Second and third trimester intrauterine fetal death WHO misoprostol guidelines

Draft 2/26/07, Page 1

CHAPTER 8: INTRAUTERINE FETAL DEATH
AUTHORS: Rodolfo Gomez, Deborah Wing, Christian Fiala
INTRODUCTION
The frequency of intrauterine fetal death 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 some 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), 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 IUFD.
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, diarrhea 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. The additional use of cervical
laminaria with misoprostol does not increase its efficacy (Jain 1996) (Level I), but
pre-induction administration of oral mifepristone shortens the time needed for labor
induction (Wagaarachi 2002, Fairley 2005). Mifepristone is, however, not widely
available.

There is a limited high quality and homogeneous evidence base in peer- reviewed
journals for misoprostol use for labor induction with IUFD (Neilson, 2006, Clark,
2007). 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). There is a wealth of data for second
trimester pregnancy termination which are useful and can be applied to IUFD in the
second trimester (Clark, 2007). Similarly, data for labor induction with live fetuses
can be applied to IUFD in the third trimester (Hofmeyr 2003). Further research
specifically for both second and third trimester labor induction with IUFD is needed.
DEFINITIONS
Intrauterine fetal death (IUFD): Intrauterine pregnancy beyond 12 weeks with a
dead fetus, which has not been expelled.
Disseminated intravascular coagulation: A consumptive coagulopathy occasionally
seen in conjunction with second or third trimester intrauterine 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 contraindications to vaginal delivery. The latter
includes placenta previa and transverse lie, although in those circumstances where
placenta previa and malpresentation complicate IUFDs up to 24 weeks, it may be
appropriate to use misoprostol, depending on the skills of the health care providers
and the setting.
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. 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 (Jain 1994, Jain 1996, Srisomboon 1998, Hidar 2001, Makklouf 2003,
Fadalla 2004, Niromanesh 2005,), But in the studies in which they were included
there were no cases of uterine rupture, including during early second trimester
(Nakintu 2001, Rouzi 2003, Caliskan 2005, Dodd 2005) Herabutya 2003, Pongsatha
2004, Dickinson 2005, Daponte 2006). In women with previous cesarean births,
lower doses should be used and doubling should not occur
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
various routes of administration. All have been shown to be clinically effective.
Nevertheless, the current evidence base supports the conclusion that the most
appropriate application is per vagina (Jain 1994, Fletcher 1996, Yapar 1996, Nakintu
2001, Wagaarachi 2002, Chittacharoen 2003, Hofmeyr 2003, Fawole 2004, Nyende
2004, Pongsatha 2004, Dodd 2005, Niromanesh 2005). (Level I, strong
recommendation)
For IUFD from 13 to 26 weeks (Jain 1994, leRoux 2001, Dickinson 2003, Hofmeyr
2003, Ngai 2003, Fadalla 2004, Niromanesh 2005)
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)
Repeat the dose every 6 to12 hours for a total of 4 doses.(Level I, strong
recommendation) If the first dose does not lead to effective contractions the
subsequent dose could be doubled as follows:
o 13 to 17 weeks: 400 mcg
o 18 and 26 weeks: 200 mcg (Level IV)
o The maximum daily dosing should not exceed:
o 13 to 17 weeks: 1600 mcg o 18 to 26 weeks: 800 mcg
For IUFD beyond 26 weeks (Bugalho 1994, Hofmeyr 2003, Chittacharoen 2003,
Nakintu 2001, Nyende 2004, Fawole 2005)
If the cervix is unripe, insert 25 to 50 mcg of misoprostol into the posterior
vaginal fornix. If necessary, repeat every 4 hours (Level I, strong
recommendation).If the first dose does not lead to effective contractions the
subsequent dose could be doubled to 50 or 100 mcg (Level IV).
o The maximum daily dosing should not exceed: 600 mcg
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. COURSE OF TREATMENT
Effectiveness
Regardless of route of misoprostol administration, the vast majority of women (6783%) with late IUFD will deliver vaginally within 24-hours (Jain 1994, Draycott 1996,
Nakintu 2001, Chittacharoen 2003, Nyende 2004, Dodd 2005,). (Level I) The
remainder will deliver within the ensuing additional 24-hours (Mariani-Neto 1987,
Jain 1994, Draycott 1996, de Heus 2004, Nyende 2004, Dodd 2005) (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), parity and gestational
age (Hofmeyr 2003, Chittacharoen 2003, Fawole 2004).

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 2004, Fadalla 2004).
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: 1600 mcg
o 18 to 26 weeks: 800 mcg
o Beyond 26 weeks: 600 mcg
(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 (Silver, 2007).
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 (Bugalho,1994). (Level II)
EFFECTS AND SIDE EFFECTS:
The most commonly reported side effects include (Hofmeyr 2003, Neilson 2006):
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 (Hofmeyr 2003). 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 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?
Answer: The risk for uterine rupture may increase in these cases, especially in the
third trimester. Therefore, it is advisable to use lower doses of misoprostol under
close clinical monitoring (Mariani-Neto 1987, Jain 1994, Nakintu 2001, Herabutya
2003, Dickinson 2005, Pongsatha 2003, Rouzi 2003, Daponte 2006). (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 at 48 hours.
(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 orally or buccally administered misoprostol for
labor induction for IUFD?
5. Could misoprostol could be used for retained placentas in second trimester IUFD?

Condensed guidelines
DEFINITION
Intrauterine fetal death: Intrauterine pregnancy beyond 12 weeks with a dead fetus,
which has not been expelled.
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. In these cases, lower doses should be used and doubling should not
occur.The risk for disseminated intravascular coagulation needs to be addressed.
REGIMEN
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
For IUFD between 13 and 26 weeks, repeat the dose every 6 to 12 hours
for a total of four doses. If the first dose does not lead to effective contractions, it
may be appropriate to double the subsequent doses:
o 13 to 17 weeks: 200 mcg
o 18 to 26 weeks: 400 mcg
For IUFD beyond 26 weeks, repeat the dose every 4 hours. If the first
dose does not lead to effective contractions, it may be appropriate to double the
subsequent dose to 50 or 100 mcg (depending on starting dose).
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
Beyond 26 weeks: 600 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 diarrhea
Pyrexia and shivering