Fulminant hepatic failure (FHF) is defined as the development of hepatic encephalopathy within a short period (generally within 8 weeks) from the onset of original illness [1-3] (Box 1). Although hepatitis viruses B and E are the leading etiologies for fulminant viral hepatitis (FVH) in Asia and Africa [4,5], other viruses, such as herpes simplex virus (HSV), hepatitis virus A and D, parvovirus B19, chickenpox-herpes zoster, transfusion transmitted virus (TTV), and cytomegalo virus (CMV) are not uncommon [6,7]. There are still 15- 34% cases whose etiological cause cannot be identified [6,8].

Box 1: Diagnosis of Fulminant Viral Hepatitis [3].

Clinically, fulminant viral hepatitis in late pregnancy (FVHLP) presents with rapid progression and complicated clinical symptoms [8,9]. It also triggers multi-system organ failure (MSOF) which develops rapidly, and may include coagulation disorders, hepatorenal syndrome, hepatic encephalopathy, toxic enteroparalysis, acute lung injury, infection and endotoxemia, and electrolyte disturbances [10,11]. The maternal [4,12] and fetal fatality rate [5] is extremely high (table 1), ranking FVHLP one of the main indirect causes of maternal and fetal death in developing countries [15,16]. In addition to the complicated pathogenic conditions, two factors leading to failure of rescue should also be noted: the lack of awareness of FVHLP, which would lead to late recognition and incorrect diagnosis (table 2), and inappropriate obstetrical management. The latter is even more potentially harmful, since it can lead to irreversible progression of a patient’s severe condition, or even death. The nature of the disease makes it very difficult to perform a standard controlled clinical research in treatment, because when rescuing the patients, every effort is made to save their lives, hence there are only a small number of case reports and retrospective analyses available. Based on review of pathophysiological changes and a handful of literature reports, we are discussing the rationale for choice of treatment at different stages, and are proposing a routine obstetrical treatment guideline for FVHLP in the following.

Table 1: Fatality of fulminant hepatitis in pregnancy.

Table 2: Differential diagnosis of fulminant hepatitis in late pregnancy (FVHLP).

Importance of early recognition and appropriate treatment facilities

Awareness of FVHLP should be reinforced among medical staff to promote early recognition and timely treatment [25]. For pregnant patients with hepatitis, regular perinatal blood tests (aminotransferases and corresponding hepatitis markers are recommended to be monitored weekly since the second trimester) and physical examinations should be emphasized as a priority. Early clinical manifestations of FVHLP include: hypodynamia, decrease in appetite, dark amber urine, deep jaundice, nausea, vomiting, and abdominal distention [26]. Patients diagnosed with or whose symptomology suggests FVHLP should be transported to regional centers expert in its treatment before labor onset to decrease the risk for complications and fatality [27].

A major dilemma: optimal timing of delivery

For patients with FVHLP, pregnancy constitutes a heavy and continuous burden on the liver. On the other hand, labor can potentially trigger the onset of MSOF. Before delivery, most patients’ conditions are precarious at best. After stabilizing the patient with supportive medication (may vary from several hours to several days, and include intensive care unit input, replenishment of serum albumin and globulin, restoring coagulation function, reduction of transaminase and toxins, and control of hepatitis virus replication, etc.), the appropriate time for delivery should be determined to relieve the stress of pregnancy on liver. Unfortunately, any bleeding during delivery will significantly tax the liver. Accordingly, medication and supportive treatment must be rigorously maintained throughout delivery and the postpartum period. Optimal indications for delivering the baby include:

1) After the patient has been supportively treated and clinical symptoms and signs (including laboratory indices, such as coagulation function, serum albumin, transaminase, total bilirubin, etc.) have been in a steady state for 24 to 48 hours, or

2) Fetal distress is detected and the fetus is viable, or

3) After medication treatment yields no improvement in clinical conditions, such as deteriorating of hepatic encephalopathy [28].

Choice of delivery mode

Most FVHLP patients have severe coagulation disorders and hypoproteinemia. When there is trauma in the uterine cavity caused by the detachment of placenta, bleeding is not easily stopped due to shortage of blood coagulation factors and weakened uterine contractions caused by tissue edema, leading to an extremely high risk of postpartum hemorrhage [29], whereas the incision on uterus during cesarean section is much smaller in size, leading to less hemorrhage inside the uterus, and peripartum hysterectomy may be performed when postpartum hemorrhage occurs. Because of preexisting hypovolemia, postpartum hemorrhage would exacerbate liver cell damage. A prolonged vaginal delivery can potentially aggravate the condition by consuming energy and inflicting pain. A previous study has demonstrated that maternal liver function indices deteriorate significantly after vaginal delivery [30]. Recently, due to improved techniques in anesthesia, blood transfusion, anti-infective management and enhanced caesarean section skills among surgeons, risks for negative outcomes and complications in caesarean section deliveries have been reduced. Consequently, researchers and practitioners prefer caesarean section in FVHLP cases [31]. Vaginal delivery is still considered in multiparous patients who have already entered the labor process in which the cervix is mature and delivery is imminent. It has also been shown that fatality rates after caesarean sections are significantly lower than those after vaginal deliveries; among patients whose deaths were attributed to FVHLP, the majority had experienced vaginal deliveries [25,32].

Pre-operative preparation

Before delivery, necessary preparations include extensive monitoring, careful nursing and supportive treatment to ensure stable vital signs and optimize the patient’s coagulation function, serum albumin, transaminase, and total bilirubin levels. Meanwhile, complications should be prevented or promptly treated should any arise. Before a caesarean section, in addition to preparing for blood transfusion, retention of a urinary drainage tube, and newborn resuscitation, it is also crucial to be prepared to

1) Perform coloclysis to evacuate colonal content, relieve toxic enteroparalysis and prevent hepatic encephalopathy [10];

2) Maintain body temperature during the operation;

3) Insert a central venous line to provide rapid intravenous access and monitor central venous pressure. Together with blood pressure and heart rate monitoring, these allow for effective assessment of heart function, preload and blood volume, and help guide the speed and volume of infusing intraveneous fluid. For FVHLP patients, central venous cannulation should be performed by experienced doctors to avoid regional hemorrhage, hematoma, hemathorax or hemopneumothorax.

Peripartum subtotal hysterectomy

Peripartum hysterectomy may be performed emergently as a last resort to save the life of a woman with persistent bleeding, or as planned procedure, often in conjunction with cesarean delivery. It is performed in 0.05 to 0.1 percent of all deliveries and 0.5 percent of cesarean deliveries [33]. In the case of FVHLP, due to the already problematic blood clotting function, peripartum hysterectomy is a direct and more effective treatment for a highly probable postpartum hemorrhage or DIC than other medications or conservative treatment such as uterine artery ligation or embolization. A midline vertical abdominal incision should be used, which allows for satisfactory exposure of the operating field, performance of a total hysterectomy if necessary, peritoneal lavage and hand-exploration of the liver while operating. The peripartum subtotal hysterectomy is preferred, which would prevent postpartum hemorrhage and puerperal infection, reduce the development of hepatorenal syndrome and disruption of liver function indices such as bilirubin and transaminase levels. In contrast, in total hysterectomy, it is necessary to deflect the bladder flap significantly downward. Since there are rich venous plexes along the attachment between the bladder and cervix, deflection of the bladder flap might damage these venous networks and lead to profuse and even uncontrollable bleeding. Coagulation disorders in FVHLP patients make it harder to achieve hemostasis. Moreover, in late pregnancy, cardinal ligaments and uterosacral ligaments are softer and surrounded by regional edema, making it easier to injure the ureters in total hysterectomy. Subtotal hysterectomy reduces the risk for damage and bleeding of the plexus venosus and ureter, and requires less time than a total hysterectomy.

Peritoneal/abdominal lavage and drainage tube placement

Hand-explore the liver to evaluate the size and texture to make a preliminary assessment of prognosis [32,34]. After closing the posterior peritoneal membrane, rinse the abdominal cavity with povidoneiodine for 3-5 minutes, followed by irrigating with a large amount of physiological saline solution (5000 ml) to eliminate bacteria in the abdominal cavity, reduce noxious substances, prevent postoperative infection, and minimize postoperative fever [35]. Place a silica gel drainage tube at the bottom of the pelvic cavity, and sustain it for 3-7 days. The advantages of abdominal drainage are:

1) Decreasing abdominal pressure,

2) Promoting discharge of harmful substances such as bilirubin,

3) Rinsing of abdomen cavity to reduce toxin when necessary,

4) Differentiating whether the abdominal distention after operation is caused by bleeding or by ascites. The character and amount of drainage will vary based on the patient’s level of hypoproteinemia (leading to ascites) and severity of her coagulation disorder (leading to postoperative bleeding), on which in-time adjustment in medication can be based.

Treatment after delivery

The ascitic fluid collected during caesarean section should be sent for laboratory testing, including biochemical analysis, bacterial culture and drug- sensitivity testing. Hypertonic glucose injection (500g/l) 20 ml along with 8 units of insulin can be subcutaneously injected along the abdominal incision to promote wound healing [36], which is especially helpful for FVHLP patients with hypoproteinemia. Postoperative vaginal irrigation with povidone-iodine reduces the possibility of upward infection from the vagina [37], and also permits observation of vaginal bleeding. Post-operatively, vital signs, central venous pressure, and hourly urine volume should be carefully monitored. Special attention should be paid to changes in laboratory indices, such as water-electrolyte and acid-base balance, liver function, coagulation function, and routine blood counts. As necessary, adjust medication orders, carefully monitoring the volume and intravenous infusion rates. Cleanness of mouth cavity, abdominal incision, abdominal drainage tube, urinary drainage tube, and central venous cannula should be kept. Coagulation factors should be infused to improve coagulation function, as well as albumin to correct hypoproteinemia. Antiviral [38,39], anti-infectives and supportive and symptomatic treatment should be administered as needed through hospitalization, and monitor carefully for complications. Although breastfeeding does not increase the risk of mother-to-child transmission of HBV [40], it is not recommended in FVHLP patients due to their severe clinical conditions.

A proposed routine obstetrical treatment guideline

(a) Awareness of FVHLP should be reinforced among medical staff;

(b) Patients diagnosed with FVHLP should be transported to regional expert centers before labor onset;

(c) Supportive medication should be administered to prepare the patients for incoming delivery. A central venous line should be maintained to provide rapid intravenous access and monitor central venous pressure before operation;

(d) Caesarean section is recommended for the mode of delivery, followed by peripartum hysterectomy to control postpartum hemorrhage;

(e) Peritoneal/abdominal lavage and drainage tube placement are recommended following operation to decrease abdominal pressure and detect post-operational bleeding;

(f) Hypertonic glucose along with insulin topical injection is recommended to promote the healing of wound;

(g) Supportive medication, replenishment of coagulation factors, preventive antibiotics should be given as needed. Adjust the amount and order of intravenous fluid according to the character and amount of drainage and urine.

To date, FVHLP has been a challenging problem in both perinatology and hepatology. We discuss and propose a comprehensive treatment guideline for FVHLP based on available literatures and pathophysiological changes. Obstetrical treatments are of vital importance, because a patient’s condition may deteriorate rapidly after delivery without proper management. Guidelines developed with more robust research support are still needed.

There was no conflict of interest about this paper. No competing interest declared.

The authors thank Dr. Allen Nicholson, Dr. James Bloxton (Temple University), Dr. Patricia Dillon (LaSalle University), Dr. Hao Wang (Department of General Surgery, the Second Affiliated Hospital of Harbin Medical University) and Dr. Joshua Breslau (Princeton University) for their critical review and suggestions.

The research was supported by Science and Technology Project Foundations of Guangdong Province, China. No. 2005B34201006.