Pregnancy Outcomes of Patients with Acute Fatty Liver of Pregnancy

Background: Limited data exists regarding the pregnancy and infant outcomes of Acute Fatty Liver of Pregnancy (AFLP). Methods: Retrospectively collect the mothers with AFLP and without AFLP in our center from 1/2008 to 6/2018.The primary assessment was to analyze and compare the frequency of negative maternal and fetal outcomes. The secondary assessment was to identify the predictors of negative maternal and fetal outcomes. Results: Compared to 220 matched mothers, 55 AFLP mothers were younger (P<0.001 ), fewer pregnancies(P=0.033),with more pregnancy induced hypertension(P<0.001), twins(P=0.002), fetal growth restriction(P=0.044) and fetus male (P<0.001). 3 (5.5%) of AFLP patients were diagnosed in the postpartum period. The mean gestational ages were 35.25±5.80 weeks at diagnosis of AFLP before delivery and Jaundice(89.1%), nausea or vomitting(58.2%), anorexia(49.1%), fatigue(45.5%) and like cold drinks(30.9%) were the main prodromal symptoms. The median duration from diagnosis to delivery was 1.55±4.62 days and 75%(39/52) patients terminate the pregnancy at the day of diagnosis. 78.8% (41/52) patients received cesearean section for terminating the pregnancy. 53.6%(22/41) patients received preventive plasma transfusion before the surgery and no one received artificial liver support during the treatment. In comparison, higher frequency of 16 maternal complications, severe negative outcomes (27.3% vs. 0.9%) and newborn asphyxia (24.6% vs.0.9%) were observed in AFLP population. 3 mothers (mortality rates: 5.5% ) died of multiple organ system failure and 6 fetal/infant (death rates: 9.8%) died of distress. When compared to those without negative outcomes, younger mothers(P=0.042),more singleton rates (p=0.041),increased mean value of ALT(P=0.011) and T-Bilirubin(P=0.014), occurence of refractory postpartum hemorrhage (0% vs.31.3% ), hysterectomy(0% vs.12.5% ), negative marternal outcomes (16.7% vs.56.3% ) were significantly decreased in patients with postpartum hemorrhage exceeded 500ml. Conclusions: Several symptoms were found to be the main prodromal symptoms of AFLP. Higher frequency of adverse maternal and fetal outcomes was observed in mothers with AFLP than common people.We found five potential risk factors of negative fetal outcome. Intrauterine balloon pressure might prevent further postpartum bleeding , but need further verification.


Introduction
Acute fatty liver of pregnancy (AFLP) is a rare disease with an incidence of 1 per 7000 to 16,000 pregnancies. It mostly occurs in the third trimester of pregnancy or during early postpartum period 1 . Prompt recognition of the disease and early termination of pregnancy is essential to improve the overall outcome of both mothers and infants.Primipara, male fetus, and multiparous women are considered as risk factors of AFLP 2 .Genetic mutation in long-chain 3-hydroxyl coenzyme A dehydrogenase probably leads to abnormal β-oxidation of fatty acids in fetal mitochondria and contributes to microvesicular fatty infifiltration of the liver of mothers 3 .However, the pathogenesis of AFLP is not yet completely elucidated .Due to better understanding of the disease and the implementation of artifificial liver support therapy (ALST) 4 in clinic and the popularization of intensive care unit, the mortality of AFLP for both suffering mothers and infants has dramatically decreased in recent years.
However, AFLP remains a serious disease with high mortality from to 16.5%-26.7% in recent study 5 and Little data exist regarding the measures to improve disease outcome in AFLP . We conducted an comparative study about the negative maternal outcomes (maternal complications and mortality) and fetal/infant outcomes. Also, we evaluate the role of intrauterine balloon and plasma transfusion by comparing AFLP mothers with and those without negative outcomes. Patients at our clinic and in-patient services were screened for the following eligibility criteria: age between 20 and 45 years; clinical diagnosed as AFLP ( The diagnosis of AFLP was based on both clinical features and laboratory findings, including:

Materials And Methods
(a) symptoms of anorexia,nausea, vomiting , jaundice, fatigue, and abnormal liver function during the third trimester of pregnancy or early postpartum period; (b) characteristic laboratory findings (e.g. elevated alanine transaminase, bilirubin and serum creatinine levels, prolonged prothrombin time,and hypoglycaemia); (c) ultrasonography images examination showing fatty liver or liver biopsy sample, with characteristic pathological changes, where available.(d) All patients exhibited six or more of the Swansea criteria 6 , which objectively confirmed the diagnosis of AFLP. ) during the pregnancy. A group of pregnant mothers without AFLP were randomly selected (based on the birth date in the same month and age match) in a 1:4 ratio to serve as the control group.Key exclusion criteriaevidence of liver failure caused by other reasons including cirrhotic, Wilson disease,activated hepatitis B or C, hemophagocytic lymphohistiocytosis, hepatocellular carcinoma,or cytotoxic drugs.

Study Procedures and Data Collections
Using an electronic medical record system and paper charts, the following data from the clinic and inpatient services at YouAn Hospital were collected for analysis: baseline information before delivery including age,gravidity,parity, pregnancy complication and obstetric complications before AFLP including hypothyroidism during pregnancy,pregnancy induced hypertension(PIH), gestational diabetes(GDM), placenta previa,Lab of AFLP onset and the same gestational weeks in non-AFLP patients including platelet, hemoglobin, alanine transaminase(ALT), albumin, total bilirubin , p rothrombin activity and creatinine,pertinent physical findings.For women with AFLP, additional data collection was performed that included documentation of gestational weeks at the time of the diagnosis and clinical signs. Data regarding medications, pregnancy complications, and obstetric complications were also collected during the delivery or after the delivery.

Outcome Measurements
Our primary outcomes were the frequency of negative maternal outcomes ( maternal complications and mortality) and fetal/infant outcomes.Negative maternal outcomes including obsterical complications, liver failure, renal failure,coagulation disorders,shock and Infection.The aforementioned outcomes will be compared between groups.Our secondary outcomes was to identify the predictors of negative outcomes of both mothers and fetal/infant.Also we evaluate the role of intrauterine balloon in reducing postpartum hemorrhage, hysterectomy and plasma transfusion.The severe negative outcomes of mothers include death, hysterectomy, shock, multiple organ system failure(MOF),hepatorenal syndrome, hepatic encephalopathy stage III-IV, failure to complete recovery, placental abruption grade III-IV, refractory postpartum hemorrhage ( 3000ml or more), PTA<20 %, refractory infections (fungi, severe pneumonia, acute pancreatitis).Negative outcomes of fetal/infant were defined as Asphyxia of newborn (Apgar score 0-7) and fetal/infant death. (including liver failure, renal failure and coagulation disorders),

Statistical Analysis
Baseline characteristics and laboratory results were summarized for two groups by means of descriptive statistics, including percentage, means ±standard deviation (SD), and 95% CI. For the quantitative variable, the t-test was used to compare group differences. For categorical variables, the chi-square test was used for group comparisons. Significance level was set at P < 0.05; all data were analyzed by SPSS 23.0 (SPSS, IBM., NewYork).

Study Population and Baseline values
During the enrollment period, the consecutive medical records of 511 pregnant women at our center were reviewed. Among them, 236 patients were excluded due to other reasons of liver failure ( Fig. 1) and 55 were dianosed with AFLP and enrolled into group A. 220 patients without AFLP and other liver diseases were selected as control and assigned to group B. All patients in group A were were further assigned into group A1 if the intrauterine balloon was used to prevented the postpartum hemorrhage or group A2 if not. The patients who were screened and enrolled into the different study groups are shown in Fig. 1 the diagnosis of AFLP were higher in groupA than groupB.The incidence of GDM seems less in group A than in group B(5.5% vs.13.2%),but there was no significant difference between two groupP=0.11.Besides, the rates of other pathological pregnancy including hypothyrodism during pregnancy and placenta previa were not differ between groups. and prothrombin activity (40.44±23.37vs.119.05±13.23,P<0.001) were significantly lower in group A than in group B. Also, the incidence of hypoglycemia(61.8% vs.20.9%,P<0.001) was significantly higher in group A than in group B( Table 1).

Discussion/conclusions
AFLP remains a serious disease with high mortality from to 16.5%-26.7% 4-5 for severe complications such as DIC,renal function impairement, hepatic encephalopathy, hypoglycemia, MOF, etc 7 .Because the scarcity of AFLP 8 , more comparative studies are need about its clinical characteristics,treatment and outcomes.
Due to its characters of quick onset,rapid progression and fetal relation, prompt recognition and early termination of pregnancy is essential to improve the overall outcome of both mothers and infants.Primipara, male fetus, and multiparous women are considered as risk factors of AFLP 2 . Except for these factors, we also found PIH 8 and FGR were the risk factors of AFLP in chinese population. AFLP patients seems to had lessGDM (5.5% vs.13.2%) but without statistical significance. There is disagreement in the published literature regarding the symptoms and clinically common manifestations of AFLP 9-10 and we found that jaundice, nausea or vomitting, anorexia, fatigue and like cold drinks were the main prodromal symptoms. Fatigue and like cold drinks were easily ignored symptoms.Previous studies 9-11 found that classical features of ascites or bright liver were only seen in a quarter of patients who underwent abdominal ultrasonography. In were coagulation disorders,including disseminated intravascular coagulation, prothrombin time and activated partial thromboplastin time.Timely 800-1200ml plasma transfusion could supply these supplement, which make it possible for a safe surgery to immediate delivery. After the removing of the etiology of AFLP, the disabled liver cells recovered quickly. The mortality rates were 5.6%-26.7%% in previous studies in patients received ALST 4-5 . The 5.5% mortality rates in our study were not only lower previous study with ALST,but also significantly lower than the 85% in the 1980 before the advent of ALST 16 , suggesting that timely preventive plasma transfusion and immediate surgery is an effective method in improving the survival of AFLP patients. All 3 dead in our center were caused by the MOF were occured in 2008-2010 when the comprehensive support was not well. All the alive patients were occured from 2010 to 2019, which indirectly suggesting the importance of comprehensive support in the management of AFLP.
Another study revealed 2 complications, postpartum hemorrhage and multiple organ dysfunctions (MOF), were associated with the outcome of AFLP patients undergoing postpartum. Our study evaluate the role of intrauterine balloon pressure, we stratified the 28 patients with postpartum hemorrhage more than 500ml. Compared to patients who received our methods to control postpartum hemorrhage, intrauetrine sac pressure could reduce the occurence of refractory postpartum hemorrhage >2000ml in delivery(0% vs.31.3% ), Hysterectomy(0% vs.12.5% ),Negative marternal outcomes(16.7% vs.56.3% ) .
However, for the restriction of sample size , there were no statistical significance in the above complications.
Given the retrospective nature of our study, we were unable to determine the long time outcomes of AFLP.Besides,the details between the risk factors and negative fetal/infant outcomes could not be explained.Also,for the low incidence of AFLP, multicenter comparative studies were need to verify the value of preventive plasma transfusion and postpartum intrauterine balloon pressure in improving the outcomes of mothers.
In conclusion, the main prodromal symptoms of AFLP were jaundice, nausea or vomitting, anorexia, fatigue and like cold drinks among our patients. Higher frequency of adverse maternal and fetal/infant outcomes was observed in mothers with AFLP when compared to the mothers without AFLP.We found that younger mother,singleton pregnancy,higher mean values of ALT and T-Bilirubin, lower mean value of Prothrombin activity were the potential risk factors for negative fetal/infant outcome. Preventive plasma transfusion and intrauterine balloon pressure might help improve the marternal outcomes, but need further verify.

Declarations
Availability of data and materials The datasets used and/or analysed during the current study are available from the