Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes including preterm birth: a systematic review and meta-analysis

      Objective

      During pregnancy, vaginal colonization by Candida spp is common. Some studies suggest an association between asymptomatic vaginal Candida colonization and adverse pregnancy outcomes, but the evidence is inconsistent. This review aimed to systematically review the association between asymptomatic vaginal colonization by Candida spp and adverse pregnancy outcomes, including preterm birth.

      Data Sources

      We searched Ovid MEDLINE, Ovid Embase, and the Cochrane Central Register of Controlled Trials from inception to May 6, 2020 for published studies on vaginal Candida/yeast and pregnancy outcomes.

      Study Eligibility Criteria

      Cohort studies, case-control studies, and randomized controlled trials that included pregnant women who were tested for asymptomatic vaginal Candida colonization and reported on adverse pregnancy outcomes were eligible.

      Study Appraisal and Synthesis Methods

      Two reviewers independently selected and extracted the data. Critical appraisal was performed using the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies and the revised Cochrane risk-of-bias tool for randomized controlled trials.

      Results

      We found no significant difference in preterm birth rate between Candida-positive and Candida-negative women (odds ratio, 1.10; 95% confidence interval, 0.99–1.22; I2, 0%) in 15 studies among 33,321 women for either spontaneous preterm birth only (odds ratio, 1.13, 95% confidence interval, 0.97–1.31; I2, 0%) or all preterm birth (odds ratio, 1.04; 95% confidence interval, 0.79–1.35; I2, 21%). Subgroup analyses for a treatment strategy including only studies reporting on spontaneous preterm birth did not reveal any statistically significant associations either, although the odds ratio was increased for the untreated Candida-positive women (odds ratio, 1.28; 95% confidence interval, 0.90–1.81; I2, 13%) in 3 studies among 5175 women. Asymptomatic vaginal Candida colonization was not associated with small for gestational age, perinatal mortality, or any other adverse pregnancy outcome.

      Conclusion

      Asymptomatic vaginal Candida colonization is not associated with preterm birth and other adverse pregnancy outcomes. Previous studies reported that treatment of this microorganism reduces preterm birth rate. Our results suggest that this effect is unlikely to rely on treatment of vaginal Candida.

      Key words

       Why was this study conducted?

      A recent systematic review reported a reduction of preterm birth among women treated with clotrimazole for their asymptomatic vaginal Candida colonization compared with women who had untreated colonization. However, the etiologic role of vaginal Candida colonization in adverse pregnancy outcomes such as preterm birth is unclear.

       Key findings

      In a meta-analysis including 34,730 women, we found no association between asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. No association with spontaneous preterm birth was found, irrespective of treatment strategy.

       What does this add to what is known?

      This finding supports current guidelines that advise not to screen for and treat asymptomatic vaginal Candida colonization.

      Introduction

      Adverse pregnancy outcomes such as preterm birth (PTB) and fetal growth restriction are major obstetrical and public health problems. Globally, perinatal mortality accounts for >5 million deaths every year, of which approximately 2 million occur in the early neonatal period.
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      World Health Organization
      Newborns: reducing mortality.
      There is accumulating evidence that genital tract infection or inflammation and placental malperfusion syndromes could underlie both PTB and fetal growth restriction. Genital tract infection has been implicated as a risk factor for PTB and fetal growth restriction.
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      Influence of infection during pregnancy on fetal development.
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      Epidemiology and causes of preterm birth.
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      Vaginal ureaplasma parvum serovars and spontaneous preterm birth.
      Preterm prelabor rupture of membranes (pPROM), an important precursor of PTB and poor birth outcome, and PTB itself are thought to be caused by intrauterine inflammation or microbial invasion of the amniotic cavity.
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      Epidemiology and causes of preterm birth.
      ,
      • Parry S.
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      Premature rupture of the fetal membranes.
      Fetal growth restriction is also associated with increased maternal systematic inflammation, resulting in increased systemic proinflammatory cytokines and other proinflammatory markers.
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      Maternal serum and fetal cord blood C-reactive protein levels but not procalcitonin levels are increased in idiopathic intrauterine growth restriction.
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      Maternal serum soluble CD30 is increased in normal pregnancy, but decreased in preeclampsia and small for gestational age pregnancies.
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      • et al.
      Leukocytes of pregnant women with small-for-gestational age neonates have a different phenotypic and metabolic activity from those of women with preeclampsia.
      Intrauterine inflammation is emerging as the overarching pathophysiological mechanism for a range of adverse pregnancy outcomes.
      Candida can commonly colonize the vagina and may do so asymptomatically or cause symptoms like pruritus and vaginal discharge.
      • Sobel J.D.
      Vulvovaginal candidosis.
      The evidence that vaginal Candida colonization plays a direct etiologic role in adverse pregnancy outcomes is inconsistent. Recently, a meta-analysis reported that, in 685 pregnant women, treatment of asymptomatic vaginal candidiasis lowered the risk for spontaneous PTB (risk ratio [RR], 0.36; 95% confidence interval [CI], 0.17–0.75).
      • Roberts C.L.
      • Algert C.S.
      • Rickard K.L.
      • Morris J.M.
      Treatment of vaginal candidiasis for the prevention of preterm birth: a systematic review and meta-analysis.
      These findings contrast with observational evidence that has reported PTB rates were not affected by the presence of vaginal candidiasis.
      • Cotch M.F.
      • Hillier S.L.
      • Gibbs R.S.
      • Eschenbach D.A.
      Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group.
      To date, there is no aggregated evidence on whether, or to which extent, asymptomatic vaginal Candida colonization (further referred to as vaginal Candida) increases the risk for PTB or whether other birth outcomes may be affected. This review aimed to provide a systematic review and meta-analysis of observational evidence on the association of vaginal Candida among pregnant women with adverse pregnancy outcomes.

      Methods

      This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement and the Meta-analyses Of Observational Studies in Epidemiology guidelines for meta-analysis of observational studies (Appendices 1 and 2).
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      • Altman D.G.
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      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ,
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      Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.
      The protocol for the systematic review is registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42019124623).

       Eligibility criteria

      Cohort studies, case-control studies, and randomized controlled trials (RCTs), published in peer-reviewed articles, that reported the incidence of adverse pregnancy outcomes among pregnant women tested for vaginal Candida/yeast were eligible. Studies only including specific patient populations (eg, HIV-infected patients or women presenting with preterm labor) were excluded. Studies were included if they contained a Candida/yeast-negative control group, tested for Candida/yeast before the outcome occurred, tested all study participants at the same moment during pregnancy, and reported data required to construct a 2×2 contingency table. If we identified missing data necessary for eligibility, we contacted the authors directly. We excluded potentially eligible studies if we were unable to access sufficient data.

       Information sources and search strategy

      An information specialist (J.L.) performed a systematic search in OVID MEDLINE, OVID EMBASE, and the Cochrane Central Register of Controlled Trials from inception to May 6, 2020, using controlled terms (MeSH) and text words for Candida, candidiasis, yeast, and adverse pregnancy outcomes, such as PTB, pPROM, and perinatal death. To find papers that only mentioned Candida in the full text, but not in the title or abstract, a separate narrow search was performed for cohort studies and RCTs on prenatal screening and adverse pregnancy outcomes. The retrieved publications were screened in full text for any mention of Candida. Animal studies and conference abstracts were excluded (the latter only from EMBASE). No further restrictions were applied. We cross-checked reference lists and the citing articles of included papers for additional relevant studies using Web of Science. The records retrieved were imported and deduplicated in EndNote X9. The complete search strategies are presented in Appendix 3.

       Definition vaginal Candida

      We included all studies using generally accepted methods for detection of Candida spp or yeasts in vaginal samples of asymptomatic women, including microscopy, culture, and polymerase chain reaction (PCR)–based techniques.

       Definition adverse pregnancy outcome

      Relevant adverse pregnancy outcomes were based on the core outcome set for PTB research and cross-checked with other core outcome sets in women’s and newborn’s health.
      • van ʼt Hooft J.
      • Duffy J.M.
      • Daly M.
      • et al.
      A core outcome set for evaluation of interventions to prevent preterm birth.
      ,
      • Duffy J.
      • Rolph R.
      • Gale C.
      • et al.
      Core outcome sets in women’s and newborn health: a systematic review.
      The main outcomes were as follows: PTB, defined as birth at <37 weeks’ gestation; spontaneous PTB, defined as birth at <37 weeks’ gestation after spontaneous onset of labor or after pPROM (an addendum to the protocol in PROSPERO); small for gestational age, defined as birthweight below the 10th percentile for gestational age; pPROM, defined as preterm prelabor rupture of membranes at <37 weeks’ gestation; and neonatal death, defined as death during the first 28 days of life. Additional outcomes were as follows: late pregnancy loss, defined as birth between 20 and 24 weeks’ gestation; early pregnancy loss, defined as spontaneous demise of pregnancy at <20 weeks’ gestation; prelabor rupture of membranes (PROM), defined as rupture of membranes before the onset of labor; birthweight; maternal mortality; maternal morbidity; and neonatal morbidity. Because of the lack of consensus in defining stillbirth, all definitions used for stillbirth were included, in contrast to the protocol in PROSPERO.
      • Nguyen R.H.
      • Wilcox A.J.
      Terms in reproductive and perinatal epidemiology: 2. Perinatal terms.

       Study selection

      Two reviewers (H.J.S. and B.A.d.J.) independently screened the identified titles and abstracts for eligibility using the web application Rayyan.
      • Ouzzani M.
      • Hammady H.
      • Fedorowicz Z.
      • Elmagarmid A.
      Rayyan-a web and mobile app for systematic reviews.
      Subsequently, we assessed eligibility in full texts of those deemed potentially eligible after title and abstract screening. If multiple studies reported on the same outcome measures in the same study population, only 1 paper was selected for inclusion based on the most relevant and complete data.
      Any disagreements were reviewed and discussed with a third reviewer (R.C.P.) until consensus.

       Data extraction

      Two reviewers (H.J.S. and B.A.d.J.) independently extracted study characteristics using a piloted data extraction form. The data extraction form was tested in a subset before extracting data from all studies. For study size, the number of participants with vaginal Candida test results and pregnancy outcome available was mentioned and used for constructing 2×2 contingency tables. If data on treatment of Candida-positive women were missing, authors were contacted. If there were multiple time points for Candida detection, only the results for the first time point were used in our study. Authors were contacted if the treatment protocol or the composition of the control group was unclear.

       Assessment of risk of bias

      Using the full text of the eligible studies, 1 reviewer (B.A.d.J.) critically appraised cohort and case-control studies using the Newcastle-Ottawa Quality Assessment Scale (NOS) for cohort and case-control studies. The NOS consisted of 8 items with a total maximum score of 9. We considered a study scoring of ≥7 as good quality, ≥5 as fair quality, and ≤4 as poor quality. For RCTs the revised Cochrane risk-of-bias tool (RoB 2.0) was used, which gives an overall risk-of-bias judgment expressed as “low risk of bias,” “some concerns,” or “high risk of bias.” A second reviewer (H.J.S.) independently critically appraised 10% of the included studies. We did not exclude studies based on a low score in quality assessment.

       Data synthesis

      We constructed 2×2 contingency tables for each outcome measure reported in the included studies and calculated odds ratio (OR) and 95% confidence intervals (CIs). We conducted meta-analyses and obtained summary estimates for outcomes reported in at least 2 studies using random effects model and Mantel-Haenszel weighting scheme. In addendum to the protocol in PROSPERO, subgroup analyses for the outcome PTB were performed for spontaneous PTB, antifungal treatment, method of Candida testing, and gestational age at testing. We evaluated heterogeneity across studies by calculating the I2 statistic. If meta-analysis yielded an I2 statistic exceeding 75%, indicating significant statistical heterogeneity, we did not calculate a summary point estimate. We analyzed data and constructed forest plots using the Review Manager (RevMan version 5.3., The Cochrane Collaboration, Copenhagen, 2014).

      Results

       Study selection

      A total of 1001 individual studies were identified by the electronic search, of which 19 were eligible for inclusion, among 34,730 women (Figure 1). Most records excluded based on title and abstract concerning premature neonates with (systemic) Candida infections. Exclusion of full-text articles had various reasons (Figure 1).
      Figure thumbnail gr1
      Figure 1Flowchart of the selection process of articles found in the electronic search
      A, Asymptomatic vaginal Candida colonization not tested according to predefined methods, for example, detected with liquid-based Papanicolaou smear. B, Not reporting on predefined outcome. C, Only randomized controlled trials, cohort studies, and case-control studies were eligible. D, Study population did not match eligibility criteria, for example, only women presenting with premature labor were included.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

       Study characteristics

      All studies indicated similar patient characteristics (Table 1). Most studies excluded patients with risk factors for PTB, for example, patients with cervical cerclage or chronic medical conditions.
      • Cotch M.F.
      • Hillier S.L.
      • Gibbs R.S.
      • Eschenbach D.A.
      Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group.
      ,
      Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery
      The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome.
      • McGregor J.A.
      • French J.I.
      • Richter R.
      • et al.
      Antenatal microbiologic and maternal risk factors associated with prematurity.
      • Germain M.
      • Krohn M.A.
      • Hillier S.L.
      • Eschenbach D.A.
      Genital flora in pregnancy and its association with intrauterine growth retardation.
      • Meis P.J.
      • Goldenberg R.L.
      • Mercer B.
      • et al.
      The preterm prediction study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      • Beltrán Montoya J.
      • Avila-Vergara M.A.
      • Vadillo-Ortega F.
      • Hernández-Guerrero C.
      • Peraza-Garay F.
      • Olivares-Morales S.
      Cervicovaginal infection as a risk factor for premature labor [Article in Spanish].
      ,
      • Payne M.S.
      • Ireland D.J.
      • Watts R.
      • et al.
      Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.
      ,
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • et al.
      Risk factors for preterm birth and low birth weight Among pregnant Indian women: A hospital-based prospective study.
      ,
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • Kamath A.
      • Aletty S.
      • Mukhopadhyay C.
      Screening of vulvovaginal infections during pregnancy in resource constrained settings: implications on preterm delivery.
      The control group consisted of all Candida-negative study participants in all but 1 study, which required control participants to also be negative for bacterial vaginosis and trichomoniasis.
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      Two studies provided point estimates that had been adjusted for confounding factors for all outcomes of interest.
      Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery
      The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome.
      ,
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      Table 1Study characteristics
      First authorYearPeriod and countrySize
      Study size based on participants with both microbiological test result and pregnancy outcome available. Therefore, study size can deviate from the study size mentioned in the original publication.
      Study typePatient characteristicsTreatmentControl group compositionMicrobiological testing
      Culture using agar-based techniques unless specified.
      Timing of testingOutcome measuresConfounding
      Cohort studies
      Minkoff
      • Minkoff H.
      • Grunebaum A.N.
      • Schwarz R.H.
      • et al.
      Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy.
      1984March to September 1982, USA188Prospective cohortSingleton pregnancy, no abortions, elective inductions, and elective cesarean deliveryNo treatmentAll Candida/yeast negativesCulture22–30 wk gestationPROMNo adjustment for confounding
      John Hopkins Study Group
      Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery
      The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome.
      1989November 1983 to January 1985, USA801Prospective cohortSingleton pregnancy, no insulin-dependent DM, severe heart disease, chronic renal disease, hemoglobinopathy, hypertension requiring medication, cerclage procedure, therapy with progestational agents, and antimicrobial agents used in past 2 wkNo treatmentAll Candida/yeast negativesCulture22–30 wk gestationPTB, SGAAdjusted for maternal age, pregnancy weight, alcohol consumption, age at first intercourse, cigarette or marijuana smoking, birthweight of previous delivery, education, marital status, income, race, and neonatal sex
      McGregor
      • McGregor J.A.
      • French J.I.
      • Richter R.
      • et al.
      Antenatal microbiologic and maternal risk factors associated with prematurity.
      1990January 1985–1986, USA196Prospective cohortSingleton pregnancy, no cervical cerclage, placenta previa, history of vaginal bleeding during pregnancy, history of preterm labor occurring in this pregnancy, antimicrobial treatment in the past 2 wk, history of douching within 24 h of examination, and unwilling or unable to sign informed consent36/83 positive, received treatment, antifungal agent not specifiedAll Candida/yeast negativesMicroscopy and cultureApproximately 24 wk gestationPTBNo adjustment for confounding
      Germain
      • Germain M.
      • Krohn M.A.
      • Hillier S.L.
      • Eschenbach D.A.
      Genital flora in pregnancy and its association with intrauterine growth retardation.
      19941984–1989, USA11,583Prospective cohortSingleton pregnancy, age >16 y, no Rh isoimmunization, use of antibiotics for 2 wks before inclusion, cervical cerclage, previous use of tocolytic, medical conditions related to prematurity, taking selected medications, and DM requiring insulin treatmentNot statedAll Candida/yeast negativesCulture23–26 wk gestationSGANo adjustment for confounding
      Meis
      • Meis P.J.
      • Goldenberg R.L.
      • Mercer B.
      • et al.
      The preterm prediction study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      1995October 1992 to July 1994, USA2929Prospective cohortSingleton pregnancy, no cervical cerclage, major congenital anomaly, placenta previa, polyhydramnios, oligohydramnios, and cervix dilated >2 cm in nulliparous women or >3 cm in parous womenNo treatmentAll Candida/yeast negativesMicroscopy22–24 wk gestationSpontaneous PTB (<35 wk gestation)No adjustment for confounding
      Cotch
      • Cotch M.F.
      • Hillier S.L.
      • Gibbs R.S.
      • Eschenbach D.A.
      Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group.
      1998Same population as Germain 199413,867Prospective cohortSingleton pregnancy, age >16 y, no Rh isoimmunization, use of antibiotics for 2 wk before the study, cervical cerclage, previous use of tocolytic agents, medical conditions related to prematurity, taking selected medications, and DM requiring insulin treatmentLesser proportion Candida positives were treated, antifungal agent not specifiedAll Candida/yeast negativesMicroscopy and culture with >2+ growth23–26 wk gestationPTB, pPROM, PROM, LBW, stillbirth, no definition given, neonatal deathNo adjustment for confounding
      Beltrán Montoya
      • Beltrán Montoya J.
      • Avila-Vergara M.A.
      • Vadillo-Ortega F.
      • Hernández-Guerrero C.
      • Peraza-Garay F.
      • Olivares-Morales S.
      Cervicovaginal infection as a risk factor for premature labor [Article in Spanish].
      2002March 1994 to September 1999, Mexico398Prospective cohortPregnant women at >16 wk gestation that followed the entire study protocol and delivery in same hospital. Exclusion: cervical insufficiency, uterine malformation or fibroids, amniocentesis, multiple pregnancy, bacteriuria, hemorrhagic complications during pregnancy, eclampsia or preeclampsia, other causes of pregnancy termination, DM, or oligohydramniosAll positives were treated, antifungal agent not specifiedAll Candida/yeast negativesMicroscopy and culture16–24 wk gestationSpontaneous PTBNo adjustment for confounding
      Garay
      • Garay G.
      • Fraca M.
      • Martinez I.
      • et al.
      Utility of vaginal pH determination in the diagnosis of vulvovaginitis and its association with obstetric pathology.
      2011Period unknown, Spain103Prospective cohortPregnant womenTreatment if patients were symptomatic, antifungal agent not specifiedAll Candida/yeast negativesCultureDuring first pregnancy control, usually between wk 11 and 14PTB, pPROMNo adjustment for confounding
      Farr
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      2015January 1, 2005, to January 1, 2014, Austria7850Retrospective cohortSingleton pregnancyAll Candida-positive women were treated with local clotrimazole 100 mg for 6 d. Recurrent colonization was retreatedBacterial vaginosis/Trichomonas vaginalis negativesMicroscopy10–16 wk gestationSpontaneous PTB, LBW, stillbirth, defined as term or PTD of a neonate that had died in utero and was born with an Apgar score of 0/0/0Adjusted for maternal age, parity, tertiary education, history of PTD, tobacco smoking, bacterial infection
      Payne
      • Payne M.S.
      • Ireland D.J.
      • Watts R.
      • et al.
      Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.
      2016Period unknown, Australia187Prospective cohortSingleton pregnancy, age 18–30 y, English speaking, exclusions: 1 or more previous PTB and/or other pregnancy complications such as preeclampsia, current antibiotics/antifungal usage, current urinary tract infection or history of recurrent vaginal thrushNo treatmentAll Candida/yeast negatives24 h of enrichment culture and 24 h of culture on selective agar13–26 wkSpontaneous PTBNo adjustment for confounding
      Schwab
      • Schwab F.D.
      • Zettler E.K.
      • Moh A.
      • Schötzau A.
      • Gross U.
      • Günthert A.R.
      Predictive factors for preterm delivery under rural conditions in post-tsunami Banda Aceh.
      2016February to June 2015, Indonesia62Prospective cohortPregnant womenNo treatmentAll Candida/yeast negativesMicroscopy12–24 wk gestationPTBNo adjustment for confounding
      Tellapragada
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • et al.
      Risk factors for preterm birth and low birth weight Among pregnant Indian women: A hospital-based prospective study.
      2016May 2011 to April 2014, India710Prospective cohortSingleton pregnancy, age >18 y, no DM, hypertension, thyroid antibodies, HIV, placenta previa, cervical insufficiency, smoking, or alcohol consumptionTreatment in 131 symptomatic women, microbiological confirmation in 44 women, antifungal agent not specifiedAll Candida/yeast negativesMicroscopy and culture8–24 wk gestationLBW, PTBNo adjustment for confounding
      Tellapragada
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • Kamath A.
      • Aletty S.
      • Mukhopadhyay C.
      Screening of vulvovaginal infections during pregnancy in resource constrained settings: implications on preterm delivery.
      2017Same population as Tellapragada 2016710Prospective cohortSingleton pregnancy, age >18 y, no DM, hypertension, thyroid antibodies, HIV, placenta previa, cervical insufficiency, smoking, or alcohol consumptionTreatment in 131 symptomatic women, microbiological confirmation in 44 women, antifungal agent not specifiedAll Candida/yeast negativesMicroscopy and culture8–24 wk gestationLate pregnancy loss (20–24 wk gestation)No adjustment for confounding
      Hu402019April to September 2012, China634Prospective cohortSingleton pregnancy, age >18 y, <13 wk at time of enrolment, living in urban area, no termination of pregnancy, no recent antibiotics exposure, not immunocompromisedAll Candida-positive women were treated with 1% clotrimazole cream 500 mg twice a d for 7 dAll Candida/yeast negativesMicroscopy4–12 wk gestationPTB, pPROM, LBWNo adjustment for confounding
      Warr
      • Warr A.J.
      • Pintye J.
      • Kinuthia J.
      • et al.
      Sexually transmitted infections during pregnancy and subsequent risk of stillbirth and infant mortality in Kenya: a prospective study.
      2019May 2011 to June 2013, Kenya1221Prospective cohortSingleton pregnancy, age >14 y, HIV negative, planned to reside in study area until 9 mo postpartum, home visit. Exclusion: spontaneous abortion <20 wk, HIV acquisition during pregnancyAll Candida-positive women were treated with clotrimazole pessary 100 mg daily for 6 dAll Candida/yeast negativesMicroscopy14–36 wk gestation (inclusion changed during course study)Stillbirth, defined as fetal death at ≥20 wk gestation and included births without signs of lifeNo adjustment for confounding
      Poojari
      • Poojari V.G.
      • Dawson S.
      • Vasudeva A.
      • et al.
      Multimodality screening for lower genital tract infections between 18 and 24 weeks of pregnancy and its efficacy in predicting spontaneous preterm delivery.
      2020Period unknown, India228Prospective cohortPregnant womenA proportion of symptomatic women were treated, antifungal agent not describedAll Candida/yeast negativesMicroscopy18–24 wk gestationSpontaneous PTB, pPROMNo adjustment for confounding
      Case-control studies
      McDonald
      • McDonald H.M.
      • O’Loughlin J.A.
      • Jolley P.
      • Vigneswaran R.
      • McDonald P.J.
      Prenatal microbiological risk factors associated with preterm birth.
      1992October 1986 to February 1990, Australia786Nested case-control from a prospective cohortCases: PTB at <37 wk gestation, with or without pPROM, pPROM Controls: delivery >37 wk gestation, admittance in same obstetrical unit Exclusions: complications which indicated preterm delivery by induction of labor or cesarean delivery, abdominal surgery during pregnancy, GIFT pregnanciesLesser proportion Candida positives were treated, antifungal agent not specifiedSee “Patients characteristics”Culture22–28 wk gestationSpontaneous PTBNot adjustment for confounding
      RCTs
      Kiss
      • Kiss H.
      • Petricevic L.
      • Husslein P.
      Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery.
      2004January 2001 to October 2002, Austria4075RCTSingleton pregnancy, without complaints (contractions, vaginal bleeding) or clinical symptoms of vaginal infectionIntervention group: local clotrimazole 100 g for 6 dAll Candida/yeast negativesMicroscopy15–19 wk gestationSpontaneous PTBNo adjustment for confounding
      Control group: no treatment
      Roberts
      • Roberts C.L.
      • Rickard K.
      • Kotsiou G.
      • Morris J.M.
      Treatment of asymptomatic vaginal candidiasis in pregnancy to prevent preterm birth: an open-label pilot randomized controlled trial.
      2011May 2008 to December 2009, Australia495RCTSingleton pregnancy, age >18 y, no symptoms of VVC and no known sensitivity to clotrimazoleIntervention group: clotrimazole 100 mg vaginal pessaries for 6 nightsAll Candida/yeast negativesCulture12–19 wk gestationSpontaneous PTBNo adjustment for confounding
      Control group: no treatment
      DM, diabetes mellitus; GIFT, gamete intrafallopian transfer; HIV, human immunodeficiency virus; LBW, low birthweight (birthweight <2500g); PROM, prelabor rupture of membranes; pPROM, preterm prelabor rupture of membranes; PTB, preterm birth; PTD, preterm delivery; RCT, randomized controlled trial; SGA, small for gestational age; USA, Unites States of America; VVC, vulvovaginal candidiasis.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      a Study size based on participants with both microbiological test result and pregnancy outcome available. Therefore, study size can deviate from the study size mentioned in the original publication.
      b Culture using agar-based techniques unless specified.
      There were considerable differences in the timing of and methods used for testing of vaginal Candida (Figure 2, Table 1). All studies used microscopy (wet mount or gram stain), culture, or a combination of these (Figure 2). No studies used PCR-based techniques. One study used a sensitive liquid culture technique compared with the other studies that used solid culture–based methods.
      • Payne M.S.
      • Ireland D.J.
      • Watts R.
      • et al.
      Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.
      Figure thumbnail gr2
      Figure 2Methods and timing of testing for Candida in vaginal samples
      Overview of the methods used for Candida testing in vaginal samples and the timing of testing during pregnancy.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

       Risk of bias of included studies

      Cohort studies scores ranged from 5 to 9 points on the NOS (Table 2). Six studies were classified as good quality and 10 as fair quality.
      • Cotch M.F.
      • Hillier S.L.
      • Gibbs R.S.
      • Eschenbach D.A.
      Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group.
      ,
      Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery
      The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome.
      • McGregor J.A.
      • French J.I.
      • Richter R.
      • et al.
      Antenatal microbiologic and maternal risk factors associated with prematurity.
      • Germain M.
      • Krohn M.A.
      • Hillier S.L.
      • Eschenbach D.A.
      Genital flora in pregnancy and its association with intrauterine growth retardation.
      • Meis P.J.
      • Goldenberg R.L.
      • Mercer B.
      • et al.
      The preterm prediction study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      ,
      • Garay G.
      • Fraca M.
      • Martinez I.
      • et al.
      Utility of vaginal pH determination in the diagnosis of vulvovaginitis and its association with obstetric pathology.
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      • Payne M.S.
      • Ireland D.J.
      • Watts R.
      • et al.
      Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.
      • Schwab F.D.
      • Zettler E.K.
      • Moh A.
      • Schötzau A.
      • Gross U.
      • Günthert A.R.
      Predictive factors for preterm delivery under rural conditions in post-tsunami Banda Aceh.
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • et al.
      Risk factors for preterm birth and low birth weight Among pregnant Indian women: A hospital-based prospective study.
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • Kamath A.
      • Aletty S.
      • Mukhopadhyay C.
      Screening of vulvovaginal infections during pregnancy in resource constrained settings: implications on preterm delivery.
      • Hu C.Y.
      • Li F.L.
      • Hua X.G.
      • Jiang W.
      • Zhang X.J.
      Longitudinal trajectory of vulvovaginal candidiasis, trichomoniasis, and bacterial vaginosis during pregnancy as well as the impact on pregnancy outcomes: a preliminary study.
      • Warr A.J.
      • Pintye J.
      • Kinuthia J.
      • et al.
      Sexually transmitted infections during pregnancy and subsequent risk of stillbirth and infant mortality in Kenya: a prospective study.
      • Poojari V.G.
      • Dawson S.
      • Vasudeva A.
      • et al.
      Multimodality screening for lower genital tract infections between 18 and 24 weeks of pregnancy and its efficacy in predicting spontaneous preterm delivery.
      The case-control study scored 5 of 9 points on the NOS and was classified as fair quality (Table 2).
      • McDonald H.M.
      • O’Loughlin J.A.
      • Jolley P.
      • Vigneswaran R.
      • McDonald P.J.
      Prenatal microbiological risk factors associated with preterm birth.
      Using the RoB 2.0 tool, the RCT by Roberts et al
      • Roberts C.L.
      • Rickard K.
      • Kotsiou G.
      • Morris J.M.
      Treatment of asymptomatic vaginal candidiasis in pregnancy to prevent preterm birth: an open-label pilot randomized controlled trial.
      was classified as “low risk of bias” (Supplemental Figure 1). The study by Kiss et al
      • Kiss H.
      • Petricevic L.
      • Husslein P.
      Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery.
      was classified as “some concerns,” mainly caused by a posthoc subgroup analysis of the outcome of interest (Supplemental Figure 1).
      Table 2Critical appraisal using the Newcastle-Ottawa Quality Assessment Scale for cohort and case-control studies
      Newcastle-Ottawa Quality Assessment Scale
      CohortSelectionComparability

      1
      OutcomeTotalQuality score
      1234123
      Minkoff et al
      • Minkoff H.
      • Grunebaum A.N.
      • Schwarz R.H.
      • et al.
      Risk factors for prematurity and premature rupture of membranes: a prospective study of the vaginal flora in pregnancy.
      1984++++++6Fair
      John Hopkins Group
      Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery
      The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome.
      1989++++++++9Good
      McGregor et al
      • McGregor J.A.
      • French J.I.
      • Richter R.
      • et al.
      Antenatal microbiologic and maternal risk factors associated with prematurity.
      1990+++++++7Good
      Germain et al
      • Germain M.
      • Krohn M.A.
      • Hillier S.L.
      • Eschenbach D.A.
      Genital flora in pregnancy and its association with intrauterine growth retardation.
      1994+++++++7Good
      Meis et al
      • Meis P.J.
      • Goldenberg R.L.
      • Mercer B.
      • et al.
      The preterm prediction study: significance of vaginal infections. National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network.
      1995++++++6Fair
      Cotch et al
      • Cotch M.F.
      • Hillier S.L.
      • Gibbs R.S.
      • Eschenbach D.A.
      Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group.
      1998++++++6Fair
      Beltrán Montoya et al
      • Beltrán Montoya J.
      • Avila-Vergara M.A.
      • Vadillo-Ortega F.
      • Hernández-Guerrero C.
      • Peraza-Garay F.
      • Olivares-Morales S.
      Cervicovaginal infection as a risk factor for premature labor [Article in Spanish].
      2002++++++6Fair
      Garay et al
      • Garay G.
      • Fraca M.
      • Martinez I.
      • et al.
      Utility of vaginal pH determination in the diagnosis of vulvovaginitis and its association with obstetric pathology.
      2011++++++6Fair
      Farr et al
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      2015++++++++9Good
      Payne et al
      • Payne M.S.
      • Ireland D.J.
      • Watts R.
      • et al.
      Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women.
      2016+++++++7Good
      Schwab et al
      • Schwab F.D.
      • Zettler E.K.
      • Moh A.
      • Schötzau A.
      • Gross U.
      • Günthert A.R.
      Predictive factors for preterm delivery under rural conditions in post-tsunami Banda Aceh.
      2016+++++5Fair
      Tellapragada et al
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • et al.
      Risk factors for preterm birth and low birth weight Among pregnant Indian women: A hospital-based prospective study.
      2016++++++6Fair
      Tellapragada et al
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • Kamath A.
      • Aletty S.
      • Mukhopadhyay C.
      Screening of vulvovaginal infections during pregnancy in resource constrained settings: implications on preterm delivery.
      2017++++++6Fair
      Hu et al
      • Hu C.Y.
      • Li F.L.
      • Hua X.G.
      • Jiang W.
      • Zhang X.J.
      Longitudinal trajectory of vulvovaginal candidiasis, trichomoniasis, and bacterial vaginosis during pregnancy as well as the impact on pregnancy outcomes: a preliminary study.
      2019++++++6Fair
      Warr et al
      • Warr A.J.
      • Pintye J.
      • Kinuthia J.
      • et al.
      Sexually transmitted infections during pregnancy and subsequent risk of stillbirth and infant mortality in Kenya: a prospective study.
      2018+++++++7Good
      Poojari et al
      • Poojari V.G.
      • Dawson S.
      • Vasudeva A.
      • et al.
      Multimodality screening for lower genital tract infections between 18 and 24 weeks of pregnancy and its efficacy in predicting spontaneous preterm delivery.
      2020+++++5Fair
      Case-control study
      McDonald et al
      • McDonald H.M.
      • O’Loughlin J.A.
      • Jolley P.
      • Vigneswaran R.
      • McDonald P.J.
      Prenatal microbiological risk factors associated with preterm birth.
      1992+++++5Fair
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

       Synthesis of results

       Preterm birth

      We included 15 studies, which included a total of 33,321 women, and reported on the association between Candida and PTB, that is, 12 cohort studies, 2 RCTs, and 1 case-control study. One study reported a significantly increased OR for PTB in Candida-positive women based on a small number of PTB cases (n=5).
      • Garay G.
      • Fraca M.
      • Martinez I.
      • et al.
      Utility of vaginal pH determination in the diagnosis of vulvovaginitis and its association with obstetric pathology.
      Overall, 9.8% of women with vaginal Candida delivered prematurely compared with 9.4% of women without vaginal Candida. On meta-analysis, vaginal Candida was not associated with PTB (OR, 1.10; 95% CI, 0.99–1.22; I2, 0%) (Figure 3). We performed subgroup analysis for spontaneous PTB only and all PTB (no differentiation between indicated and spontaneous PTBs). Vaginal Candida was not associated with spontaneous PTB (OR, 1.13; 95% CI, 0.97–1.31; I2, 0%) in 8 studies among 16,948 women (Figure 3) or all PTB (OR, 1.04; 95% CI, 0.79–1.35; I2, 21%) in 7 studies among 16,373 women.
      Figure thumbnail gr3
      Figure 3Meta-analysis for preterm birth
      Meta-analysis for PTB with subgroup analysis for spontaneous and overall PTB.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Generally, 3 different treatment strategies were used in the studies as follows: treatment of all Candida-positive women, treatment of part of these women, and treatment of none of them. To examine whether treatment strategy influenced the results, subgroup analyses were performed for each treatment strategy, focusing on spontaneous PTB. In the subgroup meta-analysis of studies with a “no treatment” strategy, we observed no association between vaginal Candida and spontaneous PTB (OR, 1.28; 95% CI, 0.90–1.81; I2, 13%) in 3 studies among 5175 women, and no association was also observed in studies with a “treat all” strategy (OR, 1.10; 95% CI, 0.87–1.40; I2, 9%) in 3 studies among 10,264 women or “treat some” strategy (OR, 1.06; 95% CI, 0.71–1.59; I2, 0%) in 3 studies among 1509 women (Figure 4). The influence of treatment method and dosing on spontaneous PTB was investigated using all studies with a “treat all” or “treat some” strategy but revealed no associations (Supplemental Figure 2).
      Figure thumbnail gr4
      Figure 4Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for different treatment options.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Clinical heterogeneity between the studies was also examined using subgroup analyses for the influence of methods used for Candida detection (microscopy, culture, or both) and timing of testing (<24 weeks’ gestation or >24 weeks’ gestation) on spontaneous PTB. None of the subgroup analyses indicated an association with vaginal Candida (Supplemental Figures 3 and 4). The influence of study design on spontaneous PTB was investigated with a sensitivity analysis, revealing no differences between RCTs (2 studies, 3 groups), prospective cohort studies (4 in total), retrospective cohort studies (1 study), and case-control studies (1 study) (Supplemental Figure 5). Several sensitivity analyses for study location also did not reveal differences (Unites States of America vs other [Supplemental Figure 6], Europe vs other [Supplemental Figure 7], Australia vs other [Supplemental Figure 8]).

       Other adverse pregnancy outcomes

      We identified ≥2 studies that reported on the following outcomes: small for gestational age, pPROM, neonatal mortality, low birthweight, PROM, and stillbirth. All studies reporting on birth defined low birthweight as birthweight below 2500 grams. In 1 study, an increased risk for small for gestational age in an offspring was found when vaginal Candida was present in the mother. The only other study to report on small for gestational age did not find an association between vaginal Candida and small for gestational age in a 14-fold larger population.
      • Germain M.
      • Krohn M.A.
      • Hillier S.L.
      • Eschenbach D.A.
      Genital flora in pregnancy and its association with intrauterine growth retardation.
      A summary point estimate could not be calculated owing to significant heterogeneity. No associations were found for the other outcomes and vaginal Candida in either the individual studies or summary statistics (Figure 5). We were unable to perform subgroup analyses owing to the small number of studies reporting on these outcomes. One study reported on pregnancy loss between 20 and 24 weeks’ gestation, which indicated no association with vaginal Candida.
      • Tellapragada C.
      • Eshwara V.K.
      • Bhat P.
      • Kamath A.
      • Aletty S.
      • Mukhopadhyay C.
      Screening of vulvovaginal infections during pregnancy in resource constrained settings: implications on preterm delivery.
      For the other defined outcomes, meta-analysis was not possible because no studies were identified.
      Figure thumbnail gr5
      Figure 5Meta-analysis for the other outcomes
      Meta-analysis for small for gestational age infants, pPROM, neonatal death, low-birthweight infants (defined as birthweight <2500 g), PROM, and stillbirth.
      Event, the occurrence of the outcome; M-H, Mantel-Haenszel; PROM, prelabor rupture of membranes; pPROM, preterm prelabor rupture of membranes.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

      Comment

       Main findings

      We found that vaginal Candida did not increase the risk for spontaneous PTB, irrespective of the antifungal treatment. We also did not find evidence for an association between vaginal Candida and any other adverse pregnancy outcomes.

       Strengths and Limitations

      The strengths of this review are the overall high quality of included studies, the high number of patients in the PTB meta-analysis, and the low heterogeneity among the studies. We recognize that there are some limitations to our study. We were not able to perform meta-analysis on several outcomes, such as late pregnancy loss, spontaneous demise of pregnancy at <20 weeks’ gestation, maternal mortality, maternal morbidity, and neonatal morbidity. Secondly, some the pooled effect sizes of some of the outcomes and subgroup analyses are based on a limited amount of studies, which increases the likelihood of type II error. It is possible that vaginal Candida is associated with PTB or another adverse pregnancy outcome with bigger sample size. Finally, this systematic review included exclusively observational evidence, which can pose a risk for confounding. In particular, ethnicity is an important risk factor for both PTB and vaginal Candida, which we were not able to account for in our analyses.
      • Geiger A.M.
      • Foxman B.
      Risk factors for vulvovaginal candidiasis: a case-control study among university students.
      ,
      • Schaaf J.M.
      • Liem S.M.
      • Mol B.W.
      • Abu-Hanna A.
      • Ravelli A.C.
      Ethnic and racial disparities in the risk of preterm birth: a systematic review and meta-analysis.
      Two included studies had corrected for possible confounders: none of which reported a change in effect estimate size of their null findings after correction (data not indicated), suggesting that confounding did not play a major role in the lack of effect observed in these studies.
      Association of Chlamydia trachomatis and Mycoplasma hominis with intrauterine growth retardation and preterm delivery
      The John Hopkins Study of Cervicitis and Adverse Pregnancy Outcome.
      ,
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      However, residual confounding was always possible.

       Comparison with existing literature

      Our review’s findings are at odds with a recent systematic review, which reported that local antifungal agents would lower spontaneous PTB risk among women with asymptomatic vaginal Candida colonization.
      • Roberts C.L.
      • Algert C.S.
      • Rickard K.L.
      • Morris J.M.
      Treatment of vaginal candidiasis for the prevention of preterm birth: a systematic review and meta-analysis.
      This systematic review included only women positive for vaginal Candida (685 women in total) from 2 studies also included in our analyses.
      • Kiss H.
      • Petricevic L.
      • Husslein P.
      Prospective randomised controlled trial of an infection screening programme to reduce the rate of preterm delivery.
      ,
      • Roberts C.L.
      • Rickard K.
      • Kotsiou G.
      • Morris J.M.
      Treatment of asymptomatic vaginal candidiasis in pregnancy to prevent preterm birth: an open-label pilot randomized controlled trial.
      The authors of the systematic review explained that the results must be interpreted with caution, because the primary driver of the analysis was a posthoc subgroup analysis of 1 of the contributing trials. We investigated whether treatment of Candida-positive women explained the lack of effect on spontaneous PTB, but stratification by treatment protocol did not yield any differences in effect size. This implies that the absence of an association between vaginal Candida and spontaneous PTB in our analysis is not explained by the effects of treatment.
      In the absence of an increase in the risk for PTB attributable to vaginal Candida, the apparent protective effect of clotrimazole on PTB may be caused by its antiinflammatory properties. Inflammation is a risk factor for PTB and fetal growth restriction, and reducing local inflammation might lead to decreased adverse outcomes. In levels much lower than used for treatment, clotrimazole reduces neutrophil attraction and inflammatory cytokine production by vaginal epithelial cells in vitro.
      • Wilson D.
      • Hebecker B.
      • Moyes D.L.
      • et al.
      Clotrimazole dampens vaginal inflammation and neutrophil infiltration in response to Candida albicans infection.
      By not limiting future studies on clotrimazole to women with asymptomatic candidiasis, the effects of clotrimazole on perinatal outcomes could be more thoroughly studied. This promising pathway needs further exploration in a clinical setting.
      Another explanation for the difference between our review and previous studies might be that not only the presence of vaginal Candida can cause an increase in PTB but also recurrence of vaginal Candida or colonization with specific Candida spp. A subgroup analysis of the study by Farr et al
      • Farr A.
      • Kiss H.
      • Holzer I.
      • Husslein P.
      • Hagmann M.
      • Petricevic L.
      Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome.
      indicated that the incidence of spontaneous PTB and low birthweight was highest among women with recurrent Candida colonization compared with women without Candida. Recurrent candidiasis is more often caused by Candida glabrata, which is not susceptible to clotrimazole.
      • Richter S.S.
      • Galask R.P.
      • Messer S.A.
      • Hollis R.J.
      • Diekema D.J.
      • Pfaller M.A.
      Antifungal susceptibilities of Candida species causing vulvovaginitis and epidemiology of recurrent cases.
      One study in our analysis with 13,867 subjects compared colonized women with Candida albicans– and non-albicans–colonized women, but found no differences between the groups for PTB and low birthweight.
      • Cotch M.F.
      • Hillier S.L.
      • Gibbs R.S.
      • Eschenbach D.A.
      Epidemiology and outcomes associated with moderate to heavy Candida colonization during pregnancy. Vaginal Infections and Prematurity Study Group.
      Our study yielded insufficient papers that looked at recurrent vaginal Candida colonization or different Candida spp to further investigate this hypothesis.

       Conclusion

      In this systematic review and meta-analysis, we found that in asymptomatic pregnant women, vaginal colonization with Candida did not increase spontaneous PTB or other adverse pregnancy outcomes. These results do not support the hypothesis that the protective effect of clotrimazole found in previous studies is based on an association between vaginal Candida and PTB.

       Implications

      At the moment, standard screening for Candida during pregnancy is not included in international guidelines; our findings support this policy.
      • Pappas P.G.
      • Kauffman C.A.
      • Andes D.R.
      • et al.
      Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America.
      Our results may imply that the ability of clotrimazole to achieve PTB prevention does not operate through its antifungal properties—an area that urgently needs to be addressed in future research.

      Acknowledgments

      The authors wish to thank Dr Chaitanya (Directorate of Research (Health Sciences), Manipal University, Manipal, India), Dr Garay, Dr John-Stewart (Departments of Global Health, Epidemiology, and Medicine, University of Washington, Seattle, Washington), Dr Payne (School of Women’s and Infants’ Health, University of Western Australia, Subiaco, Australia), and Dr Zhang (Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, People’s Republic of China) for providing additional data of their studies. The contributors were not compensated for their efforts. The authors in the included articles report no conflict of interest.

      Appendix

      Figure thumbnail fx1
      Supplemental Figure 1Risk for bias graph of the included randomized controlled trials using the revised Cochrane risk-of-bias tool
      +/green, low; −/orange, some concerns; −/red, high.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx2
      Supplemental Figure 2Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB including only studies that provided treatment for some or all participants with asymptomatic vaginal Candida colonization, with subgroup analysis for treatment method and dose.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx3
      Supplemental Figure 3Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for different methods used for Candida detection (microscopy, culture, or both).
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx4
      Supplemental Figure 4Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for testing at <24 wk gestation and >24 wk gestation.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx5
      Supplemental Figure 5Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for study design.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx6
      Supplemental Figure 6Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for study location, comparing studies performed in the United States with studies performed in other countries.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx7
      Supplemental Figure 7Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for study location, comparing studies performed in Europe with studies performed in other countries.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.
      Figure thumbnail fx8
      Supplemental Figure 8Meta-analysis for spontaneous PTB
      Meta-analysis for spontaneous PTB with subgroup analysis for study location, comparing studies performed in Australia with studies performed in other countries.
      M-H, Mantel-Haenszel; PTB, preterm birth.
      Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

      Supplementary Data

      • Appendix 1

        PRISMA statement and checklist

        PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.

        Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

      • Appendix 2

        MOOSE checklist

        MOOSE, Meta-analyses Of Observational Studies in Epidemiology.

        Schuster. Asymptomatic vaginal Candida colonization and adverse pregnancy outcomes. AJOG MFM 2020.

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