Etiology and prevention of stillbirth
Ruth C. Fretts, MD, MPH*
Harvard Vanguard Medical Associates, Wellesley, MA
Received for publication February 10, 2005; revised March 26, 2005; accepted March 29, 2005
Objective: This is a systematic review of the literature on the causes of stillbirth and clinical
opinion regarding strategies for its prevention.
Study design: We reviewed the causes of stillbirth by performing a Medline search limited to
articles in English published in core clinical journals from January 1, 1995, to January 1, 2005.
Articles before this date were included if they added historical information relevant to the topic. A
total of 1445 articles obtained, 113 were the basis of this review and chosen based on the criterion
that stillbirth or fetal death was central to the article.
Results: Fifteen risk factors for stillbirths were identified and the prevalence of these conditions
and associated risks are presented The most prevalent risk factors for stillbirth are prepregnancy
obesity, socioeconomic factors, and advanced maternal age. Biologic markers associated with
increased stillbirth risk are also reviewed, and strategies for its prevention identified.
Conclusion: Identification of risk factors for stillbirth assists the clinician in performing a risk
assessment for each patient. Unexplained stillbirths and stillbirths related to growth restriction
are the 2 categories of death that contribute the most to late fetal losses. Late pregnancy is
associated with an increasing risk of stillbirth, and clinicians should have a low threshold to
evaluate fetal growth. The value of antepartum testing is related to the underlying risk of stillbirth
and, although the strategy of antepartum testing in patients with increased risk will decrease the
risk of late fetal loss, it is of necessity associated with higher intervention rates.
? 2005 Mosby, Inc. All rights reserved.
A Medline search was used with the MeSh terms
‘‘etiology,’’ ‘‘causality,’’ ‘‘pregnancy outcome,’’ ‘‘fetal
death,’’ ‘‘stillbirth,’’ as was limited to human subjects,
English articles with abstracts in core clinical journals
from January 1, 1995, to January 1, 2005, identified
1445 papers. Articles were chosen if they had sufficient
statistical power to address the risk factor of interest and
were performed in developed countries. A total of 113
were identified with this search and an additional 9 were
cited for their historical information.
Scope of the problem
Although stillbirth is infrequent, it occurs 10 times more
often than sudden infant death.1In the United States,
stillbirth accounts for a large proportion of all perinatal
losses, although its causes remain incompletely un-
derstood. In developing nations, preterm births and
stillbirths are grossly underreported, thus making inter-
national comparisons difficult. Even in developed na-
tions, there is considerable variability in the threshold
* Reprint requests: Ruth C. Fretts, MD, MPH, Harvard Vanguard
Medical Associated 230 Worchester St, Wellesley, MA 02481.
0002-9378/$ - see front matter ? 2005 Mosby, Inc. All rights reserved.
American Journal of Obstetrics and Gynecology (2005) 193, 1923–35
for reporting stillbirth. These include differences in
either the length of gestation or the birth weight.2-4
The World Health Organization (WHO) classification of
stillbirth is defined as fetal loss in pregnancies beyond 20
weeks of gestation, or, if the gestational age is not
known, a birth weight of 500 g or more, which corre-
sponds to 22 weeks of gestation in a normally develop-
In the United States during 2002, there were approx-
imately 26,000 stillbirths, a rate of 6.4/1,000 total births.
There also were about 28,000 infant deaths (equaling a
rate of 7.0/1,000 live births), and 19,000 neonatal deaths
(4.7/1,000 live births).6Black women have more than
twice the rate of stillbirth of white women and, although
to, and quality of, medical care, other factors probably
play arole aswell.6-8Within theUnited States, there isno
national program of review for these losses. Death certif-
icates are filled out by the delivering clinician typically
before autopsy and other data relevant to the stillbirth
evaluation are available. Also, there is no international
consensus on the classification of perinatal loss.
Since the 1950s, there has been a decline in rate of
stillbirth, but it has not declined to the same extent as
the neonatal death rate (Figure 1). Indeed, recent data
from the United Kingdom show that there has been a
slight increase in the stillbirth rate, related perhaps to
the growing number of pregnancies in older women, as
well as to increased numbers of multiple pregnancies,
due in large part to an increase in assisted reproduction
In large databases, fetal death is stratified by gesta-
tional age into early losses (ie, 20-28 weeks) and late
fetal death (29 weeks or more; Figure 2).6Presumably,
this approach was used initially to divide those preg-
nancies that might be salvageable (ie, late losses), from
very early term losses, the majority of which would not
be salvageable. Recent advances in neonatal care make
this distinction somewhat arbitrary, but the causes of
fetal death do vary according to gestational age.10The
prevention of early fetal losses, in which a large pro-
portion is related to infection, has been the most difficult
to impact to date.10Ideally, of course, stillbirths deserve
the same systematic evaluation as sudden infant deaths.
If an obvious cause of death is not found, then by
exclusion the stillbirth is usually considered ‘‘unex-
plained.’’ Only when fetal deaths are reported according
to the specific causes of fetal demise can appropriate
strategies be designed to reduce these losses.
Causes of stillbirth
One of the largest and most comprehensive analyses of
the causes of fetal death has been compiled and reported
with the use of a Canadian database maintained at
McGill University.10This analysis evaluated 709 still-
births among 88,651 births with a 97% autopsy rate.
This study was able to track changes in the specific
causes of stillbirth over 3 decades (Figure 3). Since the
1960s, when the database was created, the greatest
reductions in stillbirth occurred when strategies were
developed to intervene in specific causes of fetal demise.
Since the introduction of Rh immune prophylaxis, for
example, there has been a 95% reduction in stillbirths
because of Rh isoimmunization. Stillbirths during labor
(intrapartum asphyxia) also decreased by 95% after the
introduction of intrapartum monitoring (Figure 3).
Currently, these causes of stillbirth account for less
than 1 fetal death per 10,000 births. Higher rates of
intrapartum asphyxia in fetuses weighing more than 2.5
kg suggests deficiencies in obstetric quality of care.11,12
Interestingly, in the McGill experience throughout the
30-year study period, there was a low rate of stillbirths
among women who had preeclampsia or diabetes (ie,
less than 2/10,000), due in large part to aggressive
management of these conditions.
Among other causes of stillbirth, the small-for-
gestational-age (SGA) (ie, !2.4th percentile) fetus had
an incidence of stillbirth of 46.8 per 1000, whereas the
appropriate-for-gestational-age fetus had a rate of 4.0
per 1000 (odds ratio [OR] = 11.8; 95% CI 8.1-17.1).10
The identification and appropriate management of the
growth-restricted fetus remains a significant opportunity
for stillbirth prevention. Indeed, although 25% of
Infant death rates, fetal death rates, and neonatal
of gestation) fetal deaths.6
Early (20-28 weeks of gestation) andlate(29C weeks
stillbirths that occurred in women carrying a SGA fetus
had known risk factors such as maternal hypertension,
most pregnancies that ended in stillbirth in nonanoma-
lous growth-restricted fetuses had not been identified as
having a problem with fetal growth.
Between 24 and 27 weeks of gestation, the most
common causes of stillbirth were related to infection
(19%), abruption (14%), or significant lethal anomalies
(14%), and 21% were ‘‘unexplained.’’ As noted previ-
ously, stillbirths related to infection occur most fre-
quently in fetuses weighing less than 1000 g. The
stillbirth rates due to infection, like that of preterm
birth, have been quite resistant to change despite the
availability and wide use of antibiotics.10The risk of a
fetal death due to abruption has actually decreased
modestly over several decades, although it also remains
a significant cause of perinatal morbidity and mortality.
After 28 weeks of gestation, the most common category
of a stillbirth is that of ‘‘unexplained,’’ followed by
deaths related to fetal malnutrition, and abruption
(Table I.) The proportion of fetal deaths that have no
known cause after complete pathologic evaluation in-
creases as gestational age advances.10A fetal death that
is unexplained by fetal, placental, maternal, or obstetric
factors is the most frequent type of fetal demise, repre-
senting between 25% and 60% of all fetal deaths.13-17
It is also one of obstetrics’ most distressing outcomes,
because preventative effective strategies have not yet
been identified, in large part because unexplained
fetal demise is, by definition, a diagnosis of exclusion
and depends on the rigorousness of the stillbirth
In the first comprehensive analysis of a single large
database, Yudkin et al13evaluated the timing of fetal
demise in 40,635 deliveries in Oxford, England, from
1978 to 1985, in all gestations of 28 weeks or greater. In
their examination of 63 unexplained fetal deaths (ie,
43% of all fetal deaths) in this cohort, they found that
the risk of unexplained fetal demise more than doubled
in pregnancies of greater than 40 weeks of gestation. In
the largest study of unexplained stillbirth to date, Huang
changing pattern of fetal death 1961-1986. Obstet Gynecol 1992;79;37.
*P ! .5 for 1961-1969 compared with 1980-1988 rates. Reprinted from Fretts RC, Boyd ME, Usher RH, Usher HA. The
et al14described a number of apparent risk factors for
unexplained stillbirth in a cohort of women from 1978
to 1996. These risk factors included advanced maternal
age (ie, 40 years or older, OR = 3.7, 95% CI 1.3-10.6),
low educational attainment (OR = 2.5. 95% CI 1.1-
5.5), alterations in fetal growth (ie, between the 2.4-10.0
percentile OR = 2.8, 95% CI 1.5-5.2), infants larger
than the 87th percentile (OR = 2.4, 95% CI 1.3-4.4),
primiparity (OR = 1.9, 95% CI 1.1-3.1), parity 3 or
greater (OR = 2.4, 95% CI 1.0-5.7), and the presence of
cord loops (OR = 1.7, 95% CI 1.0-2.97).
Froen et al,15using a large data set from Norway,
reported findings similar to those of Huang et al,14
although with slightly higher risk estimates for advanced
maternal age (ie, 35 years or older, OR = 5.1, 95% CI
1.3-19.7), low educational attainment (OR = 3.7, 95%
CI 1.5-9.8), prepregnancy obesity, anda body mass index
(BMI) of greater than 25 (OR = 2.4, 95% CI 1.1-5.3).
Smoking is also associated with the unexplained growth-
restricted stillbirth,18,19but appeared not to be associ-
ated with stillbirths among appropriate-for-gestational
age fetuses.14With respect to the timing of unexplained
fetal deaths, these studies and others have consistently
shown increased losses late in pregnancy, with the rate
rising significantly after 37 to 39 weeks of gestation.13-15
In addition, Fretts and Usher,10using the McGill
Obstetrical Neonatal Database, found that this increase
was more pronounced in older women (Figure 4).20
Common risk factors for stillbirth
Race and socioeconomic factors
Nationally, black women consistently have had approx-
imately twice the risk of stillbirth of white women,
although typically these rates are not adjusted for
differences in obstetric and socioeconomic factors. In
Massachusetts in 2002, for example, the household
income for black families was significantly lower than
that of white families, and black women are less likely to
receive adequate prenatal care, less likely to have com-
pleted a high school education, and more likely to have
received publicly funded prenatal care.21Black mothers
who have had a stillbirth were also less likely than white
mothers to have sought obstetric care in the first 3
months of pregnancy.22
Even when evaluating only women who had received
United States, black women still had twice the risk of
stillbirth when compared with white women. The excess
of stillbirth was attributed to higher rates of diabetes,
hypertension, placental abruption, and premature rup-
ture of membranes.7Given that black women are a
relatively high-risk group for stillbirth, increasing access
to prenatal care, and the identification and management
of those medical and socioeconomic risk factors that
contribute to stillbirth obviously will be important.
Advanced maternal age
Advanced maternal age remains an independent risk
factor for stillbirth, even after accounting for medical
conditions that are more likely to occur in older women,
such as multiple gestation, hypertension, diabetes, pre-
vious abortion, and abruptio placenta, all of which are
associated with higher rates of stillbirth. Older women
are also more likely to have preterm births, and growth-
restricted infants.26-29Historically, women 35 years or
older also have had an increased risk of stillbirth related
anomalies.20Nevertheless, with the introduction of
prenatal diagnostic testing and the availability of elec-
tive abortion, where these services are available, there
has been a significant reduction in this cause of perinatal
demise.30Indeed, longitudinal databases that track
anomalies show a transfer of fetal deaths from after
20 weeks to elective terminations before 20 weeks.31
After the introduction of routine prenatal diagnosis in
the McGill population, for example, women 35 years or
older had fewer stillbirths related to lethal anomalies,
declining to that observed in younger counterparts. In
recent years in this population, the only type of stillbirth
Most frequent types of stillbirth according to
24-27 weeks 28-36 weeks 37C weeks
Fetal malnutrition was defined as an otherwise unexplained fetus
weighing less than the 2.4%, anomalies were only considered a cause
of death if they were potentially lethal. The unexplained stillbirth was
diagnosed when other causes of death were eliminated with the use of
a comprehensive evaluation that included autopsy in 97% of cases.
Adapted from Fretts et al10and Fretts and Usher.20
Fetal death in women in the older reproductive age group.
Reprinted with permission. Fretts RC, Usher RH.
that was statistically more common in older women was
the ‘‘unexplained’’ category of fetal demise, and these
were likely to occur late in pregnancy.20
The prevalence of maternal obesity is increasing steadily
and is associated with an increased risk of fetal macro-
somia and perinatal mortality.32-36The reasons for this
association are speculated to be due to behavioral, socio-
economic, as well as obstetric factors. Obese women are
more likely to smoke and to have pregnancies compli-
cated by gestational diabetes and preeclampsia.37How-
ever, even when controlling for these factors, an elevated
BMI remains a significant risk factor for stillbirth,33,36
and the association appears to increase as the gestation
advances. A number of mechanisms for the increased
risk seen in obese women have been postulated. Thinner
women may be better able to perceive decreased fetal
movements. Maternal obesity is also associated with
hyperlipidemia,38which may contribute to increased
endothelial dysfunction, platelet aggregation, as well as
to clinically significant atherosclerosis. Sleep studies of
pregnant women have shown that obese women spend
more time snoring (32% vs 1%; P ! .001), have more
apnea-hypoxia events (1.7 vs 0.2/h; P ! .05), and
have more episodes of oxygen desaturation (5.3 vs 0.3/h;
P ! .005) than nonobese pregnant women.39Snoring
has also been associated with pregnancy-induced hyper-
tension and fetal growth restriction.40Indeed, in addi-
tion to advanced maternal age and low socioeconomic
status, as discussed previously, the most prevalent risk
factor for stillbirth is prepregnancy obesity.
Our understanding of the relationship between inherited
abnormalities of blood clotting and stillbirth is seriously
deficient, in that there have been no large population-
based studies that have evaluated this association.41-44
The relationship between late fetal death and thrombo-
philia is more consistent than with early fetal losses,45
although the odds ratio ranges from as low as1.8 to
estimates as high as 12.46,47-50A meta-analysis of smaller
studies suggested that the presence of thrombophilias
does increase the risk of stillbirth (OR = 3.6; 95% CI
1.4-9.4), with the analysis of specific defects limited by
power.41Martinelli et al51found the prevalence of
mutations either in factor V or prothrombin to be
16% in those pregnancies that ended in an unexplained
loss, compared with 6% of normal pregnancies,51al-
though the value of placental disease to discriminate
unexplained losses with and without a diagnosis of
thrombophilia is in question. The authors found that
24% of the placentas were normal, whereas the remain-
ing 76% showed intravascular thrombi, decidual vascu-
lopathy, and ischemic necrosis with villous infarctions.
The placentas were abnormal in 7 of 9 (78%) women
with a mutation and in 40 of 53 (75%) stillbirths without
a mutation so that the presence of a known mutation did
not correlate with a specific placental histologic or
biochemical abnormality. In another small study of 22
women with at least 1 unexplained loss, 4 of 9 placentas
showed extensive infarcts in women who had docu-
mented thrombophilia, whereas none of the 8 without
thrombophilia exhibited similar pathologic findings.47
Systemic lupus erythematosus
Systemic lupus erythematousus (SLE) complicates less
than 1% of pregnancies but the risk of stillbirth in this
population is disproportionately high, especially in
women with preexisting renal disease.52Hypertension,
preeclampsia, and fetal growth restriction are common
in these patients.53-55Even when pregnancy is conceived
during a relatively quiescent period in terms of disease
activity, stillbirth can complicate up to 3% to 8% of
pregnancies.53-55The presence of a lupus anticoagulant
has been reported to significantly increase the risk of a
fetal loss after 20 weeks of gestation. The optimum
management of patients with SLE is uncertain, but the
use of heparin and aspirin was associated with an
improved outcome in 1 small series.45
Medical risk factors
Hypertension and diabetes are 2 of the most common
medical conditions to complicate pregnancy (7%-10%
and 3%-5%, respectively).23,52,56-59Historically, both of
these conditions have been shown to be responsible for a
significant proportion of fetal deaths. However, optimal
management, including counseling, preconceptual care,
and close medical management of these conditions, has
been shown to reduce the risk for perinatal death to a
level only marginally elevated over that of the general
population.56Management of patients remains a chal-
lenge, however, because of the increased risks of
abruptio placenta, of intrauterine growth restriction,
and of superimposed preeclampsia, which often neces-
sitates early delivery.57,58,60Other important medical
conditions associated with an increased risk of stillbirth
are listed in Table II.52
Infection and immunologic exposure
A significant proportion of perinatal morbidity and
mortality is related to infection, which often leads to
delivery of a premature liveborn or a stillborn infant.
Despite the adoption of a strategy to reduce the risk of
perinatal infection caused by group B streptococci, there
has been little change in the risk of fetal death caused by
infection because most of these deaths occur pre-
term.10,61Although there are some pathogens that are
probable causes of stillbirth, such as parvovirus 19,
cytomegalovirus, toxoplasmosis, and listeria, there are
others that may be associated with an increase in risk,
but the evidence for which remains inconclusive. For
example, colonization with Ureaplasma urealyticum,
Mycoplasma hominis, and group B streptococci has all
been associated with an increased risk of stillbirth,61
although colonization with these pathogens is also
common among healthy women.
In recent reports, Refuerzo et al62and Blackwell
et al63found that women who had had an unexplained
stillbirth, without any evidence of obvious infection, had
a higher number of ‘‘memory T cells’’ (CD45RO) than
‘‘naive T cells’’ (CD45RA) when compared with live-
born controls. Although this finding suggests that,
despite the absence of any overt evidence of clinically
significant infection, these women had had prior expo-
sure to infectious agents. Froen et al64found, in an
epidemiologic study of unexplained stillbirths, that
bacteruria or symptomatic urinary tract infections dur-
ing pregnancy were associated with a reduced risk of
fetal death, a finding not fully explained by treatment
with antibiotics. The role of the immune system has
lately become a subject of considerable interest in
perinatal birth injury. There is evidence that elevated
inflammatory processes are associated with an increase
in the risk of adverse outcomes in the premature
neonate.65Infected infants, both premature and term,
were shown to exhibit a significant increase in interleu-
kin 6 production, with C-reactive protein (CRP) in-
creasing rapidly at the onset of infection and remaining
elevated until the infection was cleared.66Animal data
suggest that the combination of subclinical infection and
a fetal inflammatory response can both cause abnor-
malities of gas exchange that result in fetal hypoxia and
Because women who choose to delay their childbearing
are also more likely to have a history of infertility and to
conceive with the aid of reproductive technologies, it is
important to evaluate the effect of infertility and infer-
tility treatment on the risk of fetal death. Patients
treated with advanced reproductive technologies expe-
rience excess perinatal mortality.68-70Although the
frequency of multiple gestations is responsible for a
Estimates of maternal risk factors and risk of stillbirth
ConditionPrevalence Estimated rate of stillbirth OR*
Treated with diet
Treated with insulin
Cholestasis of pregnancy
Smoking O10 cigarettes
BMI 25-29.9 kg/m2
BMI O 30
Low educational attainment (!12 y vs. 12 yC)
Previous growth-restricted infant (!10%)
Advanced maternal age (reference !35 y)
Black women compared with white women
* OR of the factor present compared to the risk factor absent. Some estimates of medical conditions and stillbirth risk from Simpson.52Other risk
estimates from references 24,25,29,33,34,35,38,55,58,68.
significant portion of this excess mortality, it also
appears that women who undergo either in vitro fertil-
ization (IVF) or ovarian stimulation and have a single-
ton gestation, also have a statistically increased risk of
prematurity, low birth weight, and SGA fetuses.71-74
There have been no studies that have evaluated whether
infertility itself is associated with an increase in unex-
plained fetal death. Nevertheless, many physicians who
care for infertile patients perceive these pregnancies to
be at ‘‘high risk’’ for adverse maternal and fetal out-
Over the past 2 decades, the rate of pregnancies with
twins has more than doubled, the rate of triplets has
increased 6-fold, and the number of quadruplets has
increased by 12-fold.68-70With this increase in the
number of multiple gestations, there has been a mea-
surable increase in prenatal mortality and morbidity in
industrialized countries. The main reason for this in-
crease is the use of reproductive technologies and the
associated increase in maternal age.75,76It has been
estimated that a strategy of lowering the transfer rate to
2 embryos during IVF could reduce the perinatal mor-
tality rate by 45% in the case of limiting a triplet to
twins, or 74% when limiting the quintuplet pregnancies
to twins.70The optimal duration of an otherwise un-
complicated pregnancy is shorter for multiple gesta-
tions. Kahn et al77found, for example, that it was safer
for a twin pregnancy to be delivered than undelivered at
39 weeks, and for triplets who remain undelivered at
36 weeks, an elective delivery at this time minimized
adverse fetal outcomes.
Biologic markers of increased risk
Froen et al64from Norway have demonstrated that
women with hemoconcentratation, defined as the lowest
hemoglobin measured during pregnancy greater that
13.0 g/dL, is associated with a 9-fold increase in the risk
of unexplained fetal death. Stephansson et al,78using a
Swedish database, found that both an initial elevated
hemoglobin and the failure of significant hemodilution
over the course of the pregnancy, increased the risk of
stillbirth by 2-fold, even when women with preeclampsia
and eclampsia were excluded.78Plasma volume expan-
sion and lowered hemoglobin concentration are normal
physiologic responses to pregnancy. Plasma volume
expansion appears to be important for fetal growth
and failure of sufficient hemodilution is associated with
an increased risk of stillbirth, even if the fetus is not
growth restricted. Stephansson et al78suggest that those
patients with high initial hemoglobin concentrations
should be considered at high risk for adverse obstetric
Amniotic and serum markers
Pregnancy-associated plasma protein A (PAPP-A) is a
maternal serum marker used in combination with other
tests to detect an increased risk of chromosomal abnor-
malities; it also appears to be of help in detecting, in
the second trimester, pregnancies that might be at an
increased risk for an adverse outcome. Smith et al79
assessed adverse perinatal outcomes among the 8839
patients recruited into a multicenter study. Patients with
serum markers in the lowest fifth percentile were found
to have an increased risk of premature delivery
(OR = 2.9, 95% CI 1.6-5.5), preeclampsia (OR = 2.3,
95% CI 1.6-3.3), and stillbirth (OR = 3.6, 95% CI 1.2-
11.0).79In growth-restricted fetuses, the maternal serum
alpha-fetoprotein was not particularly helpful in identi-
fying pregnancies that would later go on to an adverse
perinatal outcome, but a combination of factors, an
elevated HCG and a low unconjugated estriol, was 67%
sensitive and 70% specific in predicting a composite
‘‘adverse perinatal outcome’’ metric, which included
perinatal death and neonatal morbidity.80
Amniotic fluid abnormities also have been found to
be associated with fetal demise. Florio et al81performed
a case control study of women undergoing amniocente-
sis for routine reasons, in which 12 patients with a
stillbirth all had elevated levels of S100B (a marker of
brain damage in both adult and pediatric patients, but
which is not specific for cerebral damage),82but the 746
healthy controls did not. At least in this dataset, this test
was perfect in predicting fetal death, a very rare finding
in medicine, although these data will need to be repli-
cated.81The mechanisms linking most abnormal mater-
nal serum and amniotic markers with adverse fetal
outcomes are not known, but further study is required
before recommendations for specific clinical applica-
tions can be considered.
The data available for cost-effective stillbirth prevention
are limited. The remaining aspect of this review repre-
sents the author’s opinion based on the limited data
available. In the absence of a prior obstetric history, the
patient’s risk for stillbirth is related to her underlying
health and lifestyle. Globally, one of the largest modi-
fiable risk factors is smoking, as it is obviously tied to
the pathophysiology of many diseases. Additional med-
ical risk factors, as discussed previously, significantly
impact both maternal and child health as well, and
appropriate medical care for these conditions and
preconception counseling can have a significant impact
on outcome. The provider should perform a risk assess-
ment for each individual patient and give realistic
estimates of anticipated obstetric outcomes. Screening
for hypertension and diabetes are essential to prevent
poor pregnancy outcomes, but a number of other
factors should be included in any risk assessment,
including advanced maternal age, prepregnancy obesity,
infertility, low educational attainment as a marker of
lower socioeconomic status, and black race.7,8,25,33Al-
though the black race may be a proxy for socioeconomic
factors, it is helpful to remember that black women 35
years or older have a risk of stillbirth 4 to 5 times higher
than the national average and therefore deserve the
same vigilance afforded to other groups at high risk for
A moderate proportion of stillbirths related to con-
genital anomalies could be reduced with preconceptual
counseling and testing, adequate prenatal care, and
prenatal diagnostic testing, with elective terminations
for affected pregnancies.30During pregnancy, patients
with medical conditions need to be closely monitored to
optimize their treatment and fitness for pregnancy and
ensure fetal well-being.
In terms of reducing potentially preventable still-
births, the Confidential Inquiry into Stillbirths and
Infant Death (CISID) of Northern Ireland found that
the failure to adequately diagnose and manage fetal
growth restriction was the most common error, followed
by failure to recognize additional maternal medical risk
factors.83Given that deaths of intrauterine growth-
restricted fetuses represent 1 of the most common types
of stillbirths,84,85a significant opportunity remains to
improve outcomes. Assessment of fetal growth by
ultrasound should be considered in at-risk patients. A
customized growth chart more readily identifies the
growth-restricted fetus, and reduces ‘‘false alarms’’ in
the constitutionally small fetus.86Ideally, serial ultra-
sound reports should be reported together so that the
history of intrauterine growth over time can be more
readily appreciated. The threshold to perform an ultra-
sound in the obese patient should be low because fetal
growth is often difficult to estimate clinically.
In women who have had a previous pregnancy, a
previous preterm delivery, previous obstetric complica-
tion, delivery of a growth-restricted fetus, or a stillborn
fetus, these events significantly increase their risk for
adverse events in future pregnancies.87-89There is some
evidence, for example, that a previous cesarean section
at term might reduce placental function and therefore
increase the risk of a late antepartum unexplained
stillbirth.90Nevertheless, this association should be
confirmed by other groups before it is considered an
important risk factor.
Given all of the potential factors that influence the
risk of stillbirth, it would be helpful to have an inter-
active model that would estimate the risk of a fetal
demise in a manner similar to that used by physicians
who care for patients with cardiovascular risk factors,
who have a wealth of information to estimate the risk of
myocardial infarction and death. A risk analysis should
guide management policies and provide an evidenced-
based approach to alter the threshold at which antepar-
tum testing and early delivery is considered. Until such
evidence-based guidelines exist, the obstetric care pro-
vider must decide on the appropriate type of vigilance,
and decide when expectant care increases the risk to the
ongoing pregnancy to a degree that warrants interven-
tion for delivery.91,92
Fortunately, for the majority of obstetric patients
who are low risk, the incidence of a late stillbirth is a
relatively low (1-2/1000).93Still, there is a role for
vigilance in these pregnancies. In a reanalysis of the
results of a fetal movement counting study initially
published by Grant et al,94Froen95has appropriately re-
ignited the interest in fetal kick counting. Even low-risk
pregnancies with decreased fetal movement are known
to have a higher risk of fetal distress in labor, for being
growth restricted, and for having an increased frequency
The risk of stillbirth in late pregnancies has been ap-
preciated by many authors, as discussed previously.96-101
Antepartum surveillance with judicious delivery of fe-
tuses with poor fetal testing has been shown to im-
prove outcomes in pregnancies with growth-restricted
fetuses.102Antepartum testing is also widely used in
patients perceived to be at increased risk for fetal death,
with the use of the testing related to the underlying risk
of stillbirth.102Randomized control trials of expectant
versus induction of the postdates pregnancy are not large
However, in an analysis of the effect of labor induction
rates in the 41st week, Sue et al104found that in Canada
number of pregnancies at 41 or more weeks of gestation.
The authors correlated the increase in the number of
inductions after 41 weeks to a lowering of the stillbirth
rate.104Fretts et al,93using the McGill Obstetrical Neo-
natal Database to obtain risk estimates, performed a
decision-analysis of the risks and benefits of antepartum
decision analysis considered only late unexplained still-
birth, but this covers the majority of late stillbirths.93For
the neonate, there is no measurable long-term adverse
analysis was begun starting during the 37th week. The
major risk of antepartum testing after 36 weeks is induc-
tion of labor and its associated downstream effects, such
as a potential for an increase in the cesarean delivery
rate,105and therefore a potential increase the maternal
mortality rate. For multiparous patients, induction car-
ries a lower risk, and although induction does probably
increases the risk of cesarean delivery, it does so only
marginally.106In the initial study by Fretts et al93on the
risks and benefits of antepartum testing late in pregnancy
for older women, they constructed a sensitivity analysis
testing, testing after the 36th week with induction for a
positive test, and no testing with induction at 41 weeks.
The number of fetal deaths averted and the number of
tests, inductions, and additional cesarean deliveries per
fetal death averted were calculated assuming antepartum
testing to be 70% sensitive and 90% specific. The results
for OR 1.0 to 5.0 are presented in Table III.
Although a strategy of antepartum testing is pre-
dicted to be most successful in reducing the number of
unexplained stillbirths, it was also associated with the
highest induction rate. For nulliparous women of ad-
vanced maternal age, predicted to have an OR of 3.3
over younger women, the number of additional cesarean
deliveries performed for unsuccessful inductions was
only 14 per fetal death averted. The model also esti-
mated that it would take approximately 863 antepartum
tests and 71 additional inductions to prevent 1 unex-
plained stillbirth. Nevertheless, a strategy of liberal
antepartum testing, to identify at-risk pregnancies will
also reduce the number of patients undelivered at each
gestational age starting at the time that testing is
initiated, thereby further reducing the number of preg-
nancies still at risk of a stillbirth.
Management of stillbirth
The diagnosis of a singleton stillbirth must be confirmed
with an ultrasound examination of the fetal heart. Most
hospitals have instituted a program to help bereaved
parents cope with their loss and follow good practice
guidelines, which include the opportunity to see and
hold their infant and obtain tokens of remembrance.107
A worksheet for both parents and providers help to
streamline the management of these losses and can
facilitate the optimal investigation for determining the
cause of death. Delayed delivery after 24 hours of the
diagnosis has been associated with an increased risk of
anxiety years after the loss, when compared with women
whose labors were induced within 6 hours.108The
expectant management of a stillbirth therefore should
be discouraged, in addition to the fact that delayed
delivery is also associated with increased maternal risks
of consumptive coagulopathy.109,110The availability of
prostaglandins, in particular misoprostol, has made
induction of stillbirth safer and more efficient in women
without a previous cesarean delivery. For now, oxytocin
will remain the main method of induction for women
with a previous cesarean delivery.
After delivery, the parents and other family members
should have the opportunity to spend as much time as
needed with the deceased infant. Even in the scenario of
obvious maceration of the infant, after initial anxiety,
parents often find something to connect them to the
infant. A recent study has questioned whether holding a
stillborn child might increase the risk of later anxiety,111
this finding has not been duplicated to date.
One important aspect of a woman’s care after a
stillbirth is an appropriate and comprehensive stillbirth
assessment. It is unfortunate that the United States has
1 of the lowest rates of obtaining a comprehensive
stillbirth assessment when compared with other devel-
oped countries. This may be in part due to an increased
level of anxiety over litigation in the United States, but it
may also reflect the absence of a nationally coordinated
program to evaluate these deaths. Notwithstanding,
there are centers within the United States that can serve
as role models for a comprehensive approach to still-
birth such those at the University of Southern California
and the Wisconsin Stillbirth Service Program.112,113
Incerpi et al113,114have demonstrated that, within the
context of developing a cost-effective stillbirth assess-
ment program, the single most important test to deter-
mine the cause of a stillbirth is the autopsy, followed by
an evaluation of the placenta. For some parents, a
limited fetal evaluation will be more acceptable than a
complete autopsy, and this option should be explored if
a complete autopsy is not acceptable.115,116An external
Unexplained stillbirth risks and outcomes of weekly antepartum testing initiated at the 37th week of gestation
OR for unexplained stillbirth
Outcome* 1.0 2.03.04.05.0
Fetal deaths per 1000 with antepartum testing
Fetal deaths avertedy
Tests per pregnancy
Tests per fetal death averted
Inductions per fetal death averted
Cesarean deliveries per fetal death averted
Assuming base-case test characteristics (70% sensitivity, 90% specificity).
* Outcomes from week 37 of gestation through week 41.
yUnexplained fetal deaths averted per 1000 pregnancies compared to no testing.93
physical examination and radiologic testing performed
by the perinatal pathologist, with or without sampling
fetal tissues in situ, can provide significant information.
Although an autopsy is optimal, a postmortem magnetic
resonance image (MRI) can provide useful additional
information, although typically MRI staff are not used
to receiving these requests.117
A genetic analysis of chromosomes will reveal ab-
normalities in between 5% and 10% of stillbirths.113
After a stillbirth, the highest yield for obtaining fluid for
cytogenetic analysis will be at the time of amniocentesis
at the time of the diagnosis of the stillbirth, but this has
not been the usual practice at most centers of care within
the United States. If amniotic fluid is unavailable, a
sample of fetal blood, skin, or fascia lata will be best
sources of tissue for culture. The use of a cytogenetic
evaluation decreases with the duration of time that the
infant has been dead, so reserving placental tissue for
fluorescence in situ hybridization (FISH) in a buffered
saline solution is an alternative method of determining
whether the infant had a common chromosomal abnor-
With the use of a protocol of autopsy, evaluation of
the cord/placenta and membranes, and laboratory tests
of fasting glucose, a Kleihauer-Betke test, urine toxicol-
ogy and hemoglobin A1c in selected cases, and a
thrombophilia workup in normally formed infants,
Incerpi et al113were able to attribute a primary cause
of death in 72% of cases of stillbirth, leaving only 28%
as ‘‘unexplained.’’ Notably absent in their protocol was
the recommendation of obtaining TORCH titers, (ie,
cytomegalovirus, toxoplasmosis, herpes simplex virus,
and rubella) because these titers, in and of themselves,
almost never aid in the diagnosis of a congenital
infection in the absence of autopsy and placental find-
ings of infection. Incerpi et al120found no significant
association between antinuclear antibodies and stillbirth
in the evaluation of 286 unexplained stillbirths. Parvo-
virus 19 is most commonly associated with a fetal death
in the setting of nonimmune hydrops, but parvovirus 19
DNA can also be found in the placenta and fetus even in
the nonhydropic infant.121,122
The value of a comprehensive stillbirth assessment
cannot be underestimated, because the results are rele-
vant to assess the risk of recurrence, the development of
prenatal diagnostic recommendations for subsequent
pregnancies. Pauli’s group at the Wisconsin Stillbirth
Service, a model state-wide program for the prevention
of stillbirth, estimated that in 2001, the real cost of a
stillbirth assessment was approximately $1450 US or
approximately $12 per cared-for pregnancy, and influ-
enced subsequent perinatal care in 51% of cases.112
After studying 1631 stillbirths, the most significant
consequence of this analysis was the change in the risk
estimate of recurrence or stillbirth in 42% of cases.
Other consequences were a change in the recommenda-
tions with respect to prenatal diagnosis in 22.2% and
preconceptual management in 10.9% of subsequent
Clinicians need to be able to assess each patient’s risk
for adverse outcomes, including stillbirth, and to have a
low threshold to evaluate fetal growth in at-risk preg-
nancies. As reviewed previously, late pregnancy is also
associated with progressively increasing risk of stillbirth,
and although the strategy of antepartum testing in
patients with increased risk will decrease the risk of
late fetal loss, it is of necessity also associated with
higher intervention rates.
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