Discussion
Main Findings
There were three important findings in this study: 1) Almost a third of all women delivering term or near neonates were colonized with GBS in this hospital; 2) even after controlling for various confounders, smoking during pregnancy was more than twice more likely to result in GBS colonization among pregnant women of term or near term neonates.; 3) teen mothers less than 20 years had the highest rates of GBS colonization and the rates steadily decreased with age with the lowest rates occurring among the oldest mothers 35 year+. Interestingly this inverse relationship was only true for women who were nonsmokers.
Interpretations
This high prevalence of GBS colonization found in our study is consistent with previous studies in the USA and elsewhere.3-11 The lowest rates were observed mainly in some East Asian nations.5,11,12 The across-country differences may be due to differences in techniques.23-25 PCR testing after broth enrichment has been has been shown to be a reliable and is now the standard method for GBS testing.24 However, testing conducted intrapartum may show somewhat lower prevalence rates as compared to antepartum testing.25 If this is so, then there may be excessive use of intrapartum prophylactic antibiotics to prevent GBS sepsis in neonates. Unfortunately, intrapartum testing is not yet practical since it can take up to 2 to 3 days for the results of tests to be made available whereas knowing the results prior to delivery is very important to make a decision to treat prophylactically or not. Hopefully, new rapid PCR tests are being developed for such a purpose.25 In spite of the dramatic drop of early onset neonatal GBS sepsis in the United States, the reasons for the persisting high prevalence rates of GBS colonization during pregnancy throughout the past 4 decades need to be further explored.
This study further confirms that, potentially, more than a third of all women were eligible to receive intrapartum prophylactic antibiotics prior to delivery. This is indeed a high rate of pre-delivery antibiotics exposure of term or near term neonates. Several authors have recently suggested that at least 40% of children may be exposed to intrapartum antibiotics.26,27 Although intrapartum antibiotic prophylaxis have successfully reduced the incidence of GBS sepsis in neonates, the dangers of such prophylaxis are concerning.28 For instance, intrapartum antibiotic prophylaxis have been associated with complications such as increased prevalence of atopic dermatitis,29 antimicrobial resistance,30 and changes in the neonatal gut microbiota.31-33
The prevalence of active tobacco smoking among pregnant women in this study was 12%, and this is consistent with recent national trends.22 However, in our study, the intensity of smoking during pregnancy was rather low and most women who smoked admitted to smoking no more than 3 cigarettes each day although this may be largely an underestimate. Since this was a retrospective study the assumption is that women who admitted to smoking actually smoked throughout pregnancy. The study may, therefore, not take account of those who stopped smoking sometime during pregnancy or those who only initiated smoking sometime during pregnancy.
Few studies in the literature have explored the impact of smoking during pregnancy on GBS colonization. Our study was also able to demonstrate a significant dose-response relationship suggesting that this was not just a spurious finding. In the United States, Terry et al.34 were the first to show that smoking during pregnancy was predicted of GBS colonization but the authors did not perform a multivariable analysis to control for other confounders to determine if smoking was independently predictive. Edwards and colleagues, 35 in a large retrospective study, recently demonstrated that smoking was also predictive of GBS colonization in the in the univariate analysis but not in the multiple regression analysis. However, smoking was not the primary independent variable of their study. Two studies respectively from Korea and China,12, 36 failed to demonstrate an association of smoking during pregnancy and GBS colonization. However smoking was also not the primary independent variable of interest of these studies and there were was the additional problem of smallness of numbers in some cells. Our finding that smoking during pregnancy was predictive of GBS colonization during pregnancy is consistent with a smaller study from Iran. 37 However, their study population was different as it also included preterm neonates that were excluded in our current study. Surprisingly, Regan and colleagues demonstrated in 1991 that smoking was rather protective of GBS colonization.38 The authors offered no biological plausibility of their finding. However, only women delivering preterm neonates (<36 weeks) were enrolled in the latter study whereas our study focused only on term or near term neonates. We speculate that the population of women delivering term babies may be quite different from the population delivering only preterm babies.
The finding that tobacco smoke exposure during pregnancy is an independent risk factor for increased GBS colonization has significant public health implications. Because smoking exposure is a modifiable risk factor, women can be counseled to stop smoking during pregnancy in order to reduce colonization with this organism which can result in GBS sepsis in their newborn baby. The association between tobacco smoking and increased GBS colonization during pregnancy is biologically plausible. We speculate that tobacco smoke exposure during pregnancy may actually enhance the colonization of GBS in the gastrointestinal and the genital tracts. Indeed, previous studies have shown that tobacco smoke exposure is associated with increased colonization of the respiratory and genital tract with pathogenic bacteria,39-41possibly through alteration of the microbiome.17,19,41Tobacco smoke contains more than 4,500 chemical intoxicants42 many of which can result in increased suppression or modulation of both active and passive immune response.43 For instance, nicotine, an important component of tobacco smoke, has been shown to enhance the adherence of bacteria in mucous membranes of the respiratory tract leading to easy penetration of bacteria into the tissues to cause infections.44 This could also be true of the genital tract of pregnant women where nicotine could actually result in the persistence of GBS in the mucous membranes of the gastrointestinal and genital tracts. Indeed some studies have actually demonstrated higher nicotine levels in the cervical mucous membranes of smokers as compared to non-smokers.45,46 In another study, nicotine of the cervical mucus of female smokers resulted in DNA damage of epithelial cells of these women resulting in easy penetration of bacteria into the adjacent tissues.47 It can be speculated that the overall effect of tobacco smoke is the alteration of the microbiome of the female genital tract resulting in increased prevalence of pathogenic microorganisms such as GBS in the present study.
To our knowledge only a few studies in the United States have been conducted in recent years to determine potential sociodemographic risk factors associated with this rather high colonization rates among pregnant women. In the ‘70’s Anthony et al showed that Mexican Americans had the lowest rates as compared to Whites or Blacks.48 In our study, black mothers had the highest rates as compared to White or Hispanic/Latino mothers. These findings are consistent with those of Regan and colleagues whose study was conducted almost 30 years ago.38 The finding that younger mothers had significantly higher rates of GBS colonization was consistent with one previous study conducted more than 40 years ago by Anthony and colleagues.48 They demonstrated that younger mothers had higher rates of GBS colonization than their older counterparts. Indeed, GBS sepsis in neonates has also been shown to be more common among young mothers < 20 years, as demonstrated by Schuchat et al.49,50 This may be explained by the fact that young mothers also have higher rates of GBS colonization than their older counterparts as shown in our study. However, 10 years after the study by Anthony et al,48 Regan et al38 showed that GBS colonization was less common among women less than 20 years of age even after controlling for the other sociodemographic confounders. The difference in findings between the two studies may be due to the fact that cultures for GBS were obtained very early in gestation (23-26 weeks gestation) in the latter study, whereas the current recommendation is to obtain cultures at 35-37 weeks of gestation.1Again as stated above, our study clearly demonstrates that maternal age was only predictive of GBS colonization among the non-smoking women. Non-smokers < 20 years had the highest GBS colonization rate while those >35 years of age had the lowest rate (P of Trend =0.02; also see Fig 1).
Limitations and Significance
This study has several limitations. First the retrospective nature of the data implies that there is no causality attributed to the findings. Second, because the study only involved subjects recruited from one local hospital, there may therefore be lack of both internal and external validity of the findings as this sample was not necessarily representative of the population of the state or of the nation. Third, the information of tobacco smoking was retrospectively obtained so there is likelihood of misclassification bias. The association between tobacco smoking and GBS colonization would have been even stronger if the smoking status was determined objectively by the use of a biomarker such as serum or urine cotinine levels. This may have reduced the likelihood of misclassification bias of the smoking status of the subjects. However, some of the findings are consistent with previous works. Fourthly, we were not able to control for all the confounders such as obesity and the frequency of sexual relationships which have been shown in some studies to be predictive of GBS colonization.51 The significance of this study lies in the fact that this is the first robust study with the main focus of determining the impact of tobacco smoke on GBS colonization on women of term or near neonates. In other studies GBS was not the main focus and a test of trend was not explored.