Results
Characteristics of the study population.
The flow chart of the study is shown in Supplementary material, Figure S1. Overall, 1,223 pregnant women visited our hospital from the first trimester of pregnancy to 31 weeks of gestation and were eligible for the study. A total of 898 pregnant women agreed to participate and were enrolled in the study. Their clinical characteristics are shown in supplementary material (Table S1). 55 of all pregnant women (6.1%) were colonized with MRSA according to nasal or vaginal swabs (Figure S1). 46 pregnant women (5.1%) had MRSA colonization only from the nasal swab, and nine (1.0%) had MRSA colonization from the vaginal swab (Figure S1). We categorized the 55 MRSA-positive pregnant women as the M-group, and the remaining 843 uninfected pregnant women as the non-M group. These women were followed prospectively, and there was no loss to follow-up.
All mothers had live births, and there were no perinatal deaths during the study period. These 898 mothers, including seven with twin pregnancies, delivered 905 neonates. One twin pregnancy was included in the M-group, which resulted in 56 neonates in the M-group. Six twin pregnancies were included in the non-M group, which resulted in 849 neonates. We monitored the clinical course of all neonates throughout the study period.
Risk factors for maternal MRSA colonization
We first examined the differences in maternal backgrounds between the M-group and the non-M group (Table 1A). Among the maternal background information, the percentages of multiparous mothers and mothers who worked as healthcare providers were significantly higher in the M-group compared to the non-M group. In the M-group, 67.3% (37/55) were multiparous, and 29.1% (16/55) were healthcare providers. Only 48.4% (408/843) were multiparous, and 13.8% (116/843) were healthcare providers in the non-M group (OR: 2.09, 95%CI: 1.23 to 3.01 and OR: 2.57, 95%CI: 1.39 to 4.75, respectively). The frequency of a parity of two or more was also significantly higher in the M-group compared to the non-M group (15/55: 27.3% vs. 119/843: 14.1%, OR: 2.28, 95%CI: 1.22 to 4.26). Although not significant, the proportion of mothers who used antibiotics during pregnancy tended to be higher in the M-group than the non-M group (5/55: 9.1% vs. 32/843: 3.8%, OR: 2.53, 95%CI: 0.95 to 6.79).
We performed multivariable logistic regression analysis to determine whether multiparity, occupation (healthcare provider), and history of antibiotic use during pregnancy were independently associated with maternal MRSA colonization. We found that multiparity and occupation (healthcare provider) were independent risk factors for MRSA colonization (OR: 2.35, 95% CI; 1.25-4.42 and OR: 2.58, 95% CI; 1.39-4.79, respectively, Table 1B).
We analyzed the association between maternal background and MRSA colonization in the vagina. We compared the maternal backgrounds of vaginal MRSA-positive patients (VM group, n=9) and vaginal MRSA-negative patients (non-VM group, n=889). The results are shown in Table 1A. The multiparity rate was significantly higher in the VM group compared to the non-VM group (9/9: 100% vs. 436/889: 49.0%, OR: 19.74, 95%CI: 1.15 to 340.4). The proportion of women with a parity of two or more was also significantly higher in the VM group compared to the non-VM group (6/9: 66.6% vs. 128/889: 14.4%, OR: 11.89, 95%CI: 2.94 to 48.16). There was no significant difference in the proportion of patients who worked as healthcare providers (VM group; 0/9: 0% vs. non-VM group; 132/889: 14.8%, OR: 0.30, 95%CI: 0.017 to 5.20, Table 1A).
These analyses showed that being multiparous and a healthcare provider were independent risk factors for maternal MRSA colonization. Multiparity, particularly a parity of two or more, was obviously a significant risk factor for vaginal and maternal MRSA colonization.
Vertical transmission of MRSA to neonates at delivery
Of the 905 neonates delivered in the present study, MRSA was detected in the umbilical stump or nasal cavity at the time of delivery in eight neonates (0.8%) (Table 2A). We assessed the primary outcome of this study, the vertical transmission of MRSA to neonates during delivery and analyzed this outcome in mother-neonate pairs.
There were seven pairs (12.7%) in which neonates were MRSA-positive at the time of delivery in the M-group (n=55). There was only one pair (0.12%) with a MRSA-positive neonate at the time of delivery in the non-M group (n=843). Maternal MRSA carriers had a significantly higher risk for having neonatal MRSA colonization at the time of delivery (OR 124; 95% CI 20.3-1393, Table 2A).
Sub-analysis compared the vertical transmission rate of MRSA in mothers with MRSA in only the nasal cavity, mothers with MRSA in the vagina and non-MRSA mothers (Table 2A). We found that the vertical transmission of MRSA occurred significantly more often in mothers with MRSA in only the nasal cavity than non-MRSA mothers (3/46, 6.38%, OR 59.2, 95% CI: 6.0-581). Vertical transmission occurred even more frequently in mothers with MRSA in the vagina than non-MRSA mothers (4/ 9, 44.4%, OR 678.4, 95% CI, 64.0-7197). We analyzed the vertical transmission of MRSA based on MRSA colonization in the vagina. The vertical transmission of MRSA in the VM group was also significantly higher than the non-V-M group (V-M group: 4/9, 44.4%, non-V-M group: 4/896, 0.45%; OR: 178, 95% CI 39.9-782, Table 2B).
We used a multivariable regression model to analyze the association between maternal MRSA colonization and neonatal MRSA colonization by adjusting for parity. Maternal MRSA colonization remained significantly associated with neonatal MRSA colonization (Table 2C).
We also performed a stratified analysis to determine whether there were certain factors that increased the frequency of MRSA transmission. However, we did not find any factors that increased the vertical transmission rate of MRSA. None of the neonates born via Caesarean section (CS) had MRSA colonization, which suggests that MRSA is transmitted directly by vaginal delivery (Supplementary material, Table S2).
Maternal MRSA colonization was an independent risk factor for neonatal MRSA colonization at the time of delivery in the present analysis. Even when MRSA was detected only in the maternal nasal cavity, 6.38% of the neonates had MRSA colonization. If the pregnant women had MRSA colonization in the vagina, the vertical transmission rate of MRSA increased to 44.4% at the time of delivery.
Association between maternal and neonatal adverse outcomes and MRSA colonization
We assessed the relationship between maternal MRSA colonization and the clinical courses of mothers and their neonates. We did not find any significant difference in maternal adverse outcomes in maternal MRSA colonization (Supplementary material, Table S3). However, the frequency of SSTIs in the neonatal period was significantly higher in the neonates of the M-group than the non-M group (M-group; 3/56, 5.4%, non-M group: 7/849, 0.82%, OR 7.47, 95% CI 2.50-22.3, Table 3).
We performed the same analysis based on MRSA colonization in the vagina (Table 3A). We found that maternal vaginal MRSA colonization was also significantly associated with the occurrence of SSTIs in the neonatal period (VM group: 2/9, 22.2%, non-VM group: 8/896, 0.89%, OR:31.7 95% CI: 5.68-177). Comparison of the frequency of SSTIs in the neonatal period between the VM group and non-M group revealed a significantly higher frequency in the VM group compared to the non-M group (VM group: 2/9, 22.2%, non-M group: 8/846, 0.82%, OR:34.4 95% CI: 6.04-195, Table 3B). We also examined whether factors other than maternal MRSA colonization were associated with SSTIs, and none of these factors had a significant association with SSTIs (Supplementary material, Table S4).
Therefore, neonatal SSTI was significantly associated with maternal MRSA colonization, especially via the vertical transmission of MRSA.
Table 4 shows the details of all neonatal SSTIs. MRSA was the causative bacterium in all three cases in the M-group but only one of the seven cases in the non-M group (p=0.033). Two of the three cases in the M-group had symptoms on the day after birth, and only one of the seven cases in the non-M group showed symptoms on the day after birth. We classified all symptoms as invasive (eczema, impetigo and abscess) or noninvasive (rash, inflammation). All three cases in the M-group and one case in the non-M group showed invasive symptoms, and the M-group had a significantly higher frequency of invasive symptoms (p=0.033).
Most SSTIs resolved spontaneously within a few days or resolved with simple local disinfection procedures. However, one case of MRSA SSTI in the M-group did not resolve with local treatment and required incision and drainage procedures.