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Official reprint from UpToDate®


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Acute fatty liver of pregnancy

Authors: Richard H Lee, MD, Tram T Tran, MD


Section Editors: Keith D Lindor, MD, Charles J Lockwood, MD, MHCM
Deputy Editor: Kristen M Robson, MD, MBA, FACG

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2017. | This topic last updated: Aug 10, 2015.

INTRODUCTION — Acute fatty liver of pregnancy, characterized by microvesicular fatty infiltration of


hepatocytes, is a disorder which is unique to human pregnancy [1]. It was described in 1940 and was initially
thought to be universally fatal [2]. However, early diagnosis and prompt delivery have dramatically improved
the prognosis, and maternal mortality should now be the exception rather than the rule [1].

The major clinical features of acute fatty liver of pregnancy will be reviewed here. A general approach to the
pregnant woman who develops liver disease is presented elsewhere and has also been addressed in a
guideline issued by the American College of Gastroenterology (table 1) [3]. (See "Approach to liver disease
occurring during pregnancy".)

EPIDEMIOLOGY — Acute fatty liver of pregnancy is rare, with an approximate incidence of 1 in 7000 to 1 in
20,000 deliveries [4-8]. It is more common with multiple gestations and possibly in women who are
underweight.

One of the largest population-based studies included 1,132,964 pregnancies at 229 hospitals in the United
Kingdom between 2005 and 2006 [8]. There were a total of 57 women diagnosed with acute fatty liver of
pregnancy (5 cases per 100,000 pregnancies, 95% CI 3.8-6.5). Of these, 18 percent of women had twin
pregnancies and 20 percent were underweight (body mass index <20).

CLINICAL MANIFESTATIONS — Acute fatty liver occurs typically in the third trimester. The disease is always
present before delivery, although it is not always diagnosed prior to delivery.

The most frequent initial symptoms are nausea or vomiting (approximately 75 percent of patients), abdominal
pain (particularly epigastric, 50 percent), malaise, anorexia, and jaundice. About one-half of patients have
signs of preeclampsia at presentation or at some time during the course of illness [9].

Extrahepatic complications can occur. In one series of 32 patients with severe liver dysfunction requiring
admission to a liver failure unit, infection occurred in 17 patients and major intra-abdominal bleeding in 10
patients, some of whom required surgery [10]. Transient polyuria and polydipsia due to central diabetes
insipidus also can be seen; this is thought to be caused by decreased levels of arginine vasopressin
secondary to reduced clearance of vasopressinase by the impaired liver [11]. Rare patients develop
pancreatitis, which can be severe. Pancreatitis generally becomes apparent only after development of hepatic
and renal dysfunction [12].

Laboratory tests — Women with acute fatty liver of pregnancy have abnormal liver tests, with serum

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aminotransferase elevations usually ranging from modest values up to 500 int. unit/L. Serum bilirubin levels
are also usually elevated. The white blood cell count may be higher than is usually seen in pregnancy, a
change that is nonspecific. The platelet count may be decreased with or without other signs of disseminated
intravascular coagulation (DIC) which is associated with marked reduction in antithrombin III [13,14]. Severely
affected patients also have elevations in serum ammonia, prolongation of prothrombin time, and
hypoglycemia caused by hepatic insufficiency. Acute kidney injury and hyperuricemia are often present [15].

PATHOGENESIS — The association of cases of acute fatty liver of pregnancy with one of the inherited
defects in mitochondrial beta-oxidation of fatty acids, long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD)
deficiency, suggested that some affected women and their fetuses might have an inherited enzyme deficiency
in beta-oxidation that predisposes the mother to this disorder [16-18]. In addition, defects in short- and
medium-chain acyl-CoA dehydrogenase (SCAD; MCAD) activity in infants have also been associated with
acute fatty liver of pregnancy [19].

The LCHAD catalyzes the third step in the beta-oxidation of fatty acids in mitochondria (the formation of
3-ketoacyl-CoA from 3-hydroxyacyl-CoA). The accumulation of long-chain 3-hydroxyacyl metabolites
produced by the fetus or placenta is toxic to the liver and may be the cause of the liver disease.

The role of LCHAD in the pathogenesis of acute fatty liver of pregnancy has been illustrated in a number of
studies:

● In a report of 12 women with a previous episode of acute fatty liver of pregnancy, eight had evidence of
being heterozygous for LCHAD [20]. These eight women had nine pregnancies complicated by fatty liver;
seven of these pregnancies were also associated with preeclampsia and HELLP (presumably stressing
the woman's compromised beta-oxidation function) and seven of the nine offspring were proven or
presumed to be homozygous deficient (spilling unmetabolized long chain fatty acids into the maternal
circulation). The other two offspring had heterozygous LCHAD.

● One series focused on three families with children presenting with sudden unexplained death or
hypoglycemia and elevated liver enzymes (Reye-like syndrome) [21]. In all families, the mothers had
acute fatty liver of pregnancy during the pregnancies with the affected infants. Three children who were
studied had mutations in both alleles for LCHAD.

● The effects of fetal genotype on maternal and fetal outcomes were evaluated in 35 families with
mitochondrial trifunctional protein mutations in the United States [22]. Approximately one-half of women
who carried affected fetuses had acute fatty liver of pregnancy, and 11 percent had a HELLP syndrome.
All women who had a maternal illness carried fetuses with isolated LCHAD deficiency. No maternal or
fetal complications were associated with heterozygous or wild-type fetal genotypes.

However, some investigators have not been able to confirm the association with LCHAD [23,24]. One
possible explanation is that only specific genetic defects associated with LCHAD lead to an increased risk of
acute fatty liver of pregnancy. This hypothesis was evaluated in a study that included 24 children with
3-hydroxyacyl-CoA deficiency in whom nucleotide-sequence analysis was used to identify mutations in the
alpha subunit of a trifunctional protein [25], which is associated with the inner mitochondrial membrane and
provides the active site for LCHAD activity [26,27]. Nineteen children were either homozygotes for the
G1528C mutation in which glutamic acid was replaced with glutamine (E474Q) or compound heterozygotes
(with the glutamine mutation plus a different mutation on the other allele). Fifteen mothers of these children
(79 percent) developed acute fatty liver of pregnancy, the HELLP syndrome, or both. In contrast, pregnancy-
related liver disease was not observed during pregnancies in children who had other mutations or in
pregnancies in which the fetus had at least one wild-type allele. Another possible explanation for the absence

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of detectable LCHAD mutations is that other defects in beta oxidation of fatty acids have been described in
association with acute fatty liver of pregnancy [28].

The proportion of children with LCHAD deficiency born to mothers with acute fatty liver of pregnancy was
estimated in a cohort study that included 108 consecutive blood samples from women who developed acute
fatty liver or HELLP syndrome [29]. Mutations causing LCHAD deficiency were detected in 19 percent of
women with a maternal history of fatty liver but only one woman with HELLP syndrome. The most common
maternal mutation was the mutation G1528C mutation which alters amino acid 474 from glutamic acid to
glutamine on the protein (E474Q). Testing for the known genetic variants of this LCHAD is available and
should be considered in affected women, their infants, and fathers [21,27,30]. However, testing only for the
G1528C mutation does not rule out LCHAD deficiency, which may be caused by a number of other mutations.

When stressed, infants with LCHAD are at risk to develop fatal nonketotic hypoglycemia, imitating Reye's
syndrome or defects in urea cycle function [18]. In addition, some forms of LCHAD deficiency are associated
with neonatal dilated cardiomyopathy or progressive neuromyopathy. In one report, these features were
observed in five children who had complete deficiency of the mitochondrial trifunctional protein required for
3-hydroxyacyl-CoA dehydrogenase activity [25].

Because the diagnosis of LCHAD-deficiency in the newborn can be life-saving, all women with acute fatty
liver of pregnancy and their children should undergo molecular testing for LCHAD, at least for the most
common G1528C mutation [31,32]. If this mutation is not detected, consideration should be given towards
more extensive testing for other defects in fatty acid oxidation (eg, MCAD, SCAD) [19,28]. Testing should be
coordinated with a metabolic or genetic specialist.

DIAGNOSIS — The diagnosis of acute fatty liver of pregnancy is usually made clinically based upon the
setting, presentation, and compatible laboratory and imaging results. Laboratory tests that are helpful include
serum aminotransferases, serum bilirubin, coagulation studies, electrolytes, serum glucose, uric acid level
and creatinine, and a white blood cell count.

The major other condition that must be excluded is the HELLP syndrome, which is characterized by
hemolysis, elevated liver enzymes, and a low platelet count. There is a large clinical overlap between acute
fatty liver of pregnancy and HELLP syndrome, and it may be difficult, even impossible, to differentiate them.
However, evidence of hepatic insufficiency such as hypoglycemia or encephalopathy and abnormalities in
coagulation studies is more consistent with acute fatty liver of pregnancy. In one series of 46 women who
developed liver disease during pregnancy severe enough to require admission to a liver failure unit, 70
percent had acute fatty liver and 15 percent had HELLP [10]. Most of the remaining patients had liver disease
that was unrelated to pregnancy. (See "HELLP syndrome".)

Imaging tests of the liver are primarily used to exclude other diagnoses, such as a hepatic infarct or
hematoma [33]. Some authors have reported finding fat on either ultrasonography or computed tomography,
but these tests are most useful in retrospect, when comparing the images obtained during the height of the
illness with those obtained several months later [34,35].

Liver biopsy — Liver biopsy is diagnostic, showing the characteristic picture which is the microvesicular fatty
infiltration of the hepatocytes. The fat droplets surround centrally located nuclei, giving the cytoplasm a foamy
appearance. The fatty infiltration is prominent in central and mid zonal parts of the lobule and usually spares a
sharply defined rim of cells around the portal tracts [36]. Tissue should be set aside at the time of the
procedure for special stains (oil red O on frozen section, or electron microscopy) for confirmation of diagnosis
in patients without evident vacuolization (picture 1) [37,38]. Because liver biopsy is invasive, it is not always
performed. Liver biopsy should be approached with caution during pregnancy, and reserved for cases in

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which the diagnosis is in doubt and the appropriate treatment (delivery) is being delayed.

TREATMENT AND COURSE — Treatment of acute fatty liver of pregnancy is a combination of maternal
stabilization and prompt delivery of the fetus, regardless of gestational age.

Maternal stabilization requires glucose infusion and reversal of coagulopathy (eg, administration of fresh
frozen plasma, cryoprecipitate, packed red blood cells and platelets), as needed. Attention should be paid to
the woman's overall fluid status because the low plasmatic oncotic pressure can lead to pulmonary edema.
Hypoglycemia is common and all patients should have glucose monitored until normal liver function returns
[7]. We typically treat hypoglycemia with a continuous infusion of 10 percent dextrose solution. Some patients
with severe hypoglycemia may require multiple supplementary ampules of 50 percent dextrose [7].

The route of delivery is contingent on a combination of factors: fetal status, maternal status, and the
probability of successful labor induction. The fetus should be continuously monitored to assess for the
presence of any concerning fetal heart rate patterns. Labor induction is a reasonable option if the mother and
fetus can be stabilized and vaginal delivery is likely to be accomplished within 24 hours. Cesarean delivery is
indicated if accomplishing a successful vaginal birth within 24 hours is unlikely or if there is concern for rapidly
progressing maternal/fetal decompensation. In the setting of coagulopathy, delivery should be undertaken
with concomitant administration of appropriate blood products. (See "Clinical use of plasma components" and
"Clinical and laboratory aspects of platelet transfusion therapy".)

Patients with acute fatty liver of pregnancy are extremely susceptible to developing coagulopathies due to
decreased hepatic production of coagulation factors and/or disseminated intravascular coagulation (DIC). As
a result, these patients are at high risk for bleeding complications (eg, postpartum hemorrhage). Serial
monitoring of the patient's platelet count, international normalized ratio (INR), partial thromboplastin time, and
fibrinogen levels should be undertaken to assess for overt or evolving coagulopathy. In the setting of acute
fatty liver of pregnancy, the clinician must be aware of the normal references ranges for coagulation
parameters in pregnancy (table 2). If a patient demonstrates abnormalities in coagulation parameters outside
of normal for pregnancy (eg, third trimester fibrinogen level <300 mg/dL, INR>1.1), especially if it is near the
time of delivery, we suggest early administration of appropriate blood products. (See "Clinical use of plasma
components" and "Clinical and laboratory aspects of platelet transfusion therapy".)

The liver tests and coagulopathy usually start to normalize shortly after delivery. In one series, most
laboratory values normalized within 7 to 10 days after delivery [39]. A transient worsening of liver and renal
functions and coagulopathy may be observed during the first few days after delivery followed by a definitive
improvement [39]. In most severe cases, mostly when diagnosis has been delayed, there may be many more
days of illness requiring maximal supportive management in an intensive care unit, including mechanical
ventilation because of coma, dialysis for acute renal failure, parenteral nutrition because of associated
pancreatitis, or even surgery to treat bleeding from a preceding cesarean section.

Most severely ill patients recover and have no sequelae of the liver disease itself [7,39]. However, substantial
morbidity and mortality can occur. In a population-based study that included 57 patients with acute fatty liver
of pregnancy, one woman required a liver transplant and one woman died (case fatality rate of 1.8 percent,
95% CI 0-9 percent) [8]. There were seven deaths among 67 infants (perinatal mortality rate of 104 per 1000
births, 95% CI 32-203). In a second report with 51 women with acute fatty liver of pregnancy, there were two
maternal deaths (4 percent), and the stillbirth rate was 120 per 1000 births [39]. Other reports have also
described patients who required liver transplantation, but it is unlikely to be needed with early diagnosis and
prompt delivery [40,41].

RECURRENCE — Acute fatty liver of pregnancy can recur in subsequent pregnancies, even if the search of

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long-chain 3-hydroxyacyl CoA dehydrogenase deficiency mutation is negative [6,16,20,24,42-44]. However,


the exact risk of recurrence is unknown. Affected women should be warned of this possibility and subsequent
pregnancies can be undertaken provided that the woman understands the risks. Such patients should be
monitored by an expert in maternal-fetal medicine.

SUMMARY AND RECOMMENDATIONS

● Acute fatty liver of pregnancy, characterized by microvesicular fatty infiltration of hepatocytes, is a


disorder which is unique to human pregnancy. It is rare, with an approximate incidence of 1 in 7000 to 1
in 20,000 deliveries. It is more common with multiple gestations and possibly in women who are
underweight. (See 'Epidemiology' above.)

● Acute fatty liver occurs typically in the third trimester. The disease is always present before delivery,
although it is not always diagnosed prior to delivery. The most frequent initial symptoms are nausea or
vomiting (approximately 75 percent of patients), abdominal pain (particularly epigastric, 50 percent),
anorexia, and jaundice. About one-half of patients have signs of preeclampsia at presentation or at some
time during the course of illness. (See 'Clinical manifestations' above.)

● The diagnosis of acute fatty liver of pregnancy is usually made clinically based upon the setting,
presentation, and compatible laboratory and imaging results. Laboratory tests that are helpful include
serum aminotransferases, serum bilirubin, coagulation studies, electrolytes, serum glucose, uric acid
level and creatinine, and a white blood cell count. The major other condition that must be excluded is the
HELLP syndrome, which is characterized by hemolysis, elevated liver enzymes, and a low platelet count.
(See 'Diagnosis' above.)

● The primary treatment is prompt delivery of the fetus after maternal stabilization. (See 'Treatment and
course' above.)

● The association of cases of acute fatty liver of pregnancy with one of the inherited defects in
mitochondrial beta-oxidation of fatty acids, long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD)
deficiency, suggested that some affected women and their fetuses might have an inherited enzyme
deficiency in beta-oxidation that predisposes the mother to this disorder. We suggest that all women with
acute fatty liver of pregnancy and their children undergo molecular testing for LCHAD, at least for the
most common G1528C mutation. Additional testing for other defects in fatty acid oxidation can be
considered if this mutation is not detected. (Grade 2B). Testing is commercially available and should be
coordinated with a metabolic or genetic specialist. (See 'Pathogenesis' above.)

● Acute fatty liver can recur in subsequent pregnancies, even if the search of LCHAD mutation is negative.
Women with a history of acute fatty liver who are contemplating pregnancy should be monitored by an
expert in maternal-fetal medicine. (See 'Recurrence' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff would like to thank Dr. Yannick Bacq for his past
contributions as an author to prior versions of this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

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fatty-acid oxidation defect in the offspring. Gastroenterology 1991; 100:544.
17. Wilcken B, Leung KC, Hammond J, et al. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A
dehydrogenase deficiency. Lancet 1993; 341:407.
18. Treem WR, Rinaldo P, Hale DE, et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-
coenzyme A dehydrogenase deficiency. Hepatology 1994; 19:339.
19. Browning MF, Levy HL, Wilkins-Haug LE, et al. Fetal fatty acid oxidation defects and maternal liver
disease in pregnancy. Obstet Gynecol 2006; 107:115.
20. Treem WR, Shoup ME, Hale DE, et al. Acute fatty liver of pregnancy, hemolysis, elevated liver enzymes,
and low platelets syndrome, and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Am J
Gastroenterol 1996; 91:2293.
21. Sims HF, Brackett JC, Powell CK, et al. The molecular basis of pediatric long chain 3-hydroxyacyl-CoA
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22. Yang Z, Zhao Y, Bennett MJ, et al. Fetal genotypes and pregnancy outcomes in 35 families with
mitochondrial trifunctional protein mutations. Am J Obstet Gynecol 2002; 187:715.
23. Mansouri A, Fromenty B, Durand R, et al. Assessment of the prevalence of genetic metabolic defects in
acute fatty liver of pregnancy (letter). J Hepatol (Denmark) 1996; 25:781.
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25. Ibdah JA, Bennett MJ, Rinaldo P, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in
pregnant women. N Engl J Med 1999; 340:1723.
26. Jackson S, Kler RS, Bartlett K, et al. Combined enzyme defect of mitochondrial fatty acid oxidation. J
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27. Isaacs JD Jr, Sims HF, Powell CK, et al. Maternal acute fatty liver of pregnancy associated with fetal
trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele. Pediatr Res
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28. Matern D, Hart P, Murtha AP, et al. Acute fatty liver of pregnancy associated with short-chain
acyl-coenzyme A dehydrogenase deficiency. J Pediatr 2001; 138:585.
29. Yang Z, Yamada J, Zhao Y, et al. Prospective screening for pediatric mitochondrial trifunctional protein
defects in pregnancies complicated by liver disease. JAMA 2002; 288:2163.
30. Bellig LL. Maternal acute fatty liver of pregnancy and the associated risk for long-chain 3-hydroxyacyl-
coenzyme a dehydrogenase (LCHAD) deficiency in infants. Adv Neonatal Care 2004; 4:26.
31. Rajasri AG, Srestha R, Mitchell J. Acute fatty liver of pregnancy (AFLP)--an overview. J Obstet
Gynaecol 2007; 27:237.
32. Ibdah JA. Acute fatty liver of pregnancy: an update on pathogenesis and clinical implications. World J
Gastroenterol 2006; 12:7397.
33. Barton JR, Sibai BM. Hepatic imaging in HELLP syndrome (hemolysis, elevated liver enzymes, and low
platelet count). Am J Obstet Gynecol 1996; 174:1820.
34. Castro MA, Ouzounian JG, Colletti PM, et al. Radiologic studies in acute fatty liver of pregnancy. A
review of the literature and 19 new cases. J Reprod Med 1996; 41:839.
35. Campillo B, Bernuau J, Witz MO, et al. Ultrasonography in acute fatty liver of pregnancy. Ann Intern Med
1986; 105:383.
36. Bacq Y. Acute fatty liver of pregnancy. Semin Perinatol 1998; 22:134.
37. Riely CA, Latham PS, Romero R, Duffy TP. Acute fatty liver of pregnancy. A reassessment based on
observations in nine patients. Ann Intern Med 1987; 106:703.
38. Rolfes DB, Ishak KG. Acute fatty liver of pregnancy: a clinicopathologic study of 35 cases. Hepatology
1985; 5:1149.
39. Nelson DB, Yost NP, Cunningham FG. Acute fatty liver of pregnancy: clinical outcomes and expected
duration of recovery. Am J Obstet Gynecol 2013; 209:456.e1.
40. Ockner SA, Brunt EM, Cohn SM, et al. Fulminant hepatic failure caused by acute fatty liver of pregnancy
treated by orthotopic liver transplantation. Hepatology 1990; 11:59.
41. Amon E, Allen SR, Petrie RH, Belew JE. Acute fatty liver of pregnancy associated with preeclampsia:
management of hepatic failure with postpartum liver transplantation. Am J Perinatol 1991; 8:278.
42. MacLean MA, Cameron AD, Cumming GP, et al. Recurrence of acute fatty liver of pregnancy. Br J

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Obstet Gynaecol 1994; 101:453.


43. Barton JR, Sibai BM, Mabie WC, Shanklin DR. Recurrent acute fatty liver of pregnancy. Am J Obstet
Gynecol 1990; 163:534.
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Gastroenterol 1995; 21:243.

Topic 3619 Version 19.0

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GRAPHICS

American College of Gastroenterology Guidelines: Liver disease in the pregnant


patient

Use of gestational age of the pregnancy is the best guide to the differential diagnosis of liver disease in the pregnant
woman

Hyperemesis gravidarum should be considered in the differential diagnosis of abnormal liver tests presenting in the
first trimester

Cholestasis of pregnancy is common, and should be considered in the differential diagnosis of abnormal liver tests
presenting initially in the second trimester. Affected pregnancies are at increased risk for prematurity and stillbirth,
and early delivery should be considered when possible

HELLP (hemolysis, elevated liver tests, low platelets) syndrome and acute fatty liver of pregnancy should be
considered in the differential diagnosis of abnormal liver tests in the second half of pregnancy, usually in the third
trimester

Patients with acute fatty liver of pregnancy have true hepatic dysfunction, and may, or may not, have signs of
pre-eclampsia and HELLP syndrome

Consider viral or drug-induced hepatitis, gallstone disease, or malignancy in the differential diagnosis of abnormal
liver tests in any of the trimesters of pregnancy

Chronic hepatitis B or C poses a risk of transmission to the offspring

Data from: Riely CA. Liver disease in the pregnant patient. Am J Gastroenterol 1999; 94:1728.

Graphic 72172 Version 3.0

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Acute fatty liver of pregnancy

High power view of an oil red O stain of a liver biopsy from a patient with acute
fatty liver of pregnancy. There are vacuolated hepatocytes containing
microvesicular fat which stain red (arrows). This stain should be routinely used
for the diagnosis of acute fatty liver of pregnancy and must be performed on a
biopsy specimen that has not been fixed.

Courtesy of Caroline A Riely, MD.

Graphic 68144 Version 2.0

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Normal reference ranges in pregnant women

Nonpregnant First Second Third


References
woman* trimester trimester trimester

Hematology

Erythropoietin ¶ 4-27 12-25 8-67 14-222 1-3


(units/L)

Ferritin ¶ (ng/mL) 10-150 Δ 6-130 2-230 0-116 1-8

Folate, red blood cell 150-450 137-589 94-828 109-663 6, 9, 10


(ng/mL)

Folate, serum (ng/mL) 5.4-18.0 2.6-15.0 0.8-24.0 1.4-20.7 1, 6, 9-13

Haptoglobin (mg/mL) 25-250 130 +/- 43 115 +/- 50 135 +/- 65 93

Hemoglobin ¶ (g/dL) 12-15.8 Δ 11.6-13.9 9.7-14.8 9.5-15.0 2, 3, 6, 7, 13

Hematocrit ¶ (percent) 35.4-44.4 31.0-41.0 30.0-39.0 28.0-40.0 1, 2, 5, 6,


13-15

Iron, total binding 251-406 278-403 Not reported 359-609 7


capacity ¶ (mcg/dL)

Iron, serum ¶ (mcg/dL) 41-141 72-143 44-178 30-193 2, 7

Mean corpuscular 27-32 30-32 30-33 29-32 5


hemoglobin (pg/cell)

Mean corpuscular 79-93 81-96 82-97 81-99 5, 6, 13, 14


volume (xm 3 )

Platelet (x10 9 /L) 165-415 174-391 155-409 146-429 5, 6, 14, 16,


17

Mean platelet volume 6.4-11.0 7.7-10.3 7.8-10.2 8.2-10.4 5


(mcm 3 )

Red blood cell count 4.00-5.20 Δ 3.42-4.55 2.81-4.49 2.71-4.43 5, 6, 13, 14


(x10 6 /mm 3 )

Red cell distribution <14.5 12.5-14.1 13.4-13.6 12.7-15.3 5


width (percent)

White blood cell count 3.5-9.1 5.7-13.6 5.6-14.8 5.9-16.9 5, 6, 13, 14,
(x10 3 /mm 3 ) 18

Neutrophils 1.4-4.6 3.6-10.1 3.8-12.3 3.9-13.1 5, 14, 16, 18


(x10 3/mm 3)

Lymphocytes 0.7-4.6 1.1-3.6 0.9-3.9 1.0-3.6 5, 14, 16, 18


(x10 3/mm 3)

Monocytes 0.1-0.7 0.1-1.1 0.1-1.1 0.1-1.4 5, 14, 18


(x10 3/mm 3)

Eosinophils 0-0.6 0-0.6 0-0.6 0-0.6 14, 18


(x10 3/mm 3)

Basophils (x10 3/mm 3) 0-0.2 0-0.1 0-0.1 0-0.1 14, 18

Transferrin (mg/dL) 200-400 254-344 220-441 288-530 4, 5

Transferrin, saturation 22-46 ¶ Not reported 10-44 5-37 3


without iron (percent)

Transferrin, saturation 22-46 ¶ Not reported 18-92 9-98 3


with iron (percent)

Coagulation

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Antithrombin, functional 70-130 89-114 78-126 82-116 17, 19, 20


(percent)

D-dimer (mcg/mL) 0.22-0.74 0.05-0.95 0.32-1.29 0.13-1.7 17, 20-24, 87

Factor V (percent) 50-150 75-95 72-96 60-88 25

Factor VII (percent) 50-150 100-146 95-153 149-211 17

Factor VIII (percent) 50-150 90-210 97-312 143-353 17, 25

Factor IX (percent) 50-150 103-172 154-217 164-235 17

Factor XI (percent) 50-150 80-127 82-144 65-123 17

Factor XII (percent) 50-150 78-124 90-151 129-194 17

Fibrinogen (mg/dL) 211-496 244-510 291-538 301-696 5, 17, 20, 21,


23, 24, 87

Homocysteine (mmol/L) 4.4-10.8 3.34-11 2.0-26.9 3.2-21.4 6, 9, 10-12

International 0.9-1.04 ◊ 0.86-1.08 0.83-1.02 0.80-1.09 19, 24


Normalized Ratio

Partial thromboplastin 26.3-39.4 23.0-38.9 22.9-38.1 22.6-35.0 5, 17, 19, 24


time, activated (sec)

Plasminogen activator 17.3 +/– 5.7 17.7 +/– 1.9 Not reported 66.4 +/– 4.9 87
inhibitor-1 (PAI-1)
antigen (pg/mL)

Plasminogen activator 9.3 +/– 1.9 9.0 +/– 0.8 Not reported 31.4 +/– 3.0 87
inhibitor-1 (PAI-1)
activity (arbitrary units)

Prothrombin time (sec) 12.7-15.4 9.7-13.5 9.5-13.4 9.6-12.9 5, 17, 24

Protein C, functional 70-130 78-121 83-133 67-135 19, 25, 26


(percent)

Protein S, total 70-140 39-105 27-101 33-101 17, 25, 26


(percent)

Protein S, free (percent) 70-140 34-133 19-113 20-65 25, 26

Protein S, functional 65-140 57-95 42-68 16-42 25


activity (percent)

Tissue plasminogen 1.6-13 § 1.8-6.0 2.36-6.6 3.34-9.20 17, 19, 87


activator (ng/mL)

Tissue plasminogen 4-43 16-33 36-55 67-92 17


activator inhibitor-1
(ng/mL)

von Willebrand measurements

von Willebrand factor 75-125 62-318 90-247 84-422 20, 27, 28


antigen (percent)

ADAMTS-13, von 40-170 ¥ 40-160 22-135 38-105 20, 28


Willebrand cleaving
protease

Blood chemical constituents

Alanine transaminase 7-41 3-30 2-33 2-25 4, 5, 8, 29


(units/L)

Albumin (g/dL) 4.1-5.3 Δ 3.1-5.1 2.6-4.5 2.3-4.2 29-32

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Alkaline phosphatase 33-96 17-88 25-126 38-229 4, 5, 8, 29, 30


(units/L)

Alpha-1 antitrypsin 100-200 225-323 273-391 327-487 5


(mg/dL)

Alpha-fetoprotein — — Approximately Approximately 95


(ng/mL) 130-400 130-590

Ammonia (microM) 31 +/- 3.2 — — 27.3 +/- 1.6 94

Amylase (units/L) 20-96 24-83 16-73 15-81 4, 5, 33, 34

Anion gap (mmol/L) 7-16 13-17 12-16 12-16 5

Aspartate transaminase 12-38 3-23 3-33 4-32 4, 5, 8, 29


(units/L)

Bicarbonate (mmol/L) 22-30 20-24 20-24 20-24 5

Bilirubin, total (mg/dL) 0.3-1.3 0.1-0.4 0.1-0.8 0.1-1.1 4, 29

Bilirubin, unconjugated 0.2-0.9 0.1-0.5 0.1-0.4 0.1-0.5 5, 29


(mg/dL)

Bilirubin, conjugated 0.1-0.4 0-0.1 0-0.1 0-0.1 29


(mg/dL)

Bile acids (mmol/L) 0.3-4.8 ‡ 0-4.9 0-9.1 0-11.3 29, 35

CA-125 antigen 7.2-27.0 2/2-268 12-25.1 16.8-43.8 88, 89, 90


(units/mL)

Calcium, ionized 4.5-5.3 4.5-5.1 4.4-5.0 4.4-5.3 5, 31, 36, 37


(mg/dL)

Calcium, total (mg/dL) 8.7-10.2 8.8-10.6 8.2-9.0 8.2-9.7 4, 5, 30, 32,


36-38

Ceruloplasmin (mg/dL) 25-63 30-49 40-53 43-78 5, 39

Chloride (mEq/L) 102-109 101-105 97-109 97-109 4, 5, 40

Creatinine (mg/dL) 0.5-0.9 Δ 0.4-0.7 0.4-0.8 0.4-0.9 4, 5, 46

Gamma-glutamyl 9-58 2-23 4-22 3-26 4, 5, 8, 29


transpeptidase (units/L)

Lactate dehydrogenase 115-221 78-433 80-447 82-524 4, 5, 32, 8


(units/L)

Lipase (units/L) 3-43 21-76 26-100 41-112 33

Magnesium (mg/dL) 1.5-2.3 1.6-2.2 1.5-2.2 1.1-2.2 4, 5, 30-32,


36, 38

Osmolality (mOsm/kg 275-295 275-280 276-289 278-280 38, 41


H20)

Phosphate (mg/dL) 2.5-4.3 3.1-4.6 2.5-4.6 2.8-4.6 4, 5, 30, 31,


42

Potassium (mEq/L) 3.5-5.0 3.6-5.0 3.3-5.0 3.3-5.1 4, 5, 15, 31,


32, 38, 40

Prealbumin (mg/dL) 17-34 15-27 20-27 14-23 5

Protein, total (g/dL) 6.7-8.6 6.2-7.6 5.7-6.9 5.6-6.7 5, 31, 32

Sodium (mEq/L) 136-146 133-148 129-148 130-148 4, 5, 15, 31,


32, 38, 41

Urea nitrogen (mg/dL) 7-20 7-12 3-13 3-11 4, 5, 40

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Uric acid (mg/dL) 2.5-5.6 Δ 2.0-4.2 2.4-4.9 3.1-6.3 4, 5, 41

Metabolic and endocrine tests

Aldosterone (ng/dL) 2-9 6-104 9-104 15-101 43, 44, 45

Angiotensin converting 9-67 1-38 1-36 1-39 39, 46


enzyme (units/L)

Alpha-fetoprotein 0-8.5 Not reported 50-425 50-590 84, 86


(ng/mL)

Cortisol (mcg/dL) 0-25 7-19 10-42 12-50 5, 45

Hemoglobin A 1C 4-6 4-6 4-6 4-7 36, 47, 48


(percent)

Parathyroid hormone 8-51 10-15 18-25 9-26 30


(pg/mL)

Parathyroid hormone- <1.3 † 0.7-0.9 1.8-2.2 2.5-2.8 30


related protein (pmol/L)

Renin, plasma activity 0.3-9.0 † Not reported 7.5-54.0 5.9-58.8 40, 44


(ng/mL/hour)

Thyroid-stimulating 0.34-4.25 0.60-3.40 0.37-3.60 0.38-4.04 4, 5, 49


hormone (milli-int.
units/mL)
[American Thyroid 0.1-2.5 0.2-3.0 0.3-3.0 85
Association
recommendation]**

Thyroxine-binding 1.3-3.0 1.8-3.2 2.8-4.0 2.6-4.2 5


globulin (mg/dL)

Thyroxine, free (ng/dL) 0.8-1.7 0.8-1.2 0.6-1.0 0.5-0.8 5, 49

Thyroxine, total 5.4-11.7 6.5-10.1 7.5-10.3 6.3-9.7 5, 32


(mcg/dL)

Triiodothyronine, free 2.4-4.2 4.1-4.4 4.0-4.2 Not reported 49


(pg/mL)

Triiodothyronine, total 77-135 97-149 117-169 123-162 5


(ng/dL)

Vitamins and minerals

Copper (mcg/dL) 70-140 112-199 165-221 130-240 50, 51, 5

Selenium (mcg/L) 63-160 116-146 75-145 71-133 5, 50

Vitamin A (retinol) 20-100 32-47 35-44 29-42 5


(mcg/dL)

Vitamin B12 (pg/mL) 279-966 118-438 130-656 99-526 6, 10

Vitamin C (ascorbic 0.4-1.0 Not reported Not reported 0.9-1.3 52


acid) (mg/dL)

Vitamin D, 25-45 20-65 72-160 60-119 30, 36


1,25-dihydroxy (pg/mL)

Vitamin D, 24,25- 0.5-5.0 † 1.2-1.8 1.1-1.5 0.7-0.9 53


dihydroxy (ng/mL)

Vitamin D, 25-hydroxy 14-80 18-27 10-22 10-18 30, 53


(ng/mL)

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Vitamin E 5-18 7-13 10-16 13-23 5


(α-tocopherol)
(mcg/mL)

Zinc (mcg/dL) 75-120 57-88 51-80 50-77 5, 13, 50

Autoimmune and inflammatory mediators

C3 complement (mg/dL) 83-177 62-98 73-103 77-111 5

C4 complement (mg/dL) 16-47 18-36 18-34 22-32 5

C-reactive protein 0.2-3.0 Not reported 0.4-20.3 0.4-8.1 54


(mg/L)

Erythrocyte 0-20 Δ 4-57 7-47 13-70 55


sedimentation rate
(mm/hour)

Immunoglobulin A 70-350 95-243 99-237 112-250 5


(mg/dL)

Immunoglobulin G 700-1700 981-1267 813-1131 678-990 5


(mg/dL)

Immunoglobulin M 50-300 78-232 74-218 85-269 5


(mg/dL)

Sex hormones

Dehydroepiandrosterone 1.3-6.8 † 2.0-16.5 0.9-7.8 0.8-6.5 56


sulfate (mmol/L)

Estradiol (pg/mL) <20-443 Δ ,¶ ¶ 188-2497 1278-7192 6137-3460 56, 57

Progesterone (ng/mL) <1-20 Δ 8-48 99-342 56, 57

Prolactin (ng/mL) 0-20 36-213 110-330 137-372 30, 47, 57, 58

Sex hormone binding 18-114 Δ 39-131 214-717 216-724 56, 59


globulin (nmol/L)

Testosterone (ng/dL) 6-86 Δ 25.7-211.4 34.3-242.9 62.9-308.6 56

17-hydroxyprogesterone 0.6-10.6 Δ ,† 5.2-28.5 5.2-28.5 15.5-84 56


(nmol/L)

Lipids

Cholesterol, total <200 141-210 176-299 219-349 5, 60-62


(mg/dL)

High-density lipoprotein 40-60 40-78 52-87 48-87 5, 60-63


cholesterol (mg/dL)

Low-density lipoprotein <100 60-153 77-184 101-224 5, 60-63


cholesterol (mg/dL)

Very-low-density 6-40 † 10-18 13-23 21-36 62


lipoprotein cholesterol
(mg/dL)

Triglycerides (mg/dL) <150 40-159 75-382 131-453 4, 5, 60-63

Apolipoprotein A-I 119-240 111-150 142-253 145-262 4, 47, 61


(mg/dL)

Apolipoprotein B 52-163 58-81 66-188 85-238 4, 47, 61


(mg/dL)

Cardiac function

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Cardiac output (L/min) 4.8-6.8 5.6-9.7 5.5-9.9 4.8-8.7 64, 65, 66, 67,
68

Cardiac index 2.6-4.2 3.2-4.6 3.1-4.7 2.5-4.4 65, 68


(L/min/m 2 )

Stroke volume (mL) 79-90 77.5-107.6 70.3-107.6 54-99 65, 68, 69

Stroke index (mL/m 2 ) 46-62 39-62 30-42 65

Systemic vascular 700-1600 747-1485 692-1201 1034-1201 65, 67, 70


resistance (dyns/cm 5 )

Echocardiography

Intraventricular septal 0.7-0.9 0.63-0.83 0.65-0.85 0.66-0.9 68, 69, 70, 91,
dimension (cm) 92

Posterior ventricular 0.75-0.9 0.56-0.8 0.59-0.9 0.59-0.9 68, 69, 70, 91,
wall dimension (cm) 92

Left ventricular mass 116-143 108-167 115-150 128-162 68, 70, 91, 92
(g)

Left ventricular mass 40-78 53-79 58-82 60-88 68, 70, 91, 92
index

E/A ratio 1.4-1.75 1.6 1.4 1.3 68, 70

Left ventricular diastolic 4.3-4.8 4.3-4.6 4.4-4.9 5.1 69, 70


diameter (cm)

Left ventricular systolic 2.8-3.1 2.8-2.9 2.8-3.4 2.8-3.3 69, 70


diameter (cm)

Left vent, fractional 35-36 35-37 3.5 35-36 69, 70


shortening (percent)

Left vent ejection 60-73 61-75 61-63 60-73 69, 70


fraction (percent)

Cardiac function (blood tests)

Atrial natriuretic peptide Not reported Not reported 28.1-70.1 Not reported 73
(pg/mL)

B-type natriuretic <167 (age- and 18.4 13.5-29.5 15.5-46 71, 72, 73
peptide (pg/mL) gender-specific)

Creatine kinase 39-238 Δ 27-83 25-75 13-101 5, 74


(units/L)

Creatine kinase-MB <6 ΔΔ — — 1.8-2.4 74


(units/L)

N-terminal pro-brain 50 +/- 26 60 +/- 45 60 +/- 40 43 +/- 34 96


natriuretic peptide
(pg/mL)

Troponin I (ng/mL) 0-0.08 Not reported Not reported 0-0.064 75, 76


(intrapartum)

Blood gas

pH 7.38-7.42 7.36-7.52 7.40-7.52 7.41-7.53 31, 77


(arterial) (venous) (venous) (venous)

7.39-7.45
(arterial)

PO 2 (mmHg) 90-100 93-100 90-98 92-107 77, 78

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PCO 2 (mmHg) 38-42 Not reported Not reported 25-33 77

Bicarbonate (HCO 3 – ) 22-26 Not reported Not reported 16-22 77


(mEq/L)

Renal function tests

Effective renal plasma 492-696 Δ ,† 696-985 612-1170 595-945 79, 80


flow (mL/min)

Glomerular filtration 106-132 Δ 131-166 135-170 117-182 79, 80, 81


rate (GFR) (mL/min)

Filtration fraction 16.9-24.7 ◊ ◊ 14.7-21.6 14.3-21.9 17.1-25.1 79, 80, 81


(percent)

Osmolarity, urine 500-800 326-975 278-1066 238-1034 82


(mOsm/kg)

24-h albumin excretion <30 5-15 4-18 3-22 82, 83


(mg/24 hours)

24-h calcium excretion <7.5 † 1.6-5.2 0.3-6.9 0.8-4.2 15


(mmol/24 hours)

24-h creatinine 91-130 69-140 55-136 50-166 15, 80


clearance (mL/min)

24-h creatinine 8.8-14 † 10.6-11.6 10.3-11.5 10.2-11.4 82


excretion (mmol/24
hours)

24-h potassium 25-100 † 17-33 10-38 11-35 15


excretion (mmol/24
hours)

24-h protein excretion <150 19-141 47-186 46-185 83


(mg/24 hours)

24-h sodium excretion 100-260 † 53-215 34-213 37-149 15, 41


(mmol/24 hours)

* Unless otherwise specified, all normal reference values are from the seventeenth edition of Harrison's Principles of
Internal Medicine [84].
¶ Range includes references with and without iron supplementation.
Δ Normal reference range is specific range for females.
◊ Reference values are from Cerneca et al: Coagulation and fibrinolysis changes in normal pregnancy increased levels of
procoagulants and reduced levels of inhibitors during pregnancy induce a hypercoagulable state, combined with a reactive
fibrinolysis [19].
§ References values are from Cerneca et al and Choi et al: Tissue plasminogen activator levels change with plasma
fibrinogen concentrations during pregnancy [17,19].
¥ Reference values are from Mannuci et al: Changes in health and disease of the metalloprotease that cleaves von
Willebrand factor [28].
‡ Reference values are from Bacq Y et al: Liver function tests in normal pregnancy: a prospective study of 102 pregnant
women and 102 matched controls [29].
† Reference values are from the fifteenth edition of Harrison's Principles of Internal Medicine [85].
** The American Thyroid Association recommends these TSH ranges if individual laboratories do not determine their own
trimester-specific reference ranges.
¶¶ Range is for premenopausal females and varies by menstrual cycle phase.
ΔΔ Reference values are from Leiserowitz GS et al: Creatine kinase and its MB isoenzyme in the third trimester and the
peripartum period [74].
◊◊ Reference values are from Dunlop W: Serial changes in renal haemodynamics during normal human pregnancy [79].

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