Evaluation of Stillbirth

Evaluation of Stillbirth

Alex S. Miller

Uma M. Reddy



Stillbirth, defined as fetal death at 20 weeks or more of gestation, remains a common adverse pregnancy outcome worldwide, affecting 2.6 million third-trimester pregnancies in 2015.1 Significant disparities exist with 98% of stillbirths occurring in low-income and middle-income countries: 77% in South Asia and sub-Saharan Africa.2 As of 2015, the global rate of stillbirth was approximately 18 per 1000 births, exceeding the target set by the World Health Organization’s (WHO’s) Every Newborn Action Plan of 12 or fewer stillbirths per 1000 births in every country by 2030.2,3

In the United States, approximately 24,000 stillbirths occur annually, a rate of 5.96 per 1000 births in 2013, evenly dispersed between “early” stillbirth (20-27 weeks’ gestation) and “late” stillbirth (≥28 weeks’ gestation).4 This rate has changed minimally since 2006, while infant mortality has declined by 11%.4

Risk Factors for Stillbirth

In the United States, there is significant racial/ethnic variation among stillbirth rates. In 2013, the highest stillbirth rate occurred among non-Hispanic black women of 10.53 per 1000 births compared with 4.88 per 1000 births for non-Hispanic white women.4 In order to understand the reasons for this racial/ethnic disparity, the Stillbirth Collaborative Research Network (SCRN) conducted a population-based, case-controlled study involving 59 tertiary care and community hospitals across five geographic catchment areas. Compared with non-Hispanic white women, non-Hispanic black women were significantly more likely to have stillbirth occur prior to 24 weeks, intrapartum, and secondary to an infection or obstetric complication.5 Because of the shared pathophysiology with spontaneous preterm birth (see Chapter 49), a condition with well-documented racial disparity, interventions that reduce rates of early spontaneous preterm birth may also address this subset of stillbirths.

Stillbirth rates vary by maternal age in a parabolic distribution, with the lowest occurring in women aged 25 to 29 years (5.34 per 1000 births) and highest occurring in women younger than 15 years (15.88 per 1000 births).4 Advanced maternal age (AMA) also increases the risk of stillbirth—increases 2-fold from ages 40 to 44 years and 2.5-fold with maternal age 45 years and older (13.76 per 1000 births).4 This association persists after adjusting for maternal medical disease, race/ethnicity, and parity.6,7 A meta-analysis evaluating the effect of AMA on pregnancy outcomes noted that the increased risk of stillbirth parallels an increased risk of placental abruption, preeclampsia, and fetal growth restriction, highlighting placental dysfunction as a possible contributor to the age-related increase in stillbirth.8

Obesity also increases the risk of stillbirth in a dose-dependent fashion with a meta-analysis of 38 cohort studies revealing a relative risk of 1.21 for every increase of 5 units of maternal body mass index (BMI).9 Women with a BMI over 30 kg/m2 are twice as likely to experience stillbirth. Causes of obesity-related stillbirth include placental diseases, hypertension, fetal anomalies, and cord abnormalities (see Chapter 32).10

Other obstetric risk factors, such as increased parity, are associated with an increased risk of stillbirth, with rates more than doubled in women with four or more prior pregnancies.11 Stillbirth also occurs more frequently in multifetal gestations, with approximately a 2.5-fold increased risk in twins and 5.5-fold increased risk in triplet or higher order gestations (see Chapter 5).4 Smoking, alcohol
use, illicit drug use (see Chapter 8), low education, and inadequate prenatal care (see Chapter 54) are also associated with elevated risks of stillbirth.12

In the SCRN review of 512 stillbirths, 17% occurred intrapartum. These are generally secondary to preterm labor, premature prelabor rupture of membranes, cervical insufficiency, intra-amniotic infection, or placental abruption at a previable or periviable gestational age.5

Classification of Stillbirth

Accurate, consistent reporting of causes of stillbirth is needed to guide further efforts aiming to reduce the risk of stillbirth. Over 80 classification systems have been proposed with no current uniformly used system for stillbirth reporting.13 The SCRN developed a classification system based on the evidence in the existing literature entitled “Initial Causes of Fetal Death” or INCODE.14 This system assigned levels of certainty to causes of stillbirth, ranging from “probable,” to “possible,” and “present.” Using INCODE to analyze 512 stillbirths that had a complete evaluation, including autopsy and placental pathology, the SCRN assigned a probable cause of death in 60.9% of cases and a possible or probable cause in 76.2% of cases, with multiple probable or possible causes in 31.4% of cases.5 The most frequent cause of stillbirth (29.3% of cases) was obstetric complications, a category that included abruption, complications of multiple gestations, preterm labor, preterm rupture of membranes, and cervical insufficiency predominantly at a pre- or periviable gestation. The second most frequent category (23.6% of cases) was placental complications, which included uteroplacental insufficiency and maternal vascular disorders.5 Other etiologies of stillbirth included fetal genetic or structural anomalies (13.7% of cases), infection (12.9% of cases), umbilical abnormalities (10.4% of cases), hypertensive disorders (9.2% of cases), and maternal medical complications (7.8% of cases).5

Causes of Stillbirth


Maternal infections increase the risk of stillbirth by causing severe maternal illness, direct fetal infection, placental dysfunction, or preterm labor at a previable gestation. Worldwide, maternal infections, including syphilis and malaria, are associated with a substantial number of stillbirths, up to 50% depending on the area.1,15,16 In developed nations, this rate decreases to 10% to 20%, occurring most commonly in the setting of ascending bacterial infections in the setting of preterm premature rupture of membranes.5,17

Pathogens, including group B Streptococcus and Escherichia coli, enter the amniotic fluid either after membrane rupture or after ascension from the vagina.16 Alternatively, bacteria, such as Listeria, may spread hematogenously and reach the placental villi causing microabscesses and villous necrosis.16 Viral pathogens, such as enteroviruses, cytomegalovirus, Zika virus, and parvovirus, have also been implicated in stillbirth through both placental and fetal mechanisms.16,18 A more detailed discussion of infectious diseases affecting pregnancy is presented in Chapter 39.

Maternal Medical Conditions


Hypertension is a significant cause of stillbirth, contributing to 9.2% of stillbirths identified by the SCRN.5 In the United States in 2017, 8.6% of pregnancies were complicated by hypertensive disorders of pregnancy: 1.9% by chronic hypertension and 6.45% by preeclampsia or gestational hypertension.19 Stillbirth risk is highest in the setting of preeclampsia that is superimposed on chronic hypertension and lowest in uncomplicated chronic and gestational hypertension.20,21 A detailed discussion of hypertensive diseases in pregnancy is presented in Chapter 27.


In the United States in 2017, 7.3% of pregnancies were complicated by gestational or preexisting diabetes mellitus: 0.9% prepregnancy and 6.4% gestational diabetes.19 Preexisting diabetes increases the risk of stillbirth by a factor of 2.9.12 In a study of 5000 pregnant women with type 1 diabetes, the rate of stillbirth was five times higher than the nondiabetic population.22 Stillbirth occurs most frequently in the setting of poor glycemic control secondary to congenital abnormalities, placental insufficiency, growth restriction, macrosomia, or obstructed labor. Unlike preexisting diabetes, gestational diabetes does not have an increased stillbirth rate in most large studies.23 Perinatal outcomes are improved in the setting of improved glycemic control.24 A detailed discussion of diabetes in pregnancy is presented in Chapter 30.

Thyroid Disease

Maternal hyperthyroidism is rare in pregnancy, complicating 0.1% to 0.4% of births.25 Hyperthyroidism secondary to Graves disease is associated with fetal thyrotoxicosis in approximately 1% of cases secondary to thyroid-stimulating immunoglobulins.26 Untreated, this may cause growth restriction, hydrops, and fetal death.

Hypothyroidism is more prevalent, occurring in approximately 2% of women.27 Overt hypothyroidism places women at an increased risk for stillbirth; the risk for fetal or neonatal death increasing 1.6-fold for each doubling of the thyroid-stimulating hormone concentration.28 However, treatment of hypothyroidism is associated with a return to the baseline risk of stillbirth.29 Treatment of subclinical hypothyroidism with levothyroxine has not been associated with a reduction in stillbirth rate.30

Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is associated with stillbirth in the setting of active disease, renal involvement, and antiphospholipid syndrome. In a review of 554 women with SLE, the presence of antiphospholipid antibodies increased the risk of fetal death from 16% to 38%.31 Rarely, stillbirth may be secondary to congenital atrioventricular block, occurring secondary to transplacental passage of SS-A/Ro and SS-B/La antibodies, which cause scarring of the endocardium and permanent destruction of the atrioventricular conduction system.32 This may cause hydrops in up to 40% of cases with one-third of these cases resulting in stillbirth.32 SLE and its effects on pregnancy are discussed in Chapter 40.

Renal Disease

Approximately 4% of women of childbearing age are affected by chronic kidney disease.33 Perinatal mortality is 7% in stages 1 and 2 chronic kidney disease (glomerular filtration rate ≥ 60 mL/min) and 14% in stages 3 to 5 (glomerular filtration rate < 60 mL/min).34 Hypertension is often associated with maternal kidney disease and is associated with an additional two- to tenfold increase in adverse fetal outcomes including stillbirth.33 Altering dialysis schedules to optimize maternal and fetal outcomes has increased live birth rates to 50% to 87%.35 Kidney transplantation performed prior to pregnancy with normalization of renal function results in the most significant improvement of pregnancy outcomes. Pregnancy complicated by renal disorders is discussed in Chapter 35.

Intrahepatic Cholestasis of Pregnancy

Intrahepatic cholestasis of pregnancy (ICP), characterized by pruritus and elevated serum bile acid concentration, is associated with an increased rate of stillbirth. A prospective study in Sweden involving 45,000 pregnant women screened for ICP noted that women with bile acids greater than 40 µmol/L experienced significantly higher rates of fetal complications including asphyxia, spontaneous preterm labor, and presence of meconium.36 Increased stillbirth rates are theorized to be secondary to bile acid associated damage to the fetal cardiomyocytes causing fatal arrhythmias and vasoconstriction of the chorionic veins.37 Antenatal testing does not appear to reduce the risk of stillbirth.38 Liver diseases in pregnancy are discussed in Chapter 34.

Inherited/Acquired Thrombophilias

Antiphospholipid antibody syndrome, the most common acquired thrombophilia, is associated with an increased risk of stillbirth. The SCRN noted that elevated levels of anticardiolipin and anti-β2 glycoprotein antibodies were associated with a threefold increased risk of stillbirth.39 In contrast, the SCRN did not find an association between most heritable coagulopathies or thrombophilias with stillbirth rates with the exception of maternal homozygous factor V Leiden.40 However, prospective studies do not demonstrate a link between inherited thrombophilias and stillbirth, including factor V Leiden.41 Thrombophilias are discussed in Chapter 2.

Fetal Conditions

Genetic Abnormalities

Fetal cytogenetic abnormalities account for approximately 10% of stillbirths, and this percentage is elevated in the setting of fetal structural abnormalities.42,43 A Dutch study of 1025 stillbirths with a 68% rate of cytogenetic testing detected an overall rate of 11.9% of chromosomal abnormalities. The distribution of chromosomal abnormalities was as follows: trisomy 21 accounted for 37% of cases, trisomy 18 accounted for 23% of cases, monosomy (45,X) accounted for 16% of cases, and trisomy 13 accounted for 5% of cases.42 In addition
to aneuploidy, other chromosomal abnormalities, such as copy number variants (ie, microdeletions or duplications), likely contribute to stillbirth.44

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Evaluation of Stillbirth
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