Association between infection and fever in terminations of pregnancy using misoprostol: a retrospective cohort study

Termination of pregnancy (TOP) in case of intra uterine fetal death (IUFD) or in pregnancies complicated by congenital abnormalities is a frequently practiced procedure worldwide [1]. Worldwide, every year 22% of all pregnancies (46 million) result in an induced abortion; this includes both medical and surgical methods [1, 2]. Most terminations of pregnancy are performed before 12 weeks of gestation and are mostly performed by dilatation and curettage. Yet approximately 10 to 15% are performed in the second trimester, defined as 12 to 28 weeks of gestation, and are mostly conducted medically. These second trimester TOPs are responsible for two-thirds of all major complications in TOPs, including severe haemorrhage and infection [1, 3] In addition, the number of second trimester TOPs has increased since the introduction of prenatal screening programs following an increase in detection rate and earlier detection of fetal anomalies [1, 2].

The most efficient regimen for a medical TOP is a combination of mifepristone, an antiprogesterone, and vaginally administered misoprostol, a synthetic prostaglandin E1 analogue [4]. Misoprostol was originally developed for prevention and treatment of peptic ulcer disease. A side effect of misoprostol is uterine contractility and cervical ripening which has led to its off-label use for TOP [1, 5]. Fever is a well-described side effect of misoprostol [1, 3, 5]. The incidence of fever as a side effect of misoprostol reportedly varies from 10 up to 50% [1, 5‐11]. The majority of fever is temporary and resolves spontaneously. However, clinically, fever as a side effect of misoprostol and fever caused by intra uterine infection can be difficult to distinguish. Another explanation for the development of fever after administration of misoprostol is that prostaglandin interferes with the hypothalamus (where the body temperature is regulated) by a shift in the temperature set point, which results in a systemic response of increased temperature [12].

Recent research showed that clinical signs of an infection are not accurate in the diagnosis intra uterine infection in term parturients [13]. The significance of fever as an indicator of intra uterine infection in women undergoing TOP has never been addressed in literature. The increasing incidence of epidural analgesia during labour, which is also associated with fever, makes this distinction even more difficult [14]. One of the consequences of incorrectly interpreting fever as a sign of infection is the unnecessary administration of antibiotics adding to the growing problem of bacterial resistence [15].

The primary aim of this study is to determine the incidence and evaluate the test characteristics of fever in second trimester TOP using misoprostol for the prediction of intra uterine infection.

In the period January 2008 till October 2012, 458 terminations of pregnancy took place. A total of 403 women were included. Women were excluded for the following reasons: (1) fever before induction of labor (n = 11), (2) incomplete medical charts (n = 30) or (3) protocol violation of misoprostol dosage (n = 14).

Of all women, 168 (42%) developed fever. The majority of these patients (71.5%) had a rectal temperature between 38.0 and 38.9 °C. Most fever developed within 10 h after the start of induction and disappeared after expulsion. Compared to those who did not develop fever, women with fever more often were of advanced gestational age, more often were nulliparous, had a longer induction-expulsion time, and a higher total dosage misoprostol (Table 1).

We found an incidence of 42% of fever in terminations of pregnancy using misoprostol. Based on placenta pathology as the gold standard for defining intra uterine infection, fever had a positive predictive value of 4% in our study population, rendering it useless as a sign for the presence of an intra uterine infection. Our results show that in the majority of cases the presence of fever appears to be a side effect of misoprostol rather than a sign of an intra uterine infection. Furthermore a dose response relation was found, which makes the evidence of fever as a side effect of misoprostol stronger.

Fever is a well described side effect of misoprostol [1, 3, 5]. The mechanism of fever after administration of misoprostol, a Prostaglandin E1, has been investigated for the indication prevention of postpartum hemorrhage [12, 19]. Prostaglandins E-series are involved in the endogenous origin of fever by interfering with the hypothalamus, where body temperature is regulated, inducing a shift in the hypothalamic set point by interaction resulting in a systemic response. Due to this response, heat-creating effects are initiated to achieve increased temperature level [12]. On the other hand, fever is known to be associated with the presence of an infection. Infection is a serious maternal complication resulting in 15% of maternal death worldwide [20]. This underlines the importance of discriminating the cause of fever; drug induced or underlying intra uterine infection. The urge is for a sensitive test during labor. Since pathological conformation is the gold standard for intra uterine infection, we used the diagnosis only to confirm after delivery and to test its sensitivity. Table 1 describes the culture results. Only three out of 19 vaginal cultures turned out positive. One was positive for gardnerella vaginalis and candida albicans, which are not a likely cause of fever [21, 22]. The other showed positive for group B streptococcus (GBS). In 19% of pregnant women, GBS can be found in vaginal culture. Most of these women are asymptomatic [23]. Furthermore placentas of both patients with positive vaginal cultures did not show signs of infection.

In the majority of the cases the presence of fever seems to be a side effect and not a sign of an intra uterine infection. There were no patients in septic shock or critically ill in this study population. As in most cases fever developed within 10 h after the start of induction and disappeared after expulsion, it might be sufficient to only administer antipyretic drugs such as paracetamol, and IV-fluids. The use of antibiotics during termination of pregnancy using misoprostol is therefore debatable. Given the increased levels of antibiotic resistance [14], it is recommendable to be cautious with initiating antibiotic therapy until other clinical signs of infection are more likely. Future research should focus on prospective data collection of women with a second trimester TOP using misoprostol, with placental histopathological examination of all placentas, blood samples and cultures. Recent research has shown that procalcitonin is a useful predictor for bacterial infection [24]. It could be interesting to investigate whether procalcitonin can also be useful in the prediction of intra uterine infection in patients with second trimester TOP using misoprostol. Combining all data might lead to development of a prediction model for the presence of a intra uterine infection.

In conclusion administration of misoprostol for the indication TOP is highly associated with fever during labor, but fever has no accurate test characteristics for the presence of an intra uterine infection.