Background
Preeclampsia is a multisystem disorder and the leading cause of severe morbidity and death in pregnancy. Liver involvement in preeclampsia ranges from elevated liver enzyme levels to hepatic infarction or rupture. Endothelial dysfunction leads to changes in blood flow and congestion and may be involved in the pathophysiology of preeclampsia. Changes in splanchnic blood flow and portal congestion can lead to altered liver stiffness. Transient elastography is a noninvasive, ultrasound-based technique that measures organ stiffness and steatosis and is therefore widely used in clinical hepatology. Previous studies reported elevated liver stiffness and liver steatosis, as measured by transient elastography, in women with preeclampsia.
Objective
This study followed changes in liver stiffness and steatosis, as measured by transient elastography, from the antepartum period to 1-week postpartum among women with preeclampsia compared with healthy controls and evaluated the association between preeclampsia severity and transient elastography results.
Study Design
This prospective cohort study was conducted from 2017 through 2021. The study group comprised women with preeclampsia, and the control group comprised healthy pregnant women hospitalized for other reasons. All the participants underwent transient elastography either on diagnosis of preeclampsia (study group) or on hospital admission (control group) and again in the postpartum period. Liver stiffness measurements are expressed in kilopascals (kPa) in the range of 2.5 to 75 kPa, and liver steatosis is expressed by controlled attenuation parameter in the range of 100 to 400 dB/m.
Results
The study group comprised 36 women and the control group 37. Liver stiffness scores were significantly elevated in the study when compared with the control group, both in the antepartum period ( P <.001) and the postpartum period ( P =.025). Liver stiffness scores decreased significantly after delivery in the study and control groups ( P <.001 and P =.002, respectively). Liver steatosis scores were higher in the study group than in the control group both in the antepartum and postpartum periods ( P <.001 and P <.02, respectively). In the multivariable analysis, the diagnosis of preeclampsia correlated with higher antepartum liver stiffness scores ( P =.005). For the study group, postpartum liver stiffness and liver steatosis scores were increased among those with vs those without severe features of preeclampsia ( P =.03 and P =.04, respectively)
Conclusion
Reductions in liver stiffness and steatosis from the antepartum to the postpartum period were documented in both the preeclampsia and control groups. However, both these measures were higher in the preeclampsia group and correlated with preeclampsia severity. Larger studies may be able to determine whether transient elastography can predict the severity of preeclampsia or other related metabolic conditions that correlate with chronic hypertension.
Why was this study conducted?
Preeclampsia (PE) is a multisystem disorder that involves hemodynamic changes with increased blood pressure and parenchymal congestion. Parenchymal congestion will increase tissue stiffness as measured by elastography. Transient elastography is a well-established, noninvasive, ultrasound-based technique to measure liver stiffness. This study aimed to compare differences in the liver stiffness measurements antepartum and postpartum for women with PE and women without PE. This study also aimed to understand the pathophysiology of liver involvement in PE and to assess whether a measurement of liver stiffness might serve as a surrogate marker for the syndrome.
Key findings
Liver stiffness and steatosis, as measured by transient elastography, were markedly elevated in women with PE when compared with a control group, both in the antepartum and postpartum periods. Postpartum liver stiffness and liver steatosis scores were increased among those with vs those without severe features of PE.
What does this add to what is known?
Liver stiffness and steatosis scores are elevated in women with PE when compared with healthy pregnant women, both in the antepartum and postpartum periods, and particularly among women with severe features of PE.
Introduction
Preeclampsia (PE) is a multisystem disorder characterized by new-onset hypertension and proteinuria presenting after 20 weeks of gestation. PE has been estimated to complicate 4.6% of pregnancies. This disorder remains one of the leading causes of death and severe maternal morbidity and can lead to maternal organ dysfunction, such as renal insufficiency or hepatic, neurologic, or hematological complications. ,
Liver involvement in PE is not common; however, its presence signifies severe disease. Hepatic damage may range from elevation of liver enzyme levels to hepatic infarction and rupture. Tools for hepatic assessment in this setting are limited and include monitoring hepatic enzyme levels, such as amino aspartate transferase and alanine aminotransferase, and coagulation studies. Hepatic imaging studies are unremarkable unless a severe complication, such as subcapsular hematoma or liver infarction, occurs. A small investigational study on 16 cases with hemolysis, elevated liver enzymes, and low platelet count syndrome showed that these patients frequently exhibited areas of abnormal diffusion in the liver on diffusion-weighted magnetic resonance imaging, suggestive of acute liver injury. However, liver stiffness, as measured by transient elastography, has been shown to be altered in women with PE. ,
Transient elastography is a noninvasive, ultrasound-based technique that measures organ stiffness. , Liver stiffness can be measured by the velocity of a vibration wave that is generated on the skin and travels through the liver (shear wave). A graphical representation is provided on the screen together with a numeric score expressed in kilopascals (kPa); a higher score correlates with increased liver stiffness ( Figure 1 ). FibroScan (EchoSens, Paris, France) is a well-validated device based on transient elastography that can be performed easily with immediate results and good reproducibility, and therefore, it is widely used in the practice of hepatology. , In fact, the use of transient elastography-based devices such as FibroScan has replaced the need for a liver biopsy in many cases. For most cases in the liver clinic, FibroScan is used to assess fibrosis and even liver cirrhosis, which are represented by cutoff scores of >7 kPa and >11 kPa, respectively. However, changes and increased liver stiffness does not necessarily represent fibrosis. Increased liver stiffness can occur with severe edema and liver inflammation or secondary to high pressure–related conditions such as congestion and endothelial dysfunction. , Other than stiffness, the FibroScan probe can also evaluate liver fat, which is expressed by controlled attenuation parameter. Controlled attenuation parameter measures the attenuation of ultrasound waves (ie, the gradual decrease of amplitude and intensity of the wave through the liver tissue) and compares it with normal liver attenuation. Its measurement has demonstrated very good accuracy in assessing steatosis validated with liver biopsies. , Controlled attenuation parameter is expressed in decibels per meter (dB/m). FibroScan results are expressed by a continuous value which is directly related to the degree of stiffness or steatosis; therefore, it can be used to compare values even in the normal range.
The pathophysiology of hepatic involvement in PE is not well understood. Macroscopic hepatic changes such as hepatomegaly, microscopic hepatic findings such as periportal changes with hemorrhage, sinusoidal fibrin deposition, and hepatocyte necrosis have been reported in the setting of PE. These may represent hepatic involvement such as congestion caused by endothelial dysfunction. Such changes can be measured by transient elastography and indicate liver stiffness. We hypothesized, accordingly, that women diagnosed with PE will have a higher antepartum liver stiffness score compared with women without PE. We expected that the liver stiffness score of women with and without PE would be similar postpartum.
This study aimed to follow the changes in liver stiffness, as measured by transient elastography, from the antepartum period to 1-week postpartum among women with PE vs healthy controls.
Materials and Methods
Ethics
The study protocol met the ethical standards for human experimentation established in the Declaration of Helsinki and was approved by the institutional review board of Galilee Medical Center, Nahariya, Israel. All the participants signed informed consent forms before participation in the study.
Trial design
This prospective cohort study was conducted from 2017 through 2021.
Participants
Women were recruited while being admitted to the maternal-fetal unit of our center. The study group comprised women diagnosed with PE, and the control group comprised healthy pregnant women hospitalized for other reasons such as decreased fetal movements, uterine contraction, and labor induction.
Exclusion criteria included congenital fetal abnormalities and a history of chronic liver disease. In addition, women who were treated with magnesium for PE and who had severe features, as defined below, and who were admitted to the delivery room for stabilization and immediate labor induction were excluded from the analysis. This was because their condition did not enable their transfer to the liver unit to perform the transient elastography assessment.
PE was diagnosed by the combination of new-onset hypertension and proteinuria that first appeared after 20 weeks of gestation. Elevated blood pressure was defined as systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg on 2 occasions at least 4 hours apart; and proteinuria was defined as protein concentration of ≥300 mg in a 24-hour urine collection. PE with severe features was diagnosed according to the American College of Obstetrics and Gynecology criteria
Clinical and laboratory parameters
Clinical characteristics and obstetrical maternal and neonatal outcomes were collected. All the patients diagnosed with PE underwent the following workup: sign and symptom evaluation, blood pressure monitoring, 24-hour protein excretion in grams, body mass index (BMI) assessment, and laboratory studies including complete blood count, hepatic enzymes, and coagulation testing.
Liver stiffness and steatosis
Liver stiffness was measured by transient elastography (FibroScan) ( Video 1 ). The Fibroscan tests were performed in the liver clinic by a single trained hepatologist, blinded to the patient status, during the third trimester and 1-week postpartum in both the study and control groups. Liver stiffness measurements were expressed in kilopascals (kPa) in the range of 2.5 to 75 kPa. Liver steatosis was measured by the Fibroscan probe using the controlled attenuation parameter technique. The amount of steatosis expressed in dB/m ranged from 100 to 400 dB/m, with a controlled attenuation parameter score above 238 dB/m reflecting abnormal liver steatosis. Both measurements, liver stiffness and steatosis, are given as a continuous number, and to improve test reliability, a minimum of 10 valid readings were included with at least a 60% success rate and an interquartile range of ≤30% of the median value.
Statistical methods
Continuous variables are presented as the mean ± standard deviation (SD) or as median and range values. Qualitative variables are presented as frequencies and percentages.
Continuous variables were compared between the 2 groups using either the independent sample t test or the Mann-Whitney U test based on the sample sizes of the groups and the distribution shapes of the variables. Categorical variables were analyzed using Pearson chi-square tests or Fisher exact tests (if expectancy <5).
Multivariable linear regression analyses were performed to examine correlations of PE with liver stiffness and steatosis scores before and after birth. The following variables were considered as independent variables in the multivariable models (based on theoretical considerations and the univariate analysis): maternal age, parity, twin pregnancy, BMI, and gestational age at assessment and at delivery. Logarithmic transformations were performed when the normal distribution assumption was violated. A 2-tailed P value of <.05 was considered statistically significant.
Statistical analysis was performed using IBM SPSS Statistics for Windows, version 27.0 (IBM Corp, Armonk, NY).
Sample size determination
Based on our previous study, a difference of ≥1 kPa in antepartum liver stiffness score between the study groups was considered statistically significant. The previous study was conducted in another hospital and included only postpartum PE patients, because use of the FibroScan during pregnancy was not yet approved at that time. Based on the independent sample t test and an alpha=5%, for 35 women in each group, the power for a 2-sided hypothesis was 79% and for a 1-sided hypothesis was 87%.
Sample power was calculated before the study was conducted with the IBM SamplePower software version 3.0. The post hoc calculation was done with the Gpower software, version 3.1.9.7 (Universität Düsseldorf, Germany).
Results
Characteristics of the participants
The study group comprised 36 women and the control group comprised 37. Baseline characteristics of the 2 groups are presented in Table 1 . For the study group when compared with the control group, the proportion of women with diabetes was higher (25% vs 3%; P =.007) and the mean BMI was higher (33.61±4.67 vs 27.36±4.89; P <.01). Statistically significant differences were not found between the groups in terms of gravity, parity, maternal age, and gestational age at admission.
| Characteristics | Study group (n=36) | Control group (n=37) | P value |
|---|---|---|---|
| Age (y), mean (±SD) | 31.17 (±7.60) | 28.59 (±4.77) | .09 |
| Gravity, median (range) | 2 (1–8) | 2 (1–5) | .69 |
| Parity, median (range) | 1 (1–7) | 2 (1–5) | .40 |
| BMI, mean (±SD) | 33.61 (±4.67) | 27.36 (±4.89) | <.001 |
| Gestational age at admission (wk), mean (±SD) | 33.57 (±3.6) | 32.54 (±4.6) | .29 |
| Twin pregnancy, n (%) | 3 (8) | 6 (16) | .73 |
| History of PE, n (%) | 3 (8) | 1 (3) | .36 |
| Chronic HTN, n (%) | 3 (8) | 0 (0) | .11 |
| Family history of HTN, n (%) | 11 (31) | 7 (19) | .28 |
| Aspirin treatment, n (%) | 5 (14) | 1 (3) | .11 |
| Diabetes mellitus, n (%) | 9 (25) | 1 (3) | .007 |
Clinical and laboratory parameters
Maternal and neonatal outcomes are shown in Table 2 . The median systolic and diastolic blood pressures were higher in the study group than in the control group. A total of 26% of the women in the study group complained of headache, epigastric pain, or blurred vision, whereas 56% had physical findings associated with PE (eg, peripheral edema, epigastric or right upper quadrant tenderness, hyperreflexia). Laboratory parameters for the women in the study and control groups are presented in Table 2 .
