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Systematic Review
Revised

Smokeless tobacco use and reproductive outcomes among women: a systematic review

[version 2; peer review: 2 not approved]
PUBLISHED 03 May 2022
Author details Author details
OPEN PEER REVIEW
REVIEWER STATUS

Abstract

Background: Both smoked and smokeless tobacco use have deleterious effects on most major organ systems including the
reproductive system. We conducted a systematic review on smokeless tobacco (SLT) use and
reproductive outcomes among women.
Methods: We searched Pubmed, ProQuest, Cochrane, Wiley and Emerald databases for studies
involving smokeless tobacco use in women with any or a combination of three conditions:
infertility, menstrual disorders and pelvic inflammatory disease (PID). Eligibility criteria included
English language publications from 1st January 1990 - 31st October 2020. CADIMA software
used for filtering the studies and modified SIGN checklist for the quality assessment. The findings
are reported as per the PRISMA guidelines. The AXIS and ROBIN E tool were used for assessment of risk of bias.
Results: In total, three studies addressed our research question. Two studies addressed infertility
(prospective cohort: n=501, cross sectional: n=192) of which, the cross-sectional study compared
the mean cotinine levels between those with infertility, menstrual disorders and PID. This study
also explored the association between SLT and PID. PID was the most common gynecological
complaint. Women with PID had significantly higher urinary cotinine levels = 24.95±12.259) ng/
ml (p=0.0144). Mean urinary cotinine in women with menstrual complaints was 19.32±10.29 ng/ml. 
The other study used population-based sampling of 501 couples who attempted pregnancy (enrolled in the LIFE Study). 
Results showed that 9% and 2% (n=28) of men used snuff and chewed tobacco respectively. and  few of the women used smokeless tobacco. 
Time to pregnancy was shorter among smokeless tobacco users relative to smokers.
Conclusions: Available studies exploring associations between SLT and reproductive outcomes
are inconclusive due to limitations in the study methodologies. More studies with robust study
designs are required from low- and middle-income countries with high prevalence of SLT use.

Keywords

Smokeless Tobacco, infertility, menstruation, abnormal uterine bleeding, pelvic infections, reproductive health, women

Revised Amendments from Version 1

Information highlighting the burden of SLT use in low- and middle-income countries, time to pregnancy in the SLT users have and the been included in the discussion section.
The use of smokeless tobacco is particularly prevalent in Asian countries. India carries 83% of global burden of SLT use. There are nearly 58.2 million women consuming some form of SLT in India (GATS 2 survey 2016-17). Adverse effects of SLT use among women specifically includes infertility and poor pregnancy outcomes. Nicotine crosses the placental barrier resulting in a neuroteratogenic effect in the developing fetus.
While tobacco and its metabolic products are known to cause infertility, the time to pregnancy (TTP) interval was observed to be lesser in SLT users than smokers in the study included in our review. This aspect needs more research with comparisons drawn with smokers and tobacco nonusers.
A limited number of studies investigated the relationship between SLT use among women and pelvic infections and menstrual function.
In our review, we identified gaps in knowledge concerning the association of SLT use with reproductive outcomes in women.  Further primary research is needed to determine the impact of smoked and smokeless tobacco products on women's reproductive health.

To read any peer review reports and author responses for this article, follow the "read" links in the Open Peer Review table.

Introduction

Use of both smoked and smokeless forms of tobacco is a major cause of preventable morbidity and mortality. It kills half of all its lifetime users (WHO, 2011) and more than 8 million people each year, out of which, 1.2 million die due to second hand smoke (WHO, 2019). Toxic and carcinogenic chemicals in tobacco along with other ingredients that are added to them are known to be causally associated with several non-communicable diseases (NCDs) including cancer, especially oral cancer which is the leading cancer among men and the third most common cancer among women in India (Bhisey, 2012).

Smokeless tobacco (SLT) is “consumed without combustion at the time of use” (WHO, 2015). It is generally used orally (sucked, chewed, dipped or held in the mouth, used as dentifrice or toothpaste) or nasally resulting in nicotine absorption across the mucous membrane, along with other chemicals. Majority of SLT users, approximately 286 million people, live in low and middle-income countries in South-East Asia region. Three countries, namely India, Bangladesh, and Myanmar, host around 86% of the global users (NCI &CDC, 2014). As per Global Adult Tobacco survey 2016-17, women accounted for 2% among around 99.5 million adults current smokers. In contrast, 12.8% of women used SLT out of 199.4 million adults (GATS, 2017).

SLT use is addictive; it leads to oral health problems and plays a contributory role in the development of cardiovascular disorders, fatal ischemic heart disease, stroke, peripheral vascular diseases, peptic ulcers, type 2 diabetes, chronic rhinitis, foetal morbidity and mortality (WHO, 2015; Inamdar et al., 2015; Suliankatchi and Sinha, 2016; Hossain et al., 2017). The leading health consequences related to SLT use in Southeast Asia include cancers of numerous sites along with poor reproductive outcomes (World Health Organization. News release 11th Sept 2013).

Tobacco use in India is majorly considered a male-dominant behavior. However, over the past decade, the use of SLT products by Indian women is substantial and increasing, with adverse consequences for oral (Niaz et al., 2017; Singh et al., 2020) and perinatal health (Inamdar et al., 2015; Suliankatchi and Sinha, 2016; Nair et al., 2015). Women who use SLT are at risk of oral (Singh et al., 2020) and pharyngeal cancers (Niaz et al., 2017; Datta et al., 2014; Sinha et al., 2016; Awan and Patil, 2016), esophageal cancer (Niaz et al., 2017; Datta et al., 2014; Sinha et al., 2016; Awan and Patil, 2016), cervical cancer, ischemic heart disease (IHD) (Sinha et al., 2018) and osteoporosis (Ayo-Yusuf and Olutola, 2014). Compounds in SLT products such as nicotine act as neuro-teratogens as they can cross the placental barrier (Liao et al., 2012) affecting the fetal development along with other pregnancy complications like pre-term delivery, low-birth weight (Inamdar et al., 2015; Suliankatchi and Sinha, 2016) increased stillbirth risk (Hossain et al., 2017) and risk of cancers in the developing fetus (Rogers et al., 2009). However, there is little evidence that explores the association between SLT use and reproductive health of women. Therefore, we planned to systematically conduct a review on smokeless tobacco (SLT) use and reproductive health among women.

Methods

The protocol was registered on PROSPERO on 2nd October 2020 (CRD42020207176). This paper is reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Radhika, 2021).

We did an extensive literature search that described the association between SLT use and selected reproductive outcomes in women. For this, we selected three common reproductive outcomes, namely infertility, menstrual disorders and pelvic inflammatory disease. The search terms revolved around P (population): women, E (exposure): exposure to SLT, C (control): women who were not exposed to SLT, O (outcome): reproductive outcomes in women that included infertility, menstrual disorders, and pelvic inflammatory disorder (PID). The reference period was from 01 January 1990 to 31st October 2020.

Eligibility criteria

Publications including reviews, original trials and conference proceedings documenting any form of SLT use along with the three selected reproductive outcomes in English language within the timeframe were considered for the inclusion.

Information sources

Studies were identified by searching electronic databases (Pubmed, Wiley, Cochrane Library, Emerald and ProQuest) in addition to scanning reference lists of articles using the chosen keywords for all three reproductive outcomes separately.

Search strategy

Search strings used for infertility among women and SLT were: (Smokeless OR Chew OR Chewing OR Dipping OR Snuff OR toothpaste OR dentifrice OR paan masala OR betel quid OR betelquid OR areca nut OR arecanut) AND (Tobacco OR Tobaccos OR Gutka OR Gutkas OR Snuff OR Mint) AND (Female OR Women) AND (Infertility OR Subfertility OR Sub Fertility OR sterility OR Infertile OR sterile).

Search strings used for Menstrual disorders and SLT were: (Smokeless OR Chew OR Chewing OR Dipping OR Snuff OR toothpaste OR dentifrice OR paan masala OR betel quid OR betelquid OR areca nut OR arecanut) AND (Tobacco OR Tobaccos OR Gutka OR Gutkas OR Snuff OR Mint) AND (Female OR Women) AND (menstrual OR menstruation OR bleeding OR menorrhagia OR Hypermenorrhea OR Hypermenorrhoea OR Hypomenorrhea OR Hypomenorrhoea OR dysmenorrhea OR dysmenorrhea OR Abnormal uterine bleeding OR amenorrhea OR menometrorrhagia OR metrorrhagia OR dysfunctional uterine bleeding.

For PID and SLT use, search strings used were (Smokeless OR Chew OR Chewing OR Dipping OR Snuff OR toothpaste OR dentifrice OR paan masala OR betel quid OR areca nut) AND (Tobacco OR Tobaccos OR Gutka OR Gutkas OR Snuff OR Mint) AND (Female OR Women) AND (infection OR inflammation OR pelvic inflammatory disease OR PID OR genital infections OR genital tuberculosis OR tubo-ovarian mass OR Salpingitis OR salpingo-oophoritis OR endometritis OR adnexitis OR parametritis).

Study selection

We included studies irrespective of sample size. After duplicate removal by CADIMA, every record was screened by two reviewers independently using the title. Those accepted by both were subjected to abstract review. In case of any disagreement, arbitration was done by a senior member from the team. For the selected abstracts, full articles were obtained, and quality check was performed by two reviewers independently using the modified SIGN checklist. Those selected at this stage were eligible for the review. The study selection is mentioned according to reproductive outcomes selected and reported according to PRISMA guidelines. The AXIS tool was used to assess risk of bias (Ma et al., 2020) for cross sectional study and the ROBIN E tool was used for prospective studies.

Data items and data collection process

Full text appraisal for study selection was done by two authors independently. Title & abstract filtering was done with CADIMA. Information was extracted from all the eligible studies on a predesigned format (Tables 24) including a range of study variables relating to the design, objectives, and outcomes. For each of the reproductive outcomes, studies included were summarized separately.

Results

Search for infertility among women and SLT use resulted in 1093 results which were run through CADIMA for removal of the duplicate studies, which gave a final of 1062 results (9 from Pubmed; 44 from Wiley; 6 from Emerald; 11 from Cochrane and 992 from ProQuest). that for Menstrual disorders and SLT gave 1330 results. These results were run through CADIMA for removal of the duplicate studies, which gave a final of 1294 results (44 from Pubmed; 19 from Wiley; 25 from Cochrane and 1206 from ProQuest). For PID and SLT use, there were 3929 results. These results were run through CADIMA for removal of the duplicate studies, which gave a final of 3808 results (205 from pubmed; 27 from wiley; 46 from Cochrane and 3530 from proquest) (Table 1).

Table 1. Number of search results from each database and dates of search performed.

Reproductive outcomes among womenPubmedWileyEmraldCochraneProquestTotal
InfertilityNo. of results94761110201093
Date10-11-2011-11-2011-11-2012-11-2015-11-20
MenstruationNo. of results462602512331330
Date11-11-2012-11-2012-11-2013-11-2013-11-20
PIDNo. ofresults2113704636353929
Date11-11-2012-11-2012-11-2013-11-2025-11-20

The search revealed a total of two studies (prospective cohort, n = 501 and cross sectional, n = 192) addressing our research question related to infertility (Figure 1, Table 2).

a7bae227-70cd-4291-a0e8-f93dea52256d_figure1.gif

Figure 1. Study selection for smokeless tobacco (SLT) use and infertility among women.

IVF = in vitro fertilization.

Table 2. Data extraction sheet for smokeless tobacco (SLT) use and infertility.

TTP = time-to-pregnancy; FOR = fecundability odds ratio; OR = odds ratio; CI = confidence interval.

S. no.4I6I
TitleTime-to-Pregnancy Associated with Couples’ Use of Tobacco ProductsAssessment of urinary cotinine levels in women with gynecological complaints at a tertiary care hospital: A pilot study
AuthorsKatherine J. Sapra, Dana B. Barr, José M. Maisog, Rajeshwari Sundaram, Germaine M. Buck LouisA. G. Radhika, Sruthi Bhaskaran, Jagdish Kaur, Anshuja Singla, Tusha Sharma, B. D. Banerjee
Year of Publication20162017
CountryUSAIndia
Study objective1. To assess the relationship between couples’ preconception tobacco use (smokeless and combustible) and prospectively observed TTP.
2. To evaluate blood heavy metal and serum cotinine concentrations among various tobacco product users and nonusers to determine if specific chemicals may contribute to changes in TTP
To evaluate the urinary cotinine levels in women of reproductive age with common gynecological conditions (PID, infertility, and AUB).
Study designProspective cohortCross-sectional pilot
Study setting (hospital/community)CommunityHospital
Study populationPopulation-based sampling, 501 couples who discontinued contraception for becoming pregnant in 16 counties in Michigan and Texas, 2005–2009, enrolled in the LIFE Study. Inclusion criteria - Both partners spoke English or Spanish, were discontinuing contraception to attempt pregnancy or were off contraception not more than 2 months, males aged 18 years and above, females aged 18–40 years, had menstrual cycle length of 21–42 days, and had not received injectable contraception in the past year.Women presenting at gynecological outpatient clinic of GTB hospital among non-pregnant women of reproductive age having any of the complaints namely menstrual disturbance, infertility or pelvic inflammatory disease. Sample size 192.
Primary exposurelifetime and current use of tobacco in any form - cigarette, cigar, and chew/snuff (smokeless) usetobacco use or exposure (any form) in self or family members
Method of ascertainmentQuestionnaire administered by strained study personnel, fertility monitor, Regular use of highly sensitive home pregnancy tests and blood samples for quantification of heavy metals and cotinineInterview/questionnaire, urinary cotinine (spot urine test)
Secondary exposure(s)NoneSecondhand Exposure to smoked tobacco
Method of ascertainmentNAInterview/questionnaire, urinary cotinine (spot urine test)
Intervention (if applicable)NoneNone
Control (if applicable)never users (participants who never used any tobacco product)None
Primary outcome11% of females and 15% of males smoked cigarettes. Among men, 14% smoked cigars, 9% used snuff, and 2% used chew. Cadmium levels were higher in smokers than smokeless tobacco and never users; adjusting for cadmium attenuated the cigarette–TTP association, particularly among women. TTP was shorter among smokeless tobacco users relative to smokers (FOR: 2.86, 95% CI: 1.47, 5.57).Assessment of urinary cotinine: The mean urinary cotinine level in women exposed to SHS was 23.82 ± 12.67 ng/ml. PID was the most common gynecological complaint. Women with PID had significantly higher urinary cotinine levels compared to those with Mean urinary cotinine levels in infertile women were 22.42 ± 12.72 ng/ml
Secondary outcome(s)Compared with never tobacco users, male (FOR: 0.41, 95% CI: 0.24, 0.68) and female (FOR: 0.53, 95% CI: 0.33, 0.85) smoking were individually associated with longer TTP; males’ smoking remained significant (FOR: 0.46, 95% CI: 0.27, 0.79) when modeling partners together.NA
Sample size (group1)293 couples192
Sample size (group2)208 couplesNA
Sampling strategyParticipants were selected from marketing databases (Michigan) or state wildlife and fish registry (Texas)Urinary cotinine levels in three common categories of gynecological complaints, among non-pregnant women of reproductive age residing in East Delhi who sought treatment from gynecological outpatient clinic of Guru Tegh Bahadur Hospital. The hospital caters to patients living in urban slums in NandNagri, Seema Puri, and Seelampur. The population density in these areas is very high, with congested living conditions. Majority belong to low-income group.
Co variates/confoundersAge, race/ethnicity, educational attainment, income, and alcohol and caffeine use. Height, weight, Metals with significantly different blood level concentrations across tobacco types.Secondhand smoking
BiasesSampling bias (only 28 men smokeless tobacco users, no women used smokeless tobacco)Sample not enough and other confounding variables not considered; None of the participants admitted to smoking or use of SLT.
Measure of association (OR/RR)OR (adjusted Fecund ability Odds Ratio); FOR: 2.86, 95%Mean±SD
Lower bound1.47Infertility – 9.70
Menstrual disorders – 9.03
PID – 12.96
Upper bound5.57Infertility – 35.14
Menstrual disorders – 29.61
PID – 37.21
Sub group analysisNoneNone
Results of sub group analysisNANA

The prospective cohort study used population-based sampling with 501 couples who attempted pregnancy in Michigan and Texas, 2005–2009 (enrolled in the LIFE Study). Results showed that only 2% (n = 28) of men were SLT users and no women used smokeless tobacco. Smokers showed higher cadmium levels than SLT, adjusted for cadmium attenuated the cigarette–time-to-pregnancy (TTP) association, especially among women. Shorter TTP was observed among SLT users in comparison to smokers (FOR [fecundability odds ratio]: 2.86, 95% confidence interval [CI]: 1.47, 5.57). Compared with never users of tobacco, smoking by females (FOR: 0.53, 95% CI: 0.33, 0.85) was individually associated with longer TTP; for males, smoking remained significant (FOR: 0.46, 95% CI: 0.27, 0.79) when modeling partners together (Sapra et al., 2016).

A cross sectional study carried out in India to evaluate the urinary cotinine levels in three common categories of gynecological complaints, among 192 women of reproductive age, who were not pregnant, and sought treatment from a Government Medical college. Results showed that mean urinary cotinine level in women exposed to secondhand smoking (SHS) was 23.82±12.67 ng/ml. PID was the most common gynecological complaint. Mean urinary cotinine levels in infertile women were 22.42±12.72 ng/ml. The limitations of this study were that the sample size was not enough, other confounding variables were not considered and none of the participants admitted to smoking or use of SLT (Radhika et al., 2014; 2017).

The same study found that mean urinary cotinine levels in women with menstrual complaints was 19.32±10.29 ng/ml. Out of 1330 articles obtained on initial search, this was the only study selected in our review to study the association between SLT and menstrual problems (Figure 2, Table 3). For the question related to PID, another study (Simen-Kapeu et al., 2009) in addition to this study was selected (Figure 3, Table 4). Women with PID had significantly higher urinary cotinine levels = 24.95 (±12.259) ng/ml (p = 0.0144) (Radhika et al., 2017).

a7bae227-70cd-4291-a0e8-f93dea52256d_figure2.gif

Figure 2. Study selection for smokeless tobacco (SLT) use and menstrual disorders

Table 3. Data extraction matrix for smokeless tobacco (SLT) use and menstrual problems.

PID = pelvic inflammatory disease. SD = standard deviation.

Study ID13M
Name of the studyAssessment of urinary cotinine levels in women with gynecological complaints at a tertiary care hospital: A pilot study
AuthorsA. G. Radhika, Sruthi Bhaskaran, Jagdish Kaur, Anshuja Singla, Tusha Sharma, B. D. Banerjee
Year of Publication2017
CountryIndia
Study objectiveTo evaluate the urinary cotinine levels in women of reproductive age with common gynecological conditions (PID, infertility, and AUB).
Study designCross-sectional pilot
Study setting (hospital/community)Hospital
Study populationWomen presenting at gynecological outpatient clinic of GTB hospital among non-pregnant women of reproductive age having any of the complaints namely menstrual disturbance, infertility or pelvic inflammatory disease. Sample size 192.
Primary exposureTobacco use or exposure (any form) in self or family members
Method of ascertainmentInterview/questionnaire, urinary cotinine (spot urine test)
Secondary exposure(s)Secondhand exposure to smoked tobacco
Method of ascertainmentInterview/questionnaire, urinary cotinine (spot urine test)
Intervention (if applicable)None
Control (if applicable)None
Primary outcomeAssessment of urinary cotinine: The mean urinary cotinine level of women exposed to SHS was 23.82 ± 12.67 ng/ml. Women with menstrual complaints 19.32 ± 10.29 ng/ml, P = 0.029
Secondary outcome(s)NA
Sample size (group1)192
Sample size (group2)NA
Sampling strategyUrinary cotinine levels in three common categories of gynecological complaints, among non-pregnant women of reproductive age residing in East Delhi who sought treatment from gynecological outpatient clinic of Guru Tegh Bahadur Hospital. The hospital caters to patients living in urban slums in NandNagri, Seema Puri, and Seelampur. The population density in these areas is very high, with congested living conditions. Majority belongs to low-income group. Consecutive, spot urine sample.
Co variates/confoundersSecond-hand smoking
BiasesPatients presenting to the hospital with specific gynecological complaints. Sample not enough and other confounding variables not considered
Measure of association (OR/RR)Mean±SD
Lower boundInfertility – 9.70
Menstrual disorders – 9.03
PID – 12.96
Upper boundInfertility – 35.14
Menstrual disorders – 29.61
PID – 37.21
Sub group analysisNone
Results of sub group analysisNA
a7bae227-70cd-4291-a0e8-f93dea52256d_figure3.gif

Figure 3. Study selection for smokeless tobacco (SLT) use and pelvic inflammatory disease (PID) among women.

Table 4. Data extraction matrix for smokeless tobacco (SLT) use and pelvic inflammatory disorder.

HPV = human papillomavirus; OR = odds ratio; CI = confidence interval; LSIL = low-grade squamous intraepithelial lesion; HSIL = high-grade squamous intraepithelial lesion.

Study ID426P3697P
Name of the studyAssessment of urinary cotinine levels in women with gynecological complaints at a tertiary care hospital: A pilot studyTobacco smoking and chewing as risk factors for multiple human papillomavirus infections and cervical squamous intraepithelial lesions in two countries (Côte d’Ivoire and Finland) with different tobacco exposure.
AuthorsA. G. Radhika, Sruthi Bhaskaran, Jagdish Kaur, Anshuja Singla, Tusha Sharma, B. D. BanerjeeAline Simen- Kapeu, Guy La Ruche, VesaKataja, MerjaYliskoski, Christine Bergeron, Apollinaire Horo, Kari Syrjanen, Seppo Saarikoski, Matti Lehtinen, Francois Dabis, Annie J. Sasco
Year of Publication20172008
CountryIndiaCote d'IvoireFinland
Study objectiveTo evaluate the urinary cotinine levels in women of reproductive age with common gynecological conditions (PID, infertility, and AUB).To compare the association between tobacco smoking and chewing and the risk of multiple human papillomavirus infections and cervical squamous intraepithelial lesions (SILs) in two populations with different exposure.
Study designcross-sectional pilotComparative
(Prospective follow up study)(long term prospective study)
Study setting (hospital/community)HospitalHospital
Study populationWomen presenting at gynecological outpatient clinic of GTB hospital among non-pregnant women of reproductive age having any of the complaints namely menstrual disturbance, infertility or pelvic inflammatory disease. Sample size 192.2144 women attending 3 outpatient gynecology clinics of Abidjan, age - 20 to 50 years, no h/o lower genital tract neoplasias and absence of active pregnancy.415 Finnish women - Kuopio University Hospital between 1981 and 1998; 15-69 years of age attending municipal health centers in Kuopio province.
Primary exposuretobacco use or exposure (any form) in self or family membersActively exposed to tobacco (any form - smoking and/or chewing)Actively exposed to tobacco (any form - smoking and/or chewing)
Method of ascertainmentInterview/questionnaire, urinary cotinine (spot urine test)Interview and Cytological diagnosis - cervical specimen for HPV detection - collected with a plastic brush (Viba-Brush, CML, Nemours, France - using PCR for HPV positiveInterview and gynecological examination - colposcopy, repeat PAP smear and directed punch biopsy; formalin fixed, paraffin embedded biopsies analyzed using DNA in situ hybridization (ISH) technique.
Secondary exposure(s)Secondhand Exposure to smoked tobaccoNoneNone
Method of ascertainmentInterview/questionnaire, urinary cotinine (spot urine test)NANA
Intervention (if applicable)NoneNANA
Control (if applicable)Nonewomen with absence of cervical SILNormal cervical smears at the first study visit
Primary outcomePID (n=139) most common gynecological complaint. Assessment of urinary cotinine Mean urinary cotinine levels in women exposed to environmental tobacco smoke (SHS) was 23.82 ± 12.67 ng/ml. Women with PID had significantly higher urinary cotinine levels = 24.9548 (±12.259) ng/ml (p=0.0144) unpaired student t test236 cases; mean age 28.4 ± 6.6; LSIL (n=165), HSIL (n=71). Tobacco users (smokers and chewers) - increased risk of LSIL; Tobacco chewers, 5 times higher risk in both younger (OR: 5.5, 95% CI: 1.2-26) and older (OR: 5.5, 95% CI: 2.1-14) in comparison to non-chewers. Age-adjusted OR of cervical HSIL significantly high among tobacco chewers.88 cases; mean age 27.9 ± 7.5; LSIL (n=60), HSIL (n=28). Tobacco users (smokers and chewers)- increased risk of LSIL; Tobacco smokers; LSIL - younger (OR:1.2, 95% CI: 0.6-2.5) and older (OR:2.5, 95% CI: 0.9-6.8); HSIL - younger (OR:1.1, 95% CI: 0.4-3.1) and older (OR:2.2, 95% CI: 0.5-8.7) in comparison to non-chewers.
Secondary outcome(s)NAchlamydia trachomatis detectionchlamydia trachomatis detection, serum cotinine detection
Sample size (group1)19223688
Sample size (group2)NA1908327
Sampling strategyUrinary cotinine levels in three common categories of gynecological complaints, among non-pregnant women of reproductive age residing in East Delhi who sought treatment from gynecological outpatient clinic of Guru Tegh Bahadur Hospital. The hospital caters to patients living in urban slums in Nand Nagri, Seema Puri, and Seelampur. The population density in these areas is very high, with congested living conditions. Majority belongs to low-income group. Consecutive, spot urine sample.2144 out of 2198 women attending 3 outpatient gynecology clinics of Abidjan in the time frame April 1995 to February 1996, age - 20 to 50 years, no h/o lower genital tract neoplasias and absence of active pregnancy415 Finnish women - Kuopio University Hospital between 1981 and 1998; 15-69 years of age attending municipal health centers in Kuopio province (cervical swab taken as part of their contraception counselling)
Co variates/confoundersSecondhand smokingNoneNone
BiasesPatients presenting to the hospital with specific gynecological complaints. Sample not enough and other confounding variables not consideredSampling bias: very few Ivorian women reported smoking evaluation, for this habit alone, in the regression analysis was restricted to Finnish women.Sampling bias: very few Ivorian women reported smoking evaluation, for this habit alone, in the regression analysis was restricted to Finnish women.
Measure of association (OR/RR)Mean±SDTobacco chewers, 5 times higher risk in both younger (OR: 5.5, 95% CI: 1.2-26) and older (OR: 5.5, 95% CI: 2.1-14) in comparison to non-chewers.OR Tobacco smokers; LSIL – younger (OR:1.2, 95% CI: 0.6-2.5) and older (OR:2.5, 95% CI: 0.9-6.8); HSIL – younger (OR:1.1, 95% CI: 0.4-3.1) and older (OR:2.2, 95% CI: 0.5-8.7) in comparison to non-chewers.
Lower boundInfertility – 9.70
Menstrual disorders – 9.03
PID – 12.96
Younger – 1.2
Older – 2.1
LSIL younger – 0.6 older – 0.9
HSIL younger – 0.4 older – 0.5
Upper boundInfertility – 35.14
Menstrual disorders – 29.61
PID – 37.21
Younger – 26
Older – 14
LSIL younger – 2.5 older – 6.8
HSIL younger – 3.1 older – 8.7
Sub group analysisNoneAnalysis LSIL and HSIL in HPV positive women was done - age and tobacco exposure being the variablesAnalysis LSIL and HSIL in HPV positive women was done - age and tobacco exposure being the variables
Results of sub group analysisNAIncreased risk of LSIL and HSIL (not significant) in HPV positive women ≥ 30 years of age and actively exposed to tobacco through smoking or chewing)Increased risk of LSIL and HSIL (not significant) in HPV positive women ≥ 30 years of age and actively exposed to tobacco through smoking or chewing)

Another study (Simen-Kapeu et al., 2009) compared the association between tobacco use (smoking and chewing) and the risk of multiple human papillomavirus (HPV) infections and cervical squamous intraepithelial lesions (SILs) in two populations with different exposure. For this, baseline data from 2144 women from Cote d'Ivoire, West Africa and 415 women from Finland, Northern Europe regarding cervical screening, HPV positivity and tobacco use (smoking and chewing habits) was re-analyzed to determine the association between tobacco chewing in Cote d'Ivoire and tobacco smoking in Finland and the age stratified risk of multiple HPV infections and cervical SIL. Results show that in Côte d'Ivoire tobacco chewing (2.6%) was more common than tobacco smoking (1.4%). In 236 cases (eligible women with SIL), mean age of the women was 28.4±6.6 years with low-grade SIL in 165 and high-grade SIL in 71. Tobacco users (smokers and chewers) showed an increased risk of LSIL. Tobacco chewers were at 5 times higher risk for HSIL in both younger age group (<30 years) with OR: 5.5, 95% CI: 1.2-26 and older age group (≥30 years of age) with OR: 5.5, 95% CI: 2.1-14) in comparison to non-chewers. Age-adjusted OR of cervical HSIL was significantly higher among tobacco chewers. Increased risk of LSIL and HSIL (not significant) was found in HPV positive women ≥ 30 years of age who were actively exposed to tobacco through smoking or chewing was seen.

Having multiple HPV infections was common in HPV16 and/or HPV18 infected women (60.4% in Finland and 47.2% in Côte d'Ivoire). There was no increased risk of multiple HPV infections among tobacco consumers. It was found that women ≥ 30 years of age exposed to tobacco through smoking in Finland (OR: 2.2, 95% CI: 0.5-8.7) and chewing in Côte d'Ivoire (OR: 5.5, 95% CI: 2.1-14) had a moderately or highly increased risk of high-grade SIL, respectively. In the latter, the risk was statistically significant. Sampling bias was seen in the study as very few Ivorian women reported smoking evaluation, for this habit alone, and the regression analysis was restricted to Finnish women (Simen-Kapeu et al., 2009).

The risk of bias assessed using appraisal tool for cross sectional studies (AXIS) for one and ROBIN E for observational studies. Risk of bias for cross sectional study was high due to the small sample size but the those for the prospective studies was low.

Discussion

There is a high prevalence of SLT use in low- and middle-income countries. India, Bangladesh, Egypt, Nigeria and Philippines have a high burden of SLT use though India carries 83% of global burden. There are nearly 58.2 million women (12.8% aged more than 15 years) consuming some form of SLT in India (GATS 2 survey 2016-17). Adverse effects of SLT use among women include oro- pharyngeal cancers, ischemic heart disease and osteoporosis (Sinha et al., 2018; Spangler et al., 2001). It is associated with infertility and poor pregnancy outcomes. Nicotine crosses the placental barrier resulting in a neuroteratogenic effect in the developing fetus. A limited number of studies investigated the relationship between SLT use among women and pelvic infections and menstrual function.

This systematically conducted rapid review to study association between SLT use and reproductive health of women yielded a total of three studies with findings from four different countries, namely India, USA, Finland and Cote d’Ivore and Finland. The differences in the study methodologies precluded us from combining the study findings.

Infertility was measured in terms of TTP and Urinary cotinine levels and both were seen to be higher in SLT users. Women with PID had highest mean urinary cotinine levels among the three, followed by infertility and menstrual complaints respectively (Radhika et al., 2017). Another study showed longer TTP for cotinine levels more than 10ng/ml for SLT users (Sapra et al., 2016). Another study comparing association between tobacco smoking and chewing with risk of PID in two populations with different exposures showed that SLT users were at a five times higher risk of SIL in comparison to non-chewers irrespective of age (Simen-Kapeu et al., 2009). Results were however inconclusive regarding strong associations between SLT use and reproductive health in women.

Biologic fertility can be assessed using TTP. A study based in a community setting showed a remarkably comprehensible association between female smoking and sub-fecundity during the most recent waiting TTP (Kassa and Kebede, 2018). However, similar studies addressing the effects of SLT were not available. TTP was seen to be lesser in SLT users than smokers, however this aspect needs more research with comparisons drawn with smokers and tobacco nonusers.

Cigarette smoking was also seen to be associated with an adverse effect on ovarian function and hence on fertility among women. Evidence suggests that there is an association between cigarette smoking and reduced fertility (risk of delayed conception), even at low doses (Hatch et al., 2012; Gormack et al., 2015). Since the active metabolite is similar, it is natural to expect some effects on the reproductive outcomes i.e. menstrual function, infertility, PID and pregnancy outcomes with SLT use. However, there is a dearth of good quality studies to ascertain such an association.

Nicotine levels are found to be highest in bidis, followed by chewed tobacco and cigarettes (Amith et al., 2018). Nevertheless, SLT products are more often abused than smoked tobacco products (Sharma et al., 2015) and serum nicotine levels remain in significant amounts for a longer time period (Mala et al., 2016). Like smoked form, SLT use causes alteration of the immune response to infections and has a damaging effect on majority of organ systems in the body including the reproductive system (Willis et al., 2012). This justifies the biological plausibility between SLT and reproductive outcomes.

To conclude, the number of studies about an association between SLT use and reproductive health of women were very few despite the high prevalence of use in the South East Asia region. Impact of SLT on reproductive health of women requires more research. In this rapid review, we followed the principles of systematic review that offers strength to the study. We have considered the major reproductive outcomes comprehensively. However, we restricted our search to English papers that poses a limitation. In addition, our reference period was from 1990, though it possibly would not have made a difference even if we went beyond that timeline. Though our results show that there might be an association between the SLT and poor reproductive outcomes, we recommend more studies on this topic with robust study designs for conclusive results.

In our review, we identified gaps in knowledge concerning the association of SLT use with reproductive outcomes in women. Research is needed to determine the impact of smoked and smokeless tobacco products on women’s reproductive health.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Reporting guidelines

Figshare: PRISMA checklist for ‘Smokeless tobacco use and reproductive outcomes among women: a systematic review’. https://doi.org/10.6084/m9.figshare.16819102 (Radhika, 2021).

Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication).

Comments on this article Comments (1)

Version 2
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Revised
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VERSION 1 PUBLISHED 18 Nov 2021
Discussion is closed on this version, please comment on the latest version above.
  • Author Response 28 Apr 2022
    A.G. Radhika, Obstetrics & Gynecology, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi, 110095, India
    28 Apr 2022
    Author Response
    Response to reviewers comments

    Reviewer 1

     
    1. What were the exclusion criteria? If the E in PECO is an exposure to SLT, then studies reporting on smoking or ... Continue reading
  • Discussion is closed on this version, please comment on the latest version above.
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Radhika AG, B. Neogi S, GS P et al. Smokeless tobacco use and reproductive outcomes among women: a systematic review [version 2; peer review: 2 not approved]. F1000Research 2022, 10:1171 (https://doi.org/10.12688/f1000research.73944.2)
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 2
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PUBLISHED 03 May 2022
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Reviewer Report 14 Sep 2022
Sonali Jhanjee, National Drug Dependence Treatment Centre, Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India 
Not Approved
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I have gone through the recent revision. The status would be Not Approved this time as ... Continue reading
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Jhanjee S. Reviewer Report For: Smokeless tobacco use and reproductive outcomes among women: a systematic review [version 2; peer review: 2 not approved]. F1000Research 2022, 10:1171 (https://doi.org/10.5256/f1000research.132656.r136566)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 05 May 2022
Ruchika Gupta, Division of Cytopathology, ICMR-National Institute of Cancer Prevention and Research, Noida, Uttar Pradesh, India 
Not Approved
VIEWS 15
I have read the author's comments as well as the revised version of the article uploaded on the website. The fundamental issues raised in my first review have not yet been addressed. Hence, I'm of the opinion that the systematic review ... Continue reading
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Gupta R. Reviewer Report For: Smokeless tobacco use and reproductive outcomes among women: a systematic review [version 2; peer review: 2 not approved]. F1000Research 2022, 10:1171 (https://doi.org/10.5256/f1000research.132656.r136567)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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PUBLISHED 18 Nov 2021
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Reviewer Report 11 Mar 2022
Sonali Jhanjee, National Drug Dependence Treatment Centre, Department of Psychiatry, All India Institute of Medical Sciences, New Delhi, India 
Not Approved
VIEWS 11
The authors use the term reproductive outcomes in the title and then use the terms “reproductive outcomes” and “reproductive health” interchangeably throughout the review. It may be beneficial to use standardized definitions in the review. Rationale also needs to be ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Jhanjee S. Reviewer Report For: Smokeless tobacco use and reproductive outcomes among women: a systematic review [version 2; peer review: 2 not approved]. F1000Research 2022, 10:1171 (https://doi.org/10.5256/f1000research.77639.r123938)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 05 Jan 2022
Ruchika Gupta, Division of Cytopathology, ICMR-National Institute of Cancer Prevention and Research, Noida, Uttar Pradesh, India 
Not Approved
VIEWS 19
The objective of the systematic review, as stated by the authors, is to review the association of SLT use and reproductive health among women. The methodology, search strings, eligibility criteria are all suitable to the objective. However, I have major ... Continue reading
CITE
CITE
HOW TO CITE THIS REPORT
Gupta R. Reviewer Report For: Smokeless tobacco use and reproductive outcomes among women: a systematic review [version 2; peer review: 2 not approved]. F1000Research 2022, 10:1171 (https://doi.org/10.5256/f1000research.77639.r108658)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.

Comments on this article Comments (1)

Version 2
VERSION 2 PUBLISHED 03 May 2022
Revised
Version 1
VERSION 1 PUBLISHED 18 Nov 2021
Discussion is closed on this version, please comment on the latest version above.
  • Author Response 28 Apr 2022
    A.G. Radhika, Obstetrics & Gynecology, University College of Medical Sciences & Guru Teg Bahadur Hospital, Delhi, 110095, India
    28 Apr 2022
    Author Response
    Response to reviewers comments

    Reviewer 1

     
    1. What were the exclusion criteria? If the E in PECO is an exposure to SLT, then studies reporting on smoking or ... Continue reading
  • Discussion is closed on this version, please comment on the latest version above.
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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