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Stillbirth: Incidence, risk factors, etiology, and prevention

Stillbirth: Incidence, risk factors, 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
Literature review current through: Jun 2022. | This topic last updated: May 10, 2022.

INTRODUCTION — The term "stillbirth" generally refers to the delivery of a fetus ≥20 weeks of gestation with no signs of life. The incidence, risk factors, and etiology of stillbirth, as well as strategies for prevention, will be reviewed here. Diagnosis and management of stillbirth, parental support and counseling, and pathology evaluation are discussed separately.

(See "Stillbirth: Maternal and fetal evaluation".)

(See "Stillbirth: Maternal care".)

DEFINITION

World Health Organization definition — The World Health Organization (WHO) defines fetal death as the intrauterine death of a fetus at any time during pregnancy [1]; for international comparison, WHO recommends defining stillbirth as a baby both with no signs of life at or after 28 weeks of gestation [2]. An antepartum fetal death is a death that occurs before the onset of labor; an intrapartum fetal death occurs during labor and thus may not show signs of maceration.

United States National Center for Health Statistics definition — The United States National Center for Health Statistics defines stillbirth as a fetal death or loss that occurs after 20 weeks of pregnancy and before or during delivery, with further division into early stillbirth (20 to 27 completed weeks), late stillbirth (28 to 36 completed weeks), and term stillbirth (≥37 completed weeks) [3]. Stillbirths related to termination of pregnancy are not included. Although these divisions are somewhat arbitrary, the stratification allows for relatively reliable comparison with some international data that are limited to late fetal losses. The divisions also allow separate consideration of stillbirths that are early and difficult to prevent with any intervention from those that are late and potentially preventable by preterm delivery.

States have varying reporting requirements regarding fetal deaths; most report fetal deaths that are ≥20 weeks of gestation and/or ≥350 grams birth weight, but some report fetal deaths for all periods of gestation. This weight was chosen because it represents the 50th percentile for fetal weight at 20 weeks of gestation.

INCIDENCE

Global — Worldwide, the stillbirth rate has been falling from approximately 21.4 deaths at ≥28 weeks of gestation per 1000 births in 2000 to approximately 13.9 deaths per 1000 births in 2019 [4]. The reduction has been associated with improved access to and utilization of antenatal care and skilled birth attendants and increased attention to known maternal risks for stillbirth.

When comparing stillbirth rates globally, the rate of late stillbirths is used (those ≥28 weeks of gestation). Rates of stillbirth in low-income countries have been substantially higher (approximately 22.7 deaths per 1000 births) than in high-income countries (approximately 3 deaths per 1000 births), with most stillbirths (77 percent) occurring in subSaharan Africa and South Asia [4]. Although low-income countries have had a 3 percent decline in the stillbirth rate in the past decade, in subSaharan Africa this reduction (from 24.5 to 21.7 per 1000 births) has been offset by an increase in the total number of stillbirths (from 850,000 to 856,000).

Approximately one-half of the stillbirths in subSaharan Africa and South Asia occurred during labor and birth, largely because of a lack of skilled birthing attendants and facilities for cesarean birth [4]. By comparison, approximately 6 percent of stillbirths occurred intrapartum in western Europe and North America.

United States — The estimated rate of stillbirth in the United States is 6 per 1000 live births and stillbirths [5]. The rate had been decreasing gradually over several decades; however, there was no change in fetal death rates from 2014 to 2016 (the latest available national data) [6,7].

Approximately 50 percent of stillbirths occur between 20 and 27 weeks of gestation (primarily from 20 to 23 weeks), and the other 50 percent occur at ≥28 weeks [8]. Among all extreme preterm (<28 weeks), very preterm (28 to 31 weeks), moderate-to-late-preterm (32 to 36 weeks), and term pregnancies (≥37 weeks), the incidence of stillbirth has been reported to be 32.8, 7.2, 0.9, and 0.2 percent, respectively [6].

United Kingdom — Stillbirth rates in the United Kingdom have fallen by just over 16 percent, from 4.20 per 1000 total births in 2013 to 3.51 per 1000 total births in 2018 [9]. The reduction was mainly due to an approximately 25 percent reduction in the rate of term stillbirths, from 1.6 per 1000 total births in 2014 to 1.2 per 1000 total births in 2018. Approximately 75 percent of stillbirths occurred preterm. Living in the most deprived areas was associated with increased risk of stillbirth.

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 live births and fetal deaths at that gestational age or greater.

In the United States in 2013, the prospective rate of fetal death was higher at 20 to 22 weeks of gestation (0.52 to 0.56 per 1000 live births and fetal deaths), lower at 29 to 33 weeks of gestation (0.18 to 0.19 per 1000 live births and fetal deaths), remained relatively low until approximately 37 weeks of gestation, and then began to climb at 38 weeks of gestation, increasing to a peak at 42 weeks of gestation (0.62 per 1000 live births and fetal deaths) [8].

Limitations of stillbirth data — Data regarding the incidence of stillbirth are complicated and can be difficult to interpret for several reasons, including:

Differences in definitions among countries. Worldwide, the lower threshold for gestational age for defining stillbirth ranges from ≥16 to ≥28 weeks of gestation, and the lower threshold for birth weight ranges from ≥400 to ≥1000 grams [10].

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

Use of birth weight versus gestational age thresholds for reporting stillbirth and interpretation when these values are discordant at the threshold distinguishing a stillbirth 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 of induced fetal demise (eg, multifetal reduction) and induced labor of previable fetuses (eg, lethal anomaly) as stillbirths. In addition, the increased availability of prenatal diagnosis and pregnancy termination can reduce the number of subsequent stillbirths artificially. Potential perinatally lethal conditions (eg, anencephaly, trisomy 13) are being detected and the pregnancy terminated prior to 20 weeks, which may artificially reduce the prevalence of stillbirth (and neonatal deaths) over time if such terminations are not counted.

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

POTENTIAL ETIOLOGIES — Stillbirth is the end result of a variety of maternal, fetal, and placental disorders, which can interact to contribute to fetal demise [11]. The study of specific causes of stillbirth has been hindered by the lack of a uniform protocol for evaluating and classifying stillbirth [12] as well as declining autopsy rates.

The relative frequencies of the various causes of stillbirth appear to differ between low- and high-income countries [13-17] and between early and late gestation [18]. 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 [16].

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 cause [19].

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 [20]. This is reported to account for 25 to 60 percent of all fetal deaths [21-24]. 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) [20,25]. 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 [21-23,26]. 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 when the cause of death was unexplained ranged from 0.39 percent (Nordic-Baltic classification) to 46 percent (Keeling system) [20].

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 [21].

Congenital anomalies — Fifteen to 20 percent of stillborns have a major malformation [18,27]. 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 [28]. Malformations associated with an increased risk of fetal demise, but unrelated to structural chromosomal abnormalities, include abdominal wall defects, neural tube defects, Potter sequence, 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) [29].

Fetal growth restriction — Death of a growth-restricted fetus is the second most common type of stillbirth [18]. The stillbirth rate in such fetuses is estimated to be 10 to 47 per 1000 live births and stillbirths and increases with increasing severity of growth restriction [5,30]. The median gestational age at death of the growth-restricted fetus was 28 weeks in one study [31]. (See "Identification and diagnosis of fetal growth restriction" and "Fetal growth restriction: Evaluation and management".)

Placental dysfunction is the presumed cause of both growth restriction and stillbirth. The dysfunction may be related to maternal vasculopathies or intrinsic placental disease.

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 [32,33]. 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 [GBS], cytomegalovirus [CMV], 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 fetuses at the limit of viability following prelabor rupture of membranes [18]. 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. E. coli, GBS, CMV, enterococcus species, parvovirus, 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 [34,35]. In 2016, Zika virus was also associated with stillbirth [36], 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 [37]. Histologic 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 [38,39].

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 can also result in live birth. Although death of a karyotypically abnormal embryo or fetus is most common in the first trimester, it can occur at all stages of pregnancy [27,40,41].

In one study that karyotyped 823 stillbirths and neonatal deaths, 6.3 percent had a major chromosomal abnormality [42]. 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 [22]. 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 [29].

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 [43].

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 utilized in the evaluation of stillbirth [44]. Ongoing research includes next-generation sequencing of cardiac channelopathies [45]. (See "Prenatal diagnosis of chromosomal imbalance: Chromosomal microarray", section on 'Fetal demise'.)

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 "RhD alloimmunization in pregnancy: Management".)

Fetal arrhythmia — An unrecognized arrhythmia, such as long QT syndrome, may be a cause of unexplained fetal demise. (See "Fetal arrhythmias".)

Abruptio placentae — Abruptio placentae occurs in approximately 1 percent of pregnancies but accounts for between 10 and 20 percent of all stillbirths [18]. The risk of stillbirth 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 "Acute placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".)

Umbilical cord abnormalities — Umbilical cord complications (entrapment [eg, nuchal cord], knot, torsion, stricture, prolapse, single umbilical artery, histopathologic evidence of compromised fetal microcirculation) are often cited as a cause of fetal death in the third trimester [46-51] and accounted for 19 percent of 500 fetal deaths in a population-based study [52].

Although nuchal cords and knots are relatively common (occurring in 15 to 34 percent of pregnancies at term), 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 or neonatal 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; pathologic 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 are an integral part of the evaluation of stillbirth. (See "Stillbirth: Maternal and fetal evaluation" 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 [28]. 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'.)

Fetomaternal hemorrhage — Fetomaternal hemorrhage sufficiently large to cause fetal death has been reported in up to 5 percent of stillborns [53,54]. 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".)

RISK FACTORS

Maternal factors

Sociodemographic factors

Black race – The fetal mortality rate is highest for non-Hispanic Black individuals (10.53 deaths per 1000 live births and fetal deaths) and lowest for non-Hispanic White individuals (4.88 deaths per 1000 live births and fetal deaths) [8]. The disparity in hazard of stillbirth is widest at 20 to 23 weeks of gestation [55].

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 [56]. 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 other women to be induced at term despite their higher rates of pregnancy complications, such as diabetes mellitus, hypertension, placental abruption, and term stillbirth [55], which may also account for some of the disparity.

Younger and older age – The stillbirth rate is lowest for women ages 25 to 34 and higher for teenagers and women ≥35 years of age [8]. The risks of stillbirth for women under age 20, 35 to 39, and over 40 have been estimated to be 7 to 13 per 1000, 11 to 14 per 1000, and 11 to 21 per 1000, respectively [5]. (See "Effects of advanced maternal age on pregnancy" and "Pregnancy in adolescents".)

Older age appears to be an independent risk factor for stillbirth after adjusting for medical/obstetric conditions more common among older women (eg, hypertension, diabetes, multiple gestation, congenital and chromosomal fetal anomalies) [57,58].

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 (11 percent difference). Although unlikely to be directly attributed, marital status can affect availability of social, emotional, and financial resources.

Parity – A multiethnic, population-based study observed an increased risk for stillbirth among nulliparous women and parity ≥3 [59]. (See "Grand multiparity", section on 'Risk of pregnancy complications'.)

Adverse social and behavioral factors – A case-control study of over 1000 pregnancies from 41 maternity units in the United Kingdom observed associations between late stillbirth and severe socioeconomic deprivation, perceived stress, and domestic abuse [60]. In contrast to findings of several studies of enhanced prenatal care in various populations, a greater number of antenatal visits than recommended was associated with a reduction in stillbirth in this group (adjusted odds ratio [aOR] 0.26, 95% CI 0.16-0.42).

Previous stillbirth — Women who experienced a stillbirth in their first pregnancy are three times more likely to experience a stillbirth in their second pregnancy compared with women who had a live birth in their first pregnancy (aOR 3.38, 95% CI 2.61-4.38) [61]. The risk of stillbirth in a subsequent pregnancy has been estimated to be 9 to 20 per 1000 live births and stillbirths [5] versus 5 per 1000 in patients with a previous live birth [62]. (See 'Strategies for prevention of recurrent stillbirth' below.)

Previous adverse pregnancy outcome — Women with a previous preterm birth (PTB) or small for gestational age (SGA) infant are at increased risk of stillbirth in a subsequent pregnancy (PTB: pooled OR for subsequent stillbirth 1.70, 95% CI 1.34-2.16; SGA: pooled OR for subsequent stillbirth 1.98, 95% CI 1.70-2.31) [63]. The risk of subsequent stillbirth increases as the gestational age at PTB decreases, as the severity of SGA increases, and with PTB of an SGA infant.

The effect of cesarean delivery on future stillbirth is controversial. An association between unexplained stillbirth and a prior cesarean delivery observed in some studies may be due to residual confounding, but it is possible that scar tissue from a previous cesarean delivery may lead to abnormal placental function leading to stillbirth. (See "Cesarean birth: Postoperative issues", section on 'Unexplained stillbirth'.)

Comorbid chronic medical disorders

Diabetes — Women with diabetes are at increased risk of stillbirth, particularly at or near term. For women treated with nutritional therapy alone, the risk is estimated to be 6 to 10 per 1000 live births and stillbirths; for women treated with insulin, the risk is estimated to be 6 to 35 per 1000 live births and stillbirths [5].

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 can also play a role [64]. 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. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management", section on 'Perinatal mortality'.)

Hypertensive disorders — Hypertensive disorders are associated with a significant number of stillbirths in low-income countries [65] and in high-income countries if worsening of the maternal/fetal condition is not appreciated. The risks of stillbirth for women with chronic hypertension, preeclampsia without severe features, and preeclampsia with severe features are estimated to be 6 to 25 per 1000, 9 to 51 per 1000, and 12 to 29 per 1000 live births and stillbirths, respectively [5].

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 "Treatment of hypertension in pregnant and postpartum patients" and "Preeclampsia: Management and prognosis".)

Substance use — A meta-analysis including 57 studies found that any active maternal smoking was associated with increased risks of stillbirth (summary relative risk [RR] 1.46, 95% CI 1.38-1.54) [66]. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Stillbirth and neonatal death'.) Dual exposure to cigarette and alcohol consumption is particularly problematic [67].

In the United States Stillbirth Collaborative Research Network (SCRN), in which 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 per day [68]. The absolute risk of stillbirth at this level of smoking has been estimated to be 10 to 15 per 1000 live births and stillbirths [5]. 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 [69].

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 live births (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 live births. (See "Tobacco and nicotine use in pregnancy: Cessation strategies and treatment options" and "Substance use during pregnancy: Overview of selected drugs".)

Acquired and inherited thrombophilias

Antiphospholipid syndrome (APS) – Women with APS are at increased risk for stillbirth. In addition, ≥1 unexplained fetal death at ≥10 weeks of gestation with normal anatomy by prenatal ultrasound examination or direct postnatal examination is one of the defining pregnancy morbidities for diagnosis of APS when laboratory evidence of antiphospholipid antibodies is also present. (See "Diagnosis of antiphospholipid syndrome" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)

An isolated inherited thrombophilia is not a risk factor for stillbirth. There is less clarity on women who have multiple inherited thrombophilias. (See "Inherited thrombophilias in pregnancy".)

Obesity — Risks for fetal death, stillbirth, birth asphyxia, perinatal death, neonatal death, and infant death are all increased in the setting of maternal obesity. The stillbirth rate has been estimated to be 13 to 18 per 1000 live births and stillbirths [5]. (See "Obesity in pregnancy: Complications and maternal management", section on 'Perinatal mortality'.)

Other — Other maternal medical disorders that are associated with an increased risk for stillbirth include:

Systemic lupus erythematosus. (See "Pregnancy in women with systemic lupus erythematosus", section on 'Fetal complications'.)

Chronic kidney disease. (See "Pregnancy in women with nondialysis chronic kidney disease", section on 'Pregnancy outcomes'.)

Hypo- and hyperthyroidism. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Pregnancy complications'.)

Sleep-disordered breathing. (See "Obstructive sleep apnea in pregnancy".)

Intrahepatic cholestasis of pregnancy — Intrahepatic cholestasis of pregnancy (ICP) causes pruritus without a rash, typically in the late second trimester or the third trimester. The total bile acid level is elevated, and transaminases are often elevated. ICP has been associated with an increased risk of stillbirth, with an estimated stillbirth rate of 12 to 30 per 1000 live births and stillbirths in one review [5]. (See "Intrahepatic cholestasis of pregnancy".)

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

Structural uterine abnormalities, such as a unicornuate uterus, can be associated with cervical insufficiency, which can lead to previable PTB. 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".)

Assisted reproductive technology — Stillbirth rates appear to be slightly increased in pregnancies conceived via assisted reproductive technology. A meta-analysis of 33 cohort studies found that the crude baseline risk of stillbirth in singleton gestations following in vitro methods of conception was 4.44 of 1000 total births (odds ratio [OR] 1.41, 95% CI 1.20-1.65 compared with non-in vitro conceptions) [70]. In subgroup analysis, there was no increased risk when in vitro methods were compared with conception without in vitro methods in the context of subfertility, suggesting that the increased risk may be due to the underlying cause of infertility rather than the procedures themselves. However, the number of pregnancies in subfertile patients not exposed to in vitro methods was small and insufficient to provide a clear conclusion. (See "Assisted reproductive technology: Pregnancy and maternal outcomes".)

Fetal factors

Multiple gestation — Fetal mortality increases with increasing number of fetuses: 2.5-fold higher for twins than singletons, fivefold higher for triplets or more (eg, stillbirth rate for singletons, twins, and triplets and other high order gestations: 6, 14, and 31 per 1000 live births and stillbirths, respectively [8,71]). The increased risk in multiples is due to complications related to monochorionic placentation (eg, twin-twin transfusion syndrome, twin reverse arterial perfusion sequence, selective growth restriction) as well as complications such as fetal anomalies and nonselective growth restriction, which can occur in any pregnancy. (See "Twin pregnancy: Overview", section on 'Types of complications' and "Triplet pregnancy", section on 'Potential complications'.)

Male sex — Stillbirth is more common among male than female fetuses. In a systematic review, the crude rate for males was 6.23 stillbirths per 1000 total births versus 5.74 stillbirths per 1000 total births for females (RR 1.10, 95% CI 1.07-1.13) [72].

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".)

Postterm pregnancy — The perinatal mortality rate at ≥42 weeks of gestation is twice the rate at term, increasing fourfold at 43 weeks and five- to sevenfold at 44 weeks. The absolute rate is estimated to be 14 to 40 per 1000 live births and stillbirths [5]. (See "Postterm pregnancy", section on 'Perinatal mortality'.)

PREDICTING RISK FOR STILLBIRTH

Risk modeling – A variety of models that estimate patient-specific risk for fetal loss have been developed, but none perform well enough to be clinically useful. Two reasons are that women with risk factors do not account for the majority of stillbirths, and most risk factors do not lead to stillbirth [73]. Furthermore, most risk prediction models had a high risk of bias [74,75].

Laboratory tests – No laboratory test is clinically useful for predicting stillbirth [76].

Biochemical analytes obtained as part of population-based screening programs for Down syndrome, if abnormal, are predictive of adverse pregnancy outcome, including fetal death [77-81]. However, the utility of these tests for predicting stillbirth is low, and further investigation is needed to determine whether any type of monitoring and intervention protocol would improve pregnancy outcome and be cost-effective in managing these pregnancies. Changes in clinical management are not indicated given the absence of such data.

In a meta-analysis evaluating biochemical tests of placental function for prediction of stillbirth, human placental lactogen was the most common biochemical test studied and had poor sensitivity and specificity for stillbirth (76 and 78 percent, respectively) [82].

STRATEGIES FOR PREVENTING A FIRST STILLBIRTH IN THE GENERAL OBSTETRIC POPULATION — Developing strategies for stillbirth reduction requires an ongoing audit process to evaluate the specific causes of stillbirth and the results of intervention programs [83]. Perinatal audits have identified stillbirths resulting from deficiencies in intrapartum care, and quality improvement processes have been initiated to prevent recurrence [84-86].

Low-income countries — A systematic review identified the following 10 interventions as those with the best evidence for reducing the burden of stillbirth worldwide [87]. The list contains some interventions that are both attainable and effective for stillbirth prevention in low-income countries where the risk of stillbirth is high and availability of resources is low [16,84,87-90].

Skilled birth attendant at birth.

Availability of basic emergency obstetric care.

Availability of comprehensive emergency obstetric care.

Prevention of malaria. (See "Malaria in pregnancy: Prevention and treatment".)

Detection and treatment of syphilis. (See "Syphilis in pregnancy".)

Detection and management of hypertensive disorders of pregnancy. (See "Preeclampsia: Clinical features and diagnosis" and "Preeclampsia: Management and prognosis" and "Gestational hypertension".)

Periconceptional folic acid fortification. (See "Folic acid supplementation in pregnancy".)

Detection and management of diabetes in pregnancy. (See "Gestational diabetes mellitus: Screening, diagnosis, and prevention" and "Pregestational (preexisting) diabetes mellitus: Obstetric issues and management" and "Gestational diabetes mellitus: Obstetric issues and management".)

Detection and management of fetal growth restriction. (See "Identification and diagnosis of fetal growth restriction" and "Fetal growth restriction: Evaluation and management".)

Establishing an accurate estimated date of delivery so as to be able to identify and induce postterm pregnancies (≥41 weeks of gestation). (See "Postterm pregnancy".)

High-income countries — Many of the interventions listed above for low-income countries are also applicable to high-income countries and are already part of routine prenatal care in these countries. In addition:

Identify women with medical and obstetric disorders that carry an increased risk for stillbirth and give appropriate medical and obstetric care. Implement national perinatal audits.

Studies in high-income countries suggest that suboptimal medical/obstetric care accounts for 10 to 60 percent of perinatal deaths [83,91].

Implementing a national audit was associated with a significant reduction in late stillbirths (≥37 weeks of gestation) in the Netherlands, United Kingdom, and New Zealand after substandard care was found in 20 to 30 percent of stillbirths, with a rate as high as 60 percent for intrapartum stillbirths [86].

Improve detection and management of fetal growth restriction and management of abruptio placentae. (See "Identification and diagnosis of fetal growth restriction" and "Fetal growth restriction: Evaluation and management" and "Acute placental abruption: Management and long-term prognosis".)

Strategies should be developed toward risk assessment for and management of fetal growth restriction and abruptio placentae because population-based studies suggest that these two obstetric complications account for over 50 percent of fetal deaths [92]. As an example, the value of identifying fetal growth restriction was suggested by a large cohort study in which the stillbirth rate was 2.4 deaths per 1000 births in pregnancies without fetal growth restriction, increasing to 9.7 deaths per 1000 births with antenatally detected fetal growth restriction and 19.8 deaths per 1000 births when it was not detected [59].

Address modifiable risk factors, including preconception weight reduction in obese women, smoking cessation, avoidance of alcohol, and cessation of nonprescription use of opioids and recreational use of drugs [83].

Electively delivering pregnancies earlier rather than later in the term gestational age range will obviously prevent some term stillbirths since fetal demise can only occur in an ongoing pregnancy. (See 'Planned delivery at term' below.)

Enhance access to contraception and information about fertility and family planning to reduce pregnancy at very young and older maternal ages, which thus may reduce stillbirth.

Limit the number of embryos transferred during in vitro fertilization to reduce the number of stillbirths related to multiple gestation.

Offering prenatal screening and then diagnostic testing and termination of pregnancies with major congenital anomalies (eg, anencephaly) could reduce the proportion of stillbirths related to this etiology [93]. However, pregnancy termination merely results in some potential stillbirths and neonatal deaths being classified as abortuses.

Although nonstress tests and biophysical profiles have a role in monitoring pregnancies at high risk for stillbirth, these tests have not been studied for prevention of stillbirth in an unselected population. (See "Overview of antepartum fetal assessment".)

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 [94]. These data are discussed in detail separately. (See "Decreased fetal movement: Diagnosis, evaluation, and management".)

Increased or excessive fetal movement has been suggested as a risk factor for adverse fetal outcome based on data from a few retrospective studies, but prospective studies have not confirmed an association with stillbirth [95,96].

Planned delivery at term — The risk of stillbirth increases late in pregnancy. In a 2019 systematic review of cohort studies of term pregnancies in high-income countries (13 studies, 15 million pregnancies, over 17,800 stillbirths), the incremental increase in stillbirth per 1000 pregnancies in strictly defined low-risk singleton pregnancies that advance to the next week was 0.12 at 38+0 weeks (95% CI 0.06-0.20), 0.14 at 39+0 weeks (95% CI 0.02-0.27), 0.33 at 40+0 weeks (95% CI 0.19-0.47), 0.80 at 41+0 weeks (95% CI 0.57-1.14), and 0.88 at 42+0 weeks (95% CI 0.42-1.27) [97].

However, before inducing all women prior to their estimated date of delivery, outcomes other than stillbirth also need to be considered: neonatal morbidity is higher for low-risk deliveries planned for the early term period (37+0 to 38+6 weeks) compared with full-term birth (39+0 to 40+6 weeks), even with confirmed pulmonary maturity [98]. Furthermore, in a trial of planned induction of labor at 39+0 to 39+4 weeks versus expectant management in low-risk nulliparous women, induction did not clearly reduce a composite endpoint of adverse perinatal outcome (relative risk [RR] 0.80, 95% CI 0.64-1.00) or perinatal death (RR 0.66, 95% CI 0.12-3.33) [99].

Therefore, when making decisions about planned induction of labor to avoid stillbirth at term, patients and clinicians need to consider the body of data on fetal mortality, neonatal morbidity, and neonatal mortality with intervention versus expectant management. The issue of planned induction of labor at 39 weeks is discussed in more detail separately. (See "Induction of labor with oxytocin", section on 'Elective induction at ≥39 weeks'.)

STRATEGIES FOR PREVENTION OF RECURRENT STILLBIRTH — Subsequent pregnancies are stressful after a stillbirth. A study of eight couples who had a healthy infant after a stillborn noted that half of the mothers did not make preparations for their babies until after delivery, and seven of the eight wanted the hospital staff to recognize their previous loss and give them special understanding [100].

Thorough evaluation for the cause of the first stillbirth — A thorough maternal and stillborn evaluation is important after a stillbirth. If the etiology of the first stillbirth can be determined and intervention is possible in future pregnancies, then recurrence can be prevented. (See "Stillbirth: Maternal and fetal evaluation".)

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

There is no convincing evidence on the optimum interpregnancy interval after a stillbirth. It is reasonable to advise women to delay conception until they feel they have achieved psychological closure of the previous pregnancy loss, which typically takes at least 6 to 12 months [101]. Observational series suggest that women are more vulnerable to posttraumatic stress in the pregnancy subsequent to stillbirth when conception occurs soon after the loss [102] and that mothers who deliver their next infant around the anniversary of their first infant's death are particularly vulnerable [103]. An additional consideration is that the risk of adverse pregnancy outcomes appears to be lower when the interpregnancy interval is more than six months. (See "Interpregnancy interval: Optimizing time between pregnancies".)

The delivery mode may also play a role in providing guidance regarding the interpregnancy interval. Women who have a cesarean delivery in the third trimester are advised to wait longer than those who have had a vaginal delivery; some authors have suggested waiting 18 months until the next pregnancy. (See "Interpregnancy interval: Optimizing time between pregnancies".)

Principles of 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. When the cause of the prior stillbirth is unknown, patients' anxiety levels may be reduced with more frequent prenatal visits and frequent testing, such as nonstress tests and ultrasound examinations, although there is little evidence that intensive monitoring in future pregnancies will make a significant difference in preventing stillbirth.

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 are fourfold higher after an unexplained stillbirth [104].

Obtain at least two to three ultrasound examinations across gestation.

An ultrasound examination is performed, ideally in the first trimester, for confirmation of gestational age. Although an examination before 22 weeks is acceptable, accuracy diminishes with advancing gestational age. (See "Prenatal assessment of gestational age, date of delivery, and fetal weight".)

An ultrasound examination is performed at 18 to 22 weeks of gestation for the fetal anatomic survey.

Another ultrasound examination is performed between 24 and 30 weeks for assessment of fetal growth and amniotic fluid volume. The American College of Obstetricians and Gynecologists (ACOG) suggests sonographic screening for growth restriction after 28 weeks [5].

A history of stillbirth unrelated to fetal anomalies is associated with significantly higher frequencies of complications in the subsequent pregnancy, including preterm birth (PTB), fetal growth abnormalities, preeclampsia, and placental abruption [105,106]. The earlier the prior loss, the higher the risk for an adverse outcome [107]. 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 important and may be performed clinically or, if difficult such as in obese women, 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".)

Low-dose aspirin for women at high risk of developing preeclampsia – 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. We follow United States Preventive Services Task Force guidelines for daily low-dose aspirin for women at high risk for preeclampsia [108]. In the absence of high risk factors for preeclampsia, prophylactic low-dose aspirin is not recommended for the prevention of stillbirth [109]. Selection of candidates for low-dose aspirin prophylaxis and dosing are reviewed separately. (See "Preeclampsia: Prevention", section on 'Low-dose aspirin'.)

Although not currently recommended by ACOG [109], a meta-analysis of randomized trials found a reduction in perinatal death for aspirin doses ≥100 mg daily begun ≤16 weeks (risk ratio 0.47, 95% CI 0.25-0.88) that was independent of any reduction in rates of preeclampsia and PTB [110]. This benefit is thought to be related to aspirin's effects on early placental development and function. A limitation of the analysis is that none of the trials were designed to evaluate the impact of aspirin on perinatal outcome. Additional data are needed before a strong recommendation can be made for routine aspirin use to prevent stillbirth.

We recommend not administering anticoagulants for prevention of stillbirth. A systematic review of trials of care prior to and during subsequent pregnancies for improving outcomes following stillbirth 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 [111]. Potential complications of anticoagulation include bleeding, thrombocytopenia, and bone loss.

Antepartum fetal monitoring – In otherwise healthy women with a previous stillbirth and no other standard indications for antepartum fetal monitoring in the current pregnancy, we agree with ACOG's recommendation for initiation of antepartum fetal testing. For patients with a previous stillbirth ≥32 weeks, they suggest antenatal surveillance once or twice weekly beginning at 32+0 weeks or 1 to 2 weeks before the gestational age of the prior stillbirth [5]. For patients with prior stillbirths before 32 weeks, timing should be individualized. However, ACOG acknowledges the lack of evidence to support the benefits of antepartum surveillance in this setting.

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 three 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) [112], odds ratio (OR) 1.00 (95% CI 0.23-4.30) [104], and OR 4.18 (95% CI 1.36-12.89) [113]. 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 — 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 [114,115]. 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) [116]. 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 [114,115,117].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stillbirth".)

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

Definition – 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.)

Rate – The stillbirth rate in the United States is approximately 5.96 deaths per 1000 live births and fetal deaths. Black women have a higher rate of stillbirth than White women. The frequencies of the various etiologies of stillbirth differ among racial groups. (See 'Incidence' above.)

Risk factors – Risk factors for stillbirth include Black race, older maternal age, obesity, multiple gestation, concurrent medical disorders, smoking, and pregnancy complications. (See 'Predicting risk for stillbirth' above.)

Causes – Stillbirth is the end result of many maternal, fetal, and placental disorders (table 1). However, 25 to 60 percent remain unexplained. The proportion of unexplained cases generally reflects whether the stillbirth has been fully evaluated and if the classification system allows risk factors to be included as causes. (See 'Potential etiologies' above and 'Unexplained stillbirth' above.)

Risk reduction interventions – A variety of interventions have the potential to reduce the burden of stillbirth worldwide. The interventions for low-income countries differ from those for high-income countries because the major causes of stillbirth are different in limited-resource versus high-resource environments. Ideally, clinicians and patients will take actions to mitigate the impact of modifiable risk factors. (See 'Strategies for preventing a first stillbirth in the general obstetric population' above.)

Role of planned induction – In low-risk pregnancies, when making decisions about planned induction of labor to avoid stillbirth at term, patients and clinicians need to consider the body of data on fetal mortality, neonatal morbidity, and neonatal mortality with intervention at ≥39 weeks versus expectant management. (See 'Planned delivery at term' above and "Induction of labor with oxytocin", section on '"Elective" induction'.)

Women with a previous stillbirth

Preconception care – 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.)

Prenatal care – 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 'Principles of pregnancy management' above.)

-Early screening for diabetes – The odds of gestational diabetes are 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, repeat at 24 to 28 weeks.

-Frequency of ultrasound examinations – 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 is commonly performed at 18 to 22 weeks of gestation. (See 'Principles of pregnancy management' above.)

-Role of low-dose aspirin – Low-dose aspirin prophylaxis is indicated for women who meet United States Preventive Services Task Force criteria for high risk of developing preeclampsia. Previous stillbirth alone is not an indication for low-dose aspirin prophylaxis or anticoagulation. (See "Preeclampsia: Prevention", section on 'Candidates'.)

-Antepartum fetal testing – 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 1 to 2 weeks prior to the gestational age of the previous stillbirth and by 32 to 34 weeks of gestation. (See 'Timing of delivery' above.)

-Delivery timing – We agree with an expert consensus guideline that suggests avoiding scheduled delivery before 39 weeks if the previous stillbirth was unexplained and the current pregnancy is uncomplicated. (See 'Strategies for prevention of recurrent stillbirth' above.)

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Topic 6827 Version 82.0

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