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Original Research

Hemostatic Dysfunction With Acute Fatty


Liver of Pregnancy
David B. Nelson, MD, Nicole P. Yost, MD, and F. Gary Cunningham, MD

OBJECTIVE: To estimate the frequency of disseminated Reticulocytosis, nucleated red blood cells, and elevated
intravascular coagulation (DIC); elucidate the genesis of serum bilirubin levels reflected ongoing hemolysis.
hemostatic dysfunction; and characterize associated CONCLUSIONS: Hemostatic dysfunction with acute
hemolysis in women with acute fatty liver of pregnancy. fatty liver of pregnancy persists 45 days postpartum
METHODS: Hemostatic function was measured in 51 and results from substantive ongoing DIC in concert with
women. Disseminated intravascular coagulation was reduced procoagulant synthesis and clinically significant
assessed using the International Society of Thrombosis hemolysis.
and Haemostasis DIC score. Hepatic and hemostatic (Obstet Gynecol 2014;124:406)
function was quantified with measurement of fibrinogen, DOI: 10.1097/AOG.0000000000000296
fibrinfibrinogen split products, cholesterol, and coagu- LEVEL OF EVIDENCE: III
lation testing. As a comparison of fibrinogen synthesis,

O
these women were compared with 25 women with pla-
bstetric hemorrhage is a major cause of maternal
cental abruption. Hemolysis was assessed indirectly by
morbidity and mortality associated with acute
quantification of reticulocytosis and nucleated red blood
fatty liver of pregnancy.16 When the syndrome was
cells with determination of erythrocyte morphotypes.
first described, the accompanying profuse obstetric
RESULTS: Eighty-percent of women were classified as hemorrhage was attributed to the severe coagulopathy
having unequivocal DIC (mean score 5.961.8) at delivery,
caused by liver failure characteristic of acute fatty
which persisted 45 days postpartum. Fibrinogen regen-
liver of pregnancy.7,8 Later, however, disseminated
eration with placental abruption was rapid, whereas it
intravascular coagulation (DIC) was implicated as
remained depressed for 45 days with acute fatty liver
a primary cause of the hemostatic derangement,9
of pregnancy; fibrinfibrinogen split products were also
cleared more rapidly after abruption than women with
a concept further propagated by Castro et al1,10 in their
acute fatty liver (P,.001 for interaction for both using description of 28 women with convincing evidence of
random effects modeling). Kaplan-Meier survival analysis severe DIC. Meanwhile, our previous report of clini-
of fibrinogen recovery to a set point of 280 mg/dL after cal outcomes associated with acute fatty liver of preg-
delivery was also different between the two cohorts nancy suggested that both mechanismsdiminished
(median 1.7 compared with 4.2 days, P5.046). Continuing production of procoagulants and increased use by
hepatic dysfunction with acute fatty liver of pregnancy intravascular coagulationwere likely related to the
was exemplified by diminished procoagulant production. coagulopathy.6
There is also controversy related to whether
hemolysis is a clinically significant component in
women with acute fatty liver of pregnancy. Whereas
From the University of Texas Southwestern Medical Center at Dallas, Division of
Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Dallas,
Sheehan11 concluded that there was no discernible
Texas. hemolysis, Burroughs and colleagues7 reported that
Corresponding author: David B. Nelson, MD, Division of Maternal-Fetal accelerated red cell destruction was a major facet of
Medicine, Department of Obstetrics and Gynecology, University of Texas acute fatty liver of pregnancy. In our previous clinical
Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, observations of 51 women with acute fatty liver of
TX 75390-9032; e-mail: DavidB.Nelson@UTSouthwestern.edu.
pregnancy, we reported that brisk ongoing hemolysis
Financial Disclosure
The authors did not report any potential conflicts of interest. was a common finding that contributed to hyperbilir-
2014 by The American College of Obstetricians and Gynecologists. Published
ubinemia as well as the need for red cell transfusions.6
by Lippincott Williams & Wilkins. Because of these disparate observations, we de-
ISSN: 0029-7844/14 signed the present investigation with three principal

40 VOL. 124, NO. 1, JULY 2014 OBSTETRICS & GYNECOLOGY


aims. First, we sought to expand our previous observa-
tions concerning the frequency and severity of DIC Box 1. International Society of Thrombosis and
complicating acute fatty liver of pregnancy. Second, we Haemostasis Disseminated Intravascular
wanted to elucidate the respective contributions to Coagulation Scoring System
hemostatic dysfunction from DIC and defective procoa- 1. Risk assessment: Does the patient have an under-
gulant synthesis. Our final aim was to characterize the lying disorder known to be associated with overt
DIC?
cause and extent of associated hemolysis.
(yes=2; no=0)
If yes, proceed; if no, do not use this algorithm.
PATIENTS AND METHODS 2. Order global coagulation tests (platelet count,
From 1975 through 2012, one or more of the prothrombin time, fibrogen, soluble fibrin mono-
investigators was involved in the care of women mers, or fibrin degradation products).
3. Score global coagulation test results.
admitted to Parkland Hospital and diagnosed with
 Platelet count (.100, 0; ,100, 1; ,50, 2)
acute fatty liver of pregnancy. With approval from the  Elevated fibrin-related marker (eg, soluble
institutional review boards at the University of Texas fibrin monomers/fibrin degradation products)
Southwestern Medical Center at Dallas and Parkland (no increase, 0; moderate increase, 2; strong
Hospital, clinical and laboratory data were extracted increase, 3)
 Prolonged prothrombin time (,3 secs, 0; .3
from medical records of these women. These cases
secs but ,6 secs, 1; .6 secs, 2)
were entered into a registry specific for acute fatty  Fibrogen level (.1.0 g/L, 0; ,1.0 g/L, 1)
liver of pregnancy as previously described.6 Patient 4. Calculate score
information was deidentified and stored in a comput- 5. If $5, compatible with overt DIC; repeat scoring
erized database. Maternal demographic information, daily. If ,5, suggestive (not affirmative) for non-
overt DIC; repeat next 12 days.
clinical findings, laboratory results, management,
delivery and pregnancy outcomes, and recovery after DIC, disseminated intravascular coagulation.
delivery were reviewed. Laboratory findings were Reprinted from Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M;
those determined by methods contemporaneously in Scientific Subcommittee on Disseminated Intravascular Coag-
ulation (DIC) of the International Society on Thrombosis and
use for various biochemical, hematologic, and coagu-
Haemostasis (ISTH). Towards definition, clinical and laboratory
lation tests. Additional hematologic and coagulation criteria, and a scoring system for disseminated intravascular
studies were performed as available by certified med- coagulation. Thromb Haemost 2001;86(5):132730. Copyright
2001 John Wiley and Sons.
ical technologists in the Obstetrical Hematology
Research Laboratory.12 For clinical management,
hepatic tissue to confirm microvesicular fatty infiltra-
tion was obtained by liver biopsy in nine women International Society of Thrombosis and Haemostasis
because of uncertain diagnosis and at autopsy in the DIC score was provided for each woman at 24 hours
two who died. Clinical management was directed epochs after delivery.
using real-time results available contemporaneously Studies of hepatic and hemostatic function
from the Parkland Hospital Clinical Laboratory. included fibrinogen, fibrinfibrinogen split products,
For this observational study, women with acute coagulation studies, and cholesterol. Fibrinogen in
fatty liver of pregnancy were classified and analyzed plasma and fibrinogenfibrin split products in serum
according to the International Society of Thrombosis were measured using methods previously described
and Haemostasis DIC score (Box 1).13,14 Briefly, this by Pritchard et al.12 Briefly, plasma was collected in
scoring system uses a combination of laboratory tests citrate-Trasylol tubes and fibrinogen was quantified
to provide a five-step diagnostic algorithm to calculate using the thrombin-clottable protein method of Ratn-
the DIC score. These tests include quantification of off and Menzie.15 Serum obtained after thrombin clot-
platelets, fibrinogen, fibrin-related markers (fibrin ting was assayed for fibrinfibrinogen split products
monomers and fibrin degradation products), and pro- using the Thrombo-Wellcotest immunologic particle
thrombin time in combination with the underlying agglutination method.
disorder known to be associated with DIC.13 Compos- To portray normal fibrinogen synthesis after
ite International Society of Thrombosis and Haemo- acute defibrination in women with normal hepatic
stasis DIC scores 2 or greater are suggestive of DIC function, serial plasma fibrinogen and serum fibrin-
and scores 5 or greater are considered to define degradation product concentrations were determined
unequivocal DIC.13 This scoring system provides in a cohort of 25 women with placental abruption and
a sensitivity and specificity of DIC with 93% and hypofibrinogenemia. These women were identified
98%, respectively.14 For the current study, a composite from a repository of women with fetal demise and

VOL. 124, NO. 1, JULY 2014 Nelson et al Acute Fatty Liver of Pregnancy 41
placental abruption confirmed at delivery.16 Compar- demographic characteristics were similar to those of
isons among fibrinogen and fibrin-degradation prod- women from our general obstetric population. Blood
uct measurements for those women with acute fatty or component transfusions were required in 28 of 51
liver of pregnancy compared with women with severe women, and seven (14%) required platelet transfusions.
placental abruption were made using mixed-effect Importantly, 12 (42%) of the women were given addi-
modeling with interaction and within-subjects model- tional red cell transfusions beyond 48 hours after deliv-
ing, log likelihood x2 test for goodness of fit, and ery with indications being persistent, severe anemia.
Kaplan-Meier analysis for length of time for recovery Aside from obstetric hemorrhage associated with coa-
to specified fibrinogen values. Statistical analysis was gulopathy and acute fatty liver of pregnancy, we found
accomplished using SAS 9.2. P values ,.05 were con- only 5 of 51 women might have had an associated event
sidered statistically significant. that contributed to the hematologic aberrations; specific
Concomitant with another ongoing study,17 in comorbid conditions included three abruptions, one
some of these women, erythrocyte morphology was uterine rupture, and one subcapsular hematoma.
quantified using scanning electron microscopy. As shown in Figure 1, for the entire cohort,
Briefly, these methods included preparation of eryth- the mean International Society of Thrombosis and
rocytes from peripheral blood collected into ethylene- Haemostasis DIC score was 5.961.8 at the time of
diamine tetraacetic acid-containing tubes was fixed in delivery, confirming that 80% of these women had
1.25% glutaraldehyde, and 1,000 erythrocytes in con- unequivocal DIC defined as composite score of 5 or
tiguous fields were scanned using a JEOL JSM-35 greater. As discussed, inherent in this scoring system
electron microscope. Red cells were classified as nor- is the presence of an underlying disorder known to
mal discocytes or as abnormal schizocytes, echino- be associated with overt DIC, scored as yes or no.
cytes, or spherocytes according to Bessis.18 As evidenced by the clinical hemostatic dysfunction,
a score of 2 was applied to all members of the cohort
RESULTS on the day of delivery. Global coagulation tests were
Between 1975 and 2012, there were 51 women with then serially scored on days after delivery, and the
acute fatty liver of pregnancy cared for at our institution. most influential marker scored was elevated fibrin-
The clinical outcomes of this cohort have been pre- split products that were present in all cases studied
viously described,6 and briefly, the frequency of acute during the first 48 hours after delivery. Importantly,
fatty liver of pregnancy was 1 per 10,000 births and composite International Society of Thrombosis and
distribution over this time period was relatively homo- Haemostasis DIC scores remained elevated for up to
geneous, mean maternal age was 27.467.3 years (range 45 days suggesting persistent hemostatic dysfunction
1542 years), and 41% were nulliparous. Their overall after delivery (Fig. 1).

6
ISTH-DIC score

Fig. 1. International Society of


Thrombosis and Haemostasis (ISTH)
5 disseminated intravascular coagula-
tion (DIC) composite scores after
delivery in women with acute fatty
liver of pregnancy. Scores of 5 or
4 more represent unequivocal DIC
(dashed line). Mean score observed
after delivery listed with error bars
representing standard errors of the
3 mean (6SEM).
0 1 2 3 4 5 6 7
Nelson. Acute Fatty Liver of Pregnancy.
Days following delivery Obstet Gynecol 2014.

42 Nelson et al Acute Fatty Liver of Pregnancy OBSTETRICS & GYNECOLOGY


To demonstrate the effect of liver dysfunction on in Figure 3, these differences were also significant
procoagulant synthesis, serial plasma fibrinogen and using random effects modeling for both linear and
fibrin-degradation products were plotted and com- quadratic regression curves for days after delivery
pared for the two cohorts of women. For the 25 women (P,.001 for interaction). Although we have previ-
with placental abruption, hypofibrinogenemia, and ously described continuing hepatic dysfunction for
normal hepatic function, the mean age was 22.664.6 days after delivery, it was not possible to accurately
years (range 1631 years), 20% were nulliparous, and quantify the contribution of decreased synthesis ver-
mean gestational age and birth weight of their stillborn sus continuing consumption of fibrinogenonly that
neonates was 3561.5 weeks and 2,2906740 g, respec- both were present.
tively. In Figure 2, their serial values are compared Reticulocytosis, nucleated red blood cells, and
with women with acute fatty liver of pregnancy. serum bilirubin levels together are indicative of
The initial mean fibrinogen level (6standard error of ongoing hemolysis in the cases of acute fatty liver of
mean) for women with acute fatty liver of pregnancy pregnancy. As shown in Figure 4, levels of serum
were 188624 mg/dL compared with that of 153610 bilirubin remained increased after delivery in women
mg/dL for women with an abruption. As can be seen in with acute fatty liver of pregnancy in conjunction with
Figure 2, fibrinogen recovery for women with an elevated reticulocyte counts. Nucleated red blood
abruption was rapid, linear, and returned to near nor- cells were identified in 40% of women at delivery with
mal levels within 36 hours of delivery. For women acute fatty liver of pregnancy (Fig. 5). The median
with acute fatty liver, however, several days were (quartile1, quartile3) nucleated red blood cells at deliv-
required to reach similar levels. Random effects mod- ery was 4 (2, 11)/100 white blood cells, and these cells
eling for both linear and quadratic regression curves were present for up to 45 days postpartum. In three
were significantly different for days after delivery women, erythrocyte morphology was determined
(P,.001 for interaction). Kaplan-Meier survival analy- using scanning electron microscopy. Echinocytes
sis of fibrinogen recovery to a set point of 280 mg/dL were the predominant abnormal form (Fig. 6), and
after delivery was also statistically different between these women initially had 2239% echinocytes at the
the two groups with median times to recovery for time of delivery. This proportion compares with nor-
acute fatty liver of pregnancy and abruption being mally pregnant women whose mean value ranges
4.2 and 1.7 days, respectively (P5.046 using log- from 0.5 to 1.9%. In these women, normal discocyte
rank test). The groups of women with acute fatty liver forms were present within 23 days. During this same
of pregnancy and abruption were also compared for time, schizocyte proportions were less than 2% and
fibrin-degradation product clearance, and as shown spherocytes were negligible.

350

300

250
Fibrinogen (mg/dL)

200

Fig. 2. Plasma fibrinogen levels after


delivery for 51 cases of acute fatty 150
liver of pregnancy (AFLP) compared
with 25 cases of placental abruption.
Random effects modeling for both 100
linear and quadratic regression curves
AFLP
for days after delivery, P,.001 for
interaction. Mean fibrinogen values 50
(6standard error of mean) for all Abruption
patients available at each data point
0
listed. 0 1 2 3 4 5 6
Nelson. Acute Fatty Liver of Pregnancy.
Obstet Gynecol 2014. Days following delivery

VOL. 124, NO. 1, JULY 2014 Nelson et al Acute Fatty Liver of Pregnancy 43
140

120
Fibrin split products (Thrombo-Wellcotest)

100

AFLP
80
Abruption Fig. 3. Levels of fibrin-split products
after delivery for 51 cases of acute
60
fatty liver of pregnancy (AFLP) com-
pared with 25 cases of placental
40 abruption. Random effects modeling
for both linear and quadratic regres-
sion curves for days after delivery,
20 P,.001 for interaction. Mean fibrin-
split products values (6standard error
of mean) for all patients available at
0 each data point listed.
0 1 2 3 4 5 6
Nelson. Acute Fatty Liver of Pregnancy.
Days following delivery Obstet Gynecol 2014.

DISCUSSION twofold and the result of a combination of procoagulant


Our observations in these 51 women with acute fatty deficiency from liver failure as well as procoagulant
liver of pregnancy confirm that profound hemostatic consumption from continuing DIC. Another observation
dysfunction commonly exacerbates obstetric hemor- was that brisk hemolysis in these women substantively
rhage and contributes to the need for blood and adds to the requirement for continued transfusions well
component transfusions. At the time of delivery, half of beyond the immediate time of delivery.
these women now reported had a plasma fibrinogen level We have previously presented evidence for
less than 150 mg/dL, and 12 (48%) of these required continuing hemostatic dysfunction in these women
either fresh-frozen plasma or cryoprecipitate to achieve manifest by prolongation of the thrombin and partial
hemostasis because of dangerously depressed fibrinogen thromboplastin times for 46 days after delivery.6
concentrations in the setting of active bleeding. We also When we plotted the time course of plasma, fibrino-
found that the cause of hemostatic dysfunction was gen concentrations and fibrin degradation products

12

10

8
Bilirubin (mg/dL)

4
Fig. 4. Serum total bilirubin levels
after delivery with reticulocyte indi-
ces in women with acute fatty liver of
2
pregnancy. Mean total bilirubin and
Total bilirubin (mg/dL)
reticulocyte indices values (6stan-
Reticulocyte index dard error of mean) for all patients
0 available at each data point listed.
0 1 2 3 4 5 6 7 8
Nelson. Acute Fatty Liver of Pregnancy.
Days following delivery Obstet Gynecol 2014.

44 Nelson et al Acute Fatty Liver of Pregnancy OBSTETRICS & GYNECOLOGY


40

30

Percentage
20

Fig. 5. Percentage of 51 cases of


women with nucleated red blood 10
cells present on peripheral smear after
delivery for women with acute fatty
liver of pregnancy. Data represent
only observed values for each day
after delivery. 0
Nelson. Acute Fatty Liver of Pregnancy. 0 1 2 3 4 5 6
Obstet Gynecol 2014. Days following delivery

found that continuing fibrinogen deficiency is caused by hepatic dysfunction from acute fatty liver of pregnancy
diminished production as well as increased use (Figs. 2 whose plasma fibrinogen levels remained static over
and 3). Evidence for decreased production was seen a period of several days after delivery.
with abnormally low plasma fibrinogen concentrations At the same time, there is also evidence for
persisting for the first several days after delivery along continuing increased procoagulant consumption caused
with only mild to moderately elevated fibrin- by ongoing DIC. As shown in Figure 1, most of these
degradation products. By way of comparison, in the women had evidence for persistent consumptive coa-
same figures, fibrinogen values are plotted for 25 gulopathy as assessed by the DIC score of the Interna-
women who sustained a placental abruption severe tional Society of Thrombosis and Haemostasis.13,14 As
enough to kill the fetus. These women with hypofibri- shown in Figure 3, evidence for ongoing consumptive
nogenemia who had normal hepatic function exhibited coagulopathy is provided by the modestly elevated lev-
the anticipated response with a rapid return within els of fibrin degradation products in the face of
24 hours to a normal plasma fibrinogen concentration depressed plasma fibrinogen concentrations. Although
along with simultaneous clearance of fibrin degradation this provides evidence of ongoing DIC, we cannot
products. This was in contrast to the women with exclude the possibility that elevated fibrin degradation
product levels are at least partially related to their
diminished clearance because of hepatic dysfunction.
We also found that these women with fatty liver
of pregnancy had brisk hemolysis that continued for
several days after delivery. This was of clinical
significance because of the frequent need for ongoing
red cell transfusions after delivery and at a time after
which surgical and obstetric hemostasis was secured.
Specifically, one-fourth of these women required
additional erythrocyte transfusions for persistent
severe anemia without evidence of ongoing hemor-
rhage. There are at least three other findings that
document hemolysis. One marker is the increasing
serum bilirubin levels that continued to rise at a time
when there is improving, albeit impaired, hepatic
bilirubin clearance. As shown in Figure 4, bilirubin
Fig. 6. Scanning electron microscope displaying echinocytes concentrations peaked at 57 days after delivery at
present in a woman with acute fatty liver of pregnancy. a time when reticulocytosis was also maximal.
Nelson. Acute Fatty Liver of Pregnancy. Obstet Gynecol 2014. Another potent marker for accelerated hemolysis with

VOL. 124, NO. 1, JULY 2014 Nelson et al Acute Fatty Liver of Pregnancy 45
hemopoiesis is the appearance of remarkably elevated 4. Lau HH, Chen YY, Huang JP, Chen CY, Su TH, Chen CP.
Acute fatty liver of pregnancy in a Taiwanese tertiary care
levels of nucleated red blood cells (Fig. 5), which are center: a retrospective review. Taiwan J Obstet Gynecol
seldom encountered in adults except with massive 2010;49:1569.
hemolysis or hypoxia.1921 The third marker indica- 5. Vigil-de Gracia P, Montufar-Rueda C. Acute fatty liver of
tive of hemolysis is the remarkably high proportion of pregnancy: diagnosis, treatment, and outcome based on 35
echinocytes in the three women studied. This cell consecutive cases. J Matern Fetal Neonatal Med 2011;24:
11436.
morphotype may be induced by abnormal plasma
6. Nelson DB, Yost NP, Cunningham FG. Acute fatty liver of
and red cell membrane levels of cholesterol and other pregnancy: clinical outcomes and expected durations of recov-
blood lipids. Echinocytes either undergo premature ery. Am J Obstet Gynecol 2013;209:456.e17.
hemolysis or they can revert back to normal disco- 7. Burroughs AK, Seong NG, Dojcinov DM, Scheuer PJ,
cytes. At the same time, the paucity of schizocytes Sherlock SV. Idiopathic acute fatty liver of pregnancy in 12
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Our study has several limitations. First, because of
9. Hozbach R. Acute fatty liver of pregnancy with disseminated
the observational design, we could have missed some intravascular coagulation. Obstet Gynecol 1974;43:7404.
women with acute fatty liver of pregnancy. Second, some
10. Castro MA, Goodwin TM, Shaw KJ, Ouzounian JG,
of these women may have been incorrectly diagnosed to McGehee WG. Disseminated intravascular coagulation and
have hepatocellular steatosis. However, as we have antithrombin III depression in acute fatty liver of pregnancy.
previously described,6 the criteria for diagnosis of acute Am J Obstet Gynecol 1996;174:2116.
fatty liver of pregnancy included evidence of acute liver 11. Sheehan HL. The pathology of acute yellow atrophy and de-
layed chloroform poisoning. J Obstet Gynecol 1940;47:4962.
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12. Pritchard JA, Cunningham FG, Mason RA. Coagulation
by laboratory evidence that confirmed hepatic dysfunc-
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We also applied both the Swansea criteria proposed by 13. Taylor FBJ, Toh CH, Hoots WK, Wada H, Levi M; Scientific
Chng et al22 and the acute fatty liver of pregnancy triad Subcommittee on Disseminated Intravascular Coagulation
of Vigil-de Gracia et al5 to confirm the diagnoses. (DIC) of the International Society on Thrombosis and Haemo-
stasis (ISTH). Towards definition, clinical and laboratory crite-
Another drawback is that observations from this study ria, and a scoring system for disseminated intravascular
provide only circumstantial evidence of the hemostatic coagulation. Thromb Haemost 2001;86:132730.
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In summary, our findings support the hypothesis
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46 Nelson et al Acute Fatty Liver of Pregnancy OBSTETRICS & GYNECOLOGY