Skip to content

Advertisement

You're viewing the new version of our site. Please leave us feedback.

Learn more

BMC Pregnancy and Childbirth

Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Bacterial vaginosis and adverse outcomes among full-term infants: a cohort study

  • Adam S. Dingens1, 2, 3Email author,
  • Tessa S. Fairfortune1,
  • Susan Reed1, 3, 4 and
  • Caroline Mitchell5, 6
Contributed equally
BMC Pregnancy and ChildbirthBMC series – open, inclusive and trusted201616:278

https://doi.org/10.1186/s12884-016-1073-y

Received: 25 June 2016

Accepted: 6 September 2016

Published: 22 September 2016

Abstract

Background

Bacterial vaginosis (BV) during pregnancy is a well-established risk factor for preterm birth and other preterm pregnancy complications. Little is known about adverse neonatal outcomes associated with BV exposure in full-term births, nor its influence on adverse outcomes independent of its effect on gestational age. The purpose of this study was to examine the relationship between BV during pregnancy and adverse neonatal outcomes among full-term and preterm infants.

Methods

We conducted a retrospective cohort study of Washington State mother/infant pairs from 2003-2013, stratified by full-term (primary outcomes) and preterm births (secondary outcomes). BV-exposed and unexposed women were frequency-matched based on year of delivery. BV exposure and adverse outcomes [assisted ventilation/respiratory distress, neonatal intensive care unit (NICU) admission, neonatal sepsis, fetal mortality, and infant mortality] were identified using birth certificates, ICD-9 codes from linked hospital records, and death certificates. Associations between BV exposure and outcomes were assessed using multivariable Poisson regression, adjusted for maternal demographics, gestational age, and other pregnancy complications, including infections.

Results

A total of 12,340 mother/infant pairs were included: 2,468 BV-exposed (2198 term, 267 preterm) and 9,872 BV unexposed (9156 term, 708 preterm). Among full-term infants, BV-exposed mothers were younger, more likely to be Black or Hispanic, more likely to have had a sexually transmitted infection, and less likely to have a college degree than unexposed mothers. Term BV exposed infants were more likely to have meconium at delivery. Following adjustment, BV was associated with an increased risk of assisted ventilation/respiratory distress at birth (aRR = 1.28, 95 % CI 1.02-1.61), NICU admission (aRR = 1.42, 95 % CI 1.11-1.82), and neonatal sepsis (aRR = 1.60, 95 % CI 1.13-2.27) among full-term infants. These associations were independent of the presence of chorioamnionitis or meconium. Among preterm infants, BV-exposure was associated with an increased risk for NICU admissions only (aRR = 1.24, 95 % CI 1.04-1.46).

Conclusions

BV exposure during pregnancy is associated with adverse neonatal outcomes even among infants born full-term. These findings amongst full-term infants are novel, and highlight neonatal implications of BV in pregnancy independent of BV’s effect on preterm birth.

Keywords

Bacterial vaginosisTermAdverse neonatal outcomesNeonatal sepsis

Background

Bacterial vaginosis (BV), defined as a disturbance in the natural vaginal microbiota characterized by reduced Lactobacillus and overgrowth of anaerobic bacteria [1], is found in 9 % to 23 % of pregnant women [2]. Symptoms include vaginal discharge and malodor, but often women who have BV are asymptomatic. BV during pregnancy is an established risk factor for preterm delivery [1, 35] as well as other adverse preterm pregnancy outcomes such as premature rupture of membranes, low birth weight, chorioamnionitis, and spontaneous abortion [1, 4, 5]. A single cohort study of preterm infants suggests that BV is associated with an increased risk of adverse neonatal outcomes including: NICU admission, respiratory distress at birth, requirement of assisted ventilation at birth, and NICU stays lasting longer than 2 days [6]. Data on adverse neonatal outcomes associated with BV among infants born full-term is almost nonexistent.

We hypothesized that BV is associated with an increase in adverse neonatal outcomes due to ascending infection at all gestational ages and that the increased risks previously observed among preterm pregnancies are not solely attributable to prematurity. The primary aim of this large Washington State cohort study was to evaluate, among full-term infants, the effects of BV on five fetal/infant outcomes: assisted ventilation/respiratory distress at birth, admission to neonatal intensive care unit (NICU), neonatal sepsis, fetal mortality, and infant mortality. Our secondary aims were to evaluate these same outcomes among preterm (<37 weeks gestation) infants exposed and unexposed to BV, as well as to reaffirm the relationship between BV and preterm delivery among all infants. Women included as BV-exposed in our study were likely symptomatic women, and asymptomatic women were likely disproportionately misclassified in the unexposed group. However, this misclassification would only drive findings toward the null - any association found in our study would be perhaps, “only the tip of the iceberg”, or a marker for an important underlying etiology related to BV but not directly causal.

Methods

We conducted a population-based retrospective cohort study using data from Washington State birth certificates and birth hospitalizations from 2003-2013. These data were extracted from the Birth Events Records Database (BERD), a database linking more than 95 % of Washington State birth certificate data with maternal and infant hospitalization records from the statewide Comprehensive Hospital Abstract Report System (CHARS) [7]. Infant mortality was identified from death certificates issued through 2014. While there is underreporting of birth complications and maternal conditions on birth certificates [8], the use of hospital discharge and death certificate data improves the accuracy and completeness of both exposures and outcomes in this study. Four of our 5 outcomes: assisted ventilation/respiratory distress at birth, admission to neonatal intensive care unit (NICU), fetal mortality, and infant mortality are “hard outcomes” and it is highly unlikely that they would be inaccurate. Neonatal sepsis, our fifth outcome, is perhaps more prone to inaccurate birth certificate reporting [8], but it is also likely to be captured in linked hospital discharge data, as the sensitivity of ascertaining infection-related outcomes using ICD9 codes is near perfect [9]. All data were de-identified, and the study was determined to be exempt from review by the Washington State Institutional Review Board.

Study population

We included all BV-exposed mothers who gave birth in Washington State from 2003-2013 who met study criteria. Women were considered BV-exposed if on the birth certificate the “other” box under “Infections Present and/or Treated During this Pregnancy” was checked and the write-in space specified the infection as bacterial vaginosis (e.g., “BV”, “Bac Vag”, or “B Vaginosis”). Additional exposed women were identified using ICD-9 codes 616.10, 616.11, and 646.63 from CHARS data. BV-unexposed women did not have a write-in infection that could be identified as BV nor any BV ICD-9 codes in their delivery hospitalization records. We enrolled four unexposed women per exposed woman, frequency-matched for the infant’s year of birth. Non-singleton and births with a congenitally malformed infant were excluded.

Primary outcome measures

We measured the risk of five fetal/infant outcomes: assisted ventilation/respiratory distress at birth, NICU admission, neonatal sepsis, fetal mortality, and infant mortality. Outcomes were identified using a combination of birth certificate checkboxes, ICD-9 codes from the birth hospitalization record, and death certificates. If either the box on the birth certificate was checked, or the ICD-9 code was present, the outcome was considered to have occurred. Assisted ventilation/respiratory distress is coded on the birth certificate as “assisted ventilation required immediately following birth” and was also evaluated using ICD-9 codes 768.5 (severe birth asphyxia) and 769 (respiratory distress syndrome in a newborn). NICU admission was identified via birth certificate checkbox. Neonatal sepsis was ascertained using ICD-9 codes 771.81 (septicemia [sepsis] of newborn) and 771.83 (bacteremia of newborn) and by birth certificate checkbox. Because this study primarily used birth certificate data, fetal deaths before 20 weeks gestation (where no birth or death certificate would have been issued) were not captured. Fetal mortality at 20 weeks or greater gestation was identified from birth hospitalization records, ICD-9 code V27.1, and linked death certificates. Infant mortality is defined as death within one year of birth, and was identified via linked birth and death certificates.

Statistical analyses

We used Poisson regression to calculate risk ratios with 95 % confidence intervals for all outcomes among sub-cohorts of full-term infants (≥37 weeks gestation) and preterm infants (<37 weeks gestation), as well as the complete cohort. Gestational age was established from the birth certificate, primarily from ultrasound dating in the first or second trimester (N = 12,317); when this variable was missing, we estimated gestational age using the date of the mother’s last menstrual period (N = 23). We established a priori that maternal age and maternal race (White, Black, Hispanic, Asian, Native American, Other) would be included in the models [3, 5, 10, 11]. We also controlled for gestational age when appropriate.

In addition, we considered the following as covariates: maternal education (<high school, high school graduate/some college, college degree); delivery method (cesarean delivery or vaginal birth, either spontaneous or assisted); prenatal smoking (yes/no); nulliparity (yes/no); birth weight <2500 grams (yes/no); small for gestational age among live born infants (lowest 10th percentile, calculated from the BERD database from 1989-2002 based on Lipsky et al.) [12]; sexually transmitted infection (STI; syphilis, gonorrhea, chlamydia, or genital herpes) diagnosed and/or treated during pregnancy (yes/no); presence of hypertension, diabetes, or pre-eclampsia during pregnancy (yes/no); presence of chorioamnionitis (yes/no); and presence of moderate or heavy meconium (yes/no). Covariates with significant missing data were not included in the models. A variable was considered to be a potential confounder if controlling for the variable produced a >10 % change in the risk estimate. Confounding was assessed separately in the full-term and preterm sub-cohorts, as well in the entire cohort for all outcomes. Confounders determined not to be in the causal pathway were included in the model. Significant associations between BV and the examined outcomes were further explored with stratified analyses evaluating our hypothesis that poor outcomes were likely to be associated with an ascending infection.

All analyses were conducted using STATA 13 software (Stata Corporation, College Station, Texas).

Results

We included and analyzed 12,340 mother/infant pairs. Gestational age was missing for 11 infants; these participants were excluded from the full-term (N = 11,354) and pre-term (N = 975) sub-cohort analyses but were included for analyses of the full cohort. There were 2,198 term and 267 preterm mother/infant pairs identified that were BV exposed.

Demographic characteristics varied between BV exposed and unexposed women (Table 1). Among full-term birth, BV-exposed mother were significantly younger than unexposed mothers (<20 years: 14.7 % vs. 7.3 %), and more likely to be having their first birth (47.2 % vs. 41.4 %). They were more likely to be Black (10.7 % vs. 4.6 %) or Hispanic (19.0 % vs. 10.8 %), and less likely to have a college degree (16.5 % vs. 36.1 %). BV-exposed mothers were more likely to have smoked during pregnancy (16.5 % vs. 10.1 %), less likely to have had a cesarean delivery (21.7 % vs. 27.1 %), more likely to have a small for gestational age infant (10.3 % vs. 8.6 %), less likely to have had at least adequate prenatal care as indicated by the Kotelchuck index (59.6 % vs. 62.5 %), and more likely to have had an STI diagnosed and/or treated during their pregnancy (13.5 % vs. 4.1 %). Comorbid pregnancy conditions (diabetes, hypertension and preeclampsia) were similar between BV-exposed and BV-unexposed mothers. Term infants born to BV-exposed mothers were more likely to have moderate or heavy meconium (9.0 % vs. 5.6 %) than infants of unexposed mothers. Preterm infants born to BV-exposed mothers had a higher risk of chorioamnionitis (8.2 % vs. 5.8 %). Other demographic characteristics were similar in the full-term and preterm births, with the exception that cesarean deliveries and low birth weight infants were higher in the preterm births.
Table 1

Maternal characteristics of women with and without bacterial vaginosis during pregnancy, Washington State 2003-2013

 

Full Term (N = 11,354)

Preterm (N = 975)

Total (N = 12,340)

BV exposed

BV unexposed

BV exposed

BV unexposed

BV exposed

BV unexposed

N = 2198

N = 9156

N = 267

N = 708

N = 2468

N = 9872

 

n

%

n

%

n

%

n

%

n

%

n

%

Age (years)*

 <20

324

14.7

666

7.3

39

14.6

56

7.9

363

14.7

723

7.3

 20-24

784

35.7

2095

22.9

79

29.6

179

25.3

866

35.1

2278

23.1

 25-29

620

28.2

2593

28.3

66

24.7

166

23.5

686

27.8

2760

28.0

 30-34

317

14.4

2375

26.0

44

16.5

188

26.6

361

14.6

2564

26.0

 35+

153

7.0

1424

15.6

39

14.6

119

16.8

192

7.8

1544

15.6

Race/Ethnicity*

 White

1268

58.8

6842

71.7

152

58.9

497

71.8

1422

58.8

6981

71.7

 Black

231

10.7

416

4.6

21

8.1

36

5.2

252

10.4

452

4.6

 Asian

183

8.5

939

10.4

28

10.9

64

9.3

212

8.8

1006

10.3

 Hispanic

410

19.0

979

10.8

39

15.1

73

10.6

449

18.6

1054

10.8

 Native American

62

2.9

218

2.4

18

7.0

22

3.2

80

3.3

240

2.5

 Other

4

0.2

9

0.1

0

0.0

0

0.0

4

0.2

9

0.1

Education*

 Less than H.S.

689

31.6

1639

18.1

89

34.1

148

21.4

779

31.9

1791

18.4

 H.S. grad/some college

1132

51.9

4134

45.8

129

49.4

323

46.6

1263

51.7

4460

45.8

 College graduate

360

16.5

3263

36.1

43

16.5

222

32.0

403

16.5

3486

35.8

Nulliparous*

3733

47.2

1035

41.4

118

45.2

309

45.2

1154

47.0

4045

41.7

Cesarean delivery*

477

21.7

2479

27.1

78

29.3

269

38.1

555

22.5

2751

27.9

Low Birth Weight (<2500 g)*

41

1.9

139

1.5

158

60.1

344

49.1

199

8.1

483

4.9

Small for gestational age

227

10.3

790

8.6

22

8.2

76

10.7

249

10.1

866

8.8

 missing

0

(0)

12

(0.13)

20

(7.49)

15

(2.12)

23

(0.93)

35

(0.35)

Smoking*

360

16.5

921

10.1

42

15.9

84

12.0

404

16.5

1006

10.3

Kotelchuck Index

 Inadequate

374

17.8

1203

15.2

29

14.2

85

16.7

403

17.5

1291

15.3

 Intermediate

475

22.6

1763

22.3

39

19.1

76

14.9

514

22.3

1839

21.8

 Adequate

899

42.7

3658

46.3

52

25.5

150

29.5

951

41.2

3808

45.2

 Adequate Plus

356

16.9

1283

16.2

84

41.2

198

38.9

440

19.1

1481

17.6

 missing

94

(4.3)

1249

(13.6)

63

(23.6)

199

(28.1)

160

(6.5)

1453

(14.7)

STI*†

296

13.5

379

4.1

34

12.7

42

5.9

330

13.4

422

4.3

Maternal comorbidities‡

236

10.8

1022

11.3

53

20.0

184

26.3

289

11.7

1207

12.4

 missing

2

(0.1)

92

(1.0)

2

(0.8)

7

(1.0)

5

(0.2)

99

(1.0)

Chorioamnionitis*

62

2.8

265

2.9

22

8.2

41

5.8

84

3.4

306

3.1

Meconium (moderate/heavy)

198

9.0

510

5.6

6

2.3

19

2.7

204

8.3

530

5.4

 missing

4

(0.2)

98

(1.1)

20

(7.5)

26

(3.7)

25

(1.0)

126

(1.3)

BV bacterial vaginosis; H.S. High School, STI sexually transmitted infections

*Missing data not displayed, <3.5 % in all groups

†syphilis, gonorrhea, chlamydia, and/or genital herpes

‡hypertension, diabetes, and/or pre-eclampsia

Among full-term infants, BV exposure was significantly and positively associated with an approximately 28 % increased risk of assisted ventilation at birth, a 42 % increased risk for admission to NICU and a 60 % increased risk for neonatal sepsis after adjusting for gestational age, maternal age, and maternal race (Table 2). There was no association with fetal or infant mortality. The presence of an STI confounded the relationship between BV and fetal mortality in the full-term births and was controlled for, but presence of an STI did not confound any other outcomes in term, preterm, or all births. Additionally, no other covariates confounded the relationship between BV and any of the outcomes examined. Among full-term births, the risk ratio for the association of BV with neonatal sepsis was higher in SGA infants (adjusted risk ratio [aRR] = 2.57, 95 % confidence interval [CI] 1.04, 6.40) than in AGA and LGA infants (aRR = 1.46, 95 % CI 1.00, 2.13), but confidence intervals are overlapping. Rates of chorioamnionitis and meconium were higher in BV-exposed pregnancies, but neither modified the relationship between BV and the outcomes examined (Table 3).
Table 2

Associations between bacterial vaginosis and adverse outcomes among full-term infants (37 weeks or greater gestation), Washington State, 2003-2013, adjusted for gestational age, maternal age, and maternal race (N = 11,354)

 

BV exposed

BV unexposed

RR

95 % CI

aRR

95 % CI

N = 2198

N = 9156

n

%

n

%

    

Assisted ventilation at birth

100

4.6

331

3.6

1.26

1.01–1.57

1.28

1.02–1.61

Admission to NICU at birth

89

4.1

272

3.0

1.36

1.08–1.72

1.42

1.11–1.82

Neonatal sepsis

48

2.2

126

1.4

1.59

1.14–2.21

1.60

1.13–2.27

Fetal Mortality

3

0.1

13

0.1

0.96

0.27–3.37

1.15*

0.27–4.96

Infant mortality

4

0.2

24

0.3

0.69

0.24–2.00

0.39

0.12–1.28

BV bacterial vaginosis, RR risk ratio, aRR adjusted risk ratio, CI confidence interval, NICU neonatal intensive care unit

*further adjusted for presence of sexually transmitted infections (syphilis, gonorrhea, chlamydia, and/or genital herpes)

Table 3

Associations between bacterial vaginosis and adverse outcomes among full-term infants (37 weeks or greater gestation), Washington State, 2003-2013 (N = 11,354), adjusted for gestational age, maternal age, and maternal race, and additionally adjusted for the presence of chorioamnionitis or meconium

 

BV exposed

BV unexposed

aRR

95 % CI

N = 2198

N = 9156

n

%

n

%

  

Assisted ventilation at birth

98

4.5

328

3.6

1.28

1.02–1.61

 additionally adjusted for chorioamnionitis

98

4.5

328

3.6

1.28

1.02–1.61

 additionally adjusted for meconium

98

4.5

328

3.7

1.22

0.97–1.53

Admission to NICU at birth

88

4.1

269

3.0

1.42

1.11–1.82

 additionally adjusted for chorioamnionitis

88

4.1

269

3.0

1.45

1.13–1.85

 additionally adjusted for meconium

88

4.1

267

3.0

1.34

1.05–1.72

Neonatal sepsis

48

2.2

125

1.4

1.60

1.13–2.27

 additionally adjusted for chorioamnionitis

48

2.2

125

1.4

1.67

1.19–2.35

 additionally adjusted for meconium

48

2.2

125

1.4

1.51

1.06–2.14

Fetal Mortality

3

0.1

12

0.1

1.15*

0.27–4.96

 additionally adjusted for chorioamnionitis

3

0.1

12

0.1

1.14*

0.27–4.88

 additionally adjusted for meconium

0

0.0

3

0.0

-

-

Infant mortality

3

0.1

24

0.3

0.39

0.12–1.28

 additionally adjusted for chorioamnionitis

3

0.1

24

0.3

0.39

0.12–1.27

 additionally adjusted for meconium

3

0.1

23

0.3

0.40

0.12–1.34

BV bacterial vaginosis, aRR adjusted risk ratio, CI confidence interval, NICU neonatal intensive care unit

*further adjusted for presence of sexually transmitted infections (syphilis, gonorrhea, chlamydia, and/or genital herpes)

Among preterm infants, BV exposure was associated with a 24 % increased risk for admission to NICU after adjusting for gestational age, maternal age, and maternal race (Table 4). Assisted ventilation at birth, neonatal sepsis, infant and neonatal mortality were not associated with BV exposure.
Table 4

Associations between bacterial vaginosis and adverse outcomes among preterm infants (less than 37 weeks gestation), Washington State, 2003-2013, adjusted for gestational age, maternal age, and maternal race (N = 975)

 

BV exposed

BV unexposed

RR

95 % CI

aRR

95 % CI

N = 267

N = 708

    

n

%

n

%

    

Assisted ventilation at birth

51

19.1

94

13.3

1.44

1.05–1.96

1.23

0.89–1.73

Admission to NICU at birth

124

50.4

246

36.0

1.40

1.20–1.64

1.24

1.04–1.46

Neonatal sepsis

47

17.6

82

11.6

1.52

1.09–2.11

1.31

0.91–1.89

Fetal Mortality

21

7.9

21

3.0

2.65

1.47–4.78

1.25

0.67–2.33

Infant mortality

17

6.9

21

3.1

2.26

1.21–4.22

1.10

0.66–1.84

BV bacterial vaginosis, RR risk ratio, aRR adjusted risk ratio, CI confidence interval, NICU neonatal intensive care unit

Among all infants, preterm birth was 55 % more likely to occur in women with BV (Table 5). Assisted ventilation at birth, admission to NICU, and neonatal sepsis were also associated with BV exposure in the whole cohort. There was an association between BV and 2nd trimester (20-28 weeks gestation) fetal mortality (aRR = 10.42, 95 % CI 3.55, 30.61).
Table 5

Associations between bacterial vaginosis and adverse outcomes among all infants, Washington State, 2003-2013, adjusted for maternal age and race (N = 12,340)

 

BV exposed

BV unexposed

RR

95 % CI

aRR

95 % CI

N = 2468

N = 9872

n

%

n

%

    

Preterm birth

267

10.8

708

7.2

1.51

1.32–1.72

1.55

1.34–1.78

Assisted ventilation at birth

151

6.1

425

4.3

1.42

1.19–1.70

1.45

1.21–1.75

Admission to NICU at birth

213

8.7

519

5.3

1.65

1.42–1.92

1.73

1.47–2.03

Neonatal sepsis

95

3.9

209

2.1

1.82

1.43–2.31

1.86

1.44–2.41

Fetal Mortality

25

1.0

35

0.4

2.86

1.71–4.76

2.79*

1.54–5.05

 2nd trimester

16

0.7

7

0.1

12.22

4.29–34.79

10.42*

3.55–30.61

 3rd trimester

9

0.4

28

0.3

1.49

0.65–3.40

1.31*

0.55–3.11

Infant mortality

21

0.9

45

0.5

1.89

1.12–3.15

1.61

0.90–2.90

BV bacterial vaginosis, RR risk ratio, aRR adjusted risk ratio, CI confidence interval, NICU neonatal intensive care unit

*further adjusted for presence of a maternal comorbidity (hypertension, diabetes, and/or pre-eclampsia)

Discussion

Consistent with prior research, we found a strong association between BV and risk for preterm birth [3, 5, 10, 11, 13]. More importantly, our primary study goal was to assess term outcomes. We hypothesized that BV would increase the risk for adverse neonatal outcomes, even among infants born full-term. We found an association between BV and an increased risk of neonatal assisted ventilation/respiratory distress, admission to NICU, and neonatal sepsis in the full cohort of term and preterm infants, similar to a prior study [6]. But, notably these findings persisted when analyses were restricted to only term deliveries.

Our data demonstrate an association between BV during pregnancy and poor neonatal outcomes at term that has only been hinted at previously [4]. We had hypothesized that poor neonatal outcomes could be due to ascending infection during pregnancy that might increase risks of chorioamnionitis or poor fetal growth, which in turn might increase the risk of poor neonatal outcomes. Meta-analyses previously showed a trend for increased risk of neonatal sepsis associated with BV in infants of all gestational ages, but results were non-significant and sample sizes limited with an inability to fully explore term outcomes [3, 5]. Data from a single study, with a small sample of 151 term BV exposures and 6 instances of infectious morbidity, suggests a modest association between infectious morbidity and BV exposure early in pregnancy among full-term infants; however, this association was not formally examined [4]. BV has been associated with chorioamnionitis in primarily preterm cohorts [14, 15], and chorioamnionitis is associated with neonatal sepsis in both term and preterm infants [16, 17]. Our study of 12,340 infants showed significant associations between BV and neonatal sepsis, both in the complete cohort and in the subset of full-term infants that included 2,198 BV-exposed mother/infant pairs. BV-exposed women delivering at term also had higher rates of meconium, which has been associated with in-utero bacteria [18] and worse neonatal outcomes [19]. However, when the presence of meconium and/or chorioamnionitis were included in our models, the risk for adverse outcomes persisted, suggesting that the association between BV and neonatal compromise is not due to meconium aspiration or the direct effects of chorioamnionitis. BV is associated with upper genital tract infection in both pregnant [20] and non-pregnant [21] women, thus sub-clinical infection could be one mechanism for the poor neonatal outcomes observed.

Others have not evaluated full-term births for the association of BV with SGA or LBW. Among full-term infants in our cohort, BV-exposed infants were more likely to be SGA, but not more likely than unexposed infants to have LBW. In our full cohort, BV-exposed infants were more likely to be SGA or LBW, confirming previous reports of this association [15, 22, 23]. In other studies among preterm infants, BV has been associated with LBW [1]. In a cohort of late preterm (>33 weeks) and term infants, SGA was associated with increased NICU admission, low Apgar scores and composite neonatal morbidity [24]. In our study, SGA infants were at greater risk of NICU admission when born preterm, and greater risk of neonatal sepsis when born full-term, but these increased risks were not statistically different from LGA and AGA infants.

The increased risk of NICU admissions and respiratory distress among full-term infants exposed to BV that we observed in our cohort has not been previously described, to our knowledge. In a small cohort of preterm infants, the proportions of infants with respiratory distress, requirement of intermittent positive pressure ventilation, admission to NICU, and NICU stays over two days was higher among BV exposed than among BV-unexposed pregnancies (uncontrolled analyses) [6]. We confirmed the association between BV and NICU admission in preterm infants, controlling for gestational age and several possible confounders, strengthening the likelihood that this association is biologically true.

We did not find an increased risk for term perinatal mortality associated with BV and, to our knowledge, this has not been studied previously. BV has not been associated with perinatal mortality in previous meta-analyses of primarily preterm cohorts [3]. Perinatal mortality was not associated with overall fetal or infant mortality in our full cohort. However, when we evaluated mortality by trimester, the risk of 2nd trimester fetal mortality was increased, supporting meta-analyses that reported a 6-fold increased risk for loss between 14-24 weeks in women diagnosed with BV during early pregnancy [3].

Our study has strengths and limitations. It was large, population-based, and rich in covariates, with little missing data. While birth certificate sensitivity is poor for some variables [8, 25], we increased ascertainment of exposures and outcomes by using both birth certificates and linked hospital records. Since routine screening for BV is not standard of care, cases identified were likely symptomatic, which may limit this study’s findings to cases of symptomatic BV. While asymptomatic cases may be under-diagnosed, including asymptomatic BV-exposed mothers among the unexposed would bias results towards the null. We did not have data on BV treatment in exposed women or the trimester that BV was diagnosed. If BV treatment tempers the increased risk of the poor neonatal outcomes associated with BV, associations may be even greater than reported here. Furthermore, associations may differ according to the timing of BV treatment. Further studies are needed to address these questions. Additionally, 68 % of the women were White, limiting the generalizability of our findings. A large proportion of women were nulliparous. But as all data are de-identified, mothers who gave birth more than once during the study period may have been included multiple times, potentially introducing a clustering bias we are unable to address. Lastly, our study shows an association, but cannot confirm a causal relationship between BV and poor outcomes among term deliveries.

Conclusions

BV during pregnancy appears to increase the risk for adverse neonatal outcomes through mechanisms independent of BV’s effect on timing of delivery. These findings may have significant clinical implications if confirmed by other studies, but several questions remain, including the importance of timing of the exposure and the mechanism for these associations. While treatment of BV during pregnancy has not succeeded in reducing preterm birth [26, 27], treatments targeted specifically at improving term neonatal outcomes have not been explored as thoroughly. The Maternal Fetal Medicine Unit's treatment trial for asymptomatic BV between 16 and 24 weeks did not show a difference in birthweight, NICU admission, neonatal sepsis, or neonatal death, though data were only shown for the first outcome. The sample size of the trial was only 1,953, thus it may not have had adequate power to detect differences in these uncommon outcomes [27]. A Cochrane review [28] of seven randomized clinical trials on antibiotic prophylaxis during pregnancy for women at high risk of preterm birth had inadequate power to study the effect of prophylaxis on neonatal sepsis, did not restrict analyses to women with BV, did not report on NICU admission, and did not focus on term deliveries. There are very few prior studies directly relevant to our findings - an increased risk of neonatal assisted ventilation/respiratory distress, admission to NICU, and neonatal sepsis among BV exposed infants born at term. Our findings suggest that any study evaluating the vaginal microbiota in pregnancy should include neonatal outcomes as an endpoint, and expand our understanding of BV associated outcomes in preterm infants to term deliveries.

Abbreviations

AGA: 

Average for gestational age

aRR: 

Adjusted relative risk

BERD: 

Birth Events Record Database

BV: 

Bacterial vaginosis

CHARS: 

Comprehensive Hospital Abstract Reporting System

ICD: 

International Classification of Disease

LBW: 

Low birth weight

LGA: 

Large for gestational age

NICU: 

Neonatal intensive care unit

RR: 

Relative risk

SGA: 

Small for gestational age

STI: 

Sexually transmitted infection

Declarations

Acknowledgements

The authors wish to thank the Washington State Department of Health for data access, Mr. Bill O’Brien for programming and data management and Dr. Steve Hawes for guidance with our analyses.

Funding

AD was supported by an NSF Graduate Research Fellowship (DGE-1256082) and an NIH Interdisciplinary Training Grant (T32 CA080416). These funders played no role in the study design, data collection, analysis, writing, or decision to publish.

Availability of data and material

Data from this study will not be publicly available. Data were obtained from the Washington State Department of health under condition that data would be destroyed after completion of the project.

Authors’ contributions

AD and TF designed the study, performed the analyses, analyzed the results, and wrote the manuscript. SR and CM made major contributions to the interpretation of the data and writing of the manuscript. All authors read and approved the final manuscript.

Competing interests

CM sits on a scientific advisory board for Perrigo Pharmaceuticals. The remaining authors declare no conflicts of interest.

Ethics approval and consent to participate

All data were de-identified, and the study was determined to be exempt from review by the Washington State Institutional Review Board.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Epidemiology, University of Washington School of Public Health
(2)
University of Washington, Molecular & Cellular Biology Program
(3)
Fred Hutchinson Cancer Research Center
(4)
Harborview Medical Center
(5)
Vincent Center for Reproductive Biology, Massachusetts General Hospital
(6)
Harvard Medical School

References

  1. Hillier SL, Nugent RP, Eschenbach DA, Krohn MA, Gibbs RS, Martin DH, Cotch MF, Edelman R, Pastorek 2nd JG, Rao AV, et al. Association between bacterial vaginosis and preterm delivery of a low-birth-weight infant. The Vaginal Infections and Prematurity Study Group. N Engl J Med. 1995;333(26):1737–42.View ArticlePubMedGoogle Scholar
  2. Guise J-M, Mahon SM, Aickin M, Helfand M, Peipert JF, Westhoff C. Screening for bacterial vaginosis in pregnancy. Am J Prev Med. 2001;20(3):62–72.View ArticlePubMedGoogle Scholar
  3. Leitich H, Kiss H. Asymptomatic bacterial vaginosis and intermediate flora as risk factors for adverse pregnancy outcome. Best Pract Res Clin Obstet Gynaecol. 2007;21(3):375–90.View ArticlePubMedGoogle Scholar
  4. Kurki T, Sivonen A, Renkonen OV, Savia E, Ylikorkala O. Bacterial vaginosis in early pregnancy and pregnancy outcome. Obstet Gynecol. 1992;80(2):173–7.PubMedGoogle Scholar
  5. Leitich H, Bodner-Adler B, Brunbauer M, Kaider A, Egarter C, Husslein P. Bacterial vaginosis as a risk factor for preterm delivery: a meta-analysis. Am J Obstet Gynecol. 2003;189(1):139–47.View ArticlePubMedGoogle Scholar
  6. Laxmi U, Agrawal S, Raghunandan C, Randhawa VS, Saili A. Association of bacterial vaginosis with adverse fetomaternal outcome in women with spontaneous preterm labor: a prospective cohort study. J Matern Fetal Neonatal Med. 2012;25(1):64–7.View ArticlePubMedGoogle Scholar
  7. Herman A, McCarthy B, Bakewell J, Ward R, Mueller B, Maconochie N, Read A, Zadka P, Skjaerven R. Data linkage methods used in maternally-linked birth and infant death surveillance data sets from the United States (Georgia, Missouri, Utah and Washington State), Israel, Norway, Scotland and Western Australia. Paediatr Perinat Epidemiol. 1997;11(S1):5–22.View ArticlePubMedGoogle Scholar
  8. Lydon-Rochelle MT, Holt VL, Nelson JC, Cardenas V, Gardella C, Easterling TR, Callaghan WM. Accuracy of reporting maternal in-hospital diagnoses and intrapartum procedures in Washington State linked birth records. Paediatr Perinat Epidemiol. 2005;19(6):460–71.View ArticlePubMedGoogle Scholar
  9. Goff SL, Pekow PS, Markenson G, Knee A, Chasan-Taber L, Lindenauer PK. Validity of using ICD-9-CM codes to identify selected categories of obstetric complications, procedures and co-morbidities. Paediatr Perinat Epidemiol. 2012;26(5):421–9.View ArticlePubMedGoogle Scholar
  10. Chaim W, Mazor M, Leiberman JR. The relationship between bacterial vaginosis and preterm birth. Rev Arch Gynecol Obstet. 1997;259(2):51–8.View ArticleGoogle Scholar
  11. Manns-James L. Bacterial vaginosis and preterm birth. J Midwifery Womens Health. 2011;56(6):575–83.View ArticlePubMedGoogle Scholar
  12. Lipsky S, Easterling TR, Holt VL, Critchlow CW. Detecting small for gestational age infants: the development of a population-based reference for Washington State. Am J Perinatol. 2005;22(8):405–12.View ArticlePubMedGoogle Scholar
  13. Nelson DB, Macones G. Bacterial vaginosis in pregnancy: current findings and future directions. Epidemiol Rev. 2002;24(2):102–8.View ArticlePubMedGoogle Scholar
  14. Kekki M, Kurki T, Pelkonen J, Kurkinen-Raty M, Cacciatore B, Paavonen J. Vaginal clindamycin in preventing preterm birth and peripartal infections in asymptomatic women with bacterial vaginosis: a randomized, controlled trial. Obstet Gynecol. 2001;97(5 Pt 1):643–8.PubMedGoogle Scholar
  15. Svare JA, Schmidt H, Hansen BB, Lose G. Bacterial vaginosis in a cohort of Danish pregnant women: prevalence and relationship with preterm delivery, low birthweight and perinatal infections. BJOG. 2006;113(12):1419–25.View ArticlePubMedGoogle Scholar
  16. Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the prognosis for term infants. Obstet Gynecol. 1999;94(2):274–8.PubMedGoogle Scholar
  17. Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK, Canadian Neonatal N. A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol. 2009;200(4):372. e371-376.View ArticlePubMedGoogle Scholar
  18. Romero R, Yoon BH, Chaemsaithong P, Cortez J, Park CW, Gonzalez R, Behnke E, Hassan SS, Chaiworapongsa T, Yeo L. Bacteria and endotoxin in meconium-stained amniotic fluid at term: could intra-amniotic infection cause meconium passage? J Matern Fetal Neonatal Med. 2014;27(8):775–88.View ArticlePubMedGoogle Scholar
  19. Hiersch L, Krispin E, Aviram A, Wiznitzer A, Yogev Y, Ashwal E. Effect of meconium-stained amniotic fluid on perinatal complications in low-risk pregnancies at term. Am J Perinatol. 2015.Google Scholar
  20. Newton ER, Piper J, Peairs W. Bacterial vaginosis and intraamniotic infection. Am J Obstet Gynecol. 1997;176(3):672–7.View ArticlePubMedGoogle Scholar
  21. Andrews WW, Hauth JC, Cliver SP, Conner MG, Goldenberg RL, Goepfert AR. Association of asymptomatic bacterial vaginosis with endometrial microbial colonization and plasma cell endometritis in nonpregnant women. Am J Obstet Gynecol. 2006;195(6):1611–6.View ArticlePubMedGoogle Scholar
  22. Thorsen P, Vogel I, Olsen J, Jeune B, Westergaard JG, Jacobsson B, Moller BR. Bacterial vaginosis in early pregnancy is associated with low birth weight and small for gestational age, but not with spontaneous preterm birth: a population-based study on Danish women. J Matern Fetal Neonatal Med. 2006;19(1):1–7.View ArticlePubMedGoogle Scholar
  23. Slyker JA, Patterson J, Ambler G, Richardson BA, Maleche-Obimbo E, Bosire R, Mbori-Ngacha D, Farquhar C, John-Stewart G. Correlates and outcomes of preterm birth, low birth weight, and small for gestational age in HIV-exposed uninfected infants. BMC Pregnancy Childbirth. 2014;14:7.View ArticlePubMedPubMed CentralGoogle Scholar
  24. Anderson NH, Sadler LC, McKinlay CJ, McCowan LM. INTERGROWTH 21st versus customized birthweight standards for identification of perinatal mortality and morbidity. Am J Obstet Gynecol. 2015.Google Scholar
  25. Bradford HM, Cardenas V, Camacho-Carr K, Lydon-Rochelle MT. Accuracy of birth certificate and hospital discharge data: a certified nurse-midwife and physician comparison. Matern Child Health J. 2007;11(6):540–8.View ArticlePubMedGoogle Scholar
  26. Brocklehurst P, Gordon A, Heatley E, Milan SJ. Antibiotics for treating bacterial vaginosis in pregnancy. Cochrane Database Syst Rev. 2013;1:CD000262.Google Scholar
  27. Carey JC, Klebanoff MA, Hauth JC, Hillier SL, Thom EA, Ernest JM, Heine RP, Nugent RP, Fischer ML, Leveno KJ, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 2000;342(8):534–40.View ArticlePubMedGoogle Scholar
  28. Thinkhamrop J, Hofmeyr GJ, Adetoro O, Lumbiganon P, Ota E. Antibiotic prophylaxis during the second and third trimester to reduce adverse pregnancy outcomes and morbidity. Cochrane Database Syst Rev. 2015;6:CD002250.Google Scholar

Copyright

© The Author(s). 2016

Advertisement