Identifying Patients with Bacterial Vaginosis and Treatment
Within the pregnancy cohort two groups of women were identified and
compared. The first group consisted of women identified as having BV by
diagnostic codes (ICD-9 codes 616.10, 616.11; ICD-10 codes N76.0, N76.1,
N76.2, N76.3, N77.1) occurring at any time during pregnancy. Women in
this group were treated with Metronidazole and/or Clindamycin, as
indicated by at least one prescription record. Three time windows were
considered for the treatment: 1) duration of the pregnancy; 2) first
trimester, or 3) second trimester. The referent group consisted of women
with no BV and no treatment with either of the two medications during
pregnancy. Odds ratios for the associations with sPTB were calculated
using logistic regression along with 95% confidence intervals.
To examine the association between treatment of persistent BV and sPTB
we performed an additional analysis where the women with BV and
medication prescription filled during pregnancy were stratified based on
the number of prescriptions that were filled. To further examine the
differences between women with BV and treatments vs. referent group, we
performed survival analysis and obtained Kaplan-Meier curves for the
time of delivery for the two groups of women.
This project was deemed exempt by the Stanford Institutional Review
Board for Human Subjects.
Results:
Of 15,665,160 patients in the IBM MarketScan Commercial Database
inpatient admissions between 2007 and 2016, we extracted pregnancies
with a singleton gestation and continuous coverage during pregnancy and
excluded those with molar pregnancies, ectopic pregnancies and abortions
(figure 1). After excluding those in which the gestational age at
delivery could not be verified a total of 2,538,606 women were included
in the final analysis. A total of 216,611 (8.5%) were identified as
having a ICD-9 or ICD-10 code for BV, and of those, 63,817 women (2.5%)
had both a diagnosis of BV and filled a prescription for either
metronidazole and/or clindamycin (supplemental figure). Among the 63,817
women 72.0% filled only one prescriptions during pregnancy, 19.2 %
filled 2 prescriptions, and 8.8% filled 3 or more prescriptions (figure
2). 56% of prescriptions were filled before 20 weeks’ gestation with a
peak at 13 weeks of gestation. A second peak was found around 33 weeks’
gestation (figure 3).
Spontaneous PTB occurred in 150,118 (5.9%) women in the cohort
(supplemental table). sPTB among women treated for BV was 7.5% while
those without a diagnosis of BV had a frequency of sPTB of 5.7%.
Compared with women who were not diagnosed with BV, the odds ratio for
sPTB in those treated for BV in the first trimester was 1.42 [95% CI:
1.36,1.48], for those treated in the second trimester was 1.47 [95%
CI: 1.41, 1.53] and for those treated in both the first and second
trimester was 1.66 [95% CI: 1.52, 1.81] (Table 1).
Similarly, there was an increased risk for sPTB in women treated for BV
in more than 1 trimester compared to women without BV in pregnancy.
Specifically, the OR for those with 1 prescription was 1.30 [95% CI:
1.26, 1.35] while for those with 2 prescriptions 1.35 [95% CI:
1.26, 1.44] and those with 3 or more prescriptions 1.48 [95% CI:
1.35, 1.63] (Table 2). A Kaplan Meyer survival curve for sPTB
stratified by antibiotic treatment (metronidazole and/or clindamycin)
illustrating the difference in survival for two groups is shown in
Figure 4 and, specifically for the period from 30 to 39 weeks in Figure
5. Most of the sPTB difference between those with BV and without BV was
seen in the late preterm period, between 34 and 37 weeks’ gestation.
Discussion:
In a large US cohort of pregnant women we observed that treatment of
persistent BV, defined as either BV occurring in more than 1 trimester
or requiring more than 1 prescription, was associated with an increased
risk for sPTB relative to not having BV. These observed risks were
higher than the risk of sPTB observed for women with a single treatment
of BV. Those filling at least 3 prescriptions and those with therapy in
both the first and second trimester had an approximately 50% increased
risk for sPTB. It is unclear whether persistent BV directly led to
intra-amniotic infection and sPTB, or whether BV may be a marker of
different risk factors for sPTB that we could not account for in our
dataset.
BV can be diagnosed in several ways. The reference standard for BV
diagnosis is the Nugent score, although it’s use is generally limited to
research settings.1 Nugent scoring assigns a value to
different bacterial morphotypes seen on Gram stain of vaginal secretions
with a score > 7 interpreted as bacterial vaginosis.
More often BV is diagnosed by the presence of 3 of 4 Amsel criteria,
which has been shown to correlate with the Nugent scoring. The incidence
of BV in pregnancy likely depends on the population studied (high vs.
low risk for BV) and the method of diagnosis. In a prospective study of
148 women, 65 women (43.9%) were diagnosed in the first trimester using
a Nugent score > 7, 32 women (21.6%) were diagnosed
in the second trimester, and 28 women (18.9%) were diagnosed in the
third trimester.9 In that cohort only 48% were
negative in all trimesters and 9.4% were positive throughout pregnancy.
It’s important to note however that women were screened irrespective of
symptoms, and most women were young (mean=23), unmarried(76%), African
American (85%) and women of low income. A much lower BV incidence was
found in a multicenter double blind randomized BV therapy trial from
France, for example, in which only 5630 of 84530 women (6.6%) had BV
based on a diagnosis of a Nugent score> 7.10 The 63,817 women with BV
based on ICD-9 and ICD-10 coding along with a prescription for BV
therapy in our analysis represented 2.7% of the overall pregnancy
cohort, suggesting a relatively low prevalence group and one that was
possibly screened based on symptoms, rather than universal screening
paradigms. It is also possible that our relatively low rate resulted
from the fact that some women were prescribed metronidazole and/or
clindamycin for BV but were not coded as such. In fact, it is important
to note that 134,737 women received a prescription for metronidazole
and/or clindamycin without a code specific for BV. When we analyzed the
association between such treatment and sPTB, we found an increased risk,
although not as high as in those with both an ICD-9/10 code and
treatment (Table S1 to S5, Figure S1 to S3).
The association between BV and sPTB has been known for over 2 decades.
In a prospective study of 2929 pregnancies conducted by the Maternal
Fetal Medicine Units Network between 1992 and 1994 the presence of BV
was associated with a 2.7 relative risk of sPTB before 32 weeks
gestation.4 Subsequent cohort studies have confirmed
this association, and there are several demographic risk factors that
are similar for BV and sPTB. The precise mechanism in which BV leads to
sPTB remains unknown although an increased risk of ascending infection
has been hypothesized. A link between first trimester BV and short
cervix, a risk factor for sPTB, has also been found; unfortunately, we
were not able to assess cervical length in our
study.11 Additionally, whether persistent BV
represents a higher microbial load thereby increasing the risk of
intraamniotic infection and inflammation remains to be seen. It is also
worth noting that in our cohort, based on our Kaplan-Meier graphs, the
greatest risk was seen at late preterm gestational ages (34-37 weeks).
This is contrary to some of the earlier reports associating BV with
preterm birth before 35 weeks.4
While the association between BV and sPTB has been previously described,
studies including several prospective clinical trials have failed to
demonstrate that treating BV in pregnancy alone reduces the risk for
sPTB.10,12-14 Reasons for this remain unclear,
although possible explanations could be poor compliance, inappropriate
diagnosis, inappropriate treatment, or treatment after the beginning of
an ascending infection or short cervix. In addition, more recent studies
suggest that not all BV cases are caused by similar bacteria,
particularly across different population subgroups.15Unfortunately we were unable to determine the contribution of maternal
race/ethnicity on sPTB risk in our cohort. Moreover, previous studies
suggest that antibiotic therapy alone may increase the risk of
sPTB.16 While antibiotics alone in those screened for
BV have not been shown to reduce sPTB incidence, identifying high risk
cohorts has potential important clinical implications. For example,
transvaginal ultrasound cervical length surveillance is routinely
performed in other high risk cohorts and adjunct therapy with vaginal
progesterone therapy and/or cerclage has been shown to lower sPTB in
those with a decreasing cervical length. How to incorporate such
interventions for women with persistent BV or lasting beyond 2
trimesters remains to be seen, and future studies are warranted to
further delineate the precise pathophysiologic mechanism between BV and
sPTB so that an appropriate intervention can be identified.
Our study has several notable strengths. First, we were able to analyze
a robust cohort of over 2.5M pregnancies, from diverse geographical
areas in the United States. We defined treatment of BV via the presence
of BV by both diagnostic codes and antibiotic treatment using two of the
most common and recommended medications.1 While
clindamycin can also be used for urinary tract infections (which we
excluded in our analysis), metronidazole is rarely used in pregnancy for
indications other than BV. A less common use for metronidazole is
trichomonas infections, but we did exclude those codes in our dataset
and the incidence of trichomonas in pregnancy is much lower than BV. The
dataset allowed us to assess diagnoses and therapy over the entire
course of the pregnancy, and to link it with clinical outcome and with
medication claims. Specifically, the dataset is unique in that we were
able to delineate sPTB using a previously validated analytical approach,
excluding other indicated PTB codes such as preeclampsia.
On the other hand, our study is not without limitations. Due to the lack
of certain data collected in this administrative dataset we were unable
to account for baseline demographic information including maternal race,
ethnicity, BMI and smoking status. This is particularly important as
previous studies have shown differences in underlying vaginal microbial
signatures among different races with important implications for sPTB
risk.17,18 It is also unclear whether women diagnosed
with BV were symptomatic, and whether any additional over the counter
interventions were employed. This is an important factor to consider
since women who are screened rather than presenting with symptoms may be
deemed to be at higher risk by their providers which may lead to
selection bias. The method of BV diagnosis in the cohort is also not
available, and it is possible that women were empirically treated and
coded as having BV without an actual clinical diagnosis. Treatment
adherence/non-compliance is also an issue which may bias our results and
because we used antibiotic use to support our diagnosis of BV we were
unable to reliably determine the effect of antibiotic therapy on sPTB
risk. We were also unable to delineate the route of administration, and
whether an additional antibiotic prescription was prescribed because of
difficulty with administration route vs treatment failure. Additionally,
the dataset is a private insurance outpatient dataset and selects for a
certain demographic and therefore may not be generalizable to the US
population as whole. Finally, the increased risks observed between
treatment of persistent BV and sPTB were relative to women not having
BV. Thus, we cannot disentangle whether occurrence of BV or its
treatment was the underlying driver of the observed increased risk.
Conclusion:
In conclusion, our data indicate that persistent BV infection in
pregnancy is associated with increased sPTB risk. Given the rates of
persistent BV our data highlight the importance of clinical follow-up
after the initial diagnosis and therapy of BV in pregnancy. Future
studies are warranted to elucidate the precise mechanism in which
persistent BV may lead to sPTB and also to further clarify whether
therapy in such cases is an appropriate measure to reduce preterm birth.
Data Availability Statement:
IBM MarketScan Research Databases are available to purchase by Federal,
nonprofit, academic, pharmaceutical, and other researchers. Use of the
data is contingent on completing
a data use agreement and purchasing the data needed to support the
study. More information about licensing the IBM MarketScan Research
Databases is available at:
https://www.ibm.com/products/marketscan-research-databases
Disclosure of Interests: The authors have not financial interests to
disclose related to this work
Authors contribution: YJB, IM and GMS were involved in the conception
and planning of the study, data analysis, and manuscript development.
DKS was involved in planning the study, data analysis and manuscript
development. RSG was involved in data analysis and manuscript
development.
Ethics approval: This project was deemed exempt by the Stanford
Institutional Review Board for Human Subjects.
Funding: This work was supported by the March of Dimes Prematurity
Research Center at Stanford University and the Maternal and Child Health
Research Institute, Stanford University.
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Legends of the figures and tables:
Figure 1. Pregnancy cohort flow chart.
Figure 2. Histogram of number of women with BV that filled 1, 2, or 3
and more prescriptions for metronidazole and/or clindamycin during
pregnancy.
Figure 3. Histogram of number of women who filled a prescription per
each week of pregnancy.
Table 1. Odds ratios for spontaneous PTB according to treatment
for bacterial vaginosis by trimester of pregnancy. For each exposed
group the comparison is performed against the group of patients without
BV and without exposure to medication as shown in the last row.
Table 2. Odds ratios for spontaneous preterm births by number of
prescriptions during pregnancy. For each group the comparison is
performed against the group of patients without BV and without exposure
to medication as shown in the last row.
Figure 4. Survival curves for spontaneous preterm birth stratified by
Metronidazole and/or Clindamycin treatment.
Figure 5. Survival curves for spontaneous preterm birth stratified by
Metronidazole and/or Clindamycin treatment for 30 to 39 gestational
weeks. Dashed lines show confidence intervals.
Figure 1. Pregnancy cohort flow chart.