Second and third trimester intrauterine fetal death WHO misoprostol guidelines Draft 2/11/07, Page 1

CHAPTER 8: INTRAUTERINE FETAL DEATH

AUTHORS: Rodolfo Gomez, Deborah Wing, Christian Fiala

INTRODUCTION The frequency of intrauterine fetal death (stillbirth) with a retained fetus varies but is estimated to occur in 1% of all pregnancies. This clinical situation is psychologically stressful for the woman and her family members, and for the health professionals providing care. When a fetus dies in uterus, the options for health care are either to await onset of spontaneous labor or to induce labor (Silver, 2007). The vast majority (over 90%) of women will have labor and deliver within three weeks of the intrauterine death. Expectant management remains an acceptable option in same settings for this diagnosis. In cases where expectant management is chosen, the clinical concern will be the development of disseminated intravascular coagulation with its inherent risks of haemorrhage, blood product transfusion and maternal death. As induction of labor is a common and evidence based practice of obstetrics, in cases of intrauterine fetal death (IUFD) with a retained fetus, the choice to induce labor in a patient with ripe cervix is straightforward and the procedure often uncomplicated. But the complexity in medical management increases significantly when the cervix is unripe or unfavourable (Bishop score < 6). Inducing labor in a pregnant woman with an unripe cervix is associated with failed induction of labor and a higher risk of caesarean delivery. This problem has been dramatically reduced with the local or systemic use of prostaglandins and other mechanical methods of cervical ripening prior to intravenous oxytocin administration for labor induction. There is no gold standard, either medical or surgical, for treatment of late IUFD. Oral misoprostol administration for labor induction with an IUFD was first described in Sao Paulo, Brazil in 1987 (Mariani-Neto, 1987). Since that time, misoprostol use for obstetrical purposes has grown widely. There are dozens of reports, many policy statements, reviews, and meta-analyses describing its use for induction with live fetuses. Unfortunately, there is lack of uniformity in the dose and frequency of misoprostol dosing when used for induction of labor in the second and third trimester, and very few good quality randomized controlled trials for its use in utero fetal death.

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The issues related to proper use of misoprostol are somewhat different for women who have need for labor induction in the face of IUFD compared to those with live fetuses. This is because the issues related to fetal wellbeing are eliminated; however, the possibility of disseminated intravascular coagulation complicating IUFD jeopardizes the womens life. The concerns regarding other side effects such as uterine overactivity (hyperstimulation, hypertonus and tachysystole) and systemic response (nausea, vomiting, diarrhoea and shivering), as well as safety remain with the use of misoprostol for labor induction with IUFD as in cases where misoprostol is used for induction with live fetuses. For induction for IUFD, vaginal misoprostol is as effective as dinoprostone (Jain 1994) and gemeprost (Eng 1997), and less costly. (Level I). When vaginal misoprostol is administered simultaneously with laminaria placement, there is no increase efficacy (Jain 1996) (Level I). Pre-induction administration of oral mifepristone may enhance the success of labor induction for women with IUFD, but the existing data are sparse and further research is needed (Wagarrachi XX, Wagarrachi XX) (Level III). There is a limited high quality and homogeneous evidence base in peerreviewed journals for misoprostol use for labor induction with IUFD. The vast majority of reports are descriptive series or non-randomized prospective comparisons. Cases series report shorter time until delivery and lower doses required of misoprostol to obtain success in cases of IUFD compared with live fetuses. (Srisomboon 1998, Dodd 2005). DEFINITIONS Intrauterine fetal death: Intrauterine pregnancy beyond 12 weeks with a dead fetus, which has not been expelled; in the second and third trimester, also known as stillbirth. Disseminated intravascular coagulation: A consumptive coagulopathy occasionally seen in conjunction with second or third trimester in uterus fetal death. INDICATIONS Vaginally applied misoprostol for cervical ripening and labor induction is indicated in all cases of IUFD with a retained fetus and an unfavourable cervix. This is true regardless of stage of the pregnancy, as long as there is no contraindication for vaginal delivery or misoprostol use. Although indicated at any gestational age, it is particularly useful in the second trimester (defined as 13 to 26 weeks), when uterine evacuation often proves more difficult due to the myometrium's low responsiveness to oxytocin, lack of ready availability of surgical methods, and the risks associated with these surgeries. CONTRAINDICATIONS Allergy to prostaglandins and vaginal delivery.

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In clinical conditions which complicate IUFD as placenta praevia and transverse presentation up to 24 weeks may be appropriate to use misoprostol, depending on the skills of the health care providers and the settings in which care is being rendered. PRECAUTIONS When vaginal misoprostol is used for induction in a woman with a live fetus and a history of prior caesarean or uterine surgery, there is an increased risk of uterine rupture.56-58 The majority of studies of induction using misoprostol for second and third trimester IUFD, however, did not include women with previous uterine scars from Caesareans. But when they were included, there were no cases of uterine rupture, including during early second trimester18,45,48,49,61-65 Surveillance for disseminated intravascular coagulation should occur, although the consumption of coagulation factors is a gradual process that usually occurs over weeks after the fetal death. If the patient has disseminated intravascular coagulation, blood transfusion should be given to correct the coagulopathy prior to the induction. REGIMEN The spectrum of dosing regimens for vaginal misoprostol administration described in the literature for cervical ripening and induction of labor for second and third trimester IUFD range from 50 to 400 micrograms given every 3 to 12 hours by varies routes of administration. All have been shown to have clinical effect. 8-72 Nevertheless, the current evidence base supports the conclusion that the most appropriate application is per vagina.33,45,48-52 (Level I, strong recommendation) For IUFD from 13 to 26 weeks33,67,43,44 (Fadalla 2004)(Jain 1994) Place tablet deep within the vagina. Start with doses of: o 200 mcg if fetal death occurred between 13 and 17 weeks' gestation. (Level I, strong recommendation) o 100 mcg if fetal demise occurred between 18 and 26 weeks' gestation. (Level I, strong recommendation) o Repeat the dose every 6 to12 hours for a total of 4 doses. (Level I, strong recommendation) If the first treatment course did not lead to effective contractions the subsequent dose can be doubled as follows: o 13 to 17 weeks: 400 mcg o 18 and 26 weeks: 200 mcg (Level IV) o If expulsion has not occurred the same treatment can be repeated the following day. o The maximum daily dosing should not exceed: o 13 to 17 weeks: 1600 mcg

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o 18 to 26 weeks: 800 mcg For IUFD beyond 26 weeks53-55,25,46,73 (Nakintu 2001) If the cervix is unripe, insert 25 to 50 mcg of misoprostol into the posterior vaginal fornix. If necessary, repeat every 3 to 6 hours for a total of 4 doses (Level I, strong recommendation).If the first treatment course did not lead to effective contractions the subsequent dose can be doubled to 50 or 100 mcg. (Level IV). The maximum daily dosing should not exceed: ???? If expulsion has not occurred the same treatment can be repeated the following day. o Oxytocin administration, if necessary, may begin after 4 hours following administration of the last dose of misoprostol.74-76
COURSE OF TREATMENT

Effectiveness Regardless of route of misoprostol administration, the vast majority of women (67-83%) with late IUFD will deliver vaginally within 24-hours.48-50 (Level I) The remainder will deliver within the ensuing additional 24-hours.18,38,45,47,48,52 (Level II) If beyond this time delivery or abortion has not occurred, options include surgical termination, expectant management, or another induction attempt to be repeated in 24 hours after the first failed attempt (Level IV). These options should be weighed in the context of the urgency in evacuation of the uterus and the patients desires for expediency. Variables that influence success (defined as vaginal delivery within 24 hours) are: favourability of the cervix (Bishop score >6) and gestational age.13,50,51 Approximately 25% of women will have retained placental fragments; this is a complication that is seen more frequently with second trimester inductions for IUFD than those in the third trimester (de Heus, Fadalla). Repeated dosing Before administering a repeated dose for IUFD beyond 26 weeks, uterine activity should be evaluated. If the patient has 2 or more contractions in 10 minutes, the dose should not be repeated, because of the risk of uterine hyperstimulation. If the uterine contraction frequency diminishes, a repeat dose may be given. If, however, the uterine contraction frequency persists or the patient has demonstrated sufficient progress in cervical dilatation, intravenous oxytocin can be administered. We recommend that oxytocin should not be initiated until four hours following administration of the last dose of misoprostol. Maximum daily dosing should not exceed the following: o 13 to 17 weeks: 800 mcg o 18 to 26 weeks: 1600 mcg o Beyond 26 weeks: 200 mcg

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(Level IV, strong recommendation) Monitoring Clinical monitoring of the women should continue after delivery or expulsion because of the risk of postpartum atony and/or placenta retention. Both may cause postpartum hemorrhage. Etiologies for IUFD should be sought as appropriate for the institution.78 Similarly, bereavement and psychological support services should also be provided to women before, during and after delivery of an IUFD. Risks There are no reports of maternal mortality and few reports of added morbidities such as chorioamnionitis or excessive blood loss. In circumstances where blood product transfusion was needed, many of the women had underlying malarial parasitemia which predisposed to this need.46 (Level II) EFFECTS AND SIDE EFFECTS: The most commonly reported side effects include.24,33 Cramping: Uterine contractions are frequently painful. Pain treatment such as NSAIDs and opioids may be used. Prophylactic administration should also be considered. Gastrointestinal side effects as nausea, vomiting, and diarrhoea, up to 35% Pyrexia and shivering, up to 7% The most serious complications associated with intravaginal misoprostol use for IUFD are premature separation of placenta, post-partum haemorrhaging, and rare events such as uterine rupture [particularly when used in women with prior Cesareans] and amniotic fluid embolism. 33 This requires close vigilance in observing women who are treated with misoprostol. USE OF MISOPROSTOL IN THE COMMUNITY AND AT DIFFERENT HEALTH CARE LEVELS Patients undergoing labor induction for second or third trimester IUFD should deliver, whenever possible, in secondary or tertiary hospitals or comprehensive emergency obstetric care (EmOC) qualified facilities (Main et al 1997), based in the possible complications (Level I-II, strong recommendation). FREQUENTLY ASKED QUESTIONS Is it safe to use misoprostol for patients with IUFD and previous Caesarean sections?

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Answer: The risk for uterine rupture may increase in these cases, especially in the third trimester. Therefore, it is advisable to use lower dose of misoprostol under close clinical monitoring. 18,45,49,61-65(Level II) When should oxytocin be added after misoprostol ? Answer: Oxytocin may be added only when the cervix is ripe, and regular uterine contractions have not yet developed.. (Level II, strong recommendation) How frequently will this treatment be effective? Answer: Most studies show a success rate of close to 100 per cent. (Level I) How should pain be managed for labor induction for IUFD? Answer: Pain should be treated in accordance with local standards. These treatments may include non-steroidal anti-inflammatory agents, narcotics and epidural analgesia.

OPEN QUESTIONS AND RESEARCH SUGGESTIONS 1. Are higher misoprostol doses or shorter dosing intervals compared to the suggested regimens appropriate for labor induction with second and third trimester IUFD? 2. When available, what is the impact of pre-induction with mifepristone on the success of induction for IUFD? 3. Is it safe to give misoprostol or continue to be given after a woman achieves adequate cervical ripening and/or enters early labor? 4. What is the safety and efficacy of buccally administered misoprostol for labor induction for IUFD? 5. Could misoprostol could be used for retained placentas in second trimester IUFD?

Condensed guidelines
DEFINITION CONTRAINDICATIONS Contraindications are: Allergy to misoprostol and vaginal delivery PRECAUTIONS A history of caesarean section(s) or uterine scarring increases the risk of uterine rupture. The risk for disseminated intravascular coagulation needs to be addressed. REGIMEN

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The more advanced the pregnancy the lower the starting dose of vaginally applied misoprostol should be: For IUFD from 13 to 26 weeks: Start with doses of: 200 mcg between 13 and 17 weeks' gestation. 100 mcg between 18 and 26 weeks' gestation. For IUFD beyond 26 weeks If the cervix is unripe, 25 to 50 mcg. If the cervix is ripe, oxytocin is the treatment of choice. If not available or not effective, the same regimen as for an unripe cervix should be given. If oxytocin is necessary, begin after 4 hours following administration of the last dose of misoprostol. Repeated treatment Repeat the dose every 6 to 12 hours for a total of 4 doses. If the first treatment course did not lead to effective contractions, it may be appropriate to double the subsequent dose: o 13 to 17 weeks: 200 mcg o 18 to 26 weeks: 400 mcg o Beyond 26 weeks: 50 mcg Maximum daily dosing in each of these cases should not exceed the following: o 13 to 17 weeks: 800 mcg o 18 to 26 weeks: 1600 mcg o Beyond 26 weeks: 200 mcg If expulsion has not occurred in a timely manner, the same treatment regimen can be repeated the following day. COURSE OF TREATMENT Confirm fetal death with the available methods. Inform the patient of the clinical scenario, its risks and proposed treatments. Check platelet count and coagulation laboratory studies. Repeated doses must be avoided if the patient has 2 or more contractions in 10 minutes. EFFECT AND SIDE EFFECTS Cramping: Available pain treatment, including NSAIDS and opioids, should be given. Prophylactic treatment is also appropriate. Gastrointestinal side effects as nausea, vomiting, and diarrhoea Pyrexia and shivering

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References