Prenatal exposure to intra-amniotic infection with Ureaplasma species increases the prevalence of bronchopulmonary dysplasia

Figures & data

Figure 1. Protocols for the antibiotic treatment of preterm premature rupture of membranes and preterm labor, cervical insufficiency, and asymptomatic cervical shortening.

AMF: amniotic fluid; IL-6: interleukin-6; Regimen 1: ampicillin (ABPC) 2 g IV q6h for 2 days followed by amoxicillin 250 mg PO q6h for 5 days and clarithromycin 200 mg PO q12h for 7 days, Regimen 2: sulbactam/ABPC 1.5 g IV q6h daily and azithromycin 500 mg IV q24h for 3/7 days.

Figure 2. Flow diagram of patient selection in the present study.

PPROM: preterm premature rupture of membranes; MIAC: microbial invasion of the amniotic cavity; MIR: maternal inflammatory response; FIR: fetal inflammatory response; FIRS: fetal inflammatory response syndrome; IL-6: interleukin-6.

Table 1. Maternal demographic and clinical characteristics of study patients.

Factor	Preterm birth without MIR/FIR and FIRS	Intra-amniotic infection with Ureaplasma spp.	Intra-amniotic infection without Ureaplasma spp.	Intra-amniotic inflammation without MIAC
n	86	37	28	58	p-Value	p-Value
	A	B	C	D		A vs. B	A vs. C	A vs. D	B vs. C	B vs. D	C vs. D
Maternal age at admission (years)	32.0 [28.0, 35.0]	32.0 [30.0, 35.0]	31.5 [29.8, 34.3]	30.0 [25.3, 33.0]	0.02	1.0	1.0	0.23	1.0	0.02	0.67
Primipara (%)	23 (26.7)	20 (54.1)	9 (32.1)	33 (56.9)	0.001	0.03	1.0	0.003	0.39	1.0	0.16
Previous preterm birth (%)	13 (15.1)	3 (8.1)	3 (10.7)	9 (15.5)	0.68
Gestational age at amniocentesis (weeks)	N.A.	27.4 [24.9, 31.0]	29.6 [27.5, 32.6]	28.7 [25.3, 31.7]	0.03	N.A.	N.A.	N.A.	0.02	0.96	0.19
Interval from amniocentesis to birth (days)	N.A.	3.00 [1.00, 7.00]	1.00 [0.00, 2.00]	1.00 [0.00, 3.00]	0.005	N.A.	N.A.	N.A.	0.03	0.01	1.0
Amniotic fluid IL-6 (ng/mL) at diagnosis	N.A.	29.22 [7.51, 74.46]	23.39 [5.34, 68.69]	10.55 [4.23, 29.70]	0.08
C-reactive protein (mg/dL) at amniocentesis	N.A.	0.98 [0.45, 2.59]	0.56 [0.18, 2.87]	0.62 [0.30, 2.02]	0.43
White blood cell (/µL) at amniocentesis	N.A.	13100 [10250, 15250]	12400 [10050, 14000]	12650 [10700, 16925]	0.55
Body temperature (°C) at amniocentesis	N.A.	36.9 [36.7, 37.1]	37.0 [36.8, 37.3]	37.1 [36.6, 37.3]	0.33
Preterm premature rupture of membranes (%)	32 (37.2)	29 (78.4)	21 (75.0)	20 (34.5)	<0.001	<0.001	0.005	1.0	1.0	<0.001	0.003
Placental abruption (%)	4 (4.7)	1 (2.7)	0 (0.0)	1 (1.7)	0.56
Diabetes mellitus (%)	0 (0.0)	3 (8.1)	0 (0.0)	1 (1.7)	0.02	0.15	1	1	1	1	1
Preeclampsia (%)	2 (2.3)	0 (0.0)	0 (0.0)	0 (0.0)	0.41
Maternal antibiotics (%)	57 (66.3)	37 (100.0)	28 (100.0)	54 (93.1)	<0.001	<0.001	<0.001	<0.001	1	0.46	0.60
Maternal corticosteroid (%)	55 (64.0)	35 (94.6)	21 (75.0)	45 (77.6)	0.004	0.002	1.0	0.59	0.19	0.25	1.0
Clinical chorioamnionitis (%)	0 (0.0)	1 (2.7)	3 (10.7)	0 (0.0)	0.002	1.0	0.08	1.0	1.0	1.0	0.19
Cesarean section (%)	38 (44.2)	16 (43.2)	12 (42.9)	25 (43.1)	1.0
Maternal inflammatory response (%)	0 (0.0)	30 (83.3)	22 (78.6)	18 (32.7)	<0.001	<0.001	<0.001	<0.001	1.0	<0.001	<0.001
Fetal inflammatory response (%)	0 (0.0)	24 (64.9)	16 (57.1)	9 (15.8)	<0.001	<0.001	<0.001	0.001	1.0	<0.001	0.002

MIR: maternal inflammatory response; FIR: fetal inflammatory response; FIRS: fetal inflammatory response syndrome; MIAC: microbial invasion of the amniotic cavity.

Table 2. Perinatal data of enrolled patients.

Factor	Preterm birth without MIR/FIR and FIRS	Intra-amniotic infection with Ureaplasma spp.	Intra-amniotic infection without Ureaplasma spp.	Intra-amniotic inflammation without MIAC
n	86	37	28	58	p-Value	p-Value
	A	B	C	D		A vs. B	A vs. C	A vs. D	B vs. C	B vs. D	C vs. D
Gestational age at birth (weeks)	32.1 [30.9, 33.1]	28.0 [26.4, 31.3]	29.8 [28.1, 32.9]	29.5 [25.6, 31.7]	<0.001	<0.001	0.08	<0.001	0.17	1.0	0.33
Male (%)	55 (64.0)	20 (54.1)	16 (57.1)	34 (58.6)	0.74
Birth weight (g)	1711.0 [1417.5, 1888.5]	1172.0 [848.0, 1530.0]	1453.0 [1058.0, 1856.5]	1288.0 [827.5, 1713.5]	<0.001	<0.001	0.42	<0.001	0.03	1.0	0.57
Small for gestational age (%)	6 (7.0)	5 (13.5)	1 (3.6)	2 (3.4)	0.24
Apgar score at 1 min	8.0 [6.0, 8.0]	6.0 [4.0, 8.0]	6.0 [3.8, 8.0]	5.5 [3.0, 8.0]	0.02	0.15	0.29	0.03	1.0	1.0	1.0
Apgar score at 5 min	9.0 [8.0, 9.0]	8.0 [7.0, 9.0]	8.0 [6.8, 9.0]	8.0 [6.0, 9.0]	<0.001	0.05	0.01	0.002	1.0	1.0	1.0
Umbilical artery pH	7.32 [7.28, 7.36]	7.32 [7.27, 7.37]	7.32 [7.30, 7.35]	7.32 [7.28, 7.36]	0.82
Umbilical artery base excess	−3.0 [-5.0, −2.0]	−3.0 [-5.3, −1.8]	−4.0 [-6.0, −2.0]	−4.0 [-6.0, −2.0]	0.40
Umbilical vein blood IL-6 (pg/mL)	2.5 [1.6, 3.7]	24.3 [4.7, 53.3]	43.2 [5.4, 241.2]	4.2 [2.4, 13.7]	<0.001	<0.001	<0.001	<0.001	1.0	0.006	0.001
Fetal inflammatory response syndrome (%)	0 (0.0)	22 (64.7)	18 (64.3)	16 (30.8)	<0.001	<0.001	<0.001	<0.001	1.0	0.02	0.03
Bronchopulmonary dysplasia (BPD) (%)	3 (3.5)	15 (40.5)	1 (3.6)	15 (25.9)	<0.001	<0.001	1.0	<0.001	0.003	1.0	0.1
<26 weeks gestational age at birth	3/3 (100)	6/7 (85.7)	0/1 (0.0)	13/16 (81.2)	0.16
≥26 weeks gestational age at birth	0/83 (0.0)	9/30 (30.0)	1/27 (3.7)	2/42 (4.8)	<0.001	<0.001	1.0	0.67	0.08	0.04	1.0
BPD (moderate - severe) (%)	1 (1.2)	10 (27.0)	1 (3.6)	12 (20.7)	<0.001	<0.001	1.0	<0.001	0.11	1.0	0.32
<26 weeks gestational age at birth	1/3 (33.3)	4/7 (57.1)	0/1 (0.0)	6/16 (62.5)	0.53
≥26 weeks gestational age at birth	0/83 (0.0)	6/30 (20.0)	1/27 (3.7)	2/42 (4.8)	<0.001	0.001	1.0	0.67	0.63	0.36	1.0
Respiratory distress syndrome (%)	20 (23.3)	6 (16.2)	9 (32.1)	14 (24.1)	0.52
Neonatal sepsis (%)	0 (0.0)	0 (0.0)	6 (21.4)	0 (0.0)	<0.001	1.0	<0.001	1.0	0.03	1.0	0.005
Intraventricular hemorrhage (%)	2 (2.3)	2 (5.4)	3 (10.7)	3 (5.2)	0.34
Periventricular leukomalacia (%)	1 (1.2)	4 (10.8)	0 (0.0)	0 (0.0)	0.003	0.17	1.0	1.0	0.77	0.12	1.0
Neonatal or infant death (%)	0 (0.0)	2 (5.4)	0 (0.0)	2 (3.4)	0.15
Adverse neonatal outcomes (%)	6 (7.0)	19 (51.4)	7 (25.0)	18 (31.0)	<0.001	<0.001	0.09	0.001	0.25	0.33	1.0

MIR: maternal inflammatory response; FIR: fetal inflammatory response; FIRS: fetal inflammatory response syndrome; MIAC: microbial invasion of the amniotic cavity, adverse neonatal outcomes, neonatal or infant mortality in a hospital or the presence of bronchopulmonary dysplasia, neonatal sepsis, periventricular leukomalacia, intraventricular hemorrhage.

Table 3. Multivariate logistic regression analysis of the presence of bronchopulmonary dysplasia.

	Reference	Adjusted Odds ratio	95% CI	p-Value
Intra-amniotic infection with Ureaplasma spp.	Preterm birth without MIR/FIR and FIRS	10.5	1.55 − 71.2	0.02
Intra-amniotic infection without Ureaplasma spp.		0.7	0.05 − 10.2	0.79
Intra-amniotic inflammation without MIAC		2.39	0.37 − 15.4	0.36
Gestational age at birth	1 week	0.42	0.31 − 0.57	<0.001

MIR: maternal inflammatory response; FIR: fetal inflammatory response; FIRS: fetal inflammatory response syndrome; MIAC: microbial invasion of the amniotic cavity.

Data availability statement

Raw data are available upon reasonable request from the corresponding author.