A new anti-microbial combination prolongs the latency period, reduces acute histologic chorioamnionitis as well as funisitis, and improves neonatal outcomes in preterm PROM

Figures & data

Table 1. Demographics and clinical characteristics of the study population.

	Regimen 1 group* (n = 195)	Regimen 2 group† (n = 119)	p value
Maternal age (year)‡	30 (27–33)	32 (29–36)	<0.001
Nulliparity (%)	47.2 (92/195)	54.6 (65/119)	NS
Prior preterm birth (%)	14.9 (29/195)	11.8 (14/119)	NS
Amniotic fluid MMP-8 > 23 ng/mL (%)	41.0 (80/195)	61.3 (73/119)	<0.001
Positive amniotic fluid culture (%)	23.1 (45/195)	28.7 (33/115)	NS
Amniotic fluid MMP-8 (ng/mL)‡	7.1 (0.9–161.0)	46.3 (7.9–242.7)	<0.001
Intra-amniotic infection/inflammation (%)	45.6 (89/195)	66.4 (79/119)	<0.001
Gestational age at the time of the initiation of antibiotic treatment (weeks)‡	30.1 (27.1–32.6)	27.7 (23.4–31.6)	<0.001
Gestational age at amniocentesis (weeks)‡	30.3 (27.1–32.7)	28.0 (24.0–31.6)	<0.001
Antenatal corticosteroids administration (%)	71.5 (133/186)	84.0 (100/119)	<0.05

MMP-8, matrix metalloproteinase-8; NS, not significant.

*Regimen 1: ampicillin and/or cephalosporins, and in some patients other antibiotics were combined with them.

†Regimen 2: ceftriaxone, clarithromycin, and metronidazole

‡Median (interquartile).

Figure 1. Survival analysis of the antibiotic-to-delivery interval according to the antibiotic regimen. Patients who received regimen 2 (ceftriaxone, clarithromycin, and metronidazole) had a significantly longer median antibiotics-to-delivery interval than those who received regimen 1 (ampicillin and/or cephalosporins, in some patients other antibiotics were combined with them.) [median (interquartile) 23 d (10–51 d) versus 12 d (5–52 d), p < 0.01], which remained significant after adjusting for gestational age at the time of the initiation of antibiotic therapy, the presence of intra-amniotic infection/inflammation, and antenatal corticosteroid administration (hazards ratio 0.69, 95% (CI) 0.49–0.96; p < 0.05 by Cox proportional hazards model analysis).

Table 2. Pregnancy outcomes of the study population according to the regimen of antibiotics used.

	Regimen 1 group* (n = 195)	Regimen 2 group† (n = 119)	p value	p value‡ and odds ratio (OR)
Gestational age at delivery (weeks)§	33.0 (29.9–34.6)	31.4 (27.0–33.9)	<0.001
Cesarean delivery (%)	32.8 (62/189)	33.0 (38/115)	NS
Birthweight (g)§	1970 (1380–2410)	1640 (980–2110)	<0.001
Baby male (%)	62.0 (114/184)	59.6 (68/114)	NS
Spontaneous preterm delivery (%)
≤14 d	59.2 (100/169)	39.1 (36/92)	<0.01	<0.05 (OR 0.45)
≤7 d	43.6 (78/179)	20.2 (21/104)	<0.001	<0.01 (OR 0.40)
≤2 d	16.8 (32/190)	8.8 (10/114)	<0.05	NS (OR 0.58)
Spontaneous preterm delivery (%)
<37 weeks	82.1 (128/156)	95.8 (69/72)	0.005	0.066 (OR 3.63)
<34 weeks	60.1 (101/168)	66.7 (58/87)	NS	NS (OR 0.74)
<32 weeks¶	57.0 (65/114)	56.9 (37/65)	NS	<0.05 (OR 0.36)
Acute histologic chorioamnionitis (%)	66.7 (102/153)	50.5 (49/97)	<0.05	<0.001 (OR 0.30)
Funisitis (%)	42.9 (66/154)	13.9 (14/101)	<0.001	<0.001 (OR 0.11)

NS, not significant.

*Regimen 1: ampicillin and/or cephalosporins, and in some patients other antibiotics were combined with them.

†Regimen 2: ceftriaxone, clarithromycin, and metronidazole.

‡p value after adjusting for gestational age at the time of the initiation of antibiotic treatment, intra-amniotic infection/inflammation, and antenatal corticosteroids administration.

§Median (interquartile).

¶Among cases who were admitted due to preterm PROM before 32 weeks of gestation.

Table 3. Neonatal outcomes of the study population according to the regimen of antibiotics used.

	Regimen 1 group* (n = 195)	Regimen 2 group† (n = 119)	p value	p value‡ and odds ratio (OR) and 95% CI
Respiratory distress syndrome (%)	11.0 (19/173)	15.2 (15/99)	NS	NS (OR 0.64, 95% CI: 0.28–1.50)
Bronchopulmonary dysplasia (%)	12.7 (21/165)	28.1 (27/96)	<0.01	NS (OR 0.75, 95% CI: 0.31–1.77)
Congenital neonatal sepsis, proven (%)	4.6 (8/174)	1.0 (1/99)	NS	NS (OR 0.30, 95% CI: 0.03–2.52)
Intra-ventricular hemorrhage (%)	19.0 (32/168)	2.1 (2/97)	<0.001	0.001 (OR 0.08, 95% CI: 0.02–0.35)
Peri-ventricular leukomalacia (%)	6.1 (10/165)	1.0 (1/98)	0.058	0.055 (OR 0.11, 95% CI: 0.01–1.05)
Necrotizing enterocolitis (%)	3.5 (6/171)	9.2 (9/98)	0.051	NS (OR 1.96, 95% CI: 0.6–6.47)
Composite neonatal morbidity (%)	35.1 (60/171)	36.7 (36/98)	NS	0.099 (OR 0.59, 95% CI: 0.31–1.11)
Cerebral palsy (%)	5.7 (9/157)	0.0 (0/96)	<0.05	NA
Survival (%)	88.4 (160/181)	82.6 (95/115)	NS	NS (OR 2.01, 95% CI: 0.78–5.16)

NA, not applicable; NS, not significant; CI: confidence interval.

*Regimen 1: ampicillin and/or cephalosporins, and in some patients other antibiotics were combined with them.

†Regimen 2: ceftriaxone, clarithromycin, and metronidazole.

‡p value after adjusting for gestational age at the time of the initiation of antibiotics treatment, intra-amniotic infection/inflammation, and antenatal corticosteroids administration.

Table 4. Perinatal outcomes of patients without intra-amniotic infection/inflammation according to the regimen of antibiotics used.

	Regimen 1 group* (n = 106)	Regimen 2 group† (n = 40)	p value	p value‡ and odds ratio (OR) and 95% CI
Gestational age at amniocentesis (weeks)§	31.4 (28.6–32.8)	31.2 (28.3--32.9)	NS
Gestational age at the time of the initiation  of antibiotics treatment (weeks)§	31.4 (28.5–32.8)	31.2 (28.3–32.9)	NS
Gestational age at delivery (weeks)§	34.3 (32.9–37.2)	33.5 (31.8–34.1)	<0.01
Spontaneous preterm delivery (%)
<37 weeks	67.1 (57/85)	92.3 (24/26)	<0.05	<0.05 (OR 5.80, 95% CI: 1.16–29)
<34 weeks	37.1 (36/97)	48.5 (16/33)	NS	NS (OR 1.41, 95% CI: 0.62–3.20)
<32 weeks¶	23.2 (13/56)	28.6 (6/21)	NS	NS (OR 0.97, 95% CI: 0.29--3.24)
Spontaneous delivery (%)
≤14 d	40.6 (39/96)	43.8 (14/32)	NS	NS (OR 1.33, 95% CI: 0.52--3.37)
≤7 d	29.0 (29/100)	25.0 (9/36)	NS	NS (OR 0.99, 95% CI: 0.37--2.62)
≤2 d	6.6 (7/106)	12.8 (5/39)	NS	0.076 (OR 3.96, 95% CI: 0.86-18.16)
Acute histologic chorioamnionitis (%)	44.6 (37/83)	38.2 (13/34)	NS	NS (OR 0.74, 95% CI: 0.32–1.74)
Funisitis (%)	22.6 (19/84)	11.1 (4/36)	NS	0.059 (OR 0.32, 95% CI: 0.10–1.05)
Respiratory distress syndrome (%)	8.2 (8/98)	10.5 (4/38)	NS	NS (OR 0.75, 95% CI: 0.18–3.15)
Bronchopulmonary dysplasia (%)	4.1 (4/97)	7.9 (3/38)	NS	NS (OR 1.11, 95% CI: 0.19–6.50)
Congenital neonatal sepsis, proven (%)	4.1 (4/98)	0.0 (0/38)	NS	NA
Intra-ventricular hemorrhage (%)	8.3 (8/96)	0.0 (0/37)	NS	NA
Peri-ventricular leukomalacia (%)	2.1 (2/96)	0.0 (0/38)	NS	NA
Necrotizing enterocolitis (%)	2.1 (2/97)	10.5 (4/38)	0.053	NS (OR 3.76, 95% CI: 0.64–22.09)
Composite neonatal morbidity (%)	18.4 (18/98)	23.7 (9/38)	NS	NS (OR 1.24, 95% CI: 0.48–3.22)
Cerebral palsy (%)	2.1 (2/94)	0.0 (0/37)	NS	NA
Survival (%)	96.0 (96/100)	94.9 (37/39)	NS	NS (OR 0.70, 95% CI: 0.10–5.02)

NA, not applicable; NS, not significant; CI: confidence interval.

*Regimen 1: ampicillin and/or cephalosporins, and in some patients other antibiotics were combined with them.

†Regimen 2: ceftriaxone, clarithromycin, and metronidazole.

‡p value after adjusting for gestational age at the time of the initiation of antibiotics treatment and antenatal corticosteroids administration.

§Median (interquartile).

¶Among cases who were admitted due to preterm PROM before 32 weeks of gestation.

Table 5. Perinatal outcomes of patients with intra-amniotic infection/inflammation according to the regimen of antibiotics used.

	Regimen 1 group* (n = 89)	Regimen 2 group† (n = 79)	p value	p value‡ and odds ratio (OR) and 95% CI
Gestational age at amniocentesis (weeks)§	29.4 (26.5–32.0)	26.1 (23.0–28.9)	<0.001
Gestational age at the time of the initiation  of antibiotics treatment (weeks)§	28.9 (26.1–32.0)	25.1 (22.6–28.4)	<0.001
Gestational age at delivery (weeks)§	30.4 (27.5–32.9)	28.6 (25.4–32.6)	NS
Spontaneous preterm delivery (%)
<37 weeks	100.0 (71/71)	97.8 (45/46)	NS	NA
<34 weeks	91.5 (65/71)	77.8 (42/54)	<0.05	<0.01 (OR 0.18, 95% CI: 0.05--0.62)
<32 weeks¶	89.7 (52/58)	70.5 (31/44)	<0.05	<0.01 (OR 0.11, 95% CI: 0.03–0.44)
Spontaneous delivery (%)
≤14 d	83.6 (61/73)	36.7 (22/60)	<0.001	<0.001 (OR 0.17, 95% CI: 0.07--0.41)
≤7 d	62.0 (49/79)	17.6 (12/68)	<0.001	<0.001 (OR 0.22, 95% CI: 0.09--0.50)
≤2 d	29.8 (25/84)	6.7 (5/75)	<0.001	<0.01 (OR 0.24, 95% CI: 0.08--0.69)
Acute histologic chorioamnionitis (%)	92.9 (65/70)	57.1 (36/63)	<0.001	<0.001 (OR 0.08, 95% CI: 0.03–0.27)
Funisitis (%)	67.1 (47/70)	15.4 (10/65)	<0.001	<0.001 (OR 0.08, 95% CI: 0.03–0.20)
Respiratory distress syndrome (%)	14.7 (11/75)	18.0 (11/61)	NS	NS (OR 0.43, 95% CI: 0.14–1.36)
Bronchopulmonary dysplasia (%)	25.0 (17/68)	41.4 (24/58)	0.05	NS (OR 0.46, 95% CI: 0.16–1.36)
Congenital neonatal sepsis, proven (%)	5.3 (4/76)	1.6 (1/61)	NS	NS (OR 0.67, 95% CI: 0.06–7.95)
Intra-ventricular hemorrhage (%)	33.3 (24/72)	3.3 (2/60)	<0.001	0.001 (OR 0.06, 95% CI: 0.01–0.31)
Peri-ventricular leukomalacia (%)	11.6 (8/69)	1.7 (1/60)	<0.05	<0.05 (OR 0.07, 95% CI: 0.01–0.85)
Necrotizing enterocolitis (%)	5.4 (4/74)	8.3 (5/60)	NS	NS (OR 1.09, 95% CI: 0.22–5.52)
Composite neonatal morbidity (%)	57.5 (42/73)	45.0 (27/60)	NS	<0.01 (OR 0.24, 95% CI: 0.10–0.62)
Cerebral palsy (%)	11.1 (7/63)	0.0 (0/59)	<0.05	NA
Survival (%)	79.0 (64/81)	76.3 (58/76)	NS	<0.05 (OR 3.63, 95% CI: 1.12–11.79)

NA, not applicable; NS, not significant.

*Regimen 1: ampicillin and/or cephalosporins, and in some patients other antibiotics were combined with them.

†Regimen 2: ceftriaxone, clarithromycin, and metronidazole.

‡p value after adjusting for gestational age at the time of the initiation of antibiotics treatment and antenatal corticosteroids administration.

§Median (interquartile).

¶Among cases who were admitted due to preterm PROM before 32 weeks of gestation,

Figure 2. Survival analysis of the antibiotic-to-delivery interval according to the antibiotic regimen in patients with intra-amniotic infection/inflammation at the time of amniocentesis. A significant longer antibiotic-to-delivery interval was observed in patients with intra-amniotic infection/inflammation who received antibiotic regimen 2 (ceftriaxone, clarithromycin, and metronidazole) than in those who received antibiotic regimen 1 (ampicillin and/or cephalosporins, in some patients other antibiotics were combined with them) [median (interquartile) 29 d (10–60 d) versus 5 d (2–14 d), p < 0.001]. Multivariate survival analysis using the Cox proportional hazards model analysis also demonstrated the longer antibiotic-to-delivery interval in patients who received antibiotic regimen 2 than in those who received regimen 1 after adjusting for gestational age at the time of initiation of antibiotic treatment and antenatal corticosteroid administration (hazards ratio 0.41, 95% CI 0.27–0.63; p < 0.001).