Original ResearchHigh fibrin/fibrinogen degradation product and D-dimer levels
for the diagnosis of invasive group A streptococcal infections
during pregnancy
N. Matsumoto1,∗ , Y. Mori2
1 Matsumoto Women’s Health Clinic, Saitama (Japan)
2 Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo (Japan)

Summary
Objective: Invasive group A streptococcal (GAS) infections during pregnancy are uncommon, and, thus, their early diagnosis remains
challenging. The present study was performed to assess fibrin/fibrinogen degradation product (FDP) and D-dimer levels in pregnant
women with invasive GAS infections and establish whether they contribute to a diagnosis. Materials and Methods: Laboratory data,
including FDP and D-dimer levels, measured between fulmination and just before delivery in 46 cases, consisting of 45 previously
published cases and the present case, were examined. Results: Fetal/neonatal and maternal mortality rates were 61 and 28%, respectively.
Laboratory data obtained from 24 cases just before delivery were as follows: white blood cell count ≥ 12,000/µL, 46% of cases; platelet
count ≤ 100,000/µL, 55% of cases, and C-reactive protein (CRP) level ≥ 10 mg/dL, 40% of cases. These variables showed no sensitivity
for the diagnosis of invasive GAS infections. However, 100% of cases were positive for FDP (≥ 10 µg/dL) and D-dimer (≥ 2 µg/dL),
the levels of which were extremely high in many cases. Conclusion: FDP and D-dimer levels may contribute to the diagnosis of invasive
GAS infections during pregnancy.
Key words: Antepartum; Disseminated intravascular coagulation; Sepsis; Streptococcus pyogenes; Toxic shock syndrome.

Introduction
Perinatal invasive group A streptococcal (GAS) infections, which include perinatal GAS-induced toxic shock
syndrome, mainly occur in puerperal women. Althoughthese infections are rare in antenatal women, poorer outcomes have been reported for antenatal cases than for puerperal cases [1]. Therefore, early awareness and the rapid
initiation of therapy are important for the management ofpregnant women with invasive GAS infections [2]. However, since the primary symptoms appear to be flu-like, anearly diagnosis remains challenging for clinicians.
We herein describe a case of invasive GAS infection
during pregnancy, in which the baby and mother both survived [3]. In brief, the patient was 41 years old, para 1,
and on her 39th week of pregnancy. She presented withchills and a fever (38 ◦ C). Fetal tachycardia was noted and,thus, she was admitted for observation. Her laboratory dataon admission were as follows: white blood cell count of
8,200/µL, C-reactive protein (CRP) level of 0.52 mg/dL,
and normal levels in other tests, except for very high plasma
fibrin/fibrinogen degradation product (FDP) and D-dimer
levels of 193 and 75 µg/dL, respectively. Intravenous antibiotics were administered for the febrile condition withno detected infection. Although the patient was not in astate of shock, cardiotocography indicated that the condition of the fetus was deteriorating. Emergency cesarean

Clin. Exp. Obstet. Gynecol. - ISSN: 0390-6663
XLVⅡ, n. 4, 2020
doi: 10.31083/j.ceog.2020.04.5308

section was performed, and the baby was born without
neonatal asphyxia or any infection. Although the patientdeveloped septic shock after the procedure, she was successfully treated and, as a result, fully recovered. Since her
blood culture indicated GAS infection, she was diagnosed
with invasive GAS infection during pregnancy.
This case prompted speculation on FDP and D-dimer
levels in other patients with similar conditions. Therefore,
the present study investigated FDP and D-dimer levels in
pregnant women with invasive GAS infections and whether
they may contribute to a diagnosis.
Materials and Methods
Forty-five cases of invasive GAS infection during pregnancy from studies published in English or Japanese between 2000 and 2017 were identified [4-40]. Cases inwhich individual clinical data were not available were
excluded. The literature search included PubMed, theJapana Centra Revuo Medicina, and reference lists of previously published cases. The search terms used included:‘group A streptococcus’, ‘Streptococcus pyogenes’, ‘infection’, ‘pregnancy’, ‘perinatal’, ‘peripartum’, ‘antenatal’,‘antepartum’, ‘intrapartum’, ‘delivery’, ‘labor’, ‘abortion’,‘toxic shock’, ‘bacteremia’, ‘sepsis’, and ‘disseminated intravascular coagulation’.
The criteria for invasive GAS infections during preg-©2020 Matsumoto and Mori
Published by IMR Press.

This is an open access article under the CC BY 4.0 license(https://creativecommons.org/licenses/by/4.0/).

N. Matsumoto and Y. Mori

484

Table 1. — Summary of categorical data for clinical background, symptoms, outcomes and therapies from the 46 cases.
FactorMaternal age (y)Teens
Twenties
Thirties
Forties
ParityNulliparous
MultiparousNA
Maternal complications
Yes
No
NA
Week of pregnancy at fulmination
Abortion period (< 22 weeks)
Second trimester (22-27 weeks)
Third trimester before term (28-36 weeks)
Term (≥ 37 weeks)
Fulmination period
Antenatal (before the onset of labor)
During labor
Mode of delivery
Emergency cesarean
Vaginal delivery
Abortion
None (maternal death before delivery)
Mortality
Fetal/neonatal death
Maternal death
Fetal/neonatal asphyxia (including death)
Yes
No
NA
Symptoms at fulmination period (some are overlapping)
Fever (>38 ◦ C)
Respiratory symptoms
Abdominal pain
Gastrointestinal symptoms
Abnormally strong uterine contractions
Unconsciousness
Administration of antibiotics
Yes
No
NA
Administration of immunoglobulin
Yes
No
NA
Blood transfusion
Yes
No
NA
NA, not available.

n

%

1
9
32
4

2.2
19.6
69.6
8.7

8
37
1

19.4
80.6

10
31
5

24.4
75.6

5
4
18
19

10.9
8.7
39.1
41.3

45
1

97.8
2.2

22
17
4
3

47.8
37
8.7
6.5

28
13

60.9
28.3

34
3
9

91.9
8.1

44
20
32
17
20
5

95.7
43.5
69.6
37
43.5
10.9

40
5
1

88.9
11.1

20
25
1

44.4
55.6

24
17
5

58.5
41.5

High fibrin/fibrinogen degradation product and D-dimer levels...

485

Table 2. — Summary of laboratory test values in the 24 available cases whose laboratory tests were carried out duringfulmination and just before delivery.
Item
White blood cell count (/μL)≥ 12,000< 12,000NA
Hemoglobin concentration (g/dL)≤8>8NAPlatelet count (/μL)≤ 100,000> 100,000
NAAST (U/L)
≥ 80
< 80
NA
Serum creatinine (mg/dL)
≥ 1.2
< 1.2
NA
C-reactive protein (mg/dL)
≥ 10
< 10
NA
Fibrinogen (mg/dL)
≤ 100
> 100
NA
FDP (μg/mL)
Strong positive (≥ 40)
Positive (≥ 10)
Negative (< 10)NAD-dimer (μg/mL)
Strong positive (≥ 10)
Positive (≥ 2)
Negative (< 2)
NA

n

%

11
13
0

45.8
54.2

1
13
10

7.1
92.9

11
9
4

55
45

3
5
16

37.5
62.5

4
7
13

36.4
63.6

8
12
4

40
60

4
5
15

44.4
55.6

6
7
0
17

85.7
100
0

3
5
0
19

60
100
0

Median12,490Range
1,970-45,200

11.4

6.7-13.4

96,0005,000-421,000

44.5

15-1980.87

0.57-1.77

6.2

0.3-28.2

130

18-720352

31-1,92075

2.0-444

AST, aspartate aminotransferase; FDP, fibrin/fibrinogen degradation product; NA, not available.

nancy were as follows. Each case needed to have GAS
infection that was identified through a bacterial culture or
rapid antigen detection test (RADT) at some time point during the clinical course. The fulmination period needed tobe before delivery or abortion. Cases had to have the criteria for streptococcal toxic shock syndrome [41] or a similar clinical course to that defined by Udagawa [42]. Udagawa advocates and defines invasive GAS infection during pregnancy (perinatal-type invasive GAS infection) as
a rapidly progressive infectious and septic condition thatcauses severe morbidity and mortality of the mother andfetus/neonate through abnormally strong uterine contrac-

tions and rushed delivery induced by uterine myometrial
hematogenous infection from a remote original GAS infectious focus, such as the upper respiratory tract.
Forty-six cases, including the present case, were reviewed. The clinical background, morbidity and mortality,
administration of antibiotics and immunoglobulin, and laboratory data measured between fulmination and just before
delivery were extracted and analyzed to assess sensitivity
for the disease. Disease fulmination was defined as the period in which fever develops (38 ◦ C or higher, in principle). In two cases [23, 34], both of whom died as a resultof the disease, fulmination was regarded as the period of486

N. Matsumoto and Y. Mori

Figure 1. — Histograms of continuous clinical background data from 46 cases of invasive group A streptococcal (GAS) infections during
pregnancy. The mean maternal age was 34.5 years, the mean week of pregnancy at fulmination was 36 weeks, and mean parity was 1.
(Areas with a deep color indicate maternal death).

Figure 2. — Histograms for laboratory data from 24 available cases in which laboratory tests were performed between fulminationand just before delivery. Positive fibrin/fibrinogen degradation product (FDP) (≥ 10 µg/dL) and positive D-dimer (≥ 2 µg/dL) eachhad 100% sensitivity. Strong positive FDP (≥ 40 µg/dL) and strong positive D-dimer (≥ 10 µg/dL) had sensitivities of 86 and 60%,
respectively. (Each red horizontal bar indicates the cut-off value defined as an apparently abnormal level that needs clinical intervention.
Each arrow indicates an abnormal direction. Areas with a deep color indicate maternal death).

abnormally strong uterine contractions (no body temperature data were available for these cases in the literature).
During the analysis of laboratory data, cut-off values foreach item were defined as apparently abnormal levels thatneed clinical intervention. FDP and D-dimer cut-off values

were defined as two steps. Accordingly, two cut-off values
were defined for FDP (≥ 10 µg/dL and ≥ 40 µg/dL) andD-dimer (≥ 2 µg/dL and ≥ 10 µg/dL) based on the literature for normal ranges from maternal laboratory data [43,44], disseminated intravascular coagulation (DIC) diagnos-High fibrin/fibrinogen degradation product and D-dimer levels...

tic criteria by the Japanese Ministry of Health, Labour andWelfare [45, 46], and obstetrical DIC scoring [47].
Results
The mean maternal age was 34.5 years (range, 16 to 43
years), the mean week of pregnancy at fulmination was 36
weeks (range, 8 to 40 weeks), and mean parity was 1 (range,
0 to 6) (Figure 1). The duration from fulmination to maternal death was one day or less in eight (67%) cases, two daysin two (17%), and three days or more in two (17%). Clinicalbackgrounds, symptoms, therapies, and fetal/neonatal andmaternal mortalities are categorically summarized in Table
1. There were more multiparous than nulliparous women,
while the majority of women (76%) had no maternal complications. Among the cases included, 80% developed GAS
infection in the third trimester and 41% at term, whereas
11% developed GAS infection during the abortion period.
The fulmination period in all cases was before the onset oflabor, except in one case in which the disease fulminatedduring labor. Among the cases included, 7% died before delivery or abortion. Maternal and fetal/neonatal death rates
were 28% and 61%, respectively. Despite the exclusionof abortion cases, fetal/neonatal asphyxia or fetal/ neonatal deaths were frequently observed, such that only 8% ofcases presented with no fetal/neonatal asphyxia. The majority of cases (89%) received antibiotics, whereas only 44%
received immunoglobulin.
Laboratory data measured between fulmination and justbefore delivery were available for 24 cases [6, 8, 10-12, 15,
17, 18, 22, 25, 26, 28-30, 32, 35, 37-40]. A summary ofthe data obtained and histograms to assess distributions areshown in Table 2 and Figure 2, respectively. Regarding laboratory data, 46% of cases had a white blood cell count ≥12,000/µL, 7% had a hemoglobin concentration ≤ 8 g/dL,
55% had a platelet count ≤ 100,000/µL, 38% had an aspartate aminotransferase level ≥ 80 U/L, 36% had a serum
creatinine level ≥ 1.2 mg/dL, 40% had a CRP level ≥ 10
mg/dL, and 44% had a fibrinogen level ≤ 100 mg/dL. On
the other hand, positive FDP (≥ 10 µg/dL) and positive Ddimer (≥ 2 µg/dL) both had 100% sensitivity for detecting
invasive GAS infections during pregnancy with minimumscores of 31 µg/dL and 2.0 µg/dL, respectively. Moreover, strong positive FDP (≥ 40 µg/dL) and strong positive
D-dimer (≥ 10 µg/dL) had sensitivities of 86% and 60%,
respectively, for detecting invasive GAS infections during
pregnancy. Furthermore, in many cases, the levels of theseparameters were extremely high, as shown in Figure 2.
Discussion
The present study provides a summary of clinical backgrounds, symptoms, therapies, and severe outcomes among
pregnant women with invasive GAS infections. The resultsof laboratory tests performed between fulmination and justbefore delivery showed that FDP and D-dimer may be supportive laboratory tests for an early diagnosis of invasive
GAS infections during pregnancy in clinical practice.

487

Severe outcomes of invasive GAS infections during
pregnancy were identified and consistent with previous
findings [2]. The epidemiological finding of multiparous
women being dominant and the results of the present caseindicated that a patient’s children may be one of the factors
affecting the spread of GAS infection. The fulmination period was commonly observed during the third trimester, including term, but was also observed during the early weeks
of pregnancy in several cases. The majority of cases (89%)
had received antibiotics. However, in almost 40% of reviewed cases (17 out of 43 cases in which the period of
antibiotic initiation was known) [4, 7-12, 14-17, 19, 21, 2325, 27, 29, 31-33, 37, 39], the initiation of antimicrobial
therapy was considered to be late. The present results indicated that inadequate management was attributed to circumstances wherein clinicians initially misdiagnosed patientswith a viral infection, such as influenza, while occasionallylacking the insight to anticipate the probability of any bacterial infectious conditions, including GAS infections.
In the present study, laboratory data from tests performed between fulmination and just before delivery wereavailable for 24 cases. However, the interpretation ofthese data was associated with the following limitations.
The condition of patients upon blood sampling varied fromfebrile to almost septic and/or DIC. Furthermore, data availability was limited, such that only seven cases for FDP [3,10, 11, 15, 22, 37] and five for D-dimer [3, 11, 18, 22, 30]
were available for analysis. In addition, negative data may
have been omitted from each publication. Therefore, laboratory data were analyzed and interpreted in considerationof these limitations. Moreover, data for pregnant womenwith febrile conditions, except for those with GAS infections, were unavailable. Therefore, the sensitivity of eachlaboratory test item was only estimated. The percentagesof items over the cut-off value, which affects sensitivity,
are shown in Table 2. Accordingly, positive FDP (≥ 10µg/dL) and positive D- dimer (≥ 2 µg/dL) each had 100%
sensitivity, while strong positive FDP (≥ 40 µg/dL) andstrong positive D-dimer (≥ 10 µg/dL) had sensitivities of
86% and 60%, respectively. Moreover, high sensitivity implies a high negative predictive value. Therefore, strong
positive FDP/D-dimer test results indicate invasive GAS infections in pregnancy, whereas negative FDP/D-dimer test
results suggest their absence. Based on these results, high
FDP/D-dimer levels may alert clinicians to the possibilityof GAS infections during pregnancy.
FDP and D-dimer are both small fibrin-containing
molecules that may be measured in blood plasma. Since
D-dimer is the final product of fibrin degradation, it issmaller than FDP. These clinical laboratory tests are frequently used to diagnose DIC, deep vein thrombosis (DVT),
and pulmonary embolism (PE). Moreover, D-dimer is especially regarded as a marker of DVT and PE. Therefore, highD-dimer levels necessitate further testing in order to rule out
DVT and PE. In perinatal medicine, DVT is not uncommon.
Moreover, since leg DVT and PE generally present with

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N. Matsumoto and Y. Mori

obvious symptoms, they are harder to overlook. However,rare types of perinatal DVT, such as ovarian vein thrombosis and internal iliac vein thrombosis [48], are uncommon
and may be asymptomatic. Therefore, the early diagnosis ofthese conditions remains challenging. Moreover, in perinatal medical practice, bacterial infections have been shownto pathophysiologically induce DVT [49] and DIC. Thus,
when examining a febrile maternal patient with high FDP
and/or D-dimer levels, clinicians need to rule out DVT and
DIC, including invasive GAS infections.
The RADT for GAS infections of the throat is a diagnostic test that rapidly identifies the presence of GAS infections. The RADT has a fairly high sensitivity of approximately 85% [50]. However, since the primary infectious
focus of invasive GAS infections during pregnancy is notalways the throat, negative RADT test results do not always
rule out invasive GAS infections during pregnancy.
The results of laboratory tests performed between fulmination and just before delivery in 24 cases showed that
FDP and D-dimer may contribute to the diagnosis of invasive GAS infections during pregnancy. Despite some limitations inherent to the present study, the results obtained areof potential clinical significance, particularly for the diagnosis of invasive GAS infections during pregnancy. Nevertheless, further studies are needed to confirm the resultspresented herein.
Ethics Approval and Consent to Participate
The subjects of our case gave her informed consent
for inclusion before she participated in the study. The
study was conducted in accordance with the Declaration of
Helsinki, and the protocol was approved by the Ethics Committee of Matsumoto Women’s Health Clinic (approval
number: 202001).
Acknowledgments
A summary of this research was presented at the 71st
Academic Conference of the Japan Society of Obstetrics
and Gynecology, Nagoya, Japan, 2019.
Conflict of Interest
The authors declare no conflict of interest.
Submitted: June 27, 2019
Accepted: September 23, 2019
Published: August 15, 2020

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Corresponding Author:
NAOKI MATSUMOTO, M.D., Ph.D.
Matsumoto Women’s Health Clinic, 1-1-26 Chiyoda,
Honjo City, Saitama 367-0054 (Japan)
e-mail: research@matsumotoc.org

Clinical and Experimental Obstetrics & Gynecology
Clin Exp Obstet Gynecol 2020; 47(4): 483–489.
(IF: 0.139 (2019) )Original article
High fibrin/fibrinogen degradation product and D-dimer levels for the diagnosis ofinvasive group A streptococcal infections during pregnancy
Naoki Matsumoto, Yusuke Mori

劇症型 A 群レンサ球菌感染症「分娩型」の診断における FDP と D ダイマーの異常高値の意義
松本直樹，森祐介

日本語要約

【目的】

劇症型 A 群レンサ球菌（GAS）感染症「分娩型」はまれな周産期合併症であるため速やかに診断することが難しい。FDP および D ダイマーの測定がその診断に寄与するかを調べることを目的として本研究を行った。
【方法】 劇症型 GAS 感染症「分娩型」に相当する症例を論文から抽出し個別の情報が得られた 45 例にわれわれの経験した 1 例を加え計 46 例を対象とした。
【結果】

児死亡率は 61%，母体死亡率 28%であった。対象のうち発症から分娩直前までの

血液検査データが利用できたのは 24 例であった。白血球数≧12,000 /μL は 46%，血小板数≦
10 万 /μL は 55%，CRP≧10 mg/dL は 40%であり，これらの劇症型 GAS 感染症「分娩型」に対する感度は低かった。一方，FDP 陽性（≧10 μg/dL）と D ダイマー陽性（≧2 μg/dL）は 100%
であった。
【結論】

FDP と D ダイマーの測定が劇症型 GAS 感染症「分娩型」の早期診断に寄与するかもしれない。