Fetal sepsis: a cause of stillbirth

Abstract

Infection is considered a leading cause of fetal death, responsible for approximately 20% of cases. Such estimates are derived from the frequency of acute histological chorioamnionitis and funisitis in cases of fetal death rather than direct detection of microorganisms in the fetal compartment. We report a case of clinically unexplained fetal death at 38 weeks of gestation in an uncomplicated pregnancy resulting in delivery of an appropriate-for-gestational-age fetus. The mother did not have any clinical signs of infection. Overwhelming bacterial invasion in multiple fetal organs, including the heart, liver, spleen, and kidneys, was observed despite the lack of evidence of infection (i.e., fever or abscesses). The bacteria were visualized by using standard histologic techniques (e.g., tissue Gram stain) highlighting the value of autopsy in determining the cause of death.

Introduction

Fetal death in the third trimester occurs in approximately 2.1 million cases per year, most of which take place in low- and middle- income countries (1). In the United States, the rate of fetal death is 5.9 per 1,000 (or approximately 1 in 160 pregnancies), while it is 44 per 1,000 in Pakistan (2). Infection is thought to be responsible for 22% of cases (1), and the putative responsible microorganisms include bacteria, fungi, viruses, and parasites (3). Proving a causal role of infection in fetal death is difficult (3). Examination of the placenta is part of the standard evaluation of fetal death along with an autopsy (4, 5), and acute inflammatory lesions of the placenta, or villitis, are often interpreted as an indirect indicator of infection (3). Bacteria are rarely observed during histologic examination of the placenta or in the autopsy materials in cases of fetal death. We report herein a case of overwhelming fetal infection with bacterial invasion in multiple fetal organs demonstrated by visualization of the microorganisms during histologic examination.

Case Report

The patient was a 30-year-old primigravida who had an unremarkable prenatal course. At 38 weeks of gestation, she reported a decrease in fetal movements, and the diagnosis of fetal death was made by ultrasound examination at 37 weeks and 5 days and showed the estimated fetal weight to be 3336 grams (84^th percentile). Labor was induced and a male stillborn weighing 3400 gm was delivered vaginally. The external examination of the fetus showed skin peeling and grade 1 maceration. No fetal congenital anomalies were recognized. Internal examination showed normal morphology of the organs. The placenta showed mild acute sub-chorionitis, mild umbilical phlebitis, and funisitis. Microscopic examination revealed massive bacterial invasion in the fetal blood vessels and tissues (Figures 1–2). There was evidence of meconium aspiration in the lungs. Some degree of autolysis of the organs was observed (Figures 1–2). A Gram stain showed multiple Gram-positive bacteria (figure 3) in the organs which under oil immersion lens resembled Cocci (Figure 4).

Figure 1a-d:

a) Fetal heart blood vessel shows overwhelming presence of bacteria (H&E; 200X). The fetus had died in utero and showed grade-1 maceration with autolysis of all the internal organs; b) Spleen shows presence of bacteria in the vessel (H&E; 40X); c) Liver vessels show presence of bacteria (arrow; H&E; 100X); d) Adrenal gland capillaries with bacterial clumps (arrow; H&E; 100X)

Figure 2 a, b and c:

Kidney digital whole slide scanner view (a) showing bacteria in the hilar (red arrow) and other vessels (blue arrow). (H&E; a: 0.5X; b: 1X; c: 200X)

Figure 3:

Gram stain of kidney shows renal hilar (red arrow) and other vessels (blue arrows) with abundance of bacteria (Gram stain 0.5X)

Figure 4:

Gram stain under oil immersion lens shows Gram-positive cocci (Gram stain; OEL; 1000X)

Discussion

Infection has been considered a leading cause of fetal death, second only to severe maternal placental underperfusion (6). Yet, proving that infection causes fetal death is difficult. Perhaps, the best evidence for a causal role of infection in fetal death comes from the study of syphilis in pregnancy (7). Indeed, untreated maternal syphilis is associated with fetal death in 10% of cases, and treatment with antibiotics is associated with a lower rate of fetal death (7). Other microorganisms implicated in fetal death include parvovirus B and listeria monocytogenes (3). Fetal infection with parvovirus B can cause anemia by infecting red blood cell precursors, leading to high output fetal cardiac failure and death (8). Listeria monocytogenes can cause severe fetal septicemia (9). However, the mechanism whereby most microorganisms cause fetal death has not been established. Presumably, microorganisms induce a fetal systemic inflammatory response syndrome (10) that can worsen into a cytokine storm causing cardiac failure and death (11).

The estimates of the role of infection as a cause of stillbirth are largely based on inferences that the presence of inflammation of the placenta and umbilical cord (histological chorioamnionitis and funisitis) is evidence of infection (12–14). This reasoning is problematic because acute inflammatory lesions of the placenta may be due to sterile intra-amniotic inflammation rather than infection and because intra-amniotic infection and intra-amniotic inflammation do not inevitably lead to fetal death (10, 15–17). Indeed, acute histological chorioamnionitis and funisitis are more common in premature labor than in fetal death (18, 19). Therefore, the presence of histological chorioamnionitis does not necessarily indicate that infection is the cause of death. This also applies to the identification of microorganisms in the placenta or even in the amniotic cavity.

The detection of microorganisms in fetal blood obtained through cardiac puncture at the time of autopsy is considered reliable evidence that the fetus had bacteremia and probable sepsis. This condition has been observed in 36% of cases (20). The organisms reported include Escherichia coli, group B streptococcus, and enterococcus species (20). Table 1 summarizes the rate of positive blood cultures as part of autopsy in fetal death (20).

Table 1:

Organisms identified in fetal cultures from infection-related stillbirths²⁰

	Gestational age (weeks; values in %)
		< 24	24–28	29–31	32–36	37+	Total
Total		59	11	5	12	14	100%
Escherichia coli		20	0	0	3	6	29%
Group B Streptococcus		8	0	0	3	1	12%
Enterococcus species		6	3	0	1	2	12%
Bacillus species		3	0	0	0	2	5%
Enterobacter species		2	1	0	0	0	3%
Other		18	5	0	3	1	27%

²⁰Modified with permission from Page JM, Bardsley T, Thorsten V, Allshouse AA, Varner MW, Debbink MP, et al. Stillbirth associated with infection in a diverse U.S. cohort. Obstet Gynecol. 2019; 134(6):1187–96.

We report herein that bacteria may be found in histologic examination of the fetus even in the absence of gross evidence of infection of autopsy (e.g., the presence of an abscess). Cultures were not performed in this case because there was no suspicion of congenital fetal infection. Nonetheless, bacteria were found in multiple organs. The case illustrated here shows that autopsy may be informative, as demonstration of bacteria in fetal tissues in a patient with a fetal death without any clinical evidence of infection (e.g., symptoms of chorioamnionitis) provides persuasive evidence that an overwhelming fetal infection was present.