Evaluation of infection screening for bacterial vaginoses to prevent premature births

According to calculations by the World Health Organization (WHO), around 10% of children worldwide and around 6% of children in Europe are born prematurely (1). Births before the 37th week of pregnancy (week of pregnancy) are defined as premature births (2). In neonatal intensive care, preterm birth is still the most common cause of neonatal and early childhood morbidity and mortality and can lead to lifelong health and psychosocial impairments (3–5). The health economic consequences associated with premature birth are also considerable (6). There are many factors that can lead to premature birth. Previous abortions and premature births, the increasing age of first-time mothers and the higher incidence of multiple pregnancies due to previous fertility treatments can cause premature births (4,7,8). Maternal infections, such as bacterial vaginosis, have also been identified as a cause of premature births, although the pathophysiological connections are not yet fully understood (9,2,10,11). The early detection and treatment of bacterial vaginosis can be implemented and carried out relatively easily and therefore represents a promising possibility to prevent preterm birth and to reduce the resulting health and psychosocial consequences.

>> BIG Direktgesundheit has been offering its pregnant insured members an additional preventive service in the form of consistent infection screening (KISS) since 2010 as part of a contract in accordance with Section 73c SGB V (12). The aim of KISS is to diagnose and treat asymptomatic vaginal infections early using a vaginal swab through infection screening between the 16th and 24th weeks of pregnancy and thus reduce the number of premature births. If the result is positive, therapy is carried out taking into account the laboratory's therapy recommendations and a control swab is taken at the next routine visit (13).
Various studies and meta-analyses have examined the effectiveness of screening programs for the detection of bacterial vaginoses and their antibiotic treatment during pregnancy (10,11,14–16). The results are inconclusive regarding a reduction in preterm birth rates. While Kiss et al (2004) and McGregor et al (2010) observed a significant reduction in preterm birth rates, Okun et al (2005) and Bocklehurst et al (2013) report that early antibiotic treatment of bacterial vaginoses does not significantly reduce preterm birth rates.
The aim of this study was to evaluate the additional care offer KISS with regard to its effectiveness compared to standard care in a group of pregnant women with statutory health insurance in Germany.
methods
In a retrospective observational study with a control group design, routine data from the BIG directly healthy were used to investigate whether the rate of preterm births in a group of pregnant women who took part in KISS differed from the preterm birth rate in a comparison group in standard care.
The study population consisted of female insured persons who received antenatal care between July 1, 2010 and March 31, 2014 and gave birth to a singleton in the following 280 days or whose pregnancy ended in an abortion or a stillbirth. Pregnant women requiring antenatal care were identified in a first step using the EBM number 01770 ('care for a pregnant woman'). Births, abortions, and stillbirths were identified using the following ICD 10 codes: Z37.0, Z38.0, Z38.1, Z38.2 (term birth); P07.0, P07.2 (very early preterm birth: <28 weeks or birth weight <1000g); P07.1, P07.3, O60.1, O60.3 (late preterm birth: 28-37 weeks or birth weight between 1000 and 2500g); O00x, O01 x, O02 x, O03 x, O04 x, O05 x, O06x (abortion); Z37.1, O36.4 (stillbirth). For women with multiple pregnancy episodes during the study period, a case was randomly selected for inclusion in the study population. The primary outcome was the combined outcome of preterm birth, abortion and stillbirth.
Based on the day of birth, abortion or stillbirth, a date was calculated that should represent the beginning of the third trimester of pregnancy and thus a point in time at which screening for bacterial vaginosis should have already taken place. This date was calculated based on the duration of pregnancy documented on the day of birth (ICD 10 code O09x): date of birth - date of pregnancy + 24 weeks.
Women for whom a gestation period of less than 24 weeks was documented at the end of the pregnancy, as well as women who were not fully observable in the 18 months before and in the 280 days after the calculated start of the third trimester (index date), were excluded from the study population excluded.
The cohort of pregnant women was then divided into two groups:
(i) women who used KISS in the 8 weeks before the calculated index date (intervention group) and
(ii) Women who did not use KISS in the 8 weeks before the calculated index date (control group).

The KISS participants were compared with the non-participants using propensity score matching (PSM). The aim of the PSM is that the insured people in both groups are similar in terms of various observable socio-demographic and clinical characteristics, so that the two groups only differ in terms of participation in KISS.
The propensity score (PS), which reflects the conditional probability that a woman took part in KISS, was created depending on various sociodemographic and clinical characteristics in a pre-observation period of 18 months before the index date (17). The following variables were taken into account as covariates when calculating the PS: age, region of residence, insurance status, previous premature birth or stillbirth, previous abortion, number of prescribed medications, number of hospitalizations, previous bacterial vaginosis, pregnancy-related diseases of the pregnant woman (ICD 10 codes O10, O11, O13 , O14, O15, O20, O23, O24, O25, O32, O35.4, O35.5, O41-O46, O99.1), other serious illnesses of the mother (ICD 10 codes E05, E10, E11, E12, E13 , E14, E66, F10, F17, G35, G40, I10, K50, K51, L40, M05, M06, M08, M09, N80), monitoring of a high-risk pregnancy (Z35), prescription for anti-hypertensive drugs, prescription for insulin, Carrying out a Chlamydia trachomatis test and measures to promote fertilization.
The paired matches from the intervention and comparison groups were formed in two steps:
1.) Modeling the probability of participation in KISS for each woman using logistic regression based on observable covariates (=log(p/(1-p)).
2.) Selection of subjects from IV and VG with similar PS. The PSM was carried out without lying back and using a caliper of ≤0.2 standard deviations, i.e. the absolute difference in the PS of the matched patients in IV and VG could no longer be 0.2 standard deviations in the PS of the entire study population.
To check the balance between the paired groups, the standardized mean difference (SMD) was calculated. An SMD >10% was considered to represent inadequate balance between groups (18).
After the PSM was carried out, the rates of preterm births, abortions and stillbirths between the groups were checked for statistically significant differences using one-sided chi-square tests. The underlying hypothesis was that premature births, abortions and stillbirths occur less frequently in the IV than in the VG. The following events1 were examined as endpoints:
(a) term births,
(b) early premature births (<28 weeks or birth weight <1000g),
(c) premature birth, abortion or stillbirth,
(d) Abortions
(e) Stillbirths.
P values less than 0.05 were considered statistically significant.
Results
After applying all inclusion and exclusion criteria, a total of 11,676 women were included in the study population, of which 1,166 women took part in KISS in the eight weeks before the first day of the third trimester of pregnancy.
After carrying out the PSM, 1,164 pregnant women in the intervention and control groups were compared with regard to the relevant outcomes. Table 1 shows the selection process of the study population in detail.
Table 2 shows selected sociodemographic and clinical characteristics of both patient groups before and after PSM. The women were on average 32 years old. Around 8.6% of the women in the IV and 7.7% of the women in the VG had already had an abortion in the pre-observation period and over 40% of the women in the PS-matched groups received fertility-promoting measures before the start of the pregnancy. The PSM enabled a good balance to be achieved with regard to observable confounders. According to PSM, the SMD was below 10% for all variables considered.
The preterm birth rate in both treatment groups was approximately 9%. The rates of observed abortions and stillbirths also differ only slightly between the two treatment groups (see Table 3). In absolute terms, there were four fewer very early preterm births in the intervention group; this difference was not statistically significant (P value = 0.051). The relative frequency of the combined endpoint of preterm birth, stillbirth or abortion was slightly lower in the intervention group (10.22% vs. 10.82%, p-value=0.318). This difference was also not statistically significant.
discussion
In this study, we examined the effectiveness of a BIG bacterial vaginosis screening program in a cohort of pregnant women. Although we observed slight trends in lower preterm birth rates in favor of the screening program, none of the observed differences were statistically significant. Therefore, we cannot confirm the results of other studies that screen-and-treat programs for bacterial vaginosis in pregnancy reduce the rate of preterm birth (15,16). This result is surprising given the size of the effect reported by Kiss et al (2010). The authors reported a significant reduction in preterm births of approximately 32% between the intervention and control groups (8.2% vs. 12.1%, P-value < 0.0001). However, in contrast to our study, women who were not part of the intervention group were not treated with antibiotics. However, in our study, women who did not take part in KISS could also have been treated as part of standard care, provided the indication existed. A post hoc analysis of the data showed that approximately 10% of women in both the intervention and control groups received a prescription for an antibiotic to treat bacterial vaginosis. This could indicate that the importance of bacterial vaginosis as a risk factor for premature births is already established in standard care and that pregnant women are adequately cared for even without systematic screening for bacterial vaginosis. The undetectable difference between the two groups could therefore not be attributed to a general ineffectiveness of the screening program, but rather to a limited additional benefit compared to the already very good standard care. If the majority of bacterial vaginoses are already discovered and treated as part of regular care for pregnant women, the additional benefit of a systematic screening program such as KISS is low.
However, a small additional benefit would also be advantageous if the screening detected cases that would not otherwise have been diagnosed. The relatively cost-effective screening could be beneficial simply by preventing fewer additional premature births and their social and health comorbidities. The advice and implementation of KISS is paid 26 euros, while the care of premature births (28-37 weeks of gestation or 1000-2499g) and very early premature births (<28 weeks or <1000g at birth) costs around 8,600 euros or 74,000 euros are incurred (6). With regard to the generalizability of the results, it should be noted that the additional benefit of consistent infection screening for bacterial vaginoses may depend on the general standard of care. In countries like Germany, where the standard of care is high, the additional benefit of such a program may be rather small. In countries with poorer standards of care, however, the additional benefit could be higher.
In summary, we cannot give a final recommendation for the introduction of comprehensive infection screening for bacterial vaginoses during pregnancy. If the majority of cases are already diagnosed and treated as part of standard care, the additional benefit of screening is low. However, even a small additional benefit could justify the introduction of this relatively inexpensive intervention. A repetition of the study based on a larger study population that has since taken part in KISS and further health services research in this area in other countries and health systems would therefore be advantageous. <<