AFLP is a rare and fatal obstetric emergency that occurs in the second and third trimester of pregnancy or in the early postpartum period. It can lead to acute liver failure, AKI, multiple organ failure, and even maternal and fetal mortality. Many studies have analyzed the high-risk factors for the morbidity associated with AFLP, fatal complications, and perinatal death. Recent studies have shown that being a primigravida, multiple pregnancies, carrying a male fetus, other liver diseases during pregnancy, previous history of AFLP, and preeclampsia are the potential risk factors for AFLP(1, 14–16). The recognition of high-risk factors is helpful for the prevention and treatment of AFLP, and can consequently improve the prognosis of the mother and the child. Early diagnosis; prompt delivery; and multidisciplinary supportive care from the departments of obstetrics, blood transfusion, and the ICU have resulted in improved maternal mortality (3). Although liver biopsy is the gold standard for the diagnosis of AFLP, it is rarely performed owing to its invasive nature and owing to the fact that it can cause complications in the presence of coagulopathy. In addition, liver biopsy is just a diagnostic method and does not contribute significantly to the treatment of AFLP. Therefore, none of the patients with AFLP in this study underwent liver biopsy.
The 106 patients with AFLP who were enrolled in this study delivered 119 fetuses, including 13 twin pregnancies and 93 single pregnancies. The incidence of twin pregnancy was 12.3% (13/106), which occurred only in the surviving group; however, there was no statistically significant difference in the incidence of twin pregnancy between the survivor and non-survivor groups (13.5% vs. 0, p = 0.608). This finding is similar to the results of another retrospective study conducted in China by Cheng et al. (17) that showed that the incidence of twin pregnancy among patients with AFLP was 28.1%; however, there was a statistically significant difference between the survivor and non-survivor groups (44.4% vs. 7.1%, p = 0.02). This indicated that twin pregnancy may be a potential protective factor for patients with AFLP; however, this is contrary to the results of the prospective study conducted by Knight et al. (1). Although our study enrolled the largest number of patients among the three studies (n = 106), it was still not a sufficiently large sample. Because of the rarity of AFLP, our study does not have the power to determine whether this is a statistically significant relationship or just a chance finding. A previous study by Gao et al. showed that male fetus, intrauterine death, postpartum diagnosis of AFLP, DIC, and prolonged PT and APTT were potential risk factors for maternal mortality in AFLP, whereas a history of legal termination of pregnancy, and increased TBIL and serum Cr were independent risk factors (18). In this study, male fetuses (p = 0.580) and a history of legal termination of pregnancy (p = 0.239) showed no statistically significant difference between the two groups and were not included in the potential risk factors for maternal mortality in AFLP.
Previous studies have rarely included a prediction model for fetal mortality. In this study, a new model for predicting fetal mortality was established and the predictive value of the MELD for fetal mortality was also verified. The results of multivariate logistic regression analysis indicated that hepatic encephalopathy (p = 0.016) and thrombocytopenia (p = 0.001) were independent risk factors for fetal mortality in patients with AFLP. Hepatic encephalopathy is a comprehensive disorder of central nervous system dysfunction caused by severe liver disease. As the most direct complication of liver damage in patients with acute liver failure, it is one of the causes of death in patients with liver disease. Its occurrence suggests that patients with AFLP have had acute liver failure before delivery and the fetus has a high incidence of intrauterine distress and stillbirth. In patients with preeclampsia and HELLP syndrome, thrombocytopenia is an independent risk factor for postpartum complications such as infection, thromboembolism, and DIC, and these complications are also common in patients with AFLP (19). The retrospective study by Cheng et al. showed that carrying a male fetus and vaginal delivery were risk factors for fetal mortality; however, these two variables did not show significant positive predictive value in our study (17). Gao et al. found that fetal distress and prolonged APTT were risk factors for fetal mortality (18). The univariate analysis in our study showed that prolonged APTT was a risk factor for fetal mortality (p < 0.0001), but multivariate analysis showed no positive predictive value. The new model based on hepatic encephalopathy and thrombocytopenia was compared with the MELD with regard to the prediction of fetal mortality. The threshold of the MELD was 25.124 and the AUC was 0.694, with a sensitivity of 68.8% and a specificity of 64.4%. The threshold of the new model was 45.234 and the AUC was 0.893, with a sensitivity of 100% and a specificity of 73.3%. Thus, compared with the MELD, the new model could more accurately predict fetal mortality, with a higher sensitivity and specificity.
In this study, the common clinical symptoms of patients with AFLP were anorexia (56.6%), vomiting (48.1%), nausea (46.2%), abdominal pain (30.2%), jaundice (23.6%), hypertension (15.1%), polydipsia and polyuria (9.4%), and cerebral encephalopathy (7.5%), which was similar to the results of a national prospective study on AFLP conducted in the UK. This study, conducted between February 2005 and August 2006, reported that 60% of the patients with AFLP experienced vomiting, 56% experienced abdominal pain, 12% experienced polydipsia, and 9% had encephalopathy (1). In the present study, the common severe complications besides death were AKI (67.0%), DIC(30%), MODS(30%), postpartum hemorrhage(29%), sepsis(28%) and AHF(22.6%), which is consistent with the results of the study by Chen et al. (20). In their study, the most common maternal complication was acute renal dysfunction (79.5%), followed by DIC (47.7%) and MODS (38.6%).
Maternal and fetal mortality rates attributable to AFLP vary greatly among studies, with the maternal mortality rate ranging from 12–18% and the fetal mortality rate ranging from 7–58% (21). Our previous clinical study showed that the maternal and fetal mortality rates of 52 patients with AFLP admitted to our hospital from January 2001 to December 2011 were 8% and 23%, respectively (22). In this study, a total of 106 patients with AFLP were admitted to our hospital from September 2011 to November 2020, and 119 fetuses were delivered. The maternal and fetal mortality rates were 9.4% (10/106) and 15.1% (18/119) respectively, both of which were lower than those reported in other studies. Compared with the last decade, the maternal mortality rate has declined slightly and the fetal mortality rate has decreased significantly in our hospital. This may be related to the loosening of the two-child policy, leading to an increasing number of older mothers and, consequently, more complications during pregnancy, causing a slight increase in maternal mortality. However, with the development of multidisciplinary supportive management in our hospital, especially pediatric intensive care, the level of comprehensive treatment of the fetus has been greatly improved, leading to a significant decline in the fetal mortality rate.
In this study, prenatal nausea (p = 0.037), prolonged PT (p = 0.003), and elevated serum Cr (p = 0.003) were independent risk factors for maternal mortality in patients with AFLP. Another study reported that ascites, thrombocytopenia, and serum Cr were independent risk factors for postpartum complications in pre-eclampsia and HELLP syndrome (23). The clinical symptoms of AFLP are similar to those of HELLP syndrome, and both are pregnancy-specific liver diseases. The predictive model for AFLP also included one clinical symptom and two laboratory findings, and elevated serum Cr was an independent risk factor for both AFLP and HELLP syndrome. However, the difference between the PLT count in AFLP was statistically significant in univariate analysis (p = 0.0003) and was eliminated in multivariate logistic regression analysis. This suggests that thrombocytopenia is a potential risk factor for maternal mortality in AFLP, which needs to be verified by a larger-sample study. Transaminase levels have not been shown to be important across most disease models in liver disease, including our model for AFLP (p > 0.05). A single-center retrospective study with 130 cases (AFLP = 32; HELLP = 81; pre-eclampsia and liver disease = 17) showed that both the MELD and the new model with two objective variables, namely serum TBIL and INR, were reliable for predicting the short-term mortality in patients with pregnancy-specific liver disease (followed up until 3 months after delivery or until death) (12). In the present study, TBIL and INR were statistically significant in univariate analysis (p = 0.006 and p < 0.0001, respectively), but they were eliminated in multivariate logistic regression analysis, which also suggested that increased TBIL and prolonged INR are potential risk factors for maternal mortality in AFLP; further prospective studies with larger sample sizes are warranted to explore the risk factors for maternal mortality in patients with AFLP.
Previous clinical studies have shown that the MELD based on TBIL, Cr, and INR shows good predictive efficacy for acute liver failure and pregnancy-specific liver disease (11, 12). A study conducted in China showed that the MELD was a good predictor of all complications of AFLP, including ascites, hepatic encephalopathy, sepsis, and renal insufficiency (all AUCs > 0.8), and the optimal cut-off values were close to 30 (24). Our study also verified that both the MELD and the new model show good predictive efficacy in predicting maternal mortality in AFLP (AUC = 0.948 and 0.926, respectively).
Overall, compared with previous models based on only laboratory findings, the new predictive model for maternal mortality included one clinical symptom and two laboratory findings, which was more readily available, less expensive and easier to implement clinically. To the best of our knowledge, the symptom of nausea that we identified as an independent risk factor for AFLP has not been previously described.
This study had a long duration of almost 10 years, and is the largest single-center clinical study on AFLP so far. The number of patients with AFLP enrolled in this study is only second to that in the multicenter study by Gao et al., in which our hospital has participated in the past (18). As all patients with AFLP came from one single center, they received similar obstetric and multidisciplinary treatments after hospitalization, and some limitations of different medical levels were counter-balanced.
There are some limitations to our research. Firstly, we did not evaluate the morbidity of AFLP owing to the deficiency of data on total pregnant women during the study period. Secondly, this was a single-center and small-sample study because of the rarity of AFLP, which might reduce the general applicability of our findings, although we had extended the study period to one decade and our study was a retrospective study. Thirdly, as Shandong Provincial Hospital is a tertiary referral center for critical patients in China, some patients with AFLP were referred to our hospital after severe postpartum complications, and their condition was relatively critical. The manner and timing of medical intervention during their prenatal treatment differed, which directly affected the prognosis of the patients.