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Fetal death and stillbirth: Incidence, etiology, and prevention

Authors: Ruth C Fretts, MD, MPH, Catherine Spong, MD

Section Editor: Charles J Lockwood, MD, MHCM
Deputy Editor: Vanessa A Barss, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2018. | This topic last updated: Jan 08, 2019.

INTRODUCTION — The terms fetal death, fetal demise, stillbirth, and stillborn all refer to the delivery of a fetus
with no signs of life. The terms will be used interchangeably in this topic review. It should be noted that parent
groups prefer the term stillbirth to the other terms. The ability to call a fetal loss a stillbirth is important to
parents, in part because birth and death certificates are not generated after a miscarriage. In addition, parents
report they receive less grief support after a miscarriage than after a stillbirth and less acknowledgment of the
death of their child.

The incidence and etiology of fetal death, as well as strategies for prevention, will be reviewed here. Diagnosis
and management of fetal demise, pathological evaluation of stillborns, and parental support and counseling are
discussed separately:

● (See "Evaluation of stillbirth".)

● (See "Fetal death and stillbirth: Maternal care".)

DEFINITION

Overview — Terminology regarding fetal death and stillbirth is complicated and confusing for several reasons,
including:

● Differences in definitions among countries.

● Differences between medical definitions and regulatory criteria for reporting fetal deaths.

● Use of birth weight versus gestational age thresholds for reporting fetal death and interpretation when these
values are discordant at the threshold distinguishing a fetal death from an abortus.

● Interpretation when there is a significant difference between the gestational age of fetal demise and the
gestational age at delivery. This is particularly problematic in multiple gestations with a demised sibling
before delivery of the live sibling.

● Inconsistent categorization as stillbirth of induced fetal demise and induced labor of previable fetuses (eg,
multifetal reduction, fetal anomaly).

● Incomplete data from low-income countries where many births occur at home and in remote areas.

Worldwide, the lower threshold for gestational age for defining stillbirth ranges from ≥16 weeks to ≥28 weeks of
gestation and the lower threshold for birth weight ranges from ≥400 g to ≥1000 g [1].
Stillbirths can also be subclassified as early stillbirths, which occur at 20 to 27 weeks of gestation, or late
stillbirths, which occur at ≥28 weeks of gestation. Although this division is somewhat arbitrary, the stratification
allows for relatively reliable comparison of international data for late fetal losses and allows division of stillbirths
into those that are early and difficult to prevent with any intervention from those that are late and potentially
preventable by preterm delivery.

World Health Organization definition — The World Health Organization (WHO) defines "fetal death" as death prior
to complete expulsion from the mother, irrespective of the duration of pregnancy [2]. The diagnosis of death is
based on absence of breathing or other evidence of life such as beating of the heart, pulsation of the umbilical
cord, or definite movement of voluntary muscle. All fetal deaths ≥500 g should be reported; when weight is not
available, gestational age ≥22 weeks is used as a criterion for reporting fetal death; if neither weight nor
gestational age is available, crown-heel length ≥25 cm is used as a criterion for reporting fetal death and
distinguishing a fetal death from an abortus.

For international comparison purposes, the WHO defines "stillbirth" as a baby born with no signs of life at ≥28
weeks [3]. However, stillbirths from 22 weeks to <28 weeks of gestation accounted for one-third of all stillbirths
in 2015, suggesting that these deaths should be included in routinely reported comparisons [4].

United States National Center for Health Statistics definition — The United States National Center for Health
Statistics defines stillbirth as loss after 20 weeks of pregnancy, with further division into early stillbirth (20 to 27
weeks), late stillbirth (28 to 36 weeks), and term stillbirth (>37 weeks) [5]. States have different reporting
requirements; most report fetal deaths that are ≥20 weeks of gestation and/or ≥350 g birth weight and use 20
weeks of gestation as the gestational age threshold for distinguishing a stillbirth from the product of a
miscarriage. The International Stillbirth Alliance also suggests this cutoff [6].

INCIDENCE AND EPIDEMIOLOGY

Global — Worldwide, the stillbirth rate has been falling from approximately 35 deaths/1000 livebirths in 1980 to
approximately 15 deaths/1000 livebirths in 2015 [7]. The reduction has been associated with improved access to
and utilization of antenatal care and skilled birth attendants and attention to known maternal risks for stillbirth.

When comparing stillbirth rates globally, the rates of late stillbirths are used (those 28 weeks of gestation or
later). Approximately 98 percent of these stillbirths occur in low- and middle-income countries [8]. Rates of
stillbirth in low-income countries have been substantially higher (approximately 21 deaths/1000 livebirths) than
in high-income countries (approximately 3 deaths/1000 livebirths) [7]. However, declines in the past decade have
been reported. A study in low- and middle-income countries (Zambia, Kenya, India, Pakistan, Guatemala) found a
3 percent decline in stillbirth from 2010 to 2016 (from 31.7 deaths per 1000 livebirths and fetal deaths to 26.4
deaths per 1000 livebirths and fetal deaths) [9].

At least half of the stillbirths in low-income countries occur during labor and birth, largely because of a lack of
skilled birthing attendants and facilities for cesarean delivery [8]. Antepartum stillbirths are often related to
maternal infection or fetal growth restriction. Pregnancy-induced hypertension that is not identified and
appropriately managed with induction of labor is another common cause of both fetal and maternal death in
these countries.

United States — In the United States, the stillbirth rate is 2.84 per deaths per 1000 livebirths [7] and 5.96 deaths
per 1000 livebirths and fetal deaths [10]. Approximately 50 percent of the fetal deaths occur between 20 and 27
weeks (primarily from 20 to 23 weeks of gestation), and the other 50 percent occur at ≥28 weeks [10]. The
number of fetal deaths is higher than the number of neonatal deaths and the number of infant deaths.

Sociodemographic factors affecting the fetal death rate:

 ● Black race – The fetal mortality rate was highest for non-Hispanic blacks (10.53 deaths per 1000 livebirths
and fetal deaths) and lowest for non-Hispanic whites (4.88 deaths per 1000 livebirths and fetal deaths).
While some of this increased risk can be attributed to access to, and quality of, medical care, other factors
also contribute as black women experience a higher rate of stillbirth even when they have adequate access
to prenatal care [11]. The increased risk in black women has been attributed to poorer preconception health,
lower income, increased stress and racism, and a higher rate of infection. Genetic, behavioral, and
environmental factors may be involved in the disparity as well as unknown factors. In addition, black women
appear to be less likely than women of other races to be induced at term despite their higher rates of
diabetes mellitus, hypertension, placental abruption, and term stillbirth [12], which also may account for
some of the disparity.

● Younger and older age – The fetal mortality rate was lowest for women ages 25 to 34 and higher for
teenagers and women ≥35 years of age. Older age appeared to be an independent risk factor for fetal death
after adjusting for medical/obstetric conditions more common among older women (eg, hypertension,
diabetes, multiple gestation) [13,14] (see "Effects of advanced maternal age on pregnancy"). Unexplained
stillbirth is the only type of stillbirth that is statistically more common in older women. (See 'Unexplained
stillbirth' below.)

● Unmarried status – The fetal mortality rate for unmarried non-Hispanic white women was 44 percent higher
than for married non-Hispanic white women, whereas differences were smaller for non-Hispanic black
women (14 percent difference) and Hispanic women (difference 11 percent). Marital status can affect
availability of social, emotional, and financial resources.

Effect of plurality and fetal sex on the fetal death rate:

● Multiple gestation – Fetal mortality increases with increasing number of fetuses: 2.5-fold higher for twins
than singletons, fivefold higher for triplets or more. The increased rate in multiples is due to complications
specific to multiple gestations (such as twin-twin transfusion syndrome and twin reverse arterial perfusion
sequence) as well as complications, such as fetal anomalies and growth restriction, which can occur in any
pregnancy. Monochorionic placentation accounts for most of the increased risk. (See "Twin pregnancy:
Prenatal issues", section on 'Fetal complications'.)

● Male sex – Fetal mortality is higher for male fetuses than female fetuses among non-Hispanic white and
black women.

Prospective rate of fetal death — In clinical studies, researchers are increasingly citing the prospective fetal
mortality rate, which represents the number of fetal deaths at a given gestational age per 1000 livebirths and
fetal deaths at that gestational age or greater. In the United States in 2013, the prospective rate of fetal death at
20 to 22 weeks of gestation was high (0.52 to 0.56), declined at 29 to 33 weeks of gestation to its lowest level
(0.18 to 0.19), remained relatively low until approximately 37 weeks of gestation, and then began to climb at 38
weeks, increasing to its highest level at 42 weeks of gestation (0.62) [10].

ETIOLOGY AND RISK FACTORS — Stillbirth is the end result of a variety of maternal, fetal, and placental
disorders. The study of specific causes of stillbirth has been hindered by the lack of a uniform protocol for
evaluating and classifying stillbirth [15] as well as declining autopsy rates.

The relative frequencies of the various causes of stillbirth appear to differ between low- and high-income
countries [16-20] and between early and late gestation [21]. Obstructed/prolonged labor, preeclampsia, and
infection have been reported as common causes of stillbirth in low-income countries, whereas congenital or
karyotype anomalies, placental problems associated with growth restriction, and maternal medical diseases
appear to be common causes in high-income countries [19].
Early gestational fetal mortality appears to be related to congenital anomalies, infections, intrauterine growth
restriction, and underlying maternal medical conditions, whereas late gestational fetal mortality appears to be
due to both maternal medical disorders and obstetric disorders that generally evolve around the time of delivery,
such as placental abruption and previa, cord prolapse, marginal insertion of the umbilical cord into the placenta,
other labor and delivery complications, or unexplained.

Unexplained stillbirth — An unexplained stillbirth is a fetal death that cannot be attributed to an identifiable fetal,
placental, maternal, or obstetric etiology due to lack of sufficient information or because the cause cannot be
determined at the current level of diagnostic ability [22]. It is reported to account for 25 to 60 percent of all fetal
deaths [23-26]. Variation in the proportion of stillbirths reported as unexplained (or unknown or unclassified)
generally reflects (1) whether the stillbirth has been fully evaluated (ie, detailed evaluation of the mother, stillborn,
umbilical cord, placenta, and events leading up to stillbirth), (2) whether the classification system allows risk
factors to be included as causes, (3) subjective interpretation (speculation regarding mechanisms of death), and
(4) the population (a cause of death is more likely to be found in populations with generally high disease
burdens) [22,27]. As an example, the cause of stillbirth in a small for gestational age stillborn may be fetal growth
restriction in some systems but considered unexplained in others if the underlying etiology of the growth
restriction is unknown [23-25,28]. In these systems, growth restriction may be considered a "contributing factor"
rather than a cause. A systematic review of classification systems for stillbirths found that the percentage where
the cause of death was unexplained ranged from 0.39 percent (Nordic-Baltic classification) to 46 percent
(Keeling system) [22].

Stillbirths occurring near term are more likely to be unexplained than stillbirths occurring earlier in gestation.
Two-thirds of unexplained fetal deaths occurred after 35 weeks of gestation in one series [23].

Fetal growth restriction — Death of a growth-restricted fetus is the second most common etiology of stillbirth
[21]. Placental dysfunction is the presumed cause of both growth restriction and death. The estimated risk of
stillbirth for growth-restricted fetuses is three to seven times that of the normally grown fetus [29-35]. In a
multihospital study in the United States that included 527 stillbirths, the median gestational age at death of the
growth restricted fetus was 28 weeks [35]. (See "Fetal growth restriction: Screening and diagnosis" and "Fetal
growth restriction: Evaluation and management".)

Conditions resulting in placental dysfunction can be recurrent, but the placental complications may manifest in
different ways in different pregnancies. Growth restriction, preterm delivery, and stillbirth can all be sequelae of
impaired placental function [29,36]. The association between the birth of a small for gestational age infant in one
pregnancy and stillbirth in a subsequent pregnancy has been reported in several studies [29,31,37]. The risk of
stillbirth in a subsequent pregnancy is particularly high if the small for gestational age infant was born preterm.
An analysis of data from the Swedish Birth Register is a representative example of these data (table 1) [29].

Placental dysfunction can be related to maternal vasculopathies or intrinsic placental disease.

Abruptio placentae — Abruptio placentae occurs in approximately 1 percent of pregnancies but accounts for
between 10 and 20 percent of all stillbirths [21]. The risk of fetal death is highest when more than 50 percent of
the placental surface becomes separated or when the abruption involves the central aspect of the placenta. (See
"Placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

Infection — Infection accounts for approximately 50 percent of stillbirths in low- and middle-income countries
and 10 to 25 percent of stillbirths in high-income countries [38]. Infection may lead to fetal demise as a result of
severe systemic maternal illness (eg, pneumonia), placental dysfunction due to placental infection (eg, malaria),
or fetal systemic illness (eg, Escherichia coli, group B Streptococcus, cytomegalovirus, Zika virus).
Most studies report infection is the cause of more preterm than term stillbirths. In high-income countries, the
majority of stillbirths related to infection occur in periviable fetuses following premature rupture of membranes
[21]. The usual mechanism is ascending infection from the lower genital tract. The rate of these losses has been
relatively stable over the past 30 years. Viral pathogens are the most common source of hematogenous infection
of the placenta, although bacteria, spirochetes, fungi, and protozoa can also cause transplacental infection.
Almost any systemic infection that occurs during pregnancy can infect the placenta but usually does not lead to
fetal death from infection. Malaria is a common cause of maternal infection leading to stillbirth in endemic
areas. Parvovirus, cytomegalovirus (CMV), toxoplasmosis, listeria, and herpes simplex virus are other well-
established maternal infections that can lead to stillbirth. Parvovirus and CMV infection are relatively common
and should be considered in stillbirths of unknown etiology after autopsy [39,40]. In 2016, Zika virus was also
associated with stillbirth [41], but the epidemic has subsided.

Diagnostic criteria for determining whether a fetal death is due to infection are not well defined and are
complicated by the relatively high frequency of asymptomatic maternal vaginal carriage of some potential
pathogens [42]. Histological evidence of both placental and fetal infection should be documented when citing
infection as the cause of fetal death. In some cases, however, an infected fetus may be unable to mount an
immune response, resulting in the absence of this evidence [43,44].

Genetic abnormalities — Most aneuploidies are lethal in utero. Some aneuploidies, such as trisomy 21, 18, and
13 and monosomy X, confer an increased risk of fetal demise, but also can result in livebirth. Although death of a
karyotypically abnormal embryo or fetus is most common in the first trimester, it can occur at all stages of
pregnancy [45-47].

In one study that karyotyped 823 stillbirths and neonatal deaths, 6.3 percent had a major chromosomal
abnormality [48]. The most common abnormalities were trisomies 18, 13, and 21; sex chromosome aneuploidy;
and unbalanced translocations. The frequencies of abnormal karyotype in macerated stillbirths, nonmacerated
stillbirths, and neonatal deaths were approximately 12, 4, and 6 percent, respectively, versus 0.7 percent in live
borns [24]. A study of registry data reported stillbirth rates (after exclusion of pregnancy termination) for trisomy
21, 18 and 13 were 5, 37, and 22 percent, respectively [49].

The combination of a congenital anomaly and stillbirth increases the likelihood of a chromosomal abnormality.
In one study of 750 stillbirths, chromosomal abnormalities were identified in 38 percent of anomalous stillborns
versus 4.6 percent of stillborns that were morphologically normal [50].

Information on genetic causes of stillbirth other than aneuploidy is sparse. Single gene defects and
microdeletions are examples of genetic causes of stillbirth that may be missed by a karyotype determined by
conventional cytogenetic analysis. Microarray analysis has a higher diagnostic yield and is increasingly being
utilized in the evaluation of stillbirth [51]. Ongoing research includes next-generation sequencing of cardiac
channelopathies [52]. (See "Use of chromosomal microarray in obstetrics", section on 'Fetal demise'.)

Congenital anomalies — Fifteen to 20 percent of stillbirths have a major malformation [21,45]. This rate varies
from country to country and is greatly influenced by the availability of prenatal diagnosis and pregnancy
termination. Fetal death can be attributed to a malformation if epidemiologic data support a relationship, the
anomaly is rare in live borns, neonates with the anomaly often die, or there is biologic plausibility for an
association [53]. Malformations associated with an increased risk of fetal demise, but unrelated to structural
chromosomal abnormalities, include abdominal wall defects, neural tube defects, Potter syndrome, homozygous
achondrogenesis, thanatophoric dysplasia, lethal multiple pterygium syndrome, and amniotic band sequence. In
a study of registry data, the isolated anomalies with the highest rates of stillbirth after exclusion of pregnancy
terminations were: anencephaly (51 percent), encephalocele (15 percent), arhinencephaly/holoprosencephaly
(12 percent), hydrocephaly (9 percent), hypoplastic left or right heart (9 percent), single cardiac ventricle (9
percent), spina bifida (6 percent), gastroschisis or omphalocele (6 percent), common arterial truncus (4 percent),
and diaphragmatic hernia (3 percent) [49].

Fetomaternal hemorrhage — Fetomaternal hemorrhage sufficiently large to cause fetal death has been reported
in up to 5 percent of stillborns [54,55]. Usually there is no identifiable etiology; however, case reports have
described associations with abruptio placentae, vasa previa, chorioangioma, choriocarcinoma, maternal trauma,
cephalic version, and amniocentesis. (See "Spontaneous massive fetomaternal hemorrhage".)

Diabetes — Women with diabetes are at increased risk of stillbirth, particularly at or near term. As an example, a
multistate analysis from the United States reported that the term stillbirth rate among women with diabetes was
300/100,000 births, which was more than twice as high as the rate in the overall obstetric population of
130/100,000 births [56]. Hyperglycemia is one cause of stillbirth in diabetic pregnancies, but maternal obesity,
maternal vasculopathy, advanced maternal age, congenital anomalies, fetal cardiomyopathy, and fetal growth
restriction also can play a role [57]. The fetus of the diabetic mother is at risk for stillbirth primarily from two
mechanisms: (1) fetal hyperglycemia and hyperinsulinemia increase fetal oxygen consumption, which may
induce fetal hypoxemia and acidosis if the oxygen needs of the fetus are not met, and (2) maternal vasculopathy
and hyperglycemia can lead to reduced uteroplacental perfusion, which may be associated with reduced fetal
growth.

Hypertensive disorders — Hypertensive disorders are associated with a significant number of stillbirths in low-
income countries [8] and in high-income countries if the worsening of maternal/fetal condition is not
appreciated. Placental insufficiency and abruption are the major causes of fetal death in women with
hypertension. The appropriate management of chronic hypertension, gestational hypertension, and preeclampsia
can reduce the risk of stillbirth but preterm delivery is often necessary. (See "Gestational hypertension" and
"Management of hypertension in pregnant and postpartum women".)

Smoking, illicit drugs — A meta-analysis including 57 studies found that any active maternal smoking was
associated with increased risks of stillbirth (summary relative risk 1.46, 95% CI 1.38-1.54) [58]. (See "Cigarette
and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Stillbirth and neonatal
death'.)

In the United States Stillbirth Collaborative Research Network (SCRN), where the majority of cases and controls
agreed to be tested for evidence of smoking and illicit drugs, there was a linear relationship between the number
of cigarettes smoked and the risk of stillbirth, with a two- to threefold increased risk for women smoking ≥10
cigarettes/day [59]. In this study, passive smoking showed a similar pattern, with increasing risk with increasing
exposure. Nicotine replacement therapy is useful for helping women to stop smoking and does not appear to
increase the risk of stillbirth compared with nonsmoking women [60].

The role of illicit drug use in the risk of stillbirth has been difficult to estimate because most studies rely on self-
reporting, and drug testing generally requires consent. In the SCRN study, 7 percent of women who had a
stillbirth tested positive for an illicit drug compared with only 3.7 percent of women with livebirths (OR 1.9, 95%
CI 1.2-3.3). The most common drug detected in this study was tetrahydrocannabinolic acid, which was detected
in 3.8 percent of women with stillbirths versus 1.7 percent of women with livebirths. (See "Cigarette smoking in
pregnancy: Cessation strategies and treatment options" and "Substance use by pregnant women", section on
'Impact of selected drugs on pregnancy'.)

Umbilical cord abnormalities — Umbilical cord complications (eg, nuchal cord, knot, intrinsic cord abnormalities)
are often cited as a cause of fetal death in the third trimester [61-65] and accounted for 10 percent of 500 fetal
deaths in one population-based study [26]. Although nuchal cords and knots are relatively common (occurring in
15 to 34 percent of pregnancies at term) (see "Nuchal cord"), vascular constriction sufficiently severe to kill the
fetus rarely occurs. A nuchal cord or knot may provide the clinician and the patient with an immediate potential
explanation for the fetal demise; however, the cause of death should be attributed to a cord complication only
after a thorough search for other causes and when other findings support this diagnosis. (See "Gross
examination of the placenta", section on 'Umbilical cord' and "Nuchal cord", section on 'Fetal demise'.)

Placental abnormalities — Placental causes of stillbirth include abruptio placentae (see 'Abruptio placentae'
above), ruptured vasa previa (see "Velamentous umbilical cord insertion and vasa previa"), infection, neoplasm,
structural or vascular malformations, vasculopathy, and infarction. (See "The placental pathology report".)

Small placentas are associated with growth restriction; pathological causes of large placentas include hydrops
fetalis, maternal diabetes mellitus, and syphilis, which are also causes of stillbirth. For this reason, gross and
microscopic examination of the placenta is an integral part of the evaluation of stillbirth. (See "Evaluation of
stillbirth" and "Gross examination of the placenta".)

Confined placental mosaicism is identified in 1 to 2 percent of chorionic villus biopsy samples; 15 to 20 percent
of these pregnancies abort, develop fetal growth restriction, or end in stillbirth [53]. Outcome appears to be
determined by the specific chromosome involved (2, 3, 9, 14, 15, 16, and 18 alter outcome), whether the
abnormal line persists throughout pregnancy, the percentage of aneuploid cells, the cell line of the aneuploid
cells, and whether uniparental disomy is present. (See "Chorionic villus sampling", section on 'Confined placental
mosaicism'.)

Uterine abnormalities — Uterine rupture is a rare but devastating cause of intrapartum stillbirth. (See "Uterine
rupture: After previous cesarean delivery" and "Uterine rupture: Unscarred uterus".)

Structural uterine abnormalities, such as a unicornuate uterus, can be associated with cervical insufficiency,
which can lead to previable preterm birth. A pregnancy in a rudimentary horn may not develop to viability.

Amniotic band sequence usually causes fetal deformation but may also result in stillbirth if the umbilical cord is
constricted by a band. (See "Amniotic band sequence".)

Hydrops fetalis — Hydrops fetalis may be due to immune or nonimmune etiologies and is often fatal. Causes,
diagnosis, and management of these disorders are discussed separately. (See "Nonimmune hydrops fetalis" and
"Management of pregnancy complicated by Rhesus (D) alloimmunization".)

Arrhythmia — An unrecognized arrhythmia, such as long QT syndrome, may be a cause of unexplained fetal
demise. (See "Overview of the general approach to diagnosis and treatment of fetal arrhythmias".)

Platelet alloimmunization — Severe fetal alloimmune thrombocytopenia can result in intracranial hemorrhage

and death in utero. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy
management".)

Intrahepatic cholestasis of pregnancy — Intrahepatic cholestasis of pregnancy (ICP) causes pruritus without a

rash, typically in the late second or the third trimester. The total bile acid level is elevated, and transaminases are
often elevated. Fetal demise occurs in <5 percent of cases. (See "Intrahepatic cholestasis of pregnancy".)

PREDICTING PREGNANCIES AT RISK — Some risk factors for stillbirth are identifiable in the first trimester,
including:

● Maternal medical disorders (table 2)

● Nulliparity

● Cigarette smoking (see "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the
neonate", section on 'Stillbirth and neonatal death')
 ● Obesity (see "Obesity in pregnancy: Complications and maternal management", section on 'Asphyxia and
death')

● Advanced maternal age (see "Effects of advanced maternal age on pregnancy", section on 'Fetal death')

● Black race

● Previous stillbirth (see "Fetal death and stillbirth: Maternal care", section on 'Recurrence risk')

● Previous small for gestational age newborn or abruption

● Social issues (unmarried, history of intimate partner violence) [66-70]

● Recreational use of drugs (see "Substance use by pregnant women", section on 'Impact of selected drugs on
pregnancy')

● Conception via assisted reproductive technology (see "Pregnancy outcome after assisted reproductive
technology", section on 'Perinatal mortality')

● Maternal sleep-disordered breathing [71] (see "Obstructive sleep apnea in pregnancy")

A variety of risk factors have been evaluated in an attempt to create models that estimate patient-specific risk for
fetal loss, but none performs well enough to be clinically useful. One reason is that women with risk factors do
not account for the majority of stillbirths, and most risk factors do not lead to stillbirth [72].

Two laboratory tests commonly obtained in pregnant women have some predictive value, but no first-trimester or
early second-trimester test is clinically useful for predicting stillbirth [73].

● Biochemical tests obtained as part of population-based screening programs for Down syndrome, if
abnormal, are predictive of adverse pregnancy outcome, including fetal death. The utility of these tests for
predicting or preventing stillbirth is low, and pregnancy management is controversial. (See "First-trimester
combined test and integrated tests for screening for Down syndrome and trisomy 18", section on 'Prediction
of adverse pregnancy outcome'.)

● Hemoconcentration has been associated with an elevated risk of stillbirth. Plasma volume expansion and
lowered hemoglobin concentration are normal physiologic responses to pregnancy. Plasma volume
expansion appears to be important for fetal growth, and failure of physiologic hemodilution is associated
with an increased risk of stillbirth, even if the fetus is not growth-restricted. In an analysis of a Swedish
database, both an elevated hemoglobin at initial prenatal examination (initial hemoglobin ≥14.6 g/dL) and
failure of significant hemodilution over the course of pregnancy significantly increased the risk of
nonanomalous antepartum stillbirth (odds ratio 2.0, 95% CI 1.1-3.8), even after women with preeclampsia
and eclampsia were excluded [74]. However, this marker is uncommon: Only 5.6 percent of women with
stillbirth had an elevated hemoglobin level early in pregnancy.

STRATEGIES FOR PREVENTION OF STILLBIRTH

Basic interventions — A 2011 systematic review identified the following 10 interventions as those with the best
evidence for reducing the burden of stillbirth worldwide [75]:

● Periconceptional folic acid fortification

● Prevention of malaria

● Syphilis detection and treatment

 ● Hypertensive disorders of pregnancy detection and management

● Diabetes of pregnancy detection and management

● Fetal growth restriction detection and management [34]

● Post-term pregnancy (≥41 weeks of gestation) identification and induction

● Skilled birth attendant at birth [76]

● Availability of basic emergency obstetric care

● Availability of comprehensive emergency obstetric care

This list includes specific interventions that are effective for stillbirth prevention in low-income countries, where
the risk of stillbirth is high and availability of resources is low [19,75,77-80]. Most of these interventions are
discussed separately. (See "Folic acid supplementation in pregnancy" and "Malaria in pregnancy: Prevention and
treatment" and "Syphilis in pregnancy" and "Preeclampsia: Management and prognosis" and "Pregestational
diabetes mellitus: Obstetrical issues and management" and "Postterm pregnancy" and "Fetal growth restriction:
Evaluation and management", section on 'Pregnancy management'.)

Many of these interventions are also applicable to high-income countries, although no randomized trials have
demonstrated an effective method of reducing stillbirth in the general population of these countries. Stillbirth
prevention may be possible in some pregnancies at high risk of stillbirth (eg, fetal growth restriction, decreased
fetal movement, post-term pregnancy, maternal medical conditions) if these pregnancies are identified and
optimal medical and obstetric care are provided [80-83]. Studies in high-income countries suggest that
suboptimal medical/obstetric care accounts for 10 to 60 percent of perinatal deaths [83,84]. In population-based
studies, over 50 percent of fetal deaths have been attributed to either a fetus that is small for gestational age or
placental abruption [85]. In a large cohort study, the stillbirth rate was 2.4 deaths/1000 births in pregnancies
without fetal growth restriction, increasing to 9.7 deaths/1000 births with antenatally detected fetal growth
restriction, and 19.8 deaths/1000 births when it was not detected [34]. This suggests that strategies should be
developed toward risk assessment and management of these two conditions to reduce the number of fetal
deaths.

Appropriate medical and obstetric care can reduce the risk of stillbirth in women with some medical disorders
that carry an increased risk of stillbirth, such as poorly controlled systemic lupus erythematosus, pregestational
diabetes mellitus, or hyperthyroidism. (See "Pregestational diabetes: Preconception counseling, evaluation, and
management" and "Overview of thyroid disease in pregnancy".)

Additional interventions for significant modifiable risk factors include preconception weight reduction in obese
women, avoidance of delayed childbearing (ie, plan pregnancy before age 35 years), smoking cessation, and
avoidance of alcohol and recreational use of drugs [83]. Limiting the number of embryos transferred during in
vitro fertilization or multifetal pregnancy reduction could reduce the number of stillbirths related to multiple
gestation. (See "Strategies to control the rate of high order multiple gestation" and "Multifetal pregnancy
reduction and selective termination".)

Prenatal screening, diagnostic testing, and elective termination of pregnancies with major congenital anomalies
could reduce the proportion of stillbirths related to this etiology [86]. However, pregnancy termination merely
results in some potential stillbirths and neonatal deaths being classified as abortuses, which may not be
captured by national vital statistics. As an example, 7 percent of anencephalics in ongoing pregnancies are
stillborn [87], but pregnancy termination for this diagnosis is common (20 to 70 percent of cases) [88].
Even if the first stillbirth in an individual patient is not prevented, recurrent stillbirth may be prevented if the
etiology of the first loss can be determined and appropriate intervention is possible. This reinforces the concept
that a thorough stillbirth evaluation is important for prevention of stillbirth. (See "Fetal death and stillbirth:
Maternal care", section on 'Recurrence risk' and "Fetal death and stillbirth: Maternal care", section on 'Planning
future pregnancies'.)

Antepartum fetal monitoring — Theoretically, antepartum fetal monitoring in the late second or the third
trimester should reduce the risk of stillbirth by identifying fetuses in whom timely intervention will prevent death.
The best evidence that antepartum fetal monitoring can play a role in reducing stillbirth rates involves the use of
Doppler velocimetry for monitoring the growth-restricted fetus. The value of this approach is discussed in detail
separately (see "Fetal growth restriction: Evaluation and management", section on 'Pregnancy management').
The rationale for and the efficacy of various antepartum fetal monitoring techniques are also reviewed
elsewhere. (See "Overview of antepartum fetal surveillance".)

Monitoring fetal movement — Patients who report decreased fetal movement are at increased risk of having an
adverse pregnancy outcome, including stillbirth [89], and approximately half of stillbirths are preceded by
decreased fetal movement. In an internet-based survey of 215 women with stillbirths after 28 gestational weeks,
49 percent reported decreased and weak fetal movement before confirmation of fetal death, 18 percent reported
normal fetal movement, 16 percent described no fetal movement, 10 percent reported extremely vigorous fetal
movement followed by no movement, and 6 percent interpreted contractions as fetal movement [90]. A case-
control study of maternal perception of fetal movements in relation to late stillbirth in 41 maternity units in the
United Kingdom found that those with decreased frequency of fetal movements were at increased risk [91].

Monitoring fetal movement has been suggested as a means of identifying fetuses in whom timely intervention
will prevent death; however, the largest trial to evaluate a protocol of increasing maternal awareness and
reporting of reduced fetal movement coupled with a standard approach to evaluation and management found
that the intervention did not decrease stillbirth or perinatal mortality [92]. This topic is discussed in detail
separately. (See "Decreased fetal movement: Diagnosis, evaluation, and management".)

Perinatal audit — Developing strategies for stillbirth reduction requires an ongoing audit process to evaluate the
specific causes of stillbirth and the results of intervention programs [83]. As an example, perinatal audits have
identified stillbirths resulting from deficiencies in intrapartum care, and quality improvement processes have
been initiated to prevent recurrence [79,93]. Audits in the Netherlands, United Kingdom, and New Zealand found
substandard care in 20 to 30 percent of stillbirths, and the rate was as high as 60 percent for intrapartum
stillbirths [94]. An audit by the Confidential Inquiry into Stillbirths and Infant Death of Northern Ireland found that
failure to diagnose and appropriately manage fetal growth restriction was the most common error leading to
stillbirth, followed by failure to recognize additional maternal medical risk factors [95]. As discussed,
identification and optimal management of these disorders lowers stillbirth rates. Implementing a national audit
in the Netherlands, United Kingdom, and New Zealand has been associated with a significant reduction in late
stillbirths (≥37 weeks of gestation) [94].

Elective delivery at term — Studies consistently report that the risk of stillbirth increases late in pregnancy,
especially after 38 weeks of gestation [25,96-101]. A life-table analysis found that the risk of antepartum stillbirth
increased from 1 in 2000 women per week at 37 weeks of gestation to 1 in 500 at 42 weeks and 1 in 200 by 43
weeks [102]. Theoretically, elective delivery of women at term should prevent some stillbirths since fetal demise
can only occur in an ongoing pregnancy. However, in a trial of elective induction of labor at 39 weeks versus
expectant management in low-risk nulliparous women, induction did not reduce adverse perinatal outcome or
stillbirth [103]. Although elective induction is a reasonable option for patients who want to schedule their delivery
date, the differences in outcomes between the two approaches are small and do not warrant a strong
recommendation for one approach versus the other in low-risk women. (See "Induction of labor with oxytocin",
section on 'At 39 weeks or more'.)

However, a strategy of selective induction appears to be useful in pregnancies at high risk of stillbirth, such as
monoamniotic twin pregnancy, poor glycemic control in a pregnancy complicated by diabetes mellitus, or post-
term pregnancy. (See "Twin pregnancy: Labor and delivery" and "Pregestational diabetes mellitus: Obstetrical
issues and management" and "Postterm pregnancy".)

PREVENTION OF RECURRENT STILLBIRTH

Preconception management — Ideally, management of pregnancy in women with a prior stillbirth begins prior to
conception. Key interventions include optimizing medical status (eg, diabetes, thyroid disorders, hypertension);
discussing cessation of illicit drug, tobacco, and alcohol use, when appropriate; and optimizing body mass index,
if too low or high. (See "The preconception office visit", section on 'Maternal medical problems'.)

Pregnancy management — In women with a prior stillbirth, the challenge for the clinician is to assess the a priori
risk of stillbirth, discuss management options, determine the type and frequency of antepartum monitoring, and
determine when the maternal/fetal risks of ongoing pregnancy warrant intervention for delivery. There is no
evidence supporting any specific surveillance protocol to improve outcome of these pregnancies: we do the
following, based on data from observational studies, expert opinion, and our own clinical experience:

● Screen for diabetes – If the previous stillbirth was unexplained or related to fetal anomalies, we screen for
diabetes early in pregnancy and, if normal, repeat screening at 24 to 28 weeks. The odds of gestational
diabetes is fourfold higher after an unexplained stillbirth [104]. (See "Diabetes mellitus in pregnancy:
Screening and diagnosis", section on 'Our approach'.)

● We do not recommend any specific Down syndrome screening strategy for patients with a previous stillbirth.
However, if maternal serum biomarkers have been obtained in the course of Down syndrome screening, they
can also provide insight on the risk of adverse pregnancy outcomes, including stillbirth. As an example, a
low (<5th percentile) pregnancy-associated plasma protein A (PAPP-A) at 10 weeks is associated with a
significantly increased risk of stillbirth [105]. In the second trimester, an unexplained elevation of maternal
serum alpha fetoprotein (MSAFP) is associated with stillbirth [106]. In women with both a low PAPP-A and
high MSAFP, the risk of adverse outcome is increased synergistically [107]. On a case-by-case basis, taking
into account the degree of biomarker abnormality and the past pregnancy history, we educate patients about
the signs and symptoms of the most common complications of pregnancy and we may increase the
frequency of antenatal visits and ultrasound examination for fetal growth and amniotic fluid volume.

● Ultrasound examination

• For confirmation of gestational age, ideally in the first trimester

• For fetal anatomic survey at 18 to 22 weeks of gestation

• For assessment of fetal growth and amniotic fluid volume at 24 and 30 weeks

A history of stillbirth unrelated to fetal anomalies is associated with significantly higher frequencies of
complications in the subsequent pregnancy, including preterm birth, fetal growth abnormalities,
preeclampsia, and placental abruption [108,109]. The earlier the prior loss, the higher the risk of an adverse
outcome [110]. Therefore, close antepartum monitoring for these other outcomes is warranted. Given the
association with fetal growth restriction, accurate assessment of gestational age is essential for pregnancy
management, thus first trimester ultrasound to confirm dating is optimal.
 Serial assessment of fetal growth is also essential, and may be performed clinically, or if difficult, such as in
the setting of obesity, by serial ultrasound examinations. For women with a prior unexplained stillbirth with
growth restriction and/or evidence of uteroplacental insufficiency, ultrasound examination at 24 and 30
weeks of gestation is a common approach based on expert opinion. Doppler ultrasound of the umbilical
artery is performed if the fetus is growth restricted. (See "Fetal growth restriction: Evaluation and
management".)

● The association of both preeclampsia and fetal growth restriction with stillbirth should also prompt
consideration of low-dose aspirin prophylaxis in women with risk factors for preeclampsia (but not those
without risk factors for preeclampsia [111]). We follow United States Preventive Services Task Force
(USPSTF) guidelines for daily low-dose aspirin for women at high risk for preeclampsia [112]. In the absence
of high-risk factors for preeclampsia, prophylactic low-dose aspirin is not recommended for the prevention
of stillbirth [111]. Selection of candidates for low-dose aspirin prophylaxis and dosing are reviewed
separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

A systematic review of trials of care prior to and during subsequent pregnancies following stillbirth for improving
outcomes found insufficient evidence that low molecular weight heparin reduced the chance of recurrent
stillbirth or the chance of neonatal death or serious complications in the first month of life [113].

Antepartum fetal surveillance — In otherwise healthy women with a previous stillbirth and no other standard
indications for antepartum fetal monitoring in the current pregnancy (see "Overview of antepartum fetal
surveillance", section on 'Indications for fetal surveillance'), we agree with the American College of Obstetricians
and Gynecologists' recommendation for initiation of antepartum fetal testing one to two weeks prior to the
gestational age of the previous stillbirth [114] and by 32 to 34 weeks of gestation [115]. When the cause of the
prior stillbirth is unknown after appropriate evaluation, there is no evidence that intensive monitoring in future
uncomplicated pregnancies will make a significant difference in preventing stillbirth. The risk of recurrence is
unclear; in two studies, the reported adjusted risks for stillbirth in a subsequent pregnancy after previous
unexplained stillbirth were hazard ratio 3.11 (95% CI 0.72-13.50) [116] and odds ratio 1.00 (95% CI 0.23-4.30)
[104]. Nevertheless, patients' anxiety levels may be decreased with more frequent prenatal visits and frequent
testing, such as nonstress tests and ultrasound examinations.

Timing of delivery — For reassurance, many practitioners offer delivery before the estimated delivery date to
provide women with a previous stillbirth some psychological reassurance and a measure of control over their
pregnancy [117,118]. We agree with an expert consensus guideline that suggested avoiding scheduled delivery
before 39 weeks if the previous stillbirth was unexplained and the current pregnancy is uncomplicated (ie,
reassuring fetal testing, no maternal or fetal complications such as preeclampsia or growth restriction, no
maternal risk factors for stillbirth such as advanced maternal age or obesity) [119]. If risk factors for adverse
pregnancy outcome are present, then the timing of delivery must be individualized, balancing the maternal and
fetal/neonatal risks of intervention with the risks of expectant management.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond
the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written
at the 10th to 12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)
 ● Basics topic (see "Patient education: Stillbirth (The Basics)")

SUMMARY AND RECOMMENDATIONS

General considerations

● The definition of stillbirth varies around the world. The United States National Center for Health Statistics
defines stillbirth as loss after 20 weeks of pregnancy, with further division into early stillbirth (20 to 27
weeks), late stillbirth (28 to 36 weeks), and term stillbirth (>37 weeks). (See 'Definition' above.)

● The stillbirth rate in the United States is approximately 2.84 deaths/1000 livebirths and 5.96 deaths per 1000
livebirths and fetal deaths. Blacks have a higher rate of stillbirth than whites. The frequencies of the various
etiologies of stillbirth differ among racial groups. (See 'Incidence and epidemiology' above.)

● Stillbirth is the end result of many maternal, fetal, and placental disorders (table 3). However, many remain
unexplained. (See 'Etiology and risk factors' above.)

● Risk factors for stillbirth include black race, older maternal age, obesity, multiple gestation, concurrent
medical disorders, smoking, and pregnancy complications. Some of these risk factors are modifiable. (See
'Predicting pregnancies at risk' above.)

● Twenty-five to 60 percent of stillbirth is unexplained, especially late in gestation. The proportion generally
reflects whether the stillbirth has been fully evaluated and if the classification system allows risk factors to
be included as causes. (See 'Unexplained stillbirth' above.)

● No intervention has been proven to significantly reduce the rate of stillbirth in the general obstetric
population. Interventions such as achieving good glycemic control, induction of labor, Doppler velocimetry,
and early induction of labor are useful in selected high-risk populations. (See 'Strategies for prevention of
stillbirth' above.)

Women with a previous stillbirth

● Preconception interventions include optimizing medical status; discussing cessation of illicit drug, tobacco,
and alcohol use; and optimizing body mass index, as appropriate. (See 'Preconception management' above.)

● During pregnancy, the clinician needs to assess the a priori risk of stillbirth, decide on the appropriate type
and frequency of antepartum monitoring, and determine when the maternal/fetal risks of ongoing pregnancy
warrant intervention for delivery. (See 'Pregnancy management' above.)

● The odds of gestational diabetes is fourfold higher after an unexplained stillbirth. If the previous stillbirth
was unexplained or related to fetal anomalies, we suggest maternal assessment for diabetes early in
pregnancy and, if normal, repeated at 24 to 28 weeks. (See "Diabetes mellitus in pregnancy: Screening and
diagnosis", section on 'Our approach'.)

● Early ultrasound examination for gestational age assessment and ongoing assessment of fetal growth are
important, given the increased risk for fetal growth restriction. A fetal anatomic survey should be performed
at 18 to 22 weeks of gestation. (See 'Pregnancy management' above.)

● Low dose aspirin prophylaxis is indicated for women who meet United States Preventive Services Task
Force (USPSTF) risk criteria. (See "Preeclampsia: Prevention", section on 'Candidates'.)

● In otherwise healthy women with a previous stillbirth, we agree with the American College of Obstetricians
and Gynecologists' recommendation for initiation of antepartum fetal testing one to two weeks prior to the
gestational age of the previous stillbirth and by 32 to 34 weeks of gestation. (See 'Timing of delivery' above.)
● We agree with an expert consensus guideline that suggested avoiding scheduled delivery before 39 weeks if
the previous stillbirth was unexplained and the current pregnancy is uncomplicated. (See 'Prevention of
recurrent stillbirth' above.)

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Topic 6827 Version 62.0

GRAPHICS

Relationship between selected first and second pregnancy outcomes

Outcome of first pregnancy, live Odds ratio for stillbirth in second pregnancy Stillbirth rate per 1000
births only (95% CI) births

AGA, term 1.0 2.4

SGA, term 2.0 (1.5 to 2.6) 4.8

SGA, moderately preterm 4.0 (2.5 to 6.3) 9.5

SGA, very preterm 8.0 (4.7 to 13.7) 19.0

Analysis adjusted for factors such as cigarette smoking, maternal age, interpregnancy interval, and presence of hypertension or
antepartum bleeding.

AGA: weight appropriate for gestational age; SGA: weight small for gestational age (ie, birth weight >2 standard deviations below the mean for
gestational age [<2.5 th percentile]); moderately preterm: 32 to 36 weeks of gestation; very preterm: <32 weeks of gestation.

Adapted from: Surkan PS, Stephansson O, Dickman PW, Cnattingius S. Previous preterm and small-for-gestational-age births and the subsequent risk
of stillbirth. N Engl J Med 2004; 350:777.

Graphic 56032 Version 4.0

Estimate of stillbirth risk for selected maternal risk factors

Estimated rate of
Condition Prevalence, percent stillbirth, per 1000 total Odds ratio
births

All pregnancies   6.4 1.0

Low-risk pregnancies 80 4.0-5.5 0.86

Nulliparity 40 7-8 1.2-3.0

Hypertensive disorder
Chronic hypertension 6-10 6-25 1.5-2.7
Pregnancy-induced hypertension
Mild 5.8-7.7 9-51 1.2-4.0
Severe 1.3-3.3 12-29 1.8-4.4

Diabetes
Treated with diet 2.5-5 6-10 1.2-2.2
Treated with insulin 2.4 6-35 1.7-7.0

Systemic lupus erythematosus <1 40-150 6-20

Renal disease <1 15-200 2.2-30

Thyroid disorders 0.2-2 12-20 2.2-3.0

Thrombophilia 1-5 18-40 2.8-5.0

Cholestasis of pregnancy <0.1 12-30 1.8-4.4

Smoking >10 cigarettes 10-20 10-15 1.7-3.0

Obesity (prepregnancy)
BMI 25-29.9 kg/m 2 21 12-15 1.9-2.7
BMI >30 20 13-18 2.1-2.8

Low educational attainment 30 10-13 1.6-2.0

(<12 years versus 12+ years)

Previous growth-restricted 6.7 12-30 2-4.6

infant (<10 percent)

Previous cesarean section 24-28 6-13 1.0-2.0

Previous stillbirth 0.5-1.0 9-20 1.4-3.2

Multiple gestation 2-3.5    

Twins 2.7 12 1.0-2.8
Triplets 0.14 34 2.8-3.7

Advanced maternal age (reference <35)

35-39 15-18 11-14 1.8-2.2
40+ 2 11-21 1.8-3.3

Black compared with white 15 12-14 2.0-2.2

BMI: body mass index.

Adapted with permission from: Fretts RC. Etiology and prevention of stillbirth. Am J Obstet Gynecol 2005; 193:1923.

Graphic 71588 Version 7.0

Causes of fetal death

Perinatal infection
Bacterial
Group B Streptococcus
Escherichia coli
Listeria monocytogenes
Spirochaetal
Other bacterial

Viral
Cytomegalovirus
Parvovirus
Herpes simplex virus
Rubella virus
Other viral

Protozoal, eg, Toxoplasma

Fungal

Other specified organism

Hypertension or preeclampsia

Antepartum hemorrhage
Placental abruption

Placenta previa

Vasa previa

Other

Maternal conditions
Termination of pregnancy

Diabetes/gestational diabetes

Maternal injury
Accidental
Nonaccidental

Maternal sepsis

Systemic lupus erythematosis

Obstetric cholestasis

Other

Perinatal conditions
Twin-twin transfusion

Fetomaternal hemorrhage

Antepartum cord complications

Uterine abnormalities

Birth trauma

Alloimmune disease

Nonimmune fetal hydrops

Other
 Hypoxic peripartum death
With intrapartum complications
Uterine rupture
Cord prolapse
Shoulder dystocia
Other

Evidence of nonreassuring fetal status in a normally grown infant

No intrapartum complications and no evidence of nonreassuring fetal status

Fetal growth restriction

Unspecified or not known whether placenta examined

Spontaneous preterm birth

Intact membranes

Ruptured membranes

Unexplained antepartum death

With evidence of reduced vascular perfusion on Doppler studies and/or placental histopathology (eg, significant infarction, acute
atherosis, maternal and/or fetal vascular thrombosis, or maternal floor infarction)

With chronic villitis

No placental pathology

Other specified placental pathology

Data from: Chan A, King JF, Flenad V, et al. Classification of perinatal deaths: Development of the Australian and New Zealand classifications. J
Paediatr Child Health 2004; 40:340.

Graphic 54973 Version 6.0

Contributor Disclosures
Ruth C Fretts, MD, MPH Nothing to disclose Catherine Spong, MD Nothing to disclose Charles J Lockwood,
MD, MHCM Nothing to disclose Vanessa A Barss, MD, FACOG Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
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