Accepted Article

Article type : Clinical Article

CLINICAL ARTICLE

Antibiotic treatment of amniotic fluid “sludge” in patients during the second or

third trimester with uterine contraction

Wan Hu Jin1,2, Yoon Ha Kim1,*,†, Jong Woon Kim1,†, Tae Young Kim1, AmiKim1, Yoonmi

Yang1
1Department of Obstetrics and Gynecology, Chonnam National University Medical School,

Gwangju, South Korea

2Department of Obstetrics and Gynecology, Yanbian University Hospital, Yanji, China
† Equal contributors.

*Correspondence

Yoon Ha Kim, Department of Obstetrics and Gynecology, Chonnam National University

Medical School, 160, Baekseo-ro, Dong-gu, Gwangju, 61469, South Korea.

Email: kimyh@chonnam.ac.kr

Keywords

Amniotic fluid “sludge”; Antibiotics; Preterm birth; Preterm labor

Synopsis

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1002/IJGO.13425
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 Administration of antibiotics may eradicate amniotic fluid “sludge” in women during the
Accepted Article
second or third trimester with uterine contractions and intact membranes.

Abstract

Objective: To assess the effectiveness of antibiotic treatment in patients with amniotic

fluid (AF) “sludge” during the second or third trimester with uterine contractions and intact

membranes.

Methods: A retrospective cohort study was conducted of women at 15–32 weeks of

pregnancy with uterine contractions and intact membranes. Women with AF “sludge” were

treated with an antibiotic regimen of ceftriaxone, clarithromycin, and metronidazole. Based

on changes in AF “sludge,” patients were divided into group A (disappearance of “sludge”)

and group B (persistent “sludge”).

Results: Women in group A (n=30) delivered later than those in group B (n=28). Group A

showed a smaller initial size of “sludge” than group B (all P<0.05). Women in group A had

a lower rate of preterm birth within 7 days, and before 28, 32, and 34 weeks of pregnancy,

and composite neonatal morbidity and perinatal death than group B (all P<0.05).

Conclusion: The administration of antibiotics may eradicate AF “sludge” in women in the

second or third trimester with uterine contractions and intact membranes, which are

associated with the initial size of “sludge.” Patients with disappearing “sludge” had more

favorable pregnancy and neonatal outcomes than those with persistent “sludge.”

1 INTRODUCTION

Preterm birth (PTB) is the main cause of perinatal morbidity and mortality worldwide [1].

PTB results from preterm labor (PTL), and intra-amniotic infection or inflammation is the

most common cause of PTL [2]. Intra-amniotic infection is also a major cause of

spontaneous mid-trimester miscarriage [3]. Infection and inflammation of the amniotic fluid

are etiological factors underlying most deliveries before 32 weeks of pregnancy [4, 5].

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 Intra-amniotic infection and inflammation are the most common and possibly preventable
Accepted Article
causes of PTB. Importantly, most patients with uterine contractions such as threatened

mid-trimester abortion or PTL exhibit no clinical signs or symptoms of intra-amniotic

infection (e.g. fever, uterine tenderness). Therefore, an accurate diagnosis requires

analysis of the amniotic fluid via amniocentesis. Amniocentesis is an invasive procedure

that many providers are reluctant to perform in patients with uterine contractions, and not

all patients are eligible or indicated for the procedure.

Recent sonographic investigations suggest the presence of free-floating hyperechogenic

material termed amniotic fluid “sludge” (AFS) within the amniotic fluid close to the uterine

cervix. The AFS is associated with an increased risk of preterm delivery, microbial

invasion of the amniotic cavity (MIAC), and histological chorioamnionitis among

symptomatic and asymptomatic high-risk women scheduled for preterm delivery [6–9].

Himaya et al [8] reported that AFS serves as a non-invasive biomarker of mid-trimester

MIAC, most likely due to intra-amniotic infection and inflammation. The prevalence of AFS

was 22.6% in patients with PTL and intact membranes, and has been identified as an

independent risk factor for impending preterm delivery, histological chorioamnionitis, and

MIAC in patients with spontaneous PTL and intact membranes [7]. Romero et al [10]

reported that the overall evidence-based on macroscopic, microscopic, and

microbiological studies suggests that the AFS detected by ultrasound reflects severe

intra‐amniotic infection‐related inflammation. Paules et al [11] reported that AFS is a

marker of intra-amniotic infection.

Although the relationship between AFS with preterm delivery and infection or inflammation

in the amniotic cavity has been extensively investigated, few studies have reported on the

antibiotic treatment of AFS. Antibiotics are routinely used to treat patients with AFS in the

second or third trimester with uterine contractions and intact membranes in the study

hospital. The aim of present study was to evaluate the effectiveness of antibiotic treatment

in these patients and describe the pregnancy and neonatal outcomes.

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 2 MATERIALS AND METHODS
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Study design

A retrospective cohort study was conducted using data from Chonnam National University

Hospital. The clinical database and the digital library of ultrasound images of patients who

attended our hospital from January 2016 to June 2019 were reviewed. The inclusion

criteria were: (1) singleton pregnancy; (2) at 15–32 weeks of pregnancy; (3) presence of

uterine contraction; (4) intact membranes; and (5) the presence of AFS found on

ultrasonographic examination. The exclusion criteria were: (1) impending preterm delivery

(delivery within 48 hours of the ultrasound examination or cervical dilation >5 cm); (2)

multiple gestations; (3) preterm premature rupture of membranes (PPROM); (4) fetal

anomalies; (5) placenta previa; and (6) iatrogenic preterm delivery for maternal/fetal

reasons. The medical records of each patient included in the study were reviewed, and

the following information was collected: cervical length; gestational age at the time of

ultrasound examination; histories of previous PTB; size of AFS; and duration of antibiotics.

The present study was conducted according to the tenets of the Declaration of Helsinki

and was approved by the Institutional Review Board of Chonnam National University

Hospital. Due to the retrospective nature of the study, the need for formal informed

consent from the participants was waived by the approval committee.

Definitions and management

1. Amniotic fluid “sludge”

A transvaginal ultrasound examination was conducted to measure the cervical length and

evaluate the presence of AFS, using ultrasound systems (Samsung Medison Diagnostic

Ultrasound System Version 4.01 WS80A) equipped with endovaginal transducers with a

frequency in the range of 5–7.5 MHz. AFS was defined by the presence of dense

aggregates of particulate matter in the proximity of the internal cervical os (Fig. 1a), as

described by Espinoza et al [7]. The AFS must necessarily disaggregate by fetal

movement or manual abdominal stimulation and re-form after a few seconds. The

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 absence of disaggregation suggests the formation of clots. The size of the AFS is defined
Accepted Article
by the mean diameter of the transverse, sagittal, and coronal planes of the AFS. A

sonographic examination of the AFS was confirmed by at least two experienced

sonographers.

2. Antimicrobial regimen

The routine antimicrobial regimen for all patients included ceftriaxone 1 g (intravenous)

every 24 hours, clarithromycin 500 mg (oral) every 12 hours, and metronidazole

(intravenous) 500 mg every 8 hours [12]. The maximum duration of administration of

antibiotics in the present study was 4 weeks, given the risk of antibiotic-resistant bacteria

when broad-spectrum antibiotics are used and concern of adverse events because of

metronidazole. All patients used tocolytics (magnesium sulfate, ritodrine, or atosiban) to

maintain pregnancy. These antibiotics were stopped when either the AFS persisted and

preterm delivery occurred or when the AFS disappeared. Treatment with antibiotics was

also stopped if the patient failed to deliver after 4 weeks and the AFS persisted. During the

period of treatment, all patients underwent periodic ultrasound examination to assess the

size of the AFS and cervical length. In the present study, the patients were divided into

two groups based on whether or not the AFS persisted. Group A included patients

showing the disappearance of the AFS after treatment with antibiotics (Fig. 1). Group B

included patients with persistent AFS after treatment with antibiotics or those delivering

preterm during treatment with antibiotics.

3. Definition of variables

The diagnosis of PTL was determined by the presence of uterine contractions during

monitoring and changes in the cervix during digital examination or ultrasound before 37

weeks of pregnancy. Composite neonatal morbidity (CNM) was defined by one or more

neonatal outcomes, including respiratory distress syndrome (RDS), bronchopulmonary

dysplasia (BPD), neonatal sepsis, necrotizing enterocolitis (NEC), and intraventricular

hemorrhage (IVH) [12]. Histological chorioamnionitis was defined as the presence of

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 inflammatory cells in the chorionic plate and/or chorioamniotic membranes. Funisitis was
Accepted Article
defined as the presence of neutrophils in the wall of the umbilical vessels and/or

Wharton’s jelly, based on criteria described previously [13].

4. Prenatal and postnatal examination

A sample of lower genital tract (LGT) discharge was obtained from all patients. The

sample was subjected to a wet smear test, culture, and test for sexually transmitted

diseases. All samples of placentas and umbilical cords were sent for pathological

investigations.

Statistical analysis

Pregnancy and neonatal outcomes were compared between groups A and B. The χ2 or

Fisher exact tests were used for categorical variables and the Student t-test or Mann–

Whitney U-test for continuous variables. Kaplan–Meier survival analysis was performed to

assess the ultrasonographic examination-to-delivery intervals according to the

disappearance or persistence of AFS. Stepwise logistic regression analysis was used to

determine the factors contributing to the disappearance or persistence of the AFS. The

disappearance or persistence of AFS as an independent variable and stepwise logistic

regression analysis was performed to adjust for confounding factors (cervical length, size

of AFS, duration of antibiotics, etc.). Statistical analysis was performed using SPSS

version23.0 (IBM Corp., Armonk, NY, USA) and P<0.05 was considered statistically

significant.

3 RESULTS

During the study period, 514 women at 15–32 weeks of pregnancy, with a singleton

pregnancy, and with the presence of uterine contraction were admitted to the study

obstetric unit. The presence of AFS was found in 80 women on ultrasonography

examination, of which 16 women were excluded according to the exclusion criteria and six

women were lost follow-up. Finally, 58 women were included in the study analysis. Among

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 the 58 patients subjected to a follow-up ultrasound assessment of AFS, 51.7% showed a
Accepted Article
disappearance of AFS with antibiotic treatment and were categorized as group A. The

remaining 48.3% of patients showed persistent AFS and were included in group B (Fig. 2).

Table 1 presents the demographic and clinical characteristics of the two groups. There

was no significant difference in maternal age, body mass index, nulliparity, previous PTB,

gestational age at examination, cervical length, Bishop score, or microorganisms in the

LGT between the two groups. The women in group A had a smaller initial size of AFS than

those in group B (P=0.004), and the duration of administration of antibiotics was

significantly longer in group A than in group B (P=0.022).

Table 2 presents significant differences between the two groups, in gestational age at

delivery (P<0.001), ultrasonographic examination-to-delivery interval (P<0.001), and birth

weight (P<0.001). Group A showed a lower rate of PTB within 7 days (P=0.005), in under

28 weeks of pregnancy (P<0.001), under 32 weeks of pregnancy (P=0.008), and under 34

weeks of pregnancy (P=0.006) compared to group B. The rate of admission of newborns

to the neonatal intensive care unit (NICU) was not significantly different between the

groups, but group A showed a lower proportion of CNM (P=0.030) and neonatal death

(P<0.001) than group B. Four patients in group A delivered at term, while none of the

newborns in group B were delivered at term, and the prevalence of histological

chorioamnionitis, funisitis, and PPROM was not different between the two groups.

Kaplan–Meier survival analysis showed that group B had a shorter ultrasonographic

examination-to-delivery interval than group A (68 days, 95% confidence interval [CI] 55–

81 vs 28 days, 95% CI 15–42; P=0.001) (Fig. 3). Stepwise logistic regression analyses

indicated that the initial size of AFS (odds ratio [OR] 5.5, 95% CI 1.55–19.34; P=0.008)

and the duration of administration of antibiotics (OR 0.9, 95% CI 0.85–0.99; P=0.025)

were independent risk factors for the persistence of AFS (Table 3).

As shown in Table 4, stepwise logistic regression analysis indicated that only persistence

of AFS was an independent risk factor for PTB at less than 28 weeks of pregnancy (OR

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 8.2; 95% CI: 2.53-26.68; P<0.001), less than 32 weeks of pregnancy (OR 6.4, 95% CI
Accepted Article
1.57–25.80; P=0.009), and less than 34 weeks of pregnancy (OR 13.5, 95% CI 1.60–

114.21; P=0.017).

4 DISCUSSION

The main finding of the present study was that antibiotic treatment of patients in the

second or third trimester with uterine contractions and AFS may eradicate the AFS.

Further, the pregnancy and neonatal outcomes of the women in group A (disappearance

of AFS) were better than those in group B (persistent AFS). Besides, the size of the AFS

was used for the first time to assess the effectiveness of the treatment with antibiotics and

the initial size of the AFS was closely related to the disappearance of AFS. The larger the

initial size of the AFS, the less likely it was to disappear. Among different variables, only

the persistence of the AFS was an independent risk factor for PTB.

In the present study, the use of the combination of ceftriaxone, clarithromycin, and

metronidazole in these patients was based on multiple factors: First, several

microorganisms were isolated from patients with AFS, including Mycoplasma hominis,

Ureaplasma spp., Fusobacterium nucleatum, Candida albicans, Peptostreptococcus spp.,

Group B Streptococcus, Gardnerella vaginalis, Acinetobacter spp., Streptococcus mutans,

Aspergillus flavus, and Staphylococcus warneri [14]. Second, similar microorganisms

were isolated from patients with PPROM and the use of this antibiotic regimen reduced

the rate of intra-amniotic infection and inflammation as well as funisitis and fetal systemic

inflammatory response [12, 15]. In addition, Yoon et al [16] reported that this combination

of antibiotics successfully eradicated intra-amniotic infection or inflammation in patients

with PTL and intact membranes. Third, the combination regimen improved the

bioavailability of antibiotics and expanded coverage during pregnancy. Clarithromycin has

a much higher rate of transplacental passage than erythromycin or azithromycin, and is

therefore effective against Ureaplasma spp., which are the most common microorganisms

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 identified in the amniotic fluid of patients at risk for PTB [17]. Treatment with ceftriaxone
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provided enhanced coverage of aerobic bacteria and increased the rate of transplacental

passage [18, 19]. Metronidazole provided optimal coverage of the anaerobic organisms

frequently detected in the amniotic fluid.

A recent study demonstrated that women at 15–24 weeks of pregnancy with AFS after

intravenous antibiotic treatment with anti-inflammatory drugs showed the elimination of

AFS within 2 weeks and reduced risk of PTB [20]. Dinglas et al [21] reported

ultrasonographic results showing that the AFS in pregnant women was successfully

resolved with metronidazole, azithromycin, and amoxicillin. In the present study, treatment

with antibiotics eradicated the AFS in some patients not in others. AFS has been reported

to represent amniotic inflammation or infection due to the microbial biofilm in patients with

preterm parturition [22]. The microorganisms aggregate in structures called microbial

biofilms [23], which increases the resistance to antibiotic treatment [24]. The formation of

biofilms that are resistant to antibiotics may explain the persistence of AFS. Moreover, the

present study showed that the initial size of the AFS and duration of administration of

antibiotics were independent risk factors for persistent AFS. The larger the initial size of

the AFS, the more likely it was to be persistent, and the longer the duration of antibiotic

treatment, the less likely the persistence. In the present study, the women in group B (with

persistent AFS) showed earlier deliveries compared with those in group A (with

disappearing AFS). The duration of antibiotic treatment was also shorter in group B than in

group A, which may lead to a failure to achieve the effective bioavailability of antibiotics

and therefore be difficult to eradicate the AFS. These factors may also explain the cause

of residual AFS. Moreover, the disappearance of AFS can be attributed to the improved

bioavailability of antibiotics and expanded coverage. Therefore, whether AFS can be

eradicated by expanding the duration of administration of antibiotics requires further study

in a larger population of diverse participants.

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 In addition, studies similar to the population and gestational age of the present study have
Accepted Article
demonstrated that azithromycin reduces the risk of PTB in the presence of AFS [25]. In

the present study, the rate of PTB within 7 days, at under 28 weeks, 32 weeks, and 34

weeks of pregnancy, was significantly lower in the group with the disappearing AFS, which

may be attributed to the antibiotic treatment used to eradicate the AFS and prolong the

pregnancy. The persistence of AFS was an independent risk factor for PTB before weeks

28, 32, and 34 of pregnancy. The results were similar to previous reports, and in high-risk

patients, the presence of AFS was an independent risk factor for PTB before 28, 32, and

35 weeks [9], and before 34 weeks [6].

In the present study, the gestational age at delivery, ultrasonographic examination-

to-delivery interval, and neonatal birth weight in group B were significantly lower than in

group A. Patients with persistent AFS showed adverse neonatal outcomes compared with

those with disappearing AFS. These results may also be attributed to the high rate of

delivery before 28 weeks of pregnancy in patients with persistent AFS.

The limitations of the present study include its small sample size and retrospective design.

Some patients with impending delivery were excluded and many were excluded because

of incomplete records. All the patients in the present study were treated with antibiotics

without a control group. Besides, no culture of amniotic fluid was performed before

antibiotic treatment to assess the patients’ inflammatory status based on amniotic fluid or

microorganisms in the AFS.

In conclusion, treatment with a combination antibiotic regimen of ceftriaxone,

clarithromycin, and metronidazole may eradicate the AFS in patients during the second or

third trimester with uterine contraction with intact membranes. Moreover, the eradication

of the AFS was associated with its initial size. The disappearance of AFS was associated

with favorable pregnancy and neonatal outcomes.

Author contributions

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 YHK designed and conceived the study and revised the manuscript. WHJ designed and
Accepted Article
conceived the study, conducted the data analysis, and wrote and revised the manuscript.

JWK conducted the data analysis and revised the manuscript. TYK, YY, and AK

conducted the data collection. All authors contributed to the revision of the manuscript and

approved the final manuscript.

Conflicts of interest

The authors have no conflicts of interest.

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FIGURE LEGENDS

Figure 1. (a) Transvaginal ultrasound image showing the presence of AFS (arrows) and

short cervical length. (b) Disappearance of AFS and restoration of cervical length after

treatment with antibiotics and tocolysis. Abbreviation: AFS, amniotic fluid “sludge.”

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 Figure 2. Flow chart showing inclusion in the study of women with singleton pregnancies
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who presented with uterine contraction and intact membranes at 15–32 weeks of

pregnancy. Abbreviation: AFS, amniotic fluid “sludge.”

Figure 3. Kaplan–Meier survival analysis of the ultrasonographic examination-to-delivery

interval according to disappearance or persistence of amniotic fluid “sludge.” Group B had

a shorter ultrasonographic examination-to-delivery interval than group A (group A at 68

days [95% CI 55–81] vs group B at 28 days [95% CI 15–42]; P=0.001, log rank test).

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 Table 1. Demographic and clinical characteristics of patients according to disappearance
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and persistence of AFS.a

Variable Group A (n=30) Group B (n=28) P

Maternal age (years) 33.8±4.8 35.6±3.5 0.117

BMI (kg/m2) 25.0±4.6 25.0±4.6 0.188

Nulliparous 14 (46.7) 10 (35.7) 0.435

Previous PTB 8 (26.7) 5 (17.9) 0.534

GA at examination (weeks) 22.1±3.5 22.4±3.8 0.748

CL at examination (mm) 13.5±9.6 10.8±9.0 0.260

CL ≤25 mm 25 (83.3) 24 (85.7) 0.743

CL ≤15 mm 19 (63.3) 22 (78.6) 0.255

Initial size of AFS (cm) 1.3±0.5 1.7±0.6 0.004

Duration of administration of antibiotics 21.0±7.7 15.6±9.5 0.022

(days)

Bishop score 6.0±3.6 4.9±2.6 0.471

Presence of microorganism in LGT 5 (16.7) 10 (35.7) 0.136

Abbreviations: AFS, amniotic fluid “sludge”; BMI, body mass index; CL, cervical length;

GA, gestational age; LGT, low genital tract; PTB, preterm birth.
a Values are given as number (percentage) or mean ± standard deviation.

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 Table 2. Outcome variables according to disappearance and persistence of AFS.a
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Outcome variable Group A (n=30) Group B (n=28) P

GA at delivery (weeks) 31.8±4.1 26.2±3.9 <0.001

Ultrasonographic examination- 67.7±35.7 28.4±35.7 <0.001

to-delivery interval (days)

Birth weight (g) 1869.3±773.8 1003±608.5 <0.001

PPROM 12 (40) 10 (35.7) 0.812

Delivery within <7days 1 (3.3) 9 (32.1) 0.005

Preterm delivery <28 weeks 7 (23.3) 20 (71.4) <0.001

Preterm delivery <32 weeks 17 (56.7) 25 (89.3) 0.008

Preterm delivery <34 weeks 20 (66.7) 27 (96.4) 0.006

Term delivery 4 (13.3) 0 (0) 0.113

Histological chorioamnionitis 13 (43.3) 17 (56.7) 0.186

Funisitis 8 (26.7) 8 (28.6) 0.871

Admission to NICU 25 (83.3) 19 (67.9) 0.169

Perinatal death 0 (0) 10 (35.7) <0.001

CNM 15/25 (60.0) 17/19 (89.5) 0.030

Abbreviations: AFS, amniotic fluid “sludge”; CNM, composite of neonatal morbidity; GA,

gestational age; NICU, neonatal intensive care unit; NS, not significant; PPROM, preterm

premature rupture of membranes.

a Values are given as number (percentage) or mean ± standard deviation.

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 Table 3. Stepwise logistic regression analysis of factors affecting persistence of AFS.
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Variable OR 95% CI P

Initial size of AFS 5.5 1.55–19.34 0.008

Duration of administration of antibiotics 0.9 0.85–0.99 0.025

Abbreviations: AFS, amniotic fluid “sludge”; CI, confidence interval; OR, odds ratio.

Table 4. Persistence of amniotic fluid “sludge” as the independent variable in stepwise

logistic regression to predict preterm delivery.

OR 95% CI P

Preterm delivery <28 weeks 8.2 2.53–26.68 <0.001

Preterm delivery <32 weeks 6.4 1.57—25.80 0.009

Preterm delivery <34 weeks 13.5 1.60—114.21 0.017

Abbreviations: CI, confidence interval; OR, odds ratio.

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 ijgo_13425_f1.docx

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Figure 1. A) Transvaginal ultrasound image showing the presence of AF

"sludge"(arrows), and short cervical length. B) Disappearance of AF "sludge" and

restoration of cervical length after antibiotic treatment and tocolysis.

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 ijgo_13425_f2.docx

Figure 2. Flow diagram showing selection of study groups.

Accepted Article
Patients with uterine
contraction and intact
membranes at 15–32 weeks of
pregnancy (n=514)

Presence of AFS found on

ultrasonography examination
(n=80)
Excluded according to exclusion
criteria (n=16)

Lost to follow-up (n=6)

Finally included in study (n=58)

Disappearance of AFS Persistence of AFS

(n=30) (n=28)

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 ijgo_13425_f3.docx

Accepted Article

Figure 3. Kaplan–Meier survival analysis of the ultrasonographic examination-to-

delivery interval according to amniotic fluid “sludge” disappearance or persistence.

Group B had a shorter ultrasonographic examination-to-delivery interval than group

A. [Group A at 68 days (95% CI 55-81days) vs.Group B at 28 days (95% CI 15-

42days); P=0.001, log rank test.]

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