The urgent need to recognize and properly address prenatal-onset group B Streptococcus disease

October is the "Prenatal-onset GBS Disease Recognition Month", which brings into focus the importance of preventing neonatal infections. Neonatal infections are a remarkable cause of infant morbidity and mortality worldwide and have become the dominant component of all child mortality as overall infant mortality rates decline. Among bacteria associated with neonatal infections, Streptococcus agalactiae or group B Streptococcus (GBS) stands out as a leading agent of neonatal meningitis, pneumonia, and sepsis since the 1960s. A high global burden is associated with GBS, accounting for 518,000 preterm births, 392,000 neonatal infections and 91,000 neonatal deaths every year (World Health Organization (WHO) 2021World Health Organization (WHO). Group B streptococcus Full Value of Vaccine Assessment. https://www.who.int/teams/immunization-vaccines-and-biologicals/immunization-analysis-and-insights/vaccine-impact-value/group-b-streptococcus-full-value-of-vaccine-assessment, 2021 (accessed August 29, 2022).Google Scholar). GBS neonatal infections can be classified according to the timing of symptoms' onset and mode of microorganism acquisition into early- and late-onset disease (Figure 1). Early-onset GBS disease (EOGBS) occurs up to 7 days after birth and is usually associated with vertical intrapartum acquisition. Late-onset disease (LOGBS) occurs between 7 and 90 days after birth and is due to horizontal postpartum acquisition from a variety of sources, including the hospital environment, the mother or other caregivers, or by breastfeeding (Steer et al., 2020Steer PJ Russell AB Kochhar S Cox P Plumb J Gopal Rao G Group B streptococcal disease in the mother and newborn-A review.Eur J Obstet Gynecol Reprod Biol. 2020; 252: 526-533https://doi.org/10.1016/j.ejogrb.2020.06.024Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar). A much less well-known form of GBS infection is the prenatal-onset GBS disease (POGBS), which occurs any time before delivery due to in utero acquisition (Figure 1). Bacteria can reach the fetus due to an ascending infection from the vagina, even in the presence of intact membranes. GBS colonizes asymptomatically the vaginal tract of 18% of pregnant women worldwide, varying from 10% to 40% according to the geographic region (Seale et al., 2017Seale AC Bianchi-Jassir F Russell NJ Kohli-Lynch M Tann CJ Hall J et al.Estimates of the Burden of Group B Streptococcal Disease Worldwide for Pregnant Women, Stillbirths, and Children.Clinical Infectious Diseases. 2017; 65: S200-S219https://doi.org/10.1093/cid/cix664Crossref PubMed Scopus (280) Google Scholar). POGBS can lead to miscarriage, stillbirth, early rupture of membranes and preterm labor. The term "prenatal-onset GBS disease (POGBS)" was first coined in 2007, and in 2010 recommended guidelines on its prevention were published by the US Centers for Disease Prevention and Control (CDC) (Centers for Disease Control and Prevention (CDC) 2010Centers for Disease Control and Prevention (CDC). Prevention of Perinatal Group B Streptococcal Disease. https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5910a1.htm, 2010 (accessed August 26, 2022).Google Scholar). Nonetheless, POGBS is still not widely recognized as a distinct entity and cases of GBS infection in unborn babies are usually classified as EOGBS. This has been justified by the apparent rare occurrence of miscarriage and stillbirth associated with GBS worldwide. However, a recent report of the World Health Organization (WHO) estimates that GBS is responsible for 46,000 cases of stillbirth every year (World Health Organization (WHO) 2021World Health Organization (WHO). Group B streptococcus Full Value of Vaccine Assessment. https://www.who.int/teams/immunization-vaccines-and-biologicals/immunization-analysis-and-insights/vaccine-impact-value/group-b-streptococcus-full-value-of-vaccine-assessment, 2021 (accessed August 29, 2022).Google Scholar), a number high enough to raise questions around the alleged rarity of POGBS. Recent studies show that the burden of POGBS has been far underestimated (Gonçalves et al., 2022Gonçalves BP Procter SR Paul P Chandna J Lewin A Seedat F et al.Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden. The Lancet.Global health. 2022; 10: e807-e819https://doi.org/10.1016/S2214-109X(22)00093-6Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Annually, 518,100 preterm births, representing 3.5% of all preterm births worldwide, are associated with GBS maternal colonization. Likewise, 46,200 stillbirths result from a GBS infection in utero. Sub-Saharan Africa and Central and South Asia bear the highest burden related to GBS, with 68,500 preterm births and 20,300 stillbirths; followed by East and Southeast Asia, North Africa and West Asia, Europe and North America, Latin America and the Caribbean, and Oceania (Gonçalves et al., 2022Gonçalves BP Procter SR Paul P Chandna J Lewin A Seedat F et al.Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden. The Lancet.Global health. 2022; 10: e807-e819https://doi.org/10.1016/S2214-109X(22)00093-6Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Furthermore, among the total number of deaths related to GBS perinatal infections, stillbirths account for 25-50% depending on the geographic region, overcoming EOGBS and LOGBS associated deaths in many countries. In Europe and North America, for example, stillbirths account for more than half of the total deaths associated with GBS (Gonçalves et al., 2022Gonçalves BP Procter SR Paul P Chandna J Lewin A Seedat F et al.Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden. The Lancet.Global health. 2022; 10: e807-e819https://doi.org/10.1016/S2214-109X(22)00093-6Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). These are estimated numbers and the true burden could be higher, mainly in under-resourced areas where there is limited screening and testing. The prevention of neonatal GBS infections has been centered on maternal screening practices and intrapartum antibiotic prophylaxis (American College of Obstetricians and Gynecologists (ACOG) 2020American College of Obstetricians and Gynecologists (ACOG). Prevention of Group B Streptococcal Early-Onset Disease in Newborns. https://www.acog.org/en/clinical/clinical-guidance/committee-opinion/articles/2020/02/prevention-of-group-b-streptococcal-early-onset-disease-in-newborns, 2020 (accessed August 26, 2022).Google Scholar). Whereas these policies have efficiently decreased the incidence of EOGBS in many countries, such strategies do not seem to have impacted the occurrence of LOD or POGBS. On the other hand, maternal vaccination could be an effective way to prevent all types of GBS diseases. In this regard, one of the goals in WHO's roadmap is to obtain at least one licensed vaccine for immunization during pregnancy by 2026 (World Health Organization (WHO) 2017World Health Organization (WHO). Group B streptococcus vaccine development technology roadmap: priority activities for development, testing, licensure and global availability of group B streptococcus vaccines. https://www.who.int/publications/i/item/WHO-IVB-17.10, 2017 (accessed August 29, 2022).Google Scholar). Despite all the obstacles faced during the 40 years since the first studies on GBS vaccine started (Baker and Kasper, 1976Baker CJ Kasper DL. Correlation of maternal antibody deficiency with susceptibility to neonatal group B streptococcal infection.N Engl J Med. 1976; 294: 753-756https://doi.org/10.1056/NEJM197604012941404Crossref PubMed Scopus (529) Google Scholar), we have now reached advanced stages in this process, which makes possible for a licensed GBS vaccine to be available within a few years (Absalon et al., 2022Absalon J Simon R Radley D Giardina PC Koury K Jansen KU et al.Advances towards licensure of a maternal vaccine for the prevention of invasive group B streptococcus disease in infants: a discussion of different approaches.Hum Vaccin Immunother. 2022; 182037350https://doi.org/10.1080/21645515.2022.2037350Crossref PubMed Scopus (13) Google Scholar). Even though no universal protocol to prevent POGBS has been established or recommended, some knowledge-based strategies can help prevent GBS infections before birth, by allowing immediate medical intervention with effective outcomes. Performing periodic urine cultures during pregnancy is one of them, since the presence of GBS in urine indicates anovaginal colonization and potential ascending infection. Also, some clinical signs and symptoms can suggest the occurrence or a higher risk of fetal infection, such as maternal fever, frantic or reduced fetal movement, vaginal bleeding, nausea, vomits, diarrhea, increased pressure in vagina or pelvis, cramping in lower abdomen, severe lower backache, and regular or frequent contractions. Vaginal colonization by GBS may cause yellow or green vaginal discharge, besides vaginal burning and irritation, which could be mistaken for yeast infection or bacterial vaginosis and thus treated incorrectly (Group B Strep International (GBSI) 2018Group B Strep International (GBSI)What Can We Currently Do to Help Prevent Prenatal-onset Group B Strep Disease?. Group B Strep International, 2018http://www.groupbstrepinternational.org/9/category/conventional-prevention-strategiesGoogle Scholar). Moreover, it is essential to avoid unneeded invasive procedures in pregnant women since they may facilitate GBS crossing the intact membranes. In view of the emerging importance of POGBS, the "Prenatal-onset GBS Disease Recognition Month" aims to increase awareness among healthcare professionals and pregnant women, by providing information on strategies that may help protect unborn babies, and to strengthen the implementation of robust surveillance systems that can ultimately contribute to improved preventive measures against POGBS. To better prevent POGBS, there's the need of research that focuses on GBS maternal colonization, which seems to be the greater risk factor for POGBS. Although the rates of GBS maternal colonization in different places of the world are widely known, research on how and why GBS can lead to miscarriage, stillbirth, or preterm birth is still incipient. The licensing of a GBS vaccine soon will open a promising avenue to prevent POGBS, the effectiveness of which requires research in real world setting. Meanwhile, the importance of routine detection of GBS maternal colonization should be emphasized among healthcare workers worldwide, and adequate support for this purpose should be available in low- and middle-income countries, where the burden is high but the access to required infrastructure is still low. All authors declare no conflicts of interest.