In our study, the most common time of onset for HLH in pregnancy was in the second trimester of pregnancy, followed by the third trimester, which is similar to the previous studies (Table 3). Our hypothesis for these phenomena is that pregnancy may be a regulatory immune state, immunologic alterations with advancing pregnancy impair the clearance of pathogens, resulting in an increased frequency of disease caused by some pathogens [8, 9].
There is currently no guideline for HLH during pregnancy. Treatments are mostly selected on clinical experience and clinical manifestations. In general, the treatment of HLH includes inhibition of life-threatening inflammatory responses using immunosuppressive agents and cytotoxic drugs, treatment of the underlying cause, or both. As for the causes of HLH in pregnancy, among the 13 patients in this study, 5 had autoimmune diseases, 1 with parvovirus B19 infection, and 7 with unclear causes. The prognosis is variable with different underlying diseases. We found that patients with autoimmune diseases and viral infections have good outcomes and the patients for whom causes were not known had worse outcomes with respect to maternal health.
The widely used standard treatment schemes at present are HLH-1994  and HLH-2004 . Medications should be carefully considered. Corticosteroids are part of the HLH-1994 and HLH-2004 regimens—reducing immune system activity and inhibiting the inflammatory response—and are classified as category C drugs by the U.S. Food and Drug Administration (FDA). During pregnancy, especially after the first trimester, women taking corticosteroids have a relatively low risk of birth defects. Regardless of the precipitating cause, corticosteroids are the first choice for most pregnant patients with HLH. In previous reports, 38 (95%, 38/40) women were treated with corticosteroids as the initial treatment, and 12 (31.6%, 12/38) manifested a curative effect. Of the 13 patients with HLH in this study, 12 (92.3%, 12/13) were treated with corticosteroids and 5 (41.7%, 5/12) showed a curative effect.
The Topo II inhibitor etoposide is one of the essential drugs in HLH-94 and HLH-04 regimens. Prognostic factors of adult hemophagocytic syndrome indicated that the use of etoposide as the first-line treatment tended to be associated with a better outcome . Etoposide is a cell cycle-specific antitumor drug that is classified as category D by the FDA. Etoposide is commonly used in the treatment of ovarian cancers, and it is considered safe for the fetus if given during the second or third trimester. No neonatal malformations have been reported . Song et al.  reported the use of etoposide in a pregnant patient with HLH. No congenital malformations were found in the fetus. However, in a study performed in mice, etoposide had adverse effects on fetal ovarian development. Exposure of pre-follicular ovaries to etoposide resulted in a near-complete elimination of germ cells prior to follicle formation . In the current study, four patients were treated with etoposide, of whom one was treated during pregnancy, and we observed no abnormalities in the neonates. Our other three patients were treated after delivery, and two achieved CR, while one died of multiple organ failure 22 days after delivery. The number of cases of etoposide application during pregnancy was small; the timing, dose and frequency of the drug—as well as the effect of the drug on the fetus—still require further investigation.
CsA may be an effective treatment for patients with HLH who do not show a response to corticosteroids . In our study, two patients were treated with CsA, including one with the combination of hydrocortisone and CsA, and one with the combination of dexamethasone, etoposide, and CsA. The FDA classifies CsA as class C drug for pregnancy. CsA can inactively cross the placenta and enter the fetal circulation . A systematic review suggested that use of CsA during pregnancy is associated with premature delivery and low birth weight, but it is difficult to determine if any risks associated with CsA therapy during pregnancy are due to drug exposure alone or to pre-existing maternal comorbidities .
Patients with HLH in pregnancy can go into remission after termination of pregnancy. Teng et al.  hypothesized that the pathogenesis of HLH during pregnancy was similar to preeclampsia, where the immature placenta releases genetically foreign material into the maternal circulation. Maternal T-lymphocytes (which are unable to recognize unfamiliar human lymphocyte antigens), may then trigger a systemic inflammatory response and cytokine storm. Termination of pregnancy may thus prevent the maternal condition from continuing to deteriorate and allow for timely chemotherapy. In previous studies, six patients (40%, 6/15 from a total of 40 cases) attained remission after termination of pregnancy [3–5, 11, 15, 27], including four with unclear causes, one complicated by SLE, and one complicated by autoimmune hemolytic anemia. In our study, termination of pregnancy was effective in two patients. However, the condition of six cases was exacerbated or did not improve after termination of pregnancy. The overall effect of termination of pregnancy is still controversial in HLH. The relationship between pregnancy and HLH requires further elucidation. If corticosteroid treatment is ineffective, termination of pregnancy may be an effective method of treatment.
There are inherent biases to our study because it was a retrospective study conducted in a referral center. The majority of patients worsen at the local hospitals. Therefore, this may have generated bias in the evaluation of treatment effects. Additionally, the details of most neonatal outcomes were relatively unclear. Therefore, it is important to perform more investigations to develop a standard treatment protocol for HLH in pregnancy.