ,
      • Caan B.
      • Quesenberry C.P.
      Differences in fertility associated with caffeinated beverage consumption.
      ,
      • Hakim R.B.
      • Gray R.H.
      • Zacur H.
      Alcohol and caffeine consumption and decreased fertility.
      ,
      • Jensen T.K.
      • Hjollund N.H.I.
      • Henriksen T.B.
      • Scheike T.
      Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy.
      ,
      • Hull M.G.
      • North K.
      • Taylor H.
      • Farrow A.
      • Ford W.C.
      Delayed conception and active and passive smoking. The avon longitudinal study of pregnancy and childhood study team.
      ,
      • Kesmodel U.
      • Wisborg K.
      • Olsen S.F.
      • Henriksen T.B.
      • Secher N.J.
      Moderate alcohol intake in pregnancy and the risk of spontaneous abortion.
      ,
      • Arakawa C.
      • Yoshinaga J.
      • Okamura K.
      • Nakai K.
      • Satoh H.
      Fish consumption and time to pregnancy in japanese women.
      ,
      • Law D.C.G.
      • Maclehose R.F.
      • Longnecker M.P.
      Obesity and time to pregnancy.
      ,
      • Strandberg-Larsen K.
      • Nielsen N.R.
      • Grønbæk M.
      • Andersen P.K.
      • Olsen J.
      • Andersen A.M.N.
      Binge drinking in pregnancy and risk of fetal death.
      ,
      • Bakker R.
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      • Obradov A.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The generation r study.
      ,
      • Mook-Kanamori D.O.
      • Steegers E.a.P.
      • Eilers P.H.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Risk factors and outcomes associated with first-trimester fetal growth restriction.
      ,
      • Prabhu N.
      • Smith N.
      • Campbell D.
      • Craig L.C.
      • Seaton A.
      • Helms P.J.
      • Devereux G.
      • Turner S.W.
      First trimester maternal tobacco smoking habits and fetal growth.
      ,
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.
      • Hatch E.E.
      An internet-based prospective study of body size and time-to-pregnancy.
      ,
      • Hatch E.E.
      • Wise L.A.
      • Mikkelsen E.M.
      • Christensen T.
      • Riis A.H.
      • Sørensen H.T.
      • Rothman K.J.
      Caffeinated beverage and soda consumption and time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sorensen H.T.
      • Riis A.H.
      • Hatch E.E.
      A prospective cohort study of physical activity and time to pregnancy.
      ,
      • Bouwland-Both M.I.
      • Steegers-Theunissen R.P.
      • Vujkovic M.
      • Lesaffre E.M.
      • Mook-Kanamori D.O.
      • Hofman A.
      • Lindemans J.
      • Russcher H.
      • Jaddoe V.W.
      • Steegers E.A.
      A periconceptional energy-rich dietary pattern is associated with early fetal growth: The generation r study.
      ,
      • Van Uitert E.M.
      • Van Der Elst-Otte N.
      • Wilbers J.J.
      • Exalto N.
      • Willemsen S.P.
      • Eilers P.H.
      • Koning A.H.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Periconception maternal characteristics and embryonic growth trajectories: The rotterdam predict study.
      ,
      • Wise L.A.
      • Palmer J.R.
      • Rosenberg L.
      Body size and time-to-pregnancy in black women.
      ,
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Hauser R.
      • Williams P.L.
      • Gillman M.W.
      • Ginsburg E.S.
      • Missmer S.A.
      • Chavarro J.E.
      Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth.
      ,
      • Hahn K.A.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Body size and risk of spontaneous abortion among danish pregnancy planners.
      ,
      • Radin R.G.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Active and passive smoking and fecundability in danish pregnancy planners.
      ,
      • Van Uitert E.M.
      • Van Ginkel S.
      • Willemsen S.P.
      • Lindemans J.
      • Koning A.H.J.
      • Eilers P.H.C.
      • Exalto N.
      • Laven J.S.E.
      • Steegers E.a.P.
      • Steegers-Theunissen R.P.M.
      An optimal periconception maternal folate status for embryonic size: The rotterdam predict study.
      ,
      • Andersen L.B.
      • Jørgensen J.S.
      • Jensen T.K.
      • Dalgård C.
      • Barington T.
      • Nielsen J.
      • Beck-Nielsen S.S.
      • Husby S.
      • Abrahamsen B.
      • Lamont R.F.
      • Christesen H.T.
      Vitamin d insufficiency is associated with increased risk of firsttrimester miscarriage in the odense child cohort.
      ,
      • Hahn K.A.
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and risk of spontaneous abortion.
      ,
      • Cueto H.T.
      • Riis A.H.
      • Hatch E.E.
      • Wise L.A.
      • Rothman K.J.
      • Sorensen H.T.
      • Mikkelsen E.M.
      Folic acid supplementation and fecundability: A danish prospective cohort study.
      ,
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Williams P.L.
      • Toth T.L.
      • Missmer S.A.
      • Chavarro J.E.
      Prepregnancy low to moderate alcohol intake is not associated with risk of spontaneous abortion or stillbirth.
      ,
      • Mckinnon C.J.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Wesselink A.K.
      • Hahn K.A.
      • Wise L.A.
      Body mass index, physical activity and fecundability in a north american preconception cohort study.
      ,
      • Mikkelsen E.M.
      • Riis A.H.
      • Wise L.A.
      • Hatch E.E.
      • Rothman K.J.
      • Cueto H.T.
      • Sørensen H.T.
      Alcohol consumption and fecundability: Prospective danish cohort study.
      ,
      • Sapra K.J.
      • Barr D.B.
      • Maisog J.M.
      • Sundaram R.
      • Buck Louis G.M.
      Time-to-pregnancy associated with couples’ use of tobacco products.
      ,
      • Wesselink A.K.
      • Wise L.A.
      • Rothman K.J.
      • Hahn K.A.
      • Mikkelsen E.M.
      • Mahalingaiah S.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort.
      ,
      • Zhou H.
      • Liu Y.
      • Liu L.
      • Zhang M.
      • Chen X.
      • Qi Y.
      Maternal pre-pregnancy risk factors for miscarriage from a prevention perspective: A cohort study in china.
      ,
      • Parisi F.
      • Rousian M.
      • Koning A.H.
      • Willemsen S.P.
      • Cetin I.
      • Steegers-Theunissen R.P.
      Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the carnegie stages.
      ), six as retrospective cohort studies (
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      ,
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      ,
      • Juhl M.
      • Andersen A.M.N.
      • Grønbæk M.
      • Olsen J.
      Moderate alcohol consumption and waiting time to pregnancy.
      ,
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      ,
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ) and three and five studies as prospective (
      • Ronnenberg A.G.
      • Goldman M.B.
      • Chen D.
      • Aitken I.W.
      • Willett W.C.
      • Selhub J.
      • Xu X.
      Preconception folate and vitamin b(6) status and clinical spontaneous abortion in chinese women.
      ,
      • Lopez-Del Burgo C.
      • Gea A.
      • De Irala J.
      • Martínez-González M.A.
      • Chavarro J.E.
      • Toledo E.
      Alcohol and difficulty conceiving in the sun cohort: A nested case-control study.
      ,
      • Somigliana E.
      • Paffoni A.
      • Lattuada D.
      • Colciaghi B.
      • Filippi F.
      • La Vecchia I.
      • Tirelli A.
      • Baffero G.M.
      • Persico N.
      • Viganò P.
      • Bolis G.
      • Fedele L.
      Serum levels of 25-hydroxyvitamin d and time to natural pregnancy.
      ) and retrospective case–control studies (
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      ,
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      ,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sørensen T.I.A.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      ,
      • Toledo E.
      • Lopez-Del Burgo C.
      • Ruiz-Zambrana A.
      • Donazar M.
      • Navarro-Blasco I.
      • Martinez-Gonzalez M.A.
      • De Irala J.
      Dietary patterns and difficulty conceiving: A nested case-control study.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ), respectively. The search term ‘yolk sac size’ yielded no results, so this parameter is not included in the review.
      Table 1Main characteristics of 49 included studies
      AuthorYearCountryStudy populationStudy designSample sizeExposure(s)Outcome(s)Quality score
      Andersen et al.2015DenmarkOdense child cohort, pregnant women January 2010–December 2012.Prospective cohort study1683Vitamin useMiscarriage5
      Arakawa et al.2006JapanWomen delivering from January 2002–March 2004 in two Japanese hospitalsProspective cohort study180DietTTP4
      Axmon et al.2000SwedenFishermen’s wives from Swedish east and west coast, born from 1945.Retrospective cohort study1335Smoking, DietFertility5
      Axmon et al.2006SwedenRandom sample of women from the general Swedish population, born from 1960 onwards.Retrospective cohort study1557Smoking, alcohol, vitamin use, drug useTTP5
      Bakker et al.2010The NetherlandsThe Generation R study; Dutch women who were resident in the study area and who delivered between April 2002 and January 2006Prospective cohort study1310CaffeineEmbryonic growth6
      Bolúmar et al.1997SpainRandom sample of women 25–44 years, five European countries (Denmark, Germany, Italy, Poland and Spain).Retrospective cohort study3092CaffeineTTP5
      Bouwland-Both et al.2013The NetherlandsThe Generation R study; Dutch women who were resident in the study area and who delivered between April 2002 and January 2006Prospective cohort study847DietEmbryonic growth5
      Caan and Quesenberry1998USAVolunteer members of the Kaiser Permanente Medical Programme who were trying to conceive (for max 3 months before entering the study).Prospective cohort study187CaffeineFecundity4
      Cnattingius et al.2000SwedenBetween 1996–1998, Uppsala Sweden, women with spontaneous abortion who presented at the department at 6–12 weeks and had a positive pregnancy testRetrospective case-control study1448Smoking, caffeineMiscarriage6
      Cueto et al.2016DenmarkThe Danish pregnancy planning study (Snart Gravid)Prospective cohort study3895Folic acid, vitamin useFecundity5
      Feodor Nilsson et al.2014DenmarkDanish national birth cohort. All pregnancies with information on risk factors for miscarriage.Retrospective cohort study88,373Alcohol, caffeine, physical activityMiscarriage6
      Florack et al.1994The NetherlandsBetween June 1987- Jan 1989, female workers 18–39 years, working in non-medical functions at Dutch Hospitals, planning pregnancyProspective cohort study259Smoking, alcohol, caffeineTTP5
      Gaskins et al.2014bUSAFemale nurses 24–44 years in the Nurses’ Health Study II. With no history of pregnancy loss in 1991 and reported at least one pregnancy during 1992–2009Prospective cohort study11,072Folic acidMiscarriage6
      Gaskins et al.2016USAFemale nurses 24–44 years in the Nurses’ Health Study II. With no history of pregnancy loss in 1991 and reported at least one pregnancy during 1992–2009Prospective cohort study27,580AlcoholMiscarriage5
      Hahn et al.2015DenmarkSnart-Gravid study; Danish women 18–40 years, resident of Denmark, stable relationship with male partner, not using fertility treatment, trying to become pregnant.Prospective cohort study5132CaffeineMiscarriage6
      Hahn et al.2014DenmarkSnart-Gravid study; Danish women 18–40 years, resident of Denmark, stable relationship with male partner, not using fertility treatment, trying to become pregnant.Prospective cohort study5132BMIMiscarriage6
      Hakim et al.1998USAWomen reproductive age, no contraceptive use, not sterilized.Prospective cohort study98Alcohol, CaffeineFecundity5
      Hatch et al.2012DenmarkDanish, 18–40 years, male partner, trying to conceive <12 monthsProspective cohort study3628CaffeineTTP5
      Hull et al.2000United KingdomCouples resident in the defined geographic area administered by the Avon Health Authority and if the expected date of birth was between April 1991–December 1992Prospective cohort study12,106SmokingTTP6
      Jensen et al.1998DenmarkDanish couples, 20–35 years, no children, trying to conceive for the first timeProspective cohort study423AlcoholFecundity4
      Juhl et al.2003DenmarkPregnant women within the first 24 weeks of pregnancy recruited to the Danish National Birth Cohort in 1997–2000.Retrospective cohort study29,844AlcoholTTP5
      Juhl et al.2001DenmarkPregnant women within the first 24 weeks of pregnancy recruited to the Danish National Birth Cohort in 1997–2000.Retrospective cohort study29,844AlcoholTTP5
      Kesmodel et al.2002DenmarkWomen attending routine antenatal care at Aarhus University Hospital Denmark from 1989–1996Prospective cohort study18,226AlcoholMiscarriage5
      Laurent et al.1992USA20- 54 years old women who were randomly selected to serve as the control group of the Cancer and Steroid Hormone Study coordinated by the Reproductive Health Division of the Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control, USAProspective cohort study2714SmokingFertility5
      Law et al.2007USAPregnant women enrolled in the Collaborative Perinatal Project at 12 study centers across the United StatesProspective cohort study7327Smoking, BMITTP5
      Lopez-del Burgo et al.2015SpainUniversity graduates from SpainProspective case-control study1372AlcoholFertility7
      McKinnon et al.2016USA and CanadaWomen 21–45 years, not using contraception, no fertility treatment, stable relationship with a man, planning a pregnancy, not pregnant. PRESTO study.Prospective cohort study1274BMI, physical activityTTP6
      Mikkelsen et al.2016DenmarkWomen 18–40 years, stable relationship with a man, trying to conceive, no fertility treatment. Snart Gravid.Prospective cohort study4210AlcoholTTP6
      Mook-Kanamori et al.2010The NetherlandsGeneration R study, mothers enrolled 2001–20015Prospective cohort study1631Smoking, alcohol, folic acid, BMIEmbryonic growth8
      Mutsaerts et al.2012The NetherlandsPregnant women in Drenthe with the expected date of delivery between April 2006 and April 2007Prospective cohort study1924Smoking, alcohol, vitamin use, BMI, physical activityTTP5
      Parazzini et al.1991ItalyJan 1987–1988, cases: women ≥2 unexplained miscarriages in first 3 months of gestation, without full-term pregnancies. Controls: women admitted for normal delivery.Retrospective case-control study270Smoking, alcohol, caffeine, BMIMiscarriage5
      Parisi et al.2017The NetherlandsPredict study. 2010–2014 women with singleton pregnancies.Prospective cohort study234Vitamin useEmbryonic growth5
      Prabhu et al.2010United KingdomMothers attending a first trimester dating ultrasound scanProspective cohort study903SmokingEmbryonic growth7
      Radin et al.2014DenmarkFemale pregnancy planners aged 18–40 yearsProspective cohort study3298SmokingFecundity3
      Ramlau-Hansen et al.2007DenmarkCouples from Danish National Birth with pregnancy(ies) between 1996 -2002Retrospective case-control study47,835BMITTP4
      Ronnenberg et al.2002ChinaFemale textile workers in Anqing, ChinaProspective case-control study458Folic acid, vitamin useMiscarriage5
      Sapra et al.2016USALIFE study 2005–2009. Couples discontinuing contraception for becoming pregnant or were off contraception for maximum 2 months. 18–40 years, cycle length 21–42 days, not received injectable contraception in the past year.Prospective cohort study501SmokingTTP6
      Somigliana et al.2016ItalyPregnant women undergoing first trimester screening for aneuploidies. Cases: seeking pregnancy 12–24 months. Controls: age-matched conceiving in less than 1 yearProspective case-control study146DietTTP5
      Strandberg-Larsen et al.2008DenmarkDanish national birth cohort, women enrolled between 1996 and 2002, interview done mid-pregnancyProspective cohort study89,201AlcoholMiscarriage7
      Toledo et al.2011SpainNested case control study selected from a prospective cohort of university graduates.Retrospective case-control study2154DietFertility5
      van Uitert et al.2013bThe NetherlandsRotterdam Predict study, an ongoing prospective periconception cohort study that is part of the preconception and antenatal care at the outpatient clinics of the Erasmus MC, University Medical Center Rotterdam. All women who were at least 18 years old with ongoing intrauterine singleton pregnancies of 6–8 weeks of gestation were eligible for participation and recruited in 2009 and 2010. Spontaneously conceived, plus intrauterine inseminationProspective cohort study87Smoking, alcohol, folic acid, BMIEmbryonic growth6
      van Uitert et al.2014The NetherlandsSingleton pregnancies recruited in 2009–2010. Predict Study. 77 patients, 440 ultrasoundsProspective cohort study440Folic acidEmbryonic growth5
      Wesselink et al.2016USA and CanadaWomen 21–45 years, not using contraception, no fertility treatment, stable relationship with a man, planning a pregnancy, not pregnant. PRESTO study.Prospective cohort study1318CaffeineTTP6
      Windham et al.1997USAWomen were recruited during 1990–1991 from a large pre-paid health plan (Kaiser Permanente Medical Care Programme) in three geographical areas in California, they were informed of the study when they called to make their first antenatal appointment.Prospective cohort study5307AlcoholMiscarriage5
      Wise et al.2010DenmarkWomen were part of the the ‘‘Snart Gravid’’ study, an internet-based prospective cohort study of women planning a pregnancy in Denmark. Recruitment began in June 2007. Eligible women were aged 18–40, residents of Denmark, in a stable relationship with a male partner, and not receiving any type of fertility treatment.Prospective cohort study1410BMITTP5
      Wise et al.2012DenmarkWomen were part of the the ‘‘Snart Gravid’’ study, an internet-based prospective cohort study of women planning a pregnancy in Denmark. Recruitment began in June 2007. Eligible women were aged 18–40, residents of Denmark, in a stable relationship with a male partner, and not receiving any type of fertility treatment.Prospective cohort study3027Physical activityTTP7
      Wise et al.2013USAWomen were part of the Black Women’s Health Survey, a prospective cohort study of 59 000 African-American women aged 21 to 69 at entry in 1995. This analysis is of the 2011 follow up, where 16462 respondedProspective cohort study2022BMITTP5
      Xu et al.2014ChinaCases–hospitalized in one of 3 hospitals in Zhengzhou City for an early miscarriage (<13 weeks) from Oct 2009-Dec 2012. 620 cases randomly selected from 3277, 1240 age matched controls, post 13 weeks, randomly selected from the same period from 21,491 outpatients attending routine prenatal care.Retrospective case-control study1860Smoking, alcohol, diet, vitamin use, BMI, physical activityMiscarriage6
      Zhou et al.2016China2013–2014 in Anhui China. 18–40 years, residents of Anhui, married, not using fertility treatment, trying to become pregnant during the next six months.Prospective cohort study2940BMIMiscarriage5
      Note: BMI = Body mass index; TTP = Time to pregnancy.

      Fecundity or fertility

      Nine studies reported associations between maternal lifestyle factors and fecundity or fertility (
      • Laurent S.L.
      • Thompson S.J.
      • Addy C.
      • Garrison C.Z.
      • Moore E.E.
      An epidemiologic study of smoking and primary infertility in women.
      ,
      • Caan B.
      • Quesenberry C.P.
      Differences in fertility associated with caffeinated beverage consumption.
      ,
      • Hakim R.B.
      • Gray R.H.
      • Zacur H.
      Alcohol and caffeine consumption and decreased fertility.
      ,
      • Jensen T.K.
      • Hjollund N.H.I.
      • Henriksen T.B.
      • Scheike T.
      Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy.
      ,
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      ,
      • Toledo E.
      • Lopez-Del Burgo C.
      • Ruiz-Zambrana A.
      • Donazar M.
      • Navarro-Blasco I.
      • Martinez-Gonzalez M.A.
      • De Irala J.
      Dietary patterns and difficulty conceiving: A nested case-control study.
      ,
      • Radin R.G.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Active and passive smoking and fecundability in danish pregnancy planners.
      ,
      • Lopez-Del Burgo C.
      • Gea A.
      • De Irala J.
      • Martínez-González M.A.
      • Chavarro J.E.
      • Toledo E.
      Alcohol and difficulty conceiving in the sun cohort: A nested case-control study.
      ,
      • Cueto H.T.
      • Riis A.H.
      • Hatch E.E.
      • Wise L.A.
      • Rothman K.J.
      • Sorensen H.T.
      • Mikkelsen E.M.
      Folic acid supplementation and fecundability: A danish prospective cohort study.
      ) (Table 2). The impact of smoking was evaluated in three studies, all showing poorer fecundity ratios with higher levels of smoking (
      • Laurent S.L.
      • Thompson S.J.
      • Addy C.
      • Garrison C.Z.
      • Moore E.E.
      An epidemiologic study of smoking and primary infertility in women.
      ,
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      ,
      • Radin R.G.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Active and passive smoking and fecundability in danish pregnancy planners.
      ). The association between alcohol and fecundity was evaluated in three studies (
      • Hakim R.B.
      • Gray R.H.
      • Zacur H.
      Alcohol and caffeine consumption and decreased fertility.
      ,
      • Jensen T.K.
      • Hjollund N.H.I.
      • Henriksen T.B.
      • Scheike T.
      Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy.
      ,
      • Lopez-Del Burgo C.
      • Gea A.
      • De Irala J.
      • Martínez-González M.A.
      • Chavarro J.E.
      • Toledo E.
      Alcohol and difficulty conceiving in the sun cohort: A nested case-control study.
      ) and showed lower conception rates with the consumption of alcohol. There was no significant relationship between caffeine consumption and conception rates in the two studies investigating this outcome (
      • Caan B.
      • Quesenberry C.P.
      Differences in fertility associated with caffeinated beverage consumption.
      ,
      • Hakim R.B.
      • Gray R.H.
      • Zacur H.
      Alcohol and caffeine consumption and decreased fertility.
      ). The association of diet was evaluated in two studies (
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      ,
      • Toledo E.
      • Lopez-Del Burgo C.
      • Ruiz-Zambrana A.
      • Donazar M.
      • Navarro-Blasco I.
      • Martinez-Gonzalez M.A.
      • De Irala J.
      Dietary patterns and difficulty conceiving: A nested case-control study.
      ).
      • Toledo E.
      • Lopez-Del Burgo C.
      • Ruiz-Zambrana A.
      • Donazar M.
      • Navarro-Blasco I.
      • Martinez-Gonzalez M.A.
      • De Irala J.
      Dietary patterns and difficulty conceiving: A nested case-control study.
      found that stronger adherence to the Mediterranean dietary pattern was associated with significantly lower odds of consulting a physician because of failure to conceive. The possible negative association of consuming fish from the Baltic sea contaminated with persistent organochlorine compounds was evaluated by
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      . This study found a significantly lower pregnancy success rate ratio in women living in the east coast of Sweden, where higher blood concentrations of persistent organochlorine compounds have been found, compared with women living in west coast. Folic acid and multivitamin supplement use were both found to be associated with increased fecundity (
      • Cueto H.T.
      • Riis A.H.
      • Hatch E.E.
      • Wise L.A.
      • Rothman K.J.
      • Sorensen H.T.
      • Mikkelsen E.M.
      Folic acid supplementation and fecundability: A danish prospective cohort study.
      ).
      Table 2Description and summary of data for nine studies that investigated associations between lifestyle factors and fecundity or fertility
      AuthorExposureExposure descriptionOutcome definitionOR (95% CI)
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      DietConsuming contaminated fish from Baltic seaSuccess rate ratio0.86 (0.75; 0.99)
      SmokingSmoking ≥10 cigarettes/day0.68 (0.51; 0.91)
      • Caan B.
      • Quesenberry C.P.
      Differences in fertility associated with caffeinated beverage consumption.
      CaffeineIntake of caffeine >106.8 mg/dayRelative Odds of becoming pregnant1.09 (0.63; 1.89)
      • Cueto H.T.
      • Riis A.H.
      • Hatch E.E.
      • Wise L.A.
      • Rothman K.J.
      • Sorensen H.T.
      • Mikkelsen E.M.
      Folic acid supplementation and fecundability: A danish prospective cohort study.
      Folic acidUse of folic acid supplement in generalFecundability ratio; the monthly conception rate among exposed relative to unexposed1.15 (1.06; 1.25)
      Use of folic acid exclusively1.15 (1.00; 1.31)
      Vitamin useUse of multivitamin supplements exclusively1.20 (1.08; 1.32)
      • Hakim R.B.
      • Gray R.H.
      • Zacur H.
      Alcohol and caffeine consumption and decreased fertility.
      AlcoholConsuming <12 grams of alcohol/weekRelative Odds of conception0.43 (0.25; 0.76)
      Consuming 13–90 grams of alcohol/week0.40 (0.21; 0.77)
      CaffeineIntake of caffeine ≥301 mg/day0.83 (0.34; 2.01)
      • Jensen T.K.
      • Hjollund N.H.I.
      • Henriksen T.B.
      • Scheike T.
      Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy.
      AlcoholConsuming 1–5 units of alcohol/weekOdds of conception0.61 (0.40; 0.93)
      Consuming 6–10 units of alcohol/week0.55 (0.36; 0.85)
      Consuming 11–15 units of alcohol/week0.34 (0.22; 0.52)
      • Laurent S.L.
      • Thompson S.J.
      • Addy C.
      • Garrison C.Z.
      • Moore E.E.
      An epidemiologic study of smoking and primary infertility in women.
      SmokingSmoking ≥20 cigarettes/dayOdds of primary infertility1.36 (1.14; 1.61)
      • Lopez-Del Burgo C.
      • Gea A.
      • De Irala J.
      • Martínez-González M.A.
      • Chavarro J.E.
      • Toledo E.
      Alcohol and difficulty conceiving in the sun cohort: A nested case-control study.
      AlcoholConsumption of alcohol ≥5 times/weekOdds ratio for presenting with difficulty becoming pregnant1.04 (0.72; 1.51)
      • Radin R.G.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Active and passive smoking and fecundability in danish pregnancy planners.
      SmokingCurrent regular smokerFecundability ratio; the monthly conception rate among exposed relative to unexposed0.89 (0.77; 1.03)
      Smoking for ≥10 years0.85 (0.72; 1.00)
      • Toledo E.
      • Lopez-Del Burgo C.
      • Ruiz-Zambrana A.
      • Donazar M.
      • Navarro-Blasco I.
      • Martinez-Gonzalez M.A.
      • De Irala J.
      Dietary patterns and difficulty conceiving: A nested case-control study.
      DietHigh adherence to Mediterrean dietary patternOdds ratio for presenting with difficulty becoming pregnant0.56 (0.35; 0.90)
      OR (95% CI) = odds ratio 95% confidence interval.

      Time to pregnancy

      The association between maternal lifestyle factors and time to pregnancy was evaluated in 19 studies (
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      ,
      • Hull M.G.
      • North K.
      • Taylor H.
      • Farrow A.
      • Ford W.C.
      Delayed conception and active and passive smoking. The avon longitudinal study of pregnancy and childhood study team.
      ,
      • Juhl M.
      • Andersen A.M.N.
      • Grønbæk M.
      • Olsen J.
      Moderate alcohol consumption and waiting time to pregnancy.
      ,
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      ,
      • Arakawa C.
      • Yoshinaga J.
      • Okamura K.
      • Nakai K.
      • Satoh H.
      Fish consumption and time to pregnancy in japanese women.
      ,
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Law D.C.G.
      • Maclehose R.F.
      • Longnecker M.P.
      Obesity and time to pregnancy.
      ,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sørensen T.I.A.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      ,
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.
      • Hatch E.E.
      An internet-based prospective study of body size and time-to-pregnancy.
      ,
      • Hatch E.E.
      • Wise L.A.
      • Mikkelsen E.M.
      • Christensen T.
      • Riis A.H.
      • Sørensen H.T.
      • Rothman K.J.
      Caffeinated beverage and soda consumption and time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sorensen H.T.
      • Riis A.H.
      • Hatch E.E.
      A prospective cohort study of physical activity and time to pregnancy.
      ,
      • Wise L.A.
      • Palmer J.R.
      • Rosenberg L.
      Body size and time-to-pregnancy in black women.
      ,
      • Mckinnon C.J.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Wesselink A.K.
      • Hahn K.A.
      • Wise L.A.
      Body mass index, physical activity and fecundability in a north american preconception cohort study.
      ,
      • Mikkelsen E.M.
      • Riis A.H.
      • Wise L.A.
      • Hatch E.E.
      • Rothman K.J.
      • Cueto H.T.
      • Sørensen H.T.
      Alcohol consumption and fecundability: Prospective danish cohort study.
      ,
      • Sapra K.J.
      • Barr D.B.
      • Maisog J.M.
      • Sundaram R.
      • Buck Louis G.M.
      Time-to-pregnancy associated with couples’ use of tobacco products.
      ,
      • Somigliana E.
      • Paffoni A.
      • Lattuada D.
      • Colciaghi B.
      • Filippi F.
      • La Vecchia I.
      • Tirelli A.
      • Baffero G.M.
      • Persico N.
      • Viganò P.
      • Bolis G.
      • Fedele L.
      Serum levels of 25-hydroxyvitamin d and time to natural pregnancy.
      ,
      • Wesselink A.K.
      • Wise L.A.
      • Rothman K.J.
      • Hahn K.A.
      • Mikkelsen E.M.
      • Mahalingaiah S.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort.
      ) (Table 3). Six studies evaluated the impact of smoking on time to pregnancy (
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Hull M.G.
      • North K.
      • Taylor H.
      • Farrow A.
      • Ford W.C.
      Delayed conception and active and passive smoking. The avon longitudinal study of pregnancy and childhood study team.
      ,
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Law D.C.G.
      • Maclehose R.F.
      • Longnecker M.P.
      Obesity and time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Sapra K.J.
      • Barr D.B.
      • Maisog J.M.
      • Sundaram R.
      • Buck Louis G.M.
      Time-to-pregnancy associated with couples’ use of tobacco products.
      ), all showing a prolonged time to pregnancy among smokers.
      Table 3Description and summary of data for 19 studies that investigated associations between lifestyle factors and time to pregnancy
      AuthorExposureExposure descriptionOutcome definitionOR (95% CI)Other
      • Arakawa C.
      • Yoshinaga J.
      • Okamura K.
      • Nakai K.
      • Satoh H.
      Fish consumption and time to pregnancy in japanese women.
      DietGeometric means of mercury concentrations in hairTime to pregnancy in months (0–12 months vs >12 months)2.01 μg/g vs 1.97 μg/g, P-value NS
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      AlcoholConsumption of alcoholFecundability ratio; the monthly conception rate among exposed relative to unexposed0.83 (0.72; 0.95)
      SmokingSmoking cigarettes daily0.93 (0.79; 1.08)
      Vitamin useUse of vitamin supplements1.04 (0.89; 1.22)
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      CaffeineNone vs ≥5 cups of coffee/dayWaiting time to first pregnancy (ref category: 6,5 months)8.2 months, P = 0.003
      none ≥501 mg/day8.9 months, P = 0.001
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      Alcohol>10 units of alcohol/weekFecundability ratio; the monthly conception rate among exposed relative to unexposed1.2 (0.7; 2.3)
      Caffeine3–7 cups of caffeine drinks/day vs <3 cups1.8 (1.1; 3.1)
      Smoking>10 cigarettes/day0.8 (0.5; 1.3)
      • Hatch E.E.
      • Wise L.A.
      • Mikkelsen E.M.
      • Christensen T.
      • Riis A.H.
      • Sørensen H.T.
      • Rothman K.J.
      Caffeinated beverage and soda consumption and time to pregnancy.
      Caffeine≥300 mg caffeine/dayFecundability ratio; the monthly conception rate among exposed relative to unexposed1.04 (0.90; 1.21)
      • Hull M.G.
      • North K.
      • Taylor H.
      • Farrow A.
      • Ford W.C.
      Delayed conception and active and passive smoking. The avon longitudinal study of pregnancy and childhood study team.
      Smoking15–19 cigarettes daily, conceive within 6 monthsOdds ratio of taking ≥12 months to conceive1.47 (1.15; 1.87)
      15–19 cigarettes daily, conceive within 12 month1.99 (1.48; 2.69)
      • Juhl M.
      • Andersen A.M.N.
      • Grønbæk M.
      • Olsen J.
      Moderate alcohol consumption and waiting time to pregnancy.
      Alcohol7.5–14 units of alcohol/week, conceive after 5 monthsOdds ratio for an increasing waiting time to pregnancy0.84 (0.76; 0.93)
      7.5–14 units of alcohol/week, conceive after 12 months0.86 (0.76; 0.98)
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      Alcohol>7 units of wine/weekOdds ratio for an increasing waiting time to pregnancy0.87 (0.78; 0.99)
      • Law D.C.G.
      • Maclehose R.F.
      • Longnecker M.P.
      Obesity and time to pregnancy.
      BMIBMI ≥30.0 kg/m2Fecundability ratio; the monthly conception rate among exposed relative to unexposed0.72 (0.63; 0.83)
      SmokingAmong smokers,
      BMI ≤18.5 kg/m20.89 (0.78; 1.01)
      BMI 25.0–29.9 kg/m20.97 (0.85; 1.11)
      BMI ≥30.0 kg/m20.83 (0.68; 1.02)
      • Mckinnon C.J.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Wesselink A.K.
      • Hahn K.A.
      • Wise L.A.
      Body mass index, physical activity and fecundability in a north american preconception cohort study.
      BMIBMI 40–44 kg/m2Fecundability ratio; the monthly conception rate among exposed relative to unexposed0.61 (0.42; 0.88)
      BMI ≥45 kg/m20.42 (0.23; 0.76)
      Physical activity≥5 hrs/week vigorous activity1.11 (0.96; 1.28)
      • Mikkelsen E.M.
      • Riis A.H.
      • Wise L.A.
      • Hatch E.E.
      • Rothman K.J.
      • Cueto H.T.
      • Sørensen H.T.
      Alcohol consumption and fecundability: Prospective danish cohort study.
      Alcohol≥14 units of alcohol/weekFecundability ratio; the monthly conception rate among exposed relative to unexposed0.82 (0.60; 1.12)
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      Alcohol>7 units of alcohol/weekRatio of the ‘hazard’ of becoming pregnant0.71 (0.53; 0.96)
      BMIBMI ≥30 kg/m20.87 (0.76; 1.01)
      Physical activity≥4 times/week1.04 (0.92; 1.18)
      Smoking≥10 cigarettes/day0.96 (0.84; 1.10)
      Vitamin useUse of vitamin supplements0.59 (0.86; 1.05)
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sørensen T.I.A.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      BMIBMI 25.0–29.9 kg/m2Odds ratio of taking >12 months to conceive1.27 (1.18; 1.36)

      1.78 (1.63; 1.95)
      BMI ≥30 kg/m2
      • Sapra K.J.
      • Barr D.B.
      • Maisog J.M.
      • Sundaram R.
      • Buck Louis G.M.
      Time-to-pregnancy associated with couples’ use of tobacco products.
      SmokingUse of cigarettesFecundability ratio; the monthly conception rate among exposed relative to unexposed0.53 (0.33; 0.85)
      • Somigliana E.
      • Paffoni A.
      • Lattuada D.
      • Colciaghi B.
      • Filippi F.
      • La Vecchia I.
      • Tirelli A.
      • Baffero G.M.
      • Persico N.
      • Viganò P.
      • Bolis G.
      • Fedele L.
      Serum levels of 25-hydroxyvitamin d and time to natural pregnancy.
      DietConcentration of 25(OH)D <20 ng/mlOdds ratio of longer time to pregnancy0.84 (0.42; 1.66)
      • Wesselink A.K.
      • Wise L.A.
      • Rothman K.J.
      • Hahn K.A.
      • Mikkelsen E.M.
      • Mahalingaiah S.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort.
      Caffeine≥300 mg caffeine/dayFecundability ratio; the monthly conception rate among exposed relative to unexposed1.15 (0.90; 1.48)
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.
      • Hatch E.E.
      An internet-based prospective study of body size and time-to-pregnancy.
      BMIBMI 25–29 kg/m2Fecundability ratio; the monthly conception rate among exposed relative to unexposed0.72 (0.58; 0.90)
      BMI 30–34 kg/m20.60 (0.42; 0.85)
      BMI ≥35 kg/m20.48 (0.31; 0.74)
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sorensen H.T.
      • Riis A.H.
      • Hatch E.E.
      A prospective cohort study of physical activity and time to pregnancy.
      Physical activity≥5 hrs/week vigorous activityFecundability ratio; the monthly conception rate among exposed relative to unexposed0.68 (0.54; 0.85)
      ≥5 hrs/week moderate activity1.18 (0.98; 1.43)
      • Wise L.A.
      • Palmer J.R.
      • Rosenberg L.
      Body size and time-to-pregnancy in black women.
      BMIBMI ≥35 kg/m2Fecundability ratio; the monthly conception rate among exposed relative to unexposed0.73 (0.61; 0.87)
      Note: BMI = body mass index; NS = not statistically significant; OR (95% CI) = Odds ratio 95% Confidence interval.
      The possible association of alcohol consumption and time to pregnancy was also reported in six studies (
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Juhl M.
      • Andersen A.M.N.
      • Grønbæk M.
      • Olsen J.
      Moderate alcohol consumption and waiting time to pregnancy.
      ,
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      ,
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Mikkelsen E.M.
      • Riis A.H.
      • Wise L.A.
      • Hatch E.E.
      • Rothman K.J.
      • Cueto H.T.
      • Sørensen H.T.
      Alcohol consumption and fecundability: Prospective danish cohort study.
      ), but showed inconsistent results.
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      reported that women consuming >7 units of alcohol per week have a significantly longer time to pregnancy compared with women consuming less units per week, the same accounts for
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      , as they report a significant prolonged time to pregnancy for women consuming alcohol compared with women not consuming alcohol, whereas
      • Juhl M.
      • Andersen A.M.N.
      • Grønbæk M.
      • Olsen J.
      Moderate alcohol consumption and waiting time to pregnancy.
      ,
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      ), reported a slightly shorter time to pregnancy for women consuming alcohol weekly compared with drinking no alcohol.
      The association of consumption of caffeine and time to pregnancy was addressed in four studies (
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      ,
      • Hatch E.E.
      • Wise L.A.
      • Mikkelsen E.M.
      • Christensen T.
      • Riis A.H.
      • Sørensen H.T.
      • Rothman K.J.
      Caffeinated beverage and soda consumption and time to pregnancy.
      ,
      • Wesselink A.K.
      • Wise L.A.
      • Rothman K.J.
      • Hahn K.A.
      • Mikkelsen E.M.
      • Mahalingaiah S.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort.
      ). Significant increases in time to pregnancy were found for those women drinking ≥501 mg caffeine per day (
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      ). By contrast,
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      showed a significant decrease when drinking 3–7 cups of caffeine drinks per day compared with drinking <3 cups.
      The association of diet and vitamin supplement use was evaluated in four studies; however, none of the results were statistically significant (
      • Arakawa C.
      • Yoshinaga J.
      • Okamura K.
      • Nakai K.
      • Satoh H.
      Fish consumption and time to pregnancy in japanese women.
      ,
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Somigliana E.
      • Paffoni A.
      • Lattuada D.
      • Colciaghi B.
      • Filippi F.
      • La Vecchia I.
      • Tirelli A.
      • Baffero G.M.
      • Persico N.
      • Viganò P.
      • Bolis G.
      • Fedele L.
      Serum levels of 25-hydroxyvitamin d and time to natural pregnancy.
      ). Overall, there was a suggestion of shorter time to pregnancy when using vitamin supplements. By contrast, vitamin D deficiency does not seem to prolong the time to pregnancy.
      Six studies reported on the association of BMI and time to pregnancy, showing consistently prolonged time to pregnancy in overweight or obese women (
      • Law D.C.G.
      • Maclehose R.F.
      • Longnecker M.P.
      Obesity and time to pregnancy.
      ,
      • Ramlau-Hansen C.H.
      • Thulstrup A.M.
      • Nohr E.A.
      • Bonde J.P.
      • Sørensen T.I.A.
      • Olsen J.
      Subfecundity in overweight and obese couples.
      ,
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.
      • Hatch E.E.
      An internet-based prospective study of body size and time-to-pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Wise L.A.
      • Palmer J.R.
      • Rosenberg L.
      Body size and time-to-pregnancy in black women.
      ,
      • Mckinnon C.J.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Wesselink A.K.
      • Hahn K.A.
      • Wise L.A.
      Body mass index, physical activity and fecundability in a north american preconception cohort study.
      ). The association of physical activity was evaluated in three studies (
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ,
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sorensen H.T.
      • Riis A.H.
      • Hatch E.E.
      A prospective cohort study of physical activity and time to pregnancy.
      ,
      • Mckinnon C.J.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Wesselink A.K.
      • Hahn K.A.
      • Wise L.A.
      Body mass index, physical activity and fecundability in a north american preconception cohort study.
      ). In one study, vigorous physical activity was found to be associated with a prolonged time to pregnancy (
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sorensen H.T.
      • Riis A.H.
      • Hatch E.E.
      A prospective cohort study of physical activity and time to pregnancy.
      ), in all other studies no association with time to pregnancy was found.

      Miscarriage

      Fourteen studies evaluated the association between maternal lifestyle factors and first trimester miscarriage (
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      ,
      • Windham G.C.
      • Von Behren J.
      • Fenster L.
      • Schaefer C.
      • Swan S.H.
      Moderate maternal alcohol consumption and risk of spontaneous abortion.
      ,
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      ,
      • Kesmodel U.
      • Wisborg K.
      • Olsen S.F.
      • Henriksen T.B.
      • Secher N.J.
      Moderate alcohol intake in pregnancy and the risk of spontaneous abortion.
      ,
      • Ronnenberg A.G.
      • Goldman M.B.
      • Chen D.
      • Aitken I.W.
      • Willett W.C.
      • Selhub J.
      • Xu X.
      Preconception folate and vitamin b(6) status and clinical spontaneous abortion in chinese women.
      ,
      • Strandberg-Larsen K.
      • Nielsen N.R.
      • Grønbæk M.
      • Andersen P.K.
      • Olsen J.
      • Andersen A.M.N.
      Binge drinking in pregnancy and risk of fetal death.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ,
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Hauser R.
      • Williams P.L.
      • Gillman M.W.
      • Ginsburg E.S.
      • Missmer S.A.
      • Chavarro J.E.
      Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth.
      ,
      • Hahn K.A.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Body size and risk of spontaneous abortion among danish pregnancy planners.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ,
      • Andersen L.B.
      • Jørgensen J.S.
      • Jensen T.K.
      • Dalgård C.
      • Barington T.
      • Nielsen J.
      • Beck-Nielsen S.S.
      • Husby S.
      • Abrahamsen B.
      • Lamont R.F.
      • Christesen H.T.
      Vitamin d insufficiency is associated with increased risk of firsttrimester miscarriage in the odense child cohort.
      ,
      • Hahn K.A.
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and risk of spontaneous abortion.
      ,
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Williams P.L.
      • Toth T.L.
      • Missmer S.A.
      • Chavarro J.E.
      Prepregnancy low to moderate alcohol intake is not associated with risk of spontaneous abortion or stillbirth.
      ,
      • Zhou H.
      • Liu Y.
      • Liu L.
      • Zhang M.
      • Chen X.
      • Qi Y.
      Maternal pre-pregnancy risk factors for miscarriage from a prevention perspective: A cohort study in china.
      ) (Table 4). The impact of smoking was evaluated in three studies (
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      ,
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ) all showing a statistically significant increase in risk of miscarriage in smokers.
      Table 4Description and summary of data for 14 studies that investigated associations between lifestyle factors and first-trimester miscarriage
      AuthorExposureExposure descriptionOutcome definitionOR (95% CI)
      • Andersen L.B.
      • Jørgensen J.S.
      • Jensen T.K.
      • Dalgård C.
      • Barington T.
      • Nielsen J.
      • Beck-Nielsen S.S.
      • Husby S.
      • Abrahamsen B.
      • Lamont R.F.
      • Christesen H.T.
      Vitamin d insufficiency is associated with increased risk of firsttrimester miscarriage in the odense child cohort.
      Vitamin useConcentration of 25(OH)D of <50 vs ≥50 nmol/lHazard ratio for miscarriage2.50 (1.10; 5.69)
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      CaffeineAmong non-smokers;Odds ratios for miscarriage
      100–299 mg of caffeine/day1.8 (1.2; 2.7)
      300–499 mg of caffeine/day2.7 (1.7; 4.5)
      ≥500 mg of caffeine day4.1 (2.1; 8.1)
      SmokingSmokers compared with non-smokers1.5 (1.1; 2.1)
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      Alcohol>4 alcoholic drinks per weekHazard ratio for miscarriage2.81 (2.25; 3.50)
      Caffeinedrinking 0,5–7,5 cups of coffee/day1.28 (1.14; 1.42)
      drinking >8 cups of coffee/day2.23 (1.79; 2.78)
      Physical activity61–120 min/week regular physical activity1.83 (1.57; 2.13)
      121–180 min/week2.06 (1.72; 2.47)
      181–300 min/week2.47 (2.07; 2.93)
      >300 min/week3.29 (2.71; 3.99)
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Hauser R.
      • Williams P.L.
      • Gillman M.W.
      • Ginsburg E.S.
      • Missmer S.A.
      • Chavarro J.E.
      Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth.
      Folic acidFolate supplement use ≥1000 mcg/day, fetal loss <8 wksRelative risk of miscarriage0.79 (0.64; 0.97)
      Folate supplement use ≥1000 mcg/day, fetal loss 8–11 wks0.76 (0.63; 0.92)
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Williams P.L.
      • Toth T.L.
      • Missmer S.A.
      • Chavarro J.E.
      Prepregnancy low to moderate alcohol intake is not associated with risk of spontaneous abortion or stillbirth.
      Alcohol>10 grams of alcohol/day, miscarriage <8 weeks >10 grams of alcohol/day, miscarriage 8–11 weeksRelative risk of miscarriage1.09 (0.92; 1.30)
      1.02 (0.86; 1.22)
      • Hahn K.A.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Body size and risk of spontaneous abortion among danish pregnancy planners.
      BMIBMI ≥30 kg/m2Hazard ratio for miscarriage1.34 (1.01; 1.77)
      • Hahn K.A.
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and risk of spontaneous abortion.
      Caffeine>300 mg caffeine per day (preconceptionally)Hazard ratio for miscarriage0.93 (0.72; 1.22)
      • Kesmodel U.
      • Wisborg K.
      • Olsen S.F.
      • Henriksen T.B.
      • Secher N.J.
      Moderate alcohol intake in pregnancy and the risk of spontaneous abortion.
      Alcohol>5 alcoholic drinks per weekHazard ratio for miscarriage3.7 (2.0; 6.8)
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      AlcoholAlcohol consumption in pregnancyRelative risk of recurrent miscarriage0.9 (0.6; 1.5)
      BMIBMI ≥22.5 kg/m21.1 (0.6; 2.0)
      CaffeineCoffee consumption in pregnancy1.4 (0.7; 2.6)
      SmokingCurrent smoking in pregnancy increasing number of cigarettes/day1.4 (0.8; 2.9)
      P for trend 0.04
      • Ronnenberg A.G.
      • Goldman M.B.
      • Chen D.
      • Aitken I.W.
      • Willett W.C.
      • Selhub J.
      • Xu X.
      Preconception folate and vitamin b(6) status and clinical spontaneous abortion in chinese women.
      Folic acidLowest quintiles of plasma folate concentration (≤ 6.60 nmol/l)Adjusted Odds ratios for miscarriage1.5 (0.6; 3.8)
      Increasing folate concentrationP for trend 0.25
      Vitamin useLowest quintiles of plasma vitamin B6 concentration (≤28.9 nmol/l)2.5 (0.8; 7.8)
      Increasing vitamin B6 concentrationP for trend 0.13
      • Strandberg-Larsen K.
      • Nielsen N.R.
      • Grønbæk M.
      • Andersen P.K.
      • Olsen J.
      • Andersen A.M.N.
      Binge drinking in pregnancy and risk of fetal death.
      AlcoholBinge drinking in first 12 weeks of pregnancyHazard ratio for miscarriage0.84 (0.62; 1.14)
      • Windham G.C.
      • Von Behren J.
      • Fenster L.
      • Schaefer C.
      • Swan S.H.
      Moderate maternal alcohol consumption and risk of spontaneous abortion.
      Alcohol>3 alcoholic drinks per weekOdds ratios for miscarriage2.3 (1.1; 4.5)
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      Alcohol>4 times per week alcohol consumptionOdds ratios for miscarriage1.04 (0.79; 1.27)
      BMIPre-pregnancy BMI ≥30 kg/m21.05 (0.89; 1.25)
      DietEating fresh fruit/vegetables daily0.86 (0.49; 1.22)
      Physical activity>2 times per week, ≥0.5 hr0.72 (0.51; 0.88)
      SmokingSmoking >20 cigarettes per day during first 12 weeks of pregnancy1.59 (1.12; 3.16)
      Vitamin useVitamin supplement use0.75 (0.49; 0.91)
      • Zhou H.
      • Liu Y.
      • Liu L.
      • Zhang M.
      • Chen X.
      • Qi Y.
      Maternal pre-pregnancy risk factors for miscarriage from a prevention perspective: A cohort study in china.
      BMIPre-pregnancy BMI <18.5 kg/m2Relative risk for miscarriage2.57 (1.35; 4.89)
      Pre-pregnancy BMI 24–27.9 kg/m22.45 (1.26; 4.77)
      Pre-pregnancy BMI ≥28 kg/m22.84 (2.84; 6.57)
      Note: BMI = body mass index; OR (95% CI) = Odds ratio 95% Confidence interval.
      The seven studies reporting on the association between maternal alcohol consumption and miscarriage showed inconsistent results (
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      ,
      • Windham G.C.
      • Von Behren J.
      • Fenster L.
      • Schaefer C.
      • Swan S.H.
      Moderate maternal alcohol consumption and risk of spontaneous abortion.
      ,
      • Kesmodel U.
      • Wisborg K.
      • Olsen S.F.
      • Henriksen T.B.
      • Secher N.J.
      Moderate alcohol intake in pregnancy and the risk of spontaneous abortion.
      ,
      • Strandberg-Larsen K.
      • Nielsen N.R.
      • Grønbæk M.
      • Andersen P.K.
      • Olsen J.
      • Andersen A.M.N.
      Binge drinking in pregnancy and risk of fetal death.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ,
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Williams P.L.
      • Toth T.L.
      • Missmer S.A.
      • Chavarro J.E.
      Prepregnancy low to moderate alcohol intake is not associated with risk of spontaneous abortion or stillbirth.
      ). The study with the highest quality reported no association between binge drinking in the first 12 weeks of pregnancy and the risk of spontaneous miscarriage (
      • Strandberg-Larsen K.
      • Nielsen N.R.
      • Grønbæk M.
      • Andersen P.K.
      • Olsen J.
      • Andersen A.M.N.
      Binge drinking in pregnancy and risk of fetal death.
      ). This finding is supported by a hospital-based case-control study among Chinese women (
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ) and by
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      . In contrast,
      • Windham G.C.
      • Von Behren J.
      • Fenster L.
      • Schaefer C.
      • Swan S.H.
      Moderate maternal alcohol consumption and risk of spontaneous abortion.
      found a significant association for drinking >3 drinks per week and the risk of spontaneous miscarriage. A similar significant association was found by
      • Kesmodel U.
      • Wisborg K.
      • Olsen S.F.
      • Henriksen T.B.
      • Secher N.J.
      Moderate alcohol intake in pregnancy and the risk of spontaneous abortion.
      and
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      .
      The association between maternal caffeine consumption and miscarriage was evaluated by four studies (
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      ,
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ,
      • Hahn K.A.
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and risk of spontaneous abortion.
      ).
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      and
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      reported a significantly higher risk for miscarriage when consuming caffeine, but
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      and
      • Hahn K.A.
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and risk of spontaneous abortion.
      did not.
      The impact of diet was evaluated in one study (
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ). The authors reported on the association of eating fresh fruit/vegetables on a daily basis compared with not eating fresh fruit/vegetables daily and the risk of miscarriage and they found no significant reduction in risk.
      Four studies examined the association between folic acid and/or vitamin supplement use and miscarriage (
      • Ronnenberg A.G.
      • Goldman M.B.
      • Chen D.
      • Aitken I.W.
      • Willett W.C.
      • Selhub J.
      • Xu X.
      Preconception folate and vitamin b(6) status and clinical spontaneous abortion in chinese women.
      ,
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Hauser R.
      • Williams P.L.
      • Gillman M.W.
      • Ginsburg E.S.
      • Missmer S.A.
      • Chavarro J.E.
      Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ,
      • Andersen L.B.
      • Jørgensen J.S.
      • Jensen T.K.
      • Dalgård C.
      • Barington T.
      • Nielsen J.
      • Beck-Nielsen S.S.
      • Husby S.
      • Abrahamsen B.
      • Lamont R.F.
      • Christesen H.T.
      Vitamin d insufficiency is associated with increased risk of firsttrimester miscarriage in the odense child cohort.
      ).
      • Ronnenberg A.G.
      • Goldman M.B.
      • Chen D.
      • Aitken I.W.
      • Willett W.C.
      • Selhub J.
      • Xu X.
      Preconception folate and vitamin b(6) status and clinical spontaneous abortion in chinese women.
      showed a positive trend for an increase in the relative odds of spontaneous miscarriage as plasma folate concentration decreased (P for trend 0.07), which was weakened after adjusting for confounders. A borderline significant increase in risk of miscarriage was seen for vitamin B6 status (P for trend 0.06) but this also diminished after adjustment. However, comparing vitamin B6 status between women whose pregnancies ended in a clinically recognized spontaneous miscarriage and in those with live births, showed a significantly (P = 0.04) lower mean pre-pregnancy plasma vitamin B6 concentration in women with miscarriage. This finding is supported by a case–control study among Chinese women showing a significant reduction in risk for miscarriage among women using multivitamin supplements compared with those without using supplements (
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ).
      The association between BMI, physical activity and miscarriage was evaluated in five studies (
      • Parazzini
      • Bocciolone
      • Fedele
      Risk factors for spontaneous abortion.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ,
      • Hahn K.A.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Body size and risk of spontaneous abortion among danish pregnancy planners.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ,
      • Zhou H.
      • Liu Y.
      • Liu L.
      • Zhang M.
      • Chen X.
      • Qi Y.
      Maternal pre-pregnancy risk factors for miscarriage from a prevention perspective: A cohort study in china.
      ). Higher BMI was shown to significantly increase the risk of miscarriage in two studies (
      • Hahn K.A.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Brogly S.B.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Body size and risk of spontaneous abortion among danish pregnancy planners.
      ,
      • Zhou H.
      • Liu Y.
      • Liu L.
      • Zhang M.
      • Chen X.
      • Qi Y.
      Maternal pre-pregnancy risk factors for miscarriage from a prevention perspective: A cohort study in china.
      ), whereas two other studies showed that moderate physical activity significantly decreased the risk of miscarriage (
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ).

      Embryonic growth

      The association between maternal lifestyle factors and embryonic growth was reported in seven studies (
      • Bakker R.
      • Steegers E.a.P.
      • Obradov A.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The generation r study.
      ,
      • Mook-Kanamori D.O.
      • Steegers E.a.P.
      • Eilers P.H.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Risk factors and outcomes associated with first-trimester fetal growth restriction.
      ,
      • Prabhu N.
      • Smith N.
      • Campbell D.
      • Craig L.C.
      • Seaton A.
      • Helms P.J.
      • Devereux G.
      • Turner S.W.
      First trimester maternal tobacco smoking habits and fetal growth.
      ,
      • Bouwland-Both M.I.
      • Steegers-Theunissen R.P.
      • Vujkovic M.
      • Lesaffre E.M.
      • Mook-Kanamori D.O.
      • Hofman A.
      • Lindemans J.
      • Russcher H.
      • Jaddoe V.W.
      • Steegers E.A.
      A periconceptional energy-rich dietary pattern is associated with early fetal growth: The generation r study.
      ,
      • Van Uitert E.M.
      • Van Der Elst-Otte N.
      • Wilbers J.J.
      • Exalto N.
      • Willemsen S.P.
      • Eilers P.H.
      • Koning A.H.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Periconception maternal characteristics and embryonic growth trajectories: The rotterdam predict study.
      ,
      • Van Uitert E.M.
      • Van Ginkel S.
      • Willemsen S.P.
      • Lindemans J.
      • Koning A.H.J.
      • Eilers P.H.C.
      • Exalto N.
      • Laven J.S.E.
      • Steegers E.a.P.
      • Steegers-Theunissen R.P.M.
      An optimal periconception maternal folate status for embryonic size: The rotterdam predict study.
      ,
      • Parisi F.
      • Rousian M.
      • Koning A.H.
      • Willemsen S.P.
      • Cetin I.
      • Steegers-Theunissen R.P.
      Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the carnegie stages.
      ) (Table 5).
      • Van Uitert E.M.
      • Van Der Elst-Otte N.
      • Wilbers J.J.
      • Exalto N.
      • Willemsen S.P.
      • Eilers P.H.
      • Koning A.H.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Periconception maternal characteristics and embryonic growth trajectories: The rotterdam predict study.
      showed that periconception smoking and periconception alcohol use were independently associated with reduced embryonic growth trajectories, measured by CRL. No associations were observed with BMI and timing of folic acid supplement use.
      • Bakker R.
      • Steegers E.a.P.
      • Obradov A.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The generation r study.
      evaluated the impact of caffeine; intake of >6 units per day (>540 mg) was associated with a decline in CRL.
      Table 5Description and summary of data for 7 studies that investigated associations between lifestyle factors and embryonic growth
      AuthorExposureExposure descriptionOutcome definitionEffect estimate (95% CI)
      • Van Uitert E.M.
      • Van Der Elst-Otte N.
      • Wilbers J.J.
      • Exalto N.
      • Willemsen S.P.
      • Eilers P.H.
      • Koning A.H.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Periconception maternal characteristics and embryonic growth trajectories: The rotterdam predict study.
      AlcoholPericonception alcohol useCRL difference (mm)−0.05 (−0.069; −0.017)
      BMIBMI kg/m20.095 (−0.11; 0.17)
      Folic acidMoment of initiation of folic acid; post conception0.27 (−0.311; 0.49)
      SmokingPericonception smoking ≥10 cigarettes per day−0.46 (−0.64; −0.077)
      • Van Uitert E.M.
      • Van Ginkel S.
      • Willemsen S.P.
      • Lindemans J.
      • Koning A.H.J.
      • Eilers P.H.C.
      • Exalto N.
      • Laven J.S.E.
      • Steegers E.a.P.
      • Steegers-Theunissen R.P.M.
      An optimal periconception maternal folate status for embryonic size: The rotterdam predict study.
      Folic acidQuartile 1 (814–1223 nmol/l)CRL difference (mm)−0.49 (−0.66; −0.2)
      Quartile 2 (1224–1512 nmol/l)−0.45 (−0.64; −0.14)
      Quartile 4 (1813–2936 nmol/L)−0.54 (−0.7; −0.3)
      • Bakker R.
      • Steegers E.a.P.
      • Obradov A.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Maternal caffeine intake from coffee and tea, fetal growth, and the risks of adverse birth outcomes: The generation r study.
      Caffeine>6 units (>540 mg) of caffeine per dayCRL difference (mm)−4.54 (−8.99; −0.09)
      P for trend <0.05
      • Bouwland-Both M.I.
      • Steegers-Theunissen R.P.
      • Vujkovic M.
      • Lesaffre E.M.
      • Mook-Kanamori D.O.
      • Hofman A.
      • Lindemans J.
      • Russcher H.
      • Jaddoe V.W.
      • Steegers E.A.
      A periconceptional energy-rich dietary pattern is associated with early fetal growth: The generation r study.
      DietHigh adherence to an energy-rich dietary patternCRL difference (mm)1.62 (0.52; 2.72)
      P for trend <0.05
      • Mook-Kanamori D.O.
      • Steegers E.a.P.
      • Eilers P.H.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Risk factors and outcomes associated with first-trimester fetal growth restriction.
      AlcoholAlcohol consumption compared with no ­consumptionCRL difference (mm)0.40 (−0.31; 1.11)
      BMIPer 1 SD (4.08 units) increase in BMI−0.01 (−0.35; 0.33)
      Folic acidNo use of folic acid supplement−1.33 (−2.41; −0.24)
      SmokingSmokers compared with non-smokers−0.98 (−1.79; −0.16)
      • Parisi F.
      • Rousian M.
      • Koning A.H.
      • Willemsen S.P.
      • Cetin I.
      • Steegers-Theunissen R.P.
      Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the carnegie stages.
      Vitamin useVitamin B12 concentration of −2 SD (73.4 pmol/l)delay in Carnegie stage (days)1.4 (1.3; 1.4)
      Total Homocysteine concentration of +2 SD (10.4 μmol/l)1.6 (1.5; 1,7)
      • Prabhu N.
      • Smith N.
      • Campbell D.
      • Craig L.C.
      • Seaton A.
      • Helms P.J.
      • Devereux G.
      • Turner S.W.
      First trimester maternal tobacco smoking habits and fetal growth.
      SmokingSmokers compared with non-smokersCRL difference (mm)0.23 (−0.23; 0.70)
      Note: BMI = body mass index; 95% CI = 95% Confidence interval; CRL = crown-rump length.
      Evaluation of maternal red blood cell (RBC) folate concentrations in the first-trimester as a measure of nutrition and supplement use showed an optimum use curve, in which both lower and very high concentrations are associated with reduced embryonic growth (
      • Van Uitert E.M.
      • Van Ginkel S.
      • Willemsen S.P.
      • Lindemans J.
      • Koning A.H.J.
      • Eilers P.H.C.
      • Exalto N.
      • Laven J.S.E.
      • Steegers E.a.P.
      • Steegers-Theunissen R.P.M.
      An optimal periconception maternal folate status for embryonic size: The rotterdam predict study.
      ). Another study showed that smoking in combination with lack of use of folic acid supplements was associated with reduced embryonic size (
      • Mook-Kanamori D.O.
      • Steegers E.a.P.
      • Eilers P.H.
      • Raat H.
      • Hofman A.
      • Jaddoe V.W.V.
      Risk factors and outcomes associated with first-trimester fetal growth restriction.
      ). This association between smoking and embryonic size was not found by
      • Prabhu N.
      • Smith N.
      • Campbell D.
      • Craig L.C.
      • Seaton A.
      • Helms P.J.
      • Devereux G.
      • Turner S.W.
      First trimester maternal tobacco smoking habits and fetal growth.
      . Increasing adherence to an energy-rich dietary pattern is significantly associated with an increased CRL, as reported by
      • Bouwland-Both M.I.
      • Steegers-Theunissen R.P.
      • Vujkovic M.
      • Lesaffre E.M.
      • Mook-Kanamori D.O.
      • Hofman A.
      • Lindemans J.
      • Russcher H.
      • Jaddoe V.W.
      • Steegers E.A.
      A periconceptional energy-rich dietary pattern is associated with early fetal growth: The generation r study.
      .
      Association between embryonic morphological development according to the Carnegie stages and maternal biomarkers of the one carbon metabolism was evaluated in the study by
      • Parisi F.
      • Rousian M.
      • Koning A.H.
      • Willemsen S.P.
      • Cetin I.
      • Steegers-Theunissen R.P.
      Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the carnegie stages.
      . Low vitamin B12 concentrations were associated with a 1.4-day delay in morphological development compared with high concentrations and high total homocysteine concentrations were associated with a 1.6-day delay in morphological development compared with low concentrations.

      Discussion

      The results of this systematic review highlight the impact of maternal modifiable lifestyle factors including smoking, alcohol, caffeine, BMI, physical activity, diet and vitamin supplement use on fecundity and first trimester pregnancy outcomes.

      Smoking

      Cigarette smoke contains about 4000 compounds belonging to a variety of chemical classes known to be toxic, including polycyclic aromatic hydrocarbons (PCH), nitrosamines, heavy metals, alkaloids, aromatic amines and so forth (
      • Dechanet C.
      • Anahory T.
      • Mathieu Daude J.C.
      • Quantin X.
      • Reyftmann L.
      • Hamamah S.
      • Hedon B.
      • Dechaud H.
      Effects of cigarette smoking on reproduction.
      ). The exact mechanism remains unclear but there is strong evidence that these constituents may affect the follicular microenvironment and alter hormone concentrations in the luteal phase (
      • Homan G.F.
      • Davies M.
      • Norman R.
      The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: A review.
      ). These alterations in hormone concentrations shorten the luteal phase, which results in a shorter time period of being able to become pregnant. Besides, decreased ovarian function and reduced ovarian reserve may also be possible consequences of smoking, as shown by lower anti-Müllerian hormone (AMH) concentrations in smokers compared with non-smokers (
      • Freour T.
      • Masson D.
      • Mirallie S.
      • Jean M.
      • Bach K.
      • Dejoie T.
      • Barriere P.
      Active smoking compromises ivf outcome and affects ovarian reserve.
      ). Studies included in this review confirm these hypotheses by showing statistically significant negative associations of smoking especially with fecundity parameters (
      • Laurent S.L.
      • Thompson S.J.
      • Addy C.
      • Garrison C.Z.
      • Moore E.E.
      An epidemiologic study of smoking and primary infertility in women.
      ,
      • Axmon A.
      • Rylander L.
      • Strömberg U.
      • Hagmar L.
      Time to pregnancy and infertility among women with a high intake of fish contaminated with persistent organochlorine compounds.
      ,
      • Radin R.G.
      • Hatch E.E.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Sørensen H.T.
      • Riis A.H.
      • Wise L.A.
      Active and passive smoking and fecundability in danish pregnancy planners.
      ), although a significantly prolonged time to pregnancy was found in only two out of six studies included in this review (
      • Hull M.G.
      • North K.
      • Taylor H.
      • Farrow A.
      • Ford W.C.
      Delayed conception and active and passive smoking. The avon longitudinal study of pregnancy and childhood study team.
      ,
      • Sapra K.J.
      • Barr D.B.
      • Maisog J.M.
      • Sundaram R.
      • Buck Louis G.M.
      Time-to-pregnancy associated with couples’ use of tobacco products.
      ).
      Different compounds of cigarette smoke also impair endometrial maturation, implantation and early placentation (
      • Dechanet C.
      • Anahory T.
      • Mathieu Daude J.C.
      • Quantin X.
      • Reyftmann L.
      • Hamamah S.
      • Hedon B.
      • Dechaud H.
      Effects of cigarette smoking on reproduction.
      ). Nicotine is suspected to have an adverse effect on the decidualization process and cadmium, for example, is known to impair endometrial maturation. Moreover, several studies have indicated the negative influence of benzo(a)pyrene on angiogenesis by inhibiting endothelial cell proliferation (
      • Dechanet C.
      • Anahory T.
      • Mathieu Daude J.C.
      • Quantin X.
      • Reyftmann L.
      • Hamamah S.
      • Hedon B.
      • Dechaud H.
      Effects of cigarette smoking on reproduction.
      ). These mechanisms could explain the significant increase in the risk of first trimester miscarriage found in two large studies (
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      ,
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ). These associations are dependent on the number of cigarettes smoked per day (
      • Xu G.L.
      • Wu Y.M.
      • Yang L.M.
      • Yuan L.
      • Guo H.F.
      • Zhang F.Q.
      • Guan Y.C.
      • Yao W.
      Risk factors for early miscarriage among chinese: A hospital-based case-control study.
      ).

      Alcohol

      Although the evidence of associations between alcohol and reproductive performances are inconclusive, antenatal alcohol consumption is a known teratogen and several studies have reported an association with higher rates of early pregnancy failure and decreased fecundity (
      • Homan G.F.
      • Davies M.
      • Norman R.
      The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: A review.
      ,
      • Lassi Z.S.
      • Imam A.M.
      • Dean S.V.
      • Bhutta Z.A.
      Preconception care: Caffeine, smoking, alcohol, drugs and other environmental chemical/radiation exposure.
      ). This decrease in fecundity is supported by two studies included in this review (
      • Hakim R.B.
      • Gray R.H.
      • Zacur H.
      Alcohol and caffeine consumption and decreased fertility.
      ,
      • Jensen T.K.
      • Hjollund N.H.I.
      • Henriksen T.B.
      • Scheike T.
      Does moderate alcohol consumption affect fertility? Follow up study among couples planning first pregnancy.
      ). One of the biological explanations for these periconception complications is that hormonal fluctuations, including alcohol-induced increase of aromatization of testosterone leading to an increase in oestrogen concentrations, reduces follicle-stimulating hormone and suppresses both folliculogenesis and ovulation. Furthermore, alcohol may have a direct effect on the maturation of the ovum, ovulation, blastocyst development and implantation (
      • Gill J.
      The effects of moderate alcohol consumption on female hormone levels and reproductive function.
      ,
      • Eggert J.
      • Theobald H.
      • Engfeldt P.
      Effects of alcohol consumption on female fertility during an 18-year period.
      ). As a result, time to pregnancy may be prolonged in women who consume alcohol. In two studies included in this review, time to pregnancy was found to be increased in women who consume alcohol (
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ). In contrast, two other studies showed a significantly shorter time to pregnancy (
      • Juhl M.
      • Andersen A.M.N.
      • Grønbæk M.
      • Olsen J.
      Moderate alcohol consumption and waiting time to pregnancy.
      ,
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      ). This contradiction may be due to differences in the populations studied, residual confounding or the type of alcohol consumed. For example,
      • Juhl M.
      • Olsen J.
      • Andersen A.M.N.
      • Grønbæk M.
      Intake of wine, beer and spirits and waiting time to pregnancy.
      found a shorter time to pregnancy among wine drinkers than non-wine drinkers.
      Alcohol readily crosses the placenta, which can result in irreversible damage to the placenta and organs of the developing embryo (
      • Popova S.
      • Lange S.
      • Probst C.
      • Parunashvili N.
      • Rehm J.
      Prevalence of alcohol consumption during pregnancy and fetal alcohol spectrum disorders among the general and aboriginal populations in canada and the united states.
      ). Besides adverse pregnancy outcomes such as stillbirth, preterm birth, intrauterine growth restriction and fetal alcohol syndrome (FAS) disorders, the risk of miscarriage in the first trimester is also increased. Three out of five reviewed studies indeed showed a significantly increased risk of miscarriage with higher levels of alcohol consumption (
      • Windham G.C.
      • Von Behren J.
      • Fenster L.
      • Schaefer C.
      • Swan S.H.
      Moderate maternal alcohol consumption and risk of spontaneous abortion.
      ,
      • Kesmodel U.
      • Wisborg K.
      • Olsen S.F.
      • Henriksen T.B.
      • Secher N.J.
      Moderate alcohol intake in pregnancy and the risk of spontaneous abortion.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ). One other study showed a significant association between a reduced embryonic growth and exposure to alcohol (
      • Van Uitert E.M.
      • Van Der Elst-Otte N.
      • Wilbers J.J.
      • Exalto N.
      • Willemsen S.P.
      • Eilers P.H.
      • Koning A.H.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      Periconception maternal characteristics and embryonic growth trajectories: The rotterdam predict study.
      ). While many studies have demonstrated an association between alcohol and perinatal outcomes, the exact dose-response relationship and the differential effects of different types of alcohol, remain unknown and urgently require further research because of the large number of social alcohol consumers in the reproductive population.

      Caffeine

      It has been postulated that caffeine could affect female reproduction by increasing oestrogen production and thereby affecting ovulation (
      • Barbieri R.L.
      The initial fertility consultation: Recommendations concerning cigarette smoking, body mass index, and alcohol and caffeine consumption.
      ) and corpus luteal function (
      • Homan G.F.
      • Davies M.
      • Norman R.
      The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: A review.
      ), resulting in an increase of the time to pregnancy (
      • Sharma R.
      • Biedenharn K.R.
      • Fedor J.M.
      • Agarwal A.
      Lifestyle factors and reproductive health: Taking control of your fertility.
      ). Caffeine is known to pass the placental barrier and may lead to vasoconstriction of the uteroplacental circulation affecting embryonic and placental growth and development (
      • Chen L.W.
      • Wu Y.
      • Neelakantan N.
      • Chong M.F.
      • Pan A.
      • Van Dam R.M.
      Maternal caffeine intake during pregnancy and risk of pregnancy loss: A categorical and dose-response meta-analysis of prospective studies.
      ). Furthermore, during pregnancy the rate of caffeine metabolism decreases and the half-life doubles, leading to higher exposure of the embryo (
      • Chen L.W.
      • Wu Y.
      • Neelakantan N.
      • Chong M.F.
      • Pan A.
      • Van Dam R.M.
      Maternal caffeine intake during pregnancy and risk of pregnancy loss: A categorical and dose-response meta-analysis of prospective studies.
      ).
      A possible explanation for the heterogeneous results of the time to pregnancy in studies included in the present review (
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      ,
      • Hatch E.E.
      • Wise L.A.
      • Mikkelsen E.M.
      • Christensen T.
      • Riis A.H.
      • Sørensen H.T.
      • Rothman K.J.
      Caffeinated beverage and soda consumption and time to pregnancy.
      ,
      • Wesselink A.K.
      • Wise L.A.
      • Rothman K.J.
      • Hahn K.A.
      • Mikkelsen E.M.
      • Mahalingaiah S.
      • Hatch E.E.
      Caffeine and caffeinated beverage consumption and fecundability in a preconception cohort.
      ) may be that studies did not always control for residual confounding such as smoking, which, is known to be highly correlated with caffeine consumption (
      • Treur J.L.
      • Taylor A.E.
      • Ware J.J.
      • Mcmahon G.
      • Hottenga J.J.
      • Baselmans B.M.
      • Willemsen G.
      • Boomsma D.I.
      • Munafo M.R.
      • Vink J.M.
      Associations between smoking and caffeine consumption in two european cohorts.
      ). Moreover, the rate at which caffeine is cleared from the body, which varies between individuals and is affected by environmental factors such as smoking and diet (
      • Peck J.D.
      • Leviton A.
      • Cowan L.D.
      A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: A 2000–2009 update.
      ), may influence the biologic dose and exposure interval. Although these postulated mechanisms may explain the association found between caffeine consumption and the increased risk of miscarriage (
      • Cnattingius S.
      • Signorello L.B.
      • Annerén G.
      Caffeine intake and the risk of first-trimester spontaneous abortion.
      ,
      • Feodor Nilsson S.
      • Andersen P.K.
      • Strandberg-Larsen K.
      • Nybo Andersen A.M.
      Risk factors for miscarriage from a prevention perspective: A nationwide follow-up study.
      ), reverse causation must be taken into account. It is known that pregnancy symptoms such as nausea and vomiting, which may cause women to consume less caffeine, are more common in healthy pregnancies that result in live births than when a pregnancy ends in a miscarriage (
      • Florack E.I.M.
      • Zielhuis G.A.
      • Rolland R.
      Cigarette smoking, alcohol consumption, and caffeine intake and fecundability.
      ,
      • Bolúmar F.
      • Olsen J.
      • Rebagliato M.
      • Bisanti L.
      • Juul S.
      • Olsen J.
      • Thonneau P.
      • Karmaus W.
      • Figá-Talamanca I.
      • Bisanti L.
      • Bolúmar F.
      Caffeine intake and delayed conception: A european multicenter study on infertility and subfecundity.
      ,
      • Peck J.D.
      • Leviton A.
      • Cowan L.D.
      A review of the epidemiologic evidence concerning the reproductive health effects of caffeine consumption: A 2000–2009 update.
      ,
      • Hatch E.E.
      • Wise L.A.
      • Mikkelsen E.M.
      • Christensen T.
      • Riis A.H.
      • Sørensen H.T.
      • Rothman K.J.
      Caffeinated beverage and soda consumption and time to pregnancy.
      ).

      Diet

      Diet is known to affect female fecundity (
      • Homan G.F.
      • Davies M.
      • Norman R.
      The impact of lifestyle factors on reproductive performance in the general population and those undergoing infertility treatment: A review.
      ,
      • Sharma R.
      • Biedenharn K.R.
      • Fedor J.M.
      • Agarwal A.
      Lifestyle factors and reproductive health: Taking control of your fertility.
      ). In women of reproductive age, the adherence to the Mediterranean diet (characterized by high consumption of vegetables, fish, fruits, poultry, low-fat dairy products and olive oil (
      • Toledo E.
      • Lopez-Del Burgo C.
      • Ruiz-Zambrana A.
      • Donazar M.
      • Navarro-Blasco I.
      • Martinez-Gonzalez M.A.
      • De Irala J.
      Dietary patterns and difficulty conceiving: A nested case-control study.
      ) reduces the risk of weight gain and insulin resistance (
      • Vujkovic M.
      • De Vries J.H.
      • Lindemans J.
      • Macklon N.S.
      • Van Der Spek P.J.
      • Steegers E.A.
      • Steegers-Theunissen R.P.
      The preconception mediterranean dietary pattern in couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment increases the chance of pregnancy.
      ) and increases pregnancy rates by 40% in couples undergoing IVF/ICSI (
      • Fontana R.
      • Della Torre S.
      The deep correlation between energy metabolism and reproduction: A view on the effects of nutrition for women fertility.
      ). Olive oil is an important source of linoleic acid, which is known to improve the reproductive process (
      • Fontana R.
      • Della Torre S.
      The deep correlation between energy metabolism and reproduction: A view on the effects of nutrition for women fertility.
      ). The energy-rich dietary pattern described by
      • Bouwland-Both M.I.
      • Steegers-Theunissen R.P.
      • Vujkovic M.
      • Lesaffre E.M.
      • Mook-Kanamori D.O.
      • Hofman A.
      • Lindemans J.
      • Russcher H.
      • Jaddoe V.W.
      • Steegers E.A.
      A periconceptional energy-rich dietary pattern is associated with early fetal growth: The generation r study.
      is significantly associated with embryonic growth, as measured by CRL. Its high methionine content could explain this association, as this is an essential substrate for the one-carbon pathway. Folate, which is a substrate, and other vitamins, such as B6 and B12, which are co-factors for this pathway, could also play a role in biological processes implicated in growth and programming, especially in the periconception period (
      • Steegers-Theunissen R.P.
      • Twigt J.
      • Pestinger V.
      • Sinclair K.D.
      The periconceptional period, reproduction and long-term health of offspring: The importance of one-carbon metabolism.
      ). Furthermore, these vitamins are also associated with increased progesterone concentrations in the luteal phase, improved menstrual cycle regularity and normalization of cycle length, which have all been associated with fecundity (
      • Cueto H.T.
      • Riis A.H.
      • Hatch E.E.
      • Wise L.A.
      • Rothman K.J.
      • Sorensen H.T.
      • Mikkelsen E.M.
      Folic acid supplementation and fecundability: A danish prospective cohort study.
      ). These findings could explain the positive association of concentration of vitamin B12 on embryonic development (
      • Parisi F.
      • Rousian M.
      • Koning A.H.
      • Willemsen S.P.
      • Cetin I.
      • Steegers-Theunissen R.P.
      Periconceptional maternal one-carbon biomarkers are associated with embryonic development according to the carnegie stages.
      ) and on fecundity (
      • Cueto H.T.
      • Riis A.H.
      • Hatch E.E.
      • Wise L.A.
      • Rothman K.J.
      • Sorensen H.T.
      • Mikkelsen E.M.
      Folic acid supplementation and fecundability: A danish prospective cohort study.
      ).
      The expected positive association of multivitamin supplement use and a reduced time to pregnancy was not seen in two studies (
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ,
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ). A possible explanation is the low response rate in one study (
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      ) and the fact that the other study was designed for detection of risk factors for childhood obesity instead of fertility measures (
      • Mutsaerts M.a.Q.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.H.
      • Sauer P.J.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ). Lower miscarriage rates were found with folic acid and/or multivitamin supplement use in three of the four studies included in this review (
      • Gaskins A.J.
      • Rich-Edwards J.W.
      • Hauser R.
      • Williams P.L.
      • Gillman M.W.
      • Ginsburg E.S.
      • Missmer S.A.
      • Chavarro J.E.
      Maternal prepregnancy folate intake and risk of spontaneous abortion and stillbirth.
      ,