Reduction of intrapartum antibiotic prophylaxis by combining risk factor as‐ sessment with a rapid bedside intrapartum polymerase chain reaction testing for group B streptococci

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Methods: Three-hundred-sixty-six laboring women admitted to our maternity ward, with one or more risk factors for EOGBS, were prospectively included. Rectovaginal swab-samples were examined bedside by the GenomEra® GBS Polymerase Chain Reaction (PCR) assay upon admission. Time from administration of IAP to delivery was registered. According to national guidelines, onehundred-two women mandatorily received IAP independent of the PCR test result fulfilling one of the following three risk factors: prior infant with EOGBS, preterm labor before 35 gestational week, temperature ≥38°C during labor. Women with GBS bacteriuria during current pregnancy, rupture of membranes ≥ 18 hours IAP, and preterm labor between 35-37 gestational week, received IAP solely if the PCR test was positive. Predictive values were calculated for each risk factor.
Results: Previous GBS bacteriuria was strongly associated (PPV=71%) with a positive GBS PCR test, whilst the corresponding positive percent of ROM>18 hours and of GA 35-37 was only PPV=16% and 22%, respectively. Seventy-four women, 74/251 (31%), received IAP because they were GBS PCR positive. IAP was thus reduced by about two-thirds compared to the risk-based strategy of offering IAP to all women with one or more risk factors for EOGBS. Two women, 2/254 (0.8%), received inferior care, as they did not receive IAP within the recommended 4 hours prior to delivery due to the extra time spend on the test procedure.

Conclusion:
Bedside intrapartum PCR testing of women with risk factors for EOGBS effectively diminishes use of IAP during labor compared to the present risk factor-based strategy alone. In this project, the extra time spend on the PCR test procedure did not lead to noticeable delay in IAP.

INTRODUCTION
Early Onset Group B Streptococcal neonatal infection (EOGBS) affects 0.23-3.0 per 1.000 live births and accounts for an estimated 410.000 disease cases and 147.000 preventable stillbirths and infant deaths globally each year [1]. The recto-vaginal colonization rate of group B streptococci (GBS) in pregnant women varies from 10-35%, and without intervention, approximately 50% of the children born by colonized mothers will become colonized. One percent of the colonized children will develop EOGBS, with a mortality rate of 4-10% [2][3][4][5][6][7]. There are two well-known strategies for identifying pregnant women with infants at increased risk of EOGBS: 1) antepartum culture-based GBS rectovaginal screening at 35-37 weeks´ gestation, and 2) a risk-based approach depending on the presence of one or more of the five risk factors for EOGBS: GBS bacteriuria during current pregnancy, preterm labor < 37 gestational weeks (GA), and rupture of membranes ≥18 hours (ROM), prior infant with EOGBS, temperature ≥38.0°C during labor [2,8,9] Intrapartum antibiotic prophylaxis (IAP) effectively diminishes the perinatal vertical transmission of GBS to the child and is shown to reduce the incidence of EOGBS [2].
The correlation between antibiotic treatment in early life and disturbances in the microbiota of the intestine of the infants is receiving increased attention and concern as it may affect several aspects of child health [10,11].
According to national guidelines, IAP administration must be conducted 4 hours before delivery to ensure an adequate bactericide concentration in the fetus [2,12].
The GenomEra® GBS Polymerase Chain Reaction (PCR) assay had been implemented in our department as a standard regime for intrapartum testing about one year prior to the initialization of the study. The turnaround time for the analyses was 50 min [13].
The aim of this study was to investigate the impact on administering IAP to laboring women based on combining the risk-based strategy with the result of a rapid intrapartum GenomEra® GBS PCR assay performed bedside on a rectovaginal sample from women having risk factors for EOGBS neonatal infection.

Study settings and population
This study is a quality assessment study in the maternity ward after implementation of a new treatment modality. During the period from November 28 th 2018 to July 1 st 2019, all laboring women at the maternity ward at Lillebaelt University Hospital, Kolding, Denmark were consecutively included if they fulfilled the criteria. The cohort consists of 366 women with one or more risk factors for EOGBS is described in Fig 1.

Inclusion criteria
Laboring women were included if they presented with one or more of the following risk factors for EOGBS: GBS bacteriuria during current pregnancy, preterm labor < 37 gestational weeks (GA), and rupture of membranes ≥18h (ROM), prior infant with EOGBS, temperature ≥38.0°C during labor.

Exclusion criteria
Women younger than 18 years, women with a communication barrier, fetus mors, and pregnant women who had cesarean section. Nielsen et al [14].

Ethical clearance
This study describes a routine use of GBS PCR and IAP in a Danish group of laboring women. According to Danish legislation, quality assessment studies do not require approval from an ethics committee. The Science Ethics Committees for the Region of Southern Denmark decided that the project is not subject to notification to the scientific ethics committee system, cf. section 14, subsection 1 of the Act on the ethical treatment of health-science research projects and has confirmed no need for approval. Case number 20202000-50. After thorough information by a doctor, informed consent was expressed verbally by all participants in the presence of the doctor and a midwife and was in all cases documented in the electronic medical record of the women.

Statistics and calculations
Sample size and power calculation were not performed before study initiation. Positive and negative predictive values were calculated for each risk factor.

RESULTS
The mean age of women was 29.9 years (range 19-43 years). PCR results and predictive values for the three risk factor groups are listed in table 1 and illustrated in figure 2.   Among the 45 women that received IAP less than four hours before delivery (see Table 2), 21 spent more than four hours at the labor ward of which 7 did not receive IAP due to the extra time spend on the test.
The electronic medical records of the seven women who arrived at the labor ward in time (> 4 hours before giving birth) but did not receive IAP > 4 hours before delivery, were thoroughly investigated.
We observed the following reasons: -Two women, 2/251 (0.8%), because of extra time spent on the PCR testing procedure (one with risk factor GA 36+2 and rapid birth, and the other with GBS bacteriuria and induction of labor at GA 41+5 by amniotomy).
-Three patients, 3/251 (1.2%), because IAP was administered too late after a positive PCR result was available, presumably due to bustle at the ward.
-Two patients, 2/251 (0.8%), would not have received IAP > 4 hours before delivery regardless of the PCR test procedure. One woman with ROM>18 hours gave birth less than four hours after fulfilling this risk factor, and one woman with GBS bacteriuria and rapid birth three hours and 50 minutes after induction of labor at GA 41+5 by amniotomy.

DISCUSSION
We found that GBS bacteriuria was the risk factor with the strongest positive predictive value for actual rectovaginal GBS colonization with a positive percent of 71, and ROM>18 hours to be the weakest with a positive percent of 16. Overall, a reduction in the use of IAP by 70.5 % was achieved by use of the intrapartum PCR test for GBS among laboring women with risk factors for EOGBS.
According to national guidelines, 102 women mandatorily received IAP independent of the PCR test result fulfilling one of the following three risk factors: prior infant with EOGBS, preterm labor before 35 gestational weeks, temperature ≥38°C during labor. Women with a negative intrapartum GBS PCR test who developed fever during labor were treated with antibiotics with broader coverage than penicillin (ampicillin plus gentamicin) according to national guidelines.
We investigated the proportion of women with a risk factor for EOGBS potentially receiving inferior IAP due to extra time spend on the testing procedure. Two pregnant women with risk factors received inferior care as they did not receive IAP > 4 hours in accordance with guidelines even though they were present at the labor ward for > 4 hours. One of these two women received IAP > 2 hours. None of the children from this study developed EOGBS.
Twenty-one of the GBS PCR positive women were present at the ward for more than four hours and did not receive IAP > 4 hours before delivery; however, 13 of them received IAP more than 2 hours before delivery.

CONCLUSIONS
The intrapartum GBS PCR test procedure led to a reduction in the use of IAP by 70.5%, however, two women received inferior care, as they did not receive IAP within the recommended 4 hours.
Our data may indicate that the extra time spend on the PCR test procedure does not lead to noticeable undertreatment.