President's Message - Sepsis Around the Cradle of Humankind

Jerry J. Zimmerman, MD, PhD, FCCM

While representing the cutting edge of civilization everywhere, mothers and their newborn infants are a population particularly vulnerable to sepsis.¹ By recognizing the importance of antiseptic prophylaxis (handwashing), Ignaz Semmelweis directly confronted this particular human sepsis vulnerability and simultaneously codified maternal/ neonatal sepsis and infection prevention. Accordingly he has been hailed as the “Defender of Motherhood.”² However, despite this seminal discovery nearly 170 years ago, maternal/neonatal sepsis remains a significant global health challenge.

Maternal sepsis has been defined as life-threatening organ dysfunction resulting from infection during pregnancy, during childbirth, post-abortion, or postpartum.³ This definition of maternal sepsis expresses the thinking embedded in the 2016 Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3).⁴ Such infections are responsible for approximately 11% of maternal deaths and increase the risk of early neonatal sepsis.^5,6 Moreover, while early neonatal sepsis causes about 8% of all neonatal deaths, the proportion of late neonatal deaths attributable to sepsis is fourfold higher.⁷ Sepsis may contribute to up to 100,000 maternal deaths annually, and it kills more than 1 million newborns annually. Moreover, it has been emphasized that maternal/neonatal infection reflects much broader concerns that include inadequate public health infrastructure, lack of preventive interventions, scarcity of quality care, and inadequate early diagnosis and infection treatment.

Accordingly, the Global Maternal and Neonatal Sepsis Initiative (srhr.org/sepsis/resources) was launched in 2009 with the goal of accelerating the reduction of preventable maternal and neonatal deaths related to sepsis.⁸ This World Health Organization (WHO) and Jhpiego (Johns Hopkins Program for International Education in Gynecology and Obstetrics) initiative stresses that every pregnant or recently pregnant woman and newborn is at risk for infection, and that if infection is recognized and treated early, the transition to life-threatening sepsis can be avoided. The initiative has received broad international support from organizations such as the Surviving Sepsis Campaign, a joint collaboration of the Society of Critical Care Medicine (SCCM) and the European Society of Intensive Care Medicine (ESICM).9 The Global Maternal and Neonatal Sepsis Initiative promotes three objectives: 

• Raising awareness of maternal/neonatal sepsis among healthcare providers, policymakers, and the public
• Assessing the burden and management of maternal/ neonatal sepsis from the global perspective
• Developing and testing effective strategies to prevent, detect, and successfully manage maternal/neonatal sepsis

A key aspect of the program is to enhance prevention of maternal/neonatal sepsis using a variety of practical approaches such as promoting handwashing, ensuring clean birthing practices, reducing overcrowding in healthcare facilities, improving access to clean water and sanitation, and strengthening infection prevention and control measures. A summary of resources available from WHO for this work is available online (srhr.org/sepsis/resources). 

Epidemiology, microbiology, pathophysiology, infant and maternal risk factors, diagnostics, and management of maternal/neonatal sepsis have been reviewed in detail.¹⁰ Preterm delivery, intrapartum fever, and membrane rupture ≥ 18 hours are recognized risk factors for neonatal sepsis. Expanded prenatal maternal group B Streptococcus (GBS) screening or a risk-based strategy could potentially prevent a substantial portion of GBS cases. Neonatal sepsis caused by other organisms is more often a disease of prematurity.¹¹ Preterm birth is the leading cause of neonatal death and is a final common pathway for a variety of other neonatal pathologies.¹² It has been suggested that preventing premature births broadly will require early identification of women at risk; improved survival of preterm infants, particularly in low- and middle-income countries; quality epidemiologic data for tracking prevalence, risk factors, and interventions; and acceleration of health gains by fostering innovation and collaboration.¹³

Risk of invasive infection is higher in the neonatal period than at any other time of life.¹⁴ However, for a variety of reasons (e.g., microbiome, evolving immunity),^15,16 diagnosis of sepsis in neonates remains challenging.^17,18​

Polymerase chain reaction amplification of microbial DNA, coupled with mass spectroscopy detection, will likely shorten the time to confirmation of infection over conventional culture approaches while simultaneously providing key information regarding antimicrobial susceptibility.^19,20 Alternatively, assessing the host response to infection with mRNA gene expression is a burgeoning successful approach for diagnosing adult and pediatric sepsis.^21–24 Neonates, however, as might be suspected, manifest a unique host response to sepsis even when compared to older children.²⁵ Pathway analysis of gene expression from blood leukocytes differs markedly between neonates and young adults subjected to sepsis.²⁶ Moreover, these sophisticated diagnostic technologies, likely to be more sensitive and specific than clinical criteria for diagnosing sepsis, will not be immediately available to those areas of the world where the need is greatest.

As SCCM continues its work formulating contemporary, evidenced-based adult and pediatric sepsis definitions, teaching fundamentals of critical care, and promoting the Surviving Sepsis Campaign, it is important not to let mothers and newborns slip through the cracks. Even as SCCM investigators take aim at a new Biomedical Advanced Research and Development Authority (BARDA) sepsis moonshot, “Save Lives by Solving Sepsis,” it is important not to overlook the vulnerable mother/ baby dyad—it’s what all of us would want for mothers and newborns who are close to us.

References

1.       Bhutta ZA, Black RE. Global maternal, newborn, and child health—so near and yet so far. N Engl J Med. 2013 Dec 5;369(23):2226-2235.

2.       Potter P. Ignaz Philipp Semmelweis (1818-65). Emerg Infect Dis. 2001 Apr;7(2):368.

3.       Global Maternal and Neonatal Sepsis Initiative Working Group. The Global Maternal and Neonatal Sepsis Initiative: a call for collaboration and action by 2030. Lancet Glob Health. 2017 Apr;5(4):e390-e391.

4.       Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016 Feb 23;315(8):801-810.

5.       Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014 Jun;2(6):e323-333.

6.       Chan GJ, Lee AC, Baqui AH, Tan J, Black RE. Risk of early-onset neonatal infection with maternal infection or colonization: a global systematic review and meta-analysis. PLoS Med. 2013 Aug;10(8):e1001502.

7.       Oza S, Lawn JE, Hogan DR, Mathers C, Cousens SN. Neonatal cause-of-death estimates for the early and late neonatal periods for 194 countries: 2000-2013. Bull World Health Organ. 2015 Jan;93(1):19-28.

8.       World Health Organization. Statement on maternal sepsis. Geneva, Switzerland: World Health Organization; 2017.

9.       Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Crit Care Med. 2017 Mar;45(3):486-552.

10.   Shane AL, Sánchez PJ, Stoll BJ. Neonatal sepsis. Lancet. 2017 Oct 14;390(10104):1770-1780.

11.   Schuchat A, Zywicki SS, Dinsmoor MJ, et al. Risk factors and opportunities for prevention of early-onset neonatal sepsis: a multicenter case-control study. Pediatrics. 2000 Jan;105(1 Pt 1):21-26.

12.   Liu L, Johnson HL, Cousens S, et al; Child Health Epidemiology Reference Group of WHO and UNICEF. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet. 2012 Jun 9;379(9832):2151-2161.

13.   Lackritz EM, Wilson CB, Guttmacher AE, et al. A solution pathway for preterm birth: accelerating a priority research agenda. Lancet Glob Health. 2013;1(6):e328-330.

14.   Simonsen KA, Anderson-Berry AL, Delair SF, Davies HD. Early-onset neonatal sepsis. Clin Microbiol Rev. 2014 Jan;27(1):21-47.

15.   Bliss JM, Wynn JL. Editorial: the neonatal immune system: a unique host-microbial interface. Front Pediatr. 2017 Dec 21;5:274.

16.   Raymond SL, Stortz JA, Mira JC, Larson SD, Wynn JL, Moldawer LL. Immunological defects in neonatal sepsis and potential therapeutic approaches. Front Pediatr. 2017 Feb 7;5:14.

17.   Iroh Tam PY, Bendel CM. Diagnostics for neonatal sepsis: current approaches and future directions. Pediatr Res. 2017 Oct;82(4):574-583.

18.   Cummings JJ. The well-appearing newborn at risk for early-onset sepsis: We can do better. Pediatrics. 2017 Mar;139(3).

19.   Caliendo AM, Hodinka RL. A CRISPR way to diagnose infectious diseases. N Engl J Med. 2017 Oct;377(17):1685-1687.

20.   Paiva JA, Laupland KB. Real -time PCR for early microbiological diagnosis: is it time? Intensive Care Med. 2017 Nov;43(11):1714-1716.

21.   Ramilo O, Allman W, Chung W, et al. Gene expression patterns in blood leukocytes discriminate patients with acute infections. Blood. 2007 Mar 1;109(5):2066-2077.

22.   McHugh L, Seldon TA, Brandon RA, et al. A Molecular host response assay to discriminate between sepsis and infection-negative systemic inflammation in critically ill patients: discovery and validation in independent cohorts. PLoS Med. 2015 Dec 8;12(12):e1001916.

23.   Sweeney TE, Khatri P. Benchmarking sepsis gene expression diagnostics using public data. Crit Care Med. 2017 Jan;45(1):1-10.

24.   Prucha M, Ruryk A, Boriss H, et al. Expression profiling: toward an application in sepsis diagnostics. Shock. 2004 Jul;22(1):29-33.

25.   Wynn JL, Guthrie SO, Wong HR, et al. Postnatal age is a critical determinant of the neonatal host response to sepsis. Mol Med. 2015 Jun;21:496-504.

26.   Gentile LF, Nacionales DC, Lopez MC, et al. Protective immunity and defects in the neonatal and elderly immune response to sepsis. J Immunol. 2014 Apr 1;192(7):3156-3165.