Complement, fetal antigen, and shaking rigors in parturients.
ABSTRACT To assess the relationship, if any, between complement, fetal antigen, and shaking rigors during labor and delivery.
We recruited 13 volunteers for serial blood sampling during labor and childbirth.
Complement levels had a small but significant drop (11-15%) immediately following childbirth but had no association with fetal antigen levels or shaking rigors. Fetal antigen levels failed to show any consistent relationship with shaking rigors or the labor and delivery process.
Shaking rigors do not appear to be associated with changes in either complement or fetal antigen levels. Complement levels remain stable during labor but drop immediately following birth.
- SourceAvailable from: ncbi.nlm.nih.gov[Show abstract] [Hide abstract]
ABSTRACT: Pro-inflammatory cytokines play an important role during the process of human parturition. The focus of this review was to explore the contribution of biological, biochemical, and genetic changes in the onset of term labor. This article reviews the English-language literature on inflammatory, hormonal, and immunological factors in an effort to identify the molecular basis of human parturition. The majority of the genes and proteins up-regulated in parturition at term are related to four functional categories, mechanical stretch-mediated damage-associated molecular patterns (DAMPs) activation, response to immunity, induction of inflammatory signaling, and progressive uterine myometrial contractility and resultant term birth. Mechanical stretch could promote the entry of amniotic fluid components into the uterine vessel circulation that is the common physiologic mechanism at term prior to labor. The fetal or amniotic fluid-derived DAMPs could activate the immune system. The inflammatory mediators are produced by infiltrating activated leukocytes and by the reproductive tissues themselves such as myometrium, and subsequently lead to uterine contractions. This review supports the sterile inflammation hypothesis that there are at least two phases of human parturition: the initial wave of the entry of amniotic fluid components into uterine vasculatures would be followed by the second big wave of subsequent myometrial contraction.Frontiers in Immunology 01/2012; 3:321.
- [Show abstract] [Hide abstract]
ABSTRACT: Amniotic fluid embolism is a rare and potentially catastrophic condition that is unique to pregnancy. The presentation may range from relatively subtle clinical events to sudden maternal cardiac arrest. Despite an increased awareness of the condition, it remains a leading cause of maternal mortality. The underlying mechanisms of amniotic fluid embolism are poorly understood, but current theories support an immune-based mechanism which is triggered by potentially small amounts of amniotic fluid gaining access to the maternal circulation. This can result in a wide spectrum of clinical findings, with cardiovascular and haematological disturbances being prominent. The management of a suspected episode of amniotic fluid embolism is generally considered to be supportive, although in centres with specific expertise, echocardiography may assist in guiding management. Whilst outcomes after an episode of amniotic fluid embolism are still concerning, mortality would appear to have decreased in recent times, likely secondary to an improved awareness of the condition, advances in acute care and the inclusion of less severe episodes in case registries.International journal of obstetric anesthesia 08/2013; · 1.85 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Amniotic fluid embolism (AFE) is one of the leading causes of maternal mortality and morbidity in developed countries. Current thinking about pathophysiology has shifted away from embolism toward a maternal immune response to the fetus. Two immunologic mechanisms have been studied to date. Anaphylaxis appears to be doubtful while the available evidence supports a role for complement activation. With the mechanism remaining to be elucidated, AFE remains a clinical diagnosis. It is diagnosed based on one or more of four key signs/symptoms: cardiovascular collapse, respiratory distress, coagulopathy, and/or coma/seizures. The only laboratory test that reliably supports the diagnosis is the finding of fetal material in the maternal pulmonary circulation at autopsy. Perhaps the most compelling mystery surrounding AFE is not why one in 20,000 parturients are afflicted, but rather how the vast majority of women can tolerate the foreign antigenic presence of their fetus both within their uterus and circulation?Clinical and Developmental Immunology 01/2012; 2012:946576. · 3.06 Impact Factor
Complement, fetal antigen, and shaking rigors in parturients
MICHAEL D. BENSON1,2, HIROSHI KOBAYASHI3, LAKSHMAN R. SEHGAL1,
HIDEKAZU OI3, & ELAINE I. HANEY1
1Evanston Northwestern Healthcare, Evanston, Illinois, USA,2Department of Obstetrics and Gynecology, Northwestern
University, Feinberg School of Medicine, Chicago, Illinois, USA, and3Department of Obstetrics and Gynecology, Hamamatsu
University School of Medicine, Hamamatsu, Japan
(Received 31 May 2005; revised 14 June 2005; accepted 29 June 2005)
association with fetal antigen levels or shaking rigors. Fetal antigen levels failed to show any consistent relationship with
shaking rigors or the labor and delivery process.
Conclusion. Shaking rigors do not appear to be associated with changes in either complement or fetal antigen levels.
Complement levels remain stable during labor but drop immediately following birth.
To assess the relationship, if any, between complement, fetal antigen, and shaking rigors during labor and
We recruited 13 volunteers for serial blood sampling during labor and childbirth.
Complement levels had a small but significant drop (11–15%) immediately following childbirth but had no
Keywords: Shaking rigors, labor, fetal antigen, complement, amniotic fluid embolism
In 1963, a French physician, G. Bruniquel, sug-
gested that shaking rigors might be caused by the
entry of amniotic fluid into the maternal circulation
during labor . Recently, we published a paper in
which we demonstrated elevated amounts of fetal
antigen in the maternal circulation and depressed
complement levels in patients with amniotic fluid
embolism . Notably, our control group of two
dozen laboring patients demonstrated an 8% drop in
C3 and a 5% drop in C4. Taking these two works
together, we hypothesized that the shaking rigors
commonly seen during labor might be a symptom of
an immunologic response to transient elevations of
fetal antigen in the maternal circulation with
concomitant evidence of complement activation.
An important issue for this thesis is, ‘‘How do the
levels of complement and fetal antigen change during
Materials and methods
We recruited 13 volunteers for serial blood sampling
during labor and childbirth from the lead author’s
private practice. Volunteers received $300 in com-
pensation. The protocol received prior approval by
Evanston Northwestern Healthcare’s Institutional
Review Board, and each patient provided written,
informed consent. Inclusion criteria limited patient
enrollment to those with singleton pregnancies in
spontaneous labor at term without concomitant
illness such as pre-eclampsia. Eleven patients experi-
enced spontaneous vaginal deliveries while one was
delivered via cesarean and another via vacuum-
assisted vaginal delivery.
Serial blood sampling was accomplished by estab-
lishing an intravenous line with a slow infusion of
normal saline to maintain patency. With two three-
way stop-cocks attached close to the IV site, we were
able to remove the first milliliter of diluted blood (the
calculated dead space in the tubing) and then obtain
an additional four milliliters of blood for the actual
sample. The study design called for up to seven
samples to be obtained: (1) before four centi-
centimeters dilation, (3) between eight and ten
centimeters dilation, (4) during the second stage,
(5) following birth but before delivery of the
placenta, (6) within 20 minutes of placenta delivery,
Correspondence: Michael D. Benson, MD, FACOG, 101 Bentley Court, Deerfield, IL 60015, USA. Tel: þ1 847 945 9470. Fax: þ1 847 940 1467.
The Journal of Maternal-Fetal and Neonatal Medicine, January 2006; 19(1): 31–34
ISSN 1476-7058 print/ISSN 1476-4954 online ? 2006 Taylor & Francis
and (7) during the first episode of shaking rigors (if
The blood was promptly transported at room
temperature to the hospital laboratory where it was
spun in a refrigerated centrifuge. One milliliter of
serum was then sent for complement determination
by the hospital lab in conformity with common
clinical practice. The remaining serum was frozen
for subsequent shipment to Japan and fetal antigen
sialyl Tn (STN) determination as previously de-
Shaking rigors were assessed by the medical staff
providing clinical care for the patients during labor.
They recorded key demographics, labor progress and
events together with the onset and duration of any
shaking rigors on specially designed data sheets. This
information was then entered into an Excel spread-
sheet along with the time and values for C3, C4 and
Of the initial 13 patients, initial complement levels
and STN levels were all well within the normal range
except in one. The 13th patient had severely
depressed complement levels similar to what we
had previously observed in patients with amniotic
fluid embolism although her fetal antigen levels
remained normal. On further investigation, it was
discovered that she had presented to labor and
delivery with an undiagnosed macular eruption of
three weeks duration. She was subsequently diag-
nosed with Lupus and her complement and fetal
antigen data were excluded from analysis.
Continuous variables were analyzed using t-tests,
with paired t-tests run to assess the presence or
absence of significant changes in analytes over time.
In addition one-way ANOVA was performed to
assess continuous variables against multiple groups.
Statistics were run on the Statistical Package for the
Social Sciences, (SPSS) version 11.0, Chicago, IL.
In this study 13 patients were observed for the
occurrence of shaking rigors. We observed that 11
patients experienced at least one episode of rigors.
Only one patient had any temperature over 100.48F.
This patient did have a shaking rigor during a
temperature spike of 101.68F. All of the other
patients with rigors had them at times unrelated to
their highest temperature.
The total number of rigor episodes in the group
was 34 with an average duration of 17 minutes and a
cumulative average for all shaking episodes of 46
minutes. The average number of episodes for all
patients was 2.6 with the average number of episodes
for only those patients experiencing any rigors of 3.8.
In order to best assess this data, a detailed timeline
was constructed for each patient studied, with
relevant clinical milestones, such as epidural place-
ment and rupture of membranes noted. We found no
relationship between the length of active labor and
the presence, absence or number of rigors (n¼13,
t-test, p¼0.801; ANOVA, p¼0.772). We also found
no relationship between presence or absence of
rigors whether a patient was nulliparous or multi-
parous (n¼13, Fisher’s exact test, p¼1.000).
Eight of the 12 patients had blood sampling during
the first, second, and third stages of labor. In order to
assure valid results we only analyzed data from
patients who had samples at the correct time point
in relation to physical events. When we analyzed C3,
C4, and STN values over time (n¼8 for patients with
values at all three points in time), we found there was
a small but significant drop in C3 and C4 from
delivery to postpartum (see Table I and Figures 1
and 2). C3 dropped by 15% while C4 demonstrated
an 11% decline. No significant changes were seen
from initial assessment to delivery, and no significant
changes were seen in STN levels.
Six patients had blood drawn during a shaking
rigor. C3, C4 and STN levels were compared during
the rigor to values in the same patients from blood
drawn prior to the onset of rigors with a paired
samples t-test. No significant differences were found
(p values for C3, C4 and STN were 0.233, 0.267,
and 0.666, respectively).
Shaking rigors were observed in 84% of our small
series of patients in contrast to the 23–44% ranges
found in prior studies [4,5]. The most striking aspect
of this study was the fact that C3 and C4 demon-
strated thesame statistically
downward that was previously demonstrated in a
Table I. Complement and fetal antigen levels during the three stages of labor.
First stageSecond stage Third stage
Delivery to PP p¼0.001
Delivery to PP p50.001
M. D. Benson et al.
different group of laboring patients that served as a
control group in an amniotic fluid embolism study
. Here too, C3 declined somewhat more than C4.
In the current group of patients, the 15% drop in C3
and the 11% drop in C4 were somewhat more
pronounced than in our previous control group of 22
patients (8% and 5%, respectively). However, the
prior study compared intrapartum complement
levels with day 1 postpartum values. It is possible
that the smaller reported decline was the result of
complement levels rising slightly in the postpartum
period after reaching a nadir immediately following
birth. With serial blood sampling, we have now
demonstrated that complement levels stay constant
during labor but drop immediately following birth.
Historically, amniotic fluid embolism has been
attributed to a cause and effect relationship between
leakage of amniotic fluid or fetal material into the
maternal circulation and
serious illness. Our recent work has established that
amniotic fluid embolism patients have evidence of
elevated serum levels of fetal antigen and comple-
ment activation . While complement activation in
response to a leakage of fetal antigen into the
maternal circulation remains a possible explanation
for the illness, the results in this normal group of
patients demonstrated a complement drop without a
corresponding spike in fetal antigen levels.
The mechanism behind the frequently observed
have attempted to link shaking rigors to anesthetic
interventions or to core temperature elevations
during labor without success [6,7]. One group of
investigators sought to evaluate the possibility of a
Figure 1. C3 levels during parturition.
Figure 2. C4 levels during parturition.
Complement, fetal antigen, and shaking rigors
fetal–maternal transfusion reaction during postpar-
tum rigors but was unable to establish a convincing
link with Kleihauer–Betke tests conducted postpar-
tum . While we still suspect that the shaking rigors
may be a symptom of a maternal immune response to
the fetus during labor, the fetal antigen that we were
able to measure did not spike during these episodes,
and the complement drop appeared to be unrelated
The stability of both complement and STN levels
during serial sampling throughout labor provides
further clinical evidence that abnormal levels are
not commonly encountered in otherwise healthy
parturients. Though neither test can be considered
to beclinically diagnostic
embolism, the steady state of both markers during
uneventful labors warrants further characterization
A small degree of complement activation during
childbirth seems to be a normal physiologic event.
Nonetheless, the specific mechanism remains un-
known and seems worthy of further investigation.
While shaking rigors may still be a symptom of an
activated maternal immune system, complement
activation and the leakage of the specific fetal antigen
into the maternal circulation do not appear to be
associated with this event.
Supported by a grant from the Marvin and Kay
Lichtman Foundation and Evanston Northwestern
Healthcare Research Institute.
1. Bruniquel G. [Le friisson dit ‘‘physiologizue’’ des accouches—
sa signification pathologique.] Le Concours Medical 1963;
2. Benson MD, Kobayashi H, Silver RK, Oi H, Greenberger PA,
Terao T. Immunologic studies in presumed amniotic fluid
embolism. Obstet Gynecol 2001;97:510–514.
3. Kobayashi H, Ohi H, Terao T. A simple, noninvasive, sensitive
method for diagnosis of amniotic fluid embolism by mono-
clonal antibody TKH-w that recognizes NeuAca2-6GalNac.
Am J Obstet Gynecol 1993;168:848–853.
4. Jaameri KEU, Jahkolk A, Pertuu J. On shivering in association
with normal delivery Acta Obstet Gynecol Scand 1966;45:383.
5. Harper RG, Quintin A, Kreynin I, Brooks GZ, Farahani G,
Lesser M. Observations on the postpartum shivering phenom-
enon. J Reprod Med 1991;36:803–807.
6. Panzer O, Ghazanfari N, Sessler DI, Yusei Y, Greher M, Acka
O, Donner A, Germann P, Kurz A. Shivering and shivering-
like tremor during labor with and without epidural anesthesia.
7. Buggy D, Gardiner J. The space blanket and shivering during
extradural analgesia in labour. Acta Anaesthesiol Scand 1995;
8. Ravid D, Gidoni Y, Burchim I, Shapira H, Fejgin MD.
Postpartum chills phenomenon: Is it a feto-maternal transfu-
sion reaction? Acta Obstet Gynecol Scand 2001;80:149–152.
M. D. Benson et al.