Stillbirth

Etiology

Stillbirth is a complex outcome with multiple contributing factors, often involving a combination of maternal, fetal, placental, and environmental influences. While some cases remain unexplained, common causes include placental insufficiency, fetal genetic abnormalities, maternal medical conditions (such as hypertension and diabetes), and infections. Previous adverse pregnancy outcomes, such as preterm birth or fetal growth restriction, can also elevate the risk of stillbirth, potentially reflecting underlying placental dysfunction or maternal health concerns. Understanding these etiological factors is crucial for identifying high-risk pregnancies and informing preventive strategies.

Maternal Factors

Diabetes

Diabetes increases the risk of stillbirth up to 5 times.[5][6][7] With optimal glycemic control, the risk of stillbirth may be reduced.[8] In those with type 1 diabetes, the stillbirth rate is 16.1 per 1000 births. Poor diabetic control determined by elevated glycosylated hemoglobin before pregnancy (odds ratio [OR] 1.03) and later in pregnancy (OR 1.06) was associated with stillbirth. In those with type 2 diabetes, the stillbirth rate is 22.9/1000 births. A higher body mass index (BMI) (OR 1.07) and elevated glycosylated hemoglobin before pregnancy (OR 1.02) were associated with stillbirth. Birth weight may be affected by diabetes and is also related to the risk of stillbirth. If birth weight is less than the tenth percentile, the risk for stillbirth is elevated 6 times in mothers with type 1 diabetes and 3 times in those with type 2 diabetes compared to fetuses weighing in the tenth to 90th percentile. With type 2 diabetes, the risk for stillbirth was 2-fold higher if the birth weight was over the 95th percentile. A significantly higher number of stillborns in women with type 2 diabetes are male sex. A third of the stillbirths associated with diabetes occur at term. The highest rate of stillbirth is in the 38th week for type 1 diabetes and in the 39th week for type 2 diabetes.[9][10]

Hypertension

Hypertension disorders in pregnancy include chronic hypertension, gestational hypertension, and preeclampsia. A recent meta-analysis demonstrated that high blood pressure before or early in pregnancy has an increased odds of stillbirth (OR 2.01). This association is increased with the increased severity of hypertension. Therefore, blood pressure surveillance and management are crucial for enhancing pregnancy outcomes.[11]

Obesity

Obesity is an independent risk factor for stillbirth, even after controlling for diabetes, smoking, gestational diabetes, and preeclampsia. Obesity is a major health problem in developed countries, defined as a BMI greater than 30 kg/m². Nonobese women have a stillbirth risk of 5.5 per 1000. The risk is 8/1000 for women with a BMI of 30 to 39.9 kg/m² and 11/1000 for those with a BMI greater than 40 kg/m².[12][13][14][15] Overweight women, defined as having a BMI of 25.0 to 29.9 kg/m², have an OR of 1.37 (95% confidence interval [CI], 1.02–1.85), and class IV obese women, with a BMI greater than 50.0 kg/m², have an OR of 5.04 (95% CI, 1.79–14.07).[16]   

Substance misuse

The most common finding in pregnancy complicated by substance use is growth restriction. Placental dysfunction, vasoconstriction, hypoxia, and alterations in endogenous chemicals responsible for regulating optimal well-being are attributed to the increased risk of stillbirth associated with substance misuse.[17]

Tobacco: Smoking tobacco increases the risk of stillbirth, both antepartum and intrapartum (15/1000). Quitting by the beginning of the second trimester reduces the risk to that of a nonsmoker.[18] Compared to never smoking, active smoking is associated with an OR of 1.44 (95% CI: 1.20–1.73) for having 1 or more stillbirths. Compared with never-smokers, women exposed to second-hand smoke for greater than 10 years in childhood, 20 years in adulthood at home, or 10 years at adult work have an odds ratio of 1.55 (95% CI: 1.21–1.97) for having 1 or more stillbirths.[19] 

Alcohol: The direct cause of stillbirths associated with alcohol consumption has not been identified, yet the risk is well-documented. During pregnancy, 11.5% of women consume at least 1 drink in 30 days, and 3.9 % consume 4 or more drinks on at least 1 occasion over 30 days. The OR for stillbirth associated with alcohol use is 1.36 (95% CI: 1.05–1.76).[20] 

Illicit drugs: During pregnancy, 4.4% of women use illegal drugs. There is a 1.5 OR for stillbirth associated with opioid use in pregnancy (95% CI: 1.3–1.8) and a 5.1 OR for stillbirth associated with methamphetamine use in pregnancy (95% CI: 3.7–7.2).[17] Cannabis use beyond the first trimester is linked to an increased risk of adverse pregnancy outcomes, including stillbirth, with a primary composite outcome showing an adjusted relative risk of 1.32 (95% CI: 1.09–1.60).[21] 

Obstetric and Pregnancy-Related Conditions, Including Previous Adverse Pregnancy Outcomes

A meta-analysis of 17 studies assessed the risk of stillbirth in mothers with prior stillbirth, preterm birth (PTB), and small for gestational age (SGA) as a proxy for fetal growth restriction. The study's results found that prior PTB or SGA birth increased the risk of stillbirth in a subsequent pregnancy (adjusted OR [aOR] 2.05, 95% CI: 1.18–3.55, and aOR 1.85, 95% CI: 1.42–2.40, respectively). The risk was even greater when both factors were present, with preterm SGA births doubling the likelihood of stillbirth (aOR 3.15, 95% CI: 1.89–5.25).[22] Additionally, a history of a previous stillbirth significantly increases the risk of recurrent stillbirth (aOR 2.68, 95% CI: 2.01–3.56).[23] These findings highlight the interconnected nature of adverse birth outcomes and the need for clinical guidelines to account for the cumulative impact of prior complications.

Placental and Umbilical Cord Abnormalities

Placental

Fetal growth restriction and placental abnormalities are the most prevalent findings in stillbirth, though it is important to note that most pregnancies do not result in stillbirth.[5] Placental abnormalities can also be found in stillbirths without evidence of impaired growth. Symphysis-fundal height, used to estimate serial fetal growth at prenatal visits, has low sensitivity and specificity for detecting a small-for-gestational-age infant. Recent evidence highlights that fetoplacental Doppler and fetal growth velocity, combined with cardiotocography for short-term variability, are crucial tools for diagnosing and monitoring fetal growth restriction, optimizing surveillance, and enhancing perinatal outcomes.[24]

Current data demonstrates significant increases in the risk of stillbirth for fetuses below the tenth percentile birth weight, particularly pronounced at the extremely low end of growth and late in gestation.[25] The rate of stillbirth in the United States between 2014 and 2015 for fetuses in the lowest percentile for growth was 39.8 per 1000 births, compared to the predicted 11.7 per 1000 from the category-based analysis.[26] Placental abnormalities, such as a placental abruption, are found in 6% of stillbirths.[27] A history of placental abruption increases the risk of stillbirth. This risk is greatest for preterm fetuses. Cocaine use, smoking, hypertension, and preeclampsia increase the risk of placental abruption and stillbirth. Maternal conditions such as gestational diabetes and autoimmune diseases have also been found to increase the risk of placental abnormalities and subsequent stillbirth. Additionally, unusual placental conditions, including choriocarcinoma or chorioangioma, increase the risk of stillbirth.[28][29] 

Umbilical cord 

Umbilical cord abnormalities, including cord entrapment, obstruction (eg, torsions, strictures with thrombi, knots), cord prolapse, vasa previa, and compromised fetal microcirculation, have been implicated in stillbirth. An analysis using the International Classification of Neonatal Deaths system found that approximately 19% of stillbirths are associated with umbilical cord abnormalities.[30] While nuchal cords occur in up to 30% of normal births and are not significantly linked to stillbirth, the odds of stillbirth increase with multiple nuchal loops compared to single or no loops (OR 2.36, 95% CI: 0.99–5.62). Additionally, true cord knots are associated with a significantly higher risk of stillbirth (OR 4.65, 95% CI: 2.09–10.37).[31] Evaluation for evidence of cord obstruction or circulatory compromise is necessary when evaluating for the cause of stillbirth. 

Fetal Factors

Congenital defects

Congenital defects, defined as physical or biochemical abnormalities, occur in 1/33 pregnancies and are associated with a higher risk of stillbirth. Stillbirth risk is 11/1000 for bladder exstrophy and 490/1000 for the limb-body-wall complex; even for isolated congenital defects not affecting major organs, the risk of stillbirth increases. The risk for stillbirth associated with cleft lip with cleft palate is 10/1000,  transverse limb deficiencies 26/1000, longitudinal limb deficiencies 11/1000, and amniotic band-associated limb defects 110/1000. The increased stillbirth risk for sacral agenesis is 13/1000, isolated spina bifida 24/1000, and holoprosencephaly 30/1000 may be underestimated due to failure to account for elective termination of pregnancy.[32] Dysmorphic features or skeletal issues are found in 20% of stillborns, and up to 20% have gross malformations.[29][33]

Genomic abnormalities further contribute to the etiology of stillbirth, particularly in cases with fetal structural malformations (FSMs). The proportion of stillbirth cases with FSMs was significantly higher among those with abnormal copy number variations (CNVs) compared to those with normal CNVs (47.5% vs 19.1%; P <0.001). The most common organ system-specific FSMs associated with abnormal CNVs included cardiac defects, hydrops, craniofacial defects, and skeletal anomalies. Notably, a pathogenic deletion of 1q21.1, involving 46 genes (eg, CHD1L), was linked to skeletal defects, while a duplication of 21q22.13, involving 4 genes (SIM2, CLDN14, CHAF1B, HLCS), was associated with cardiac defects. These findings suggest that specific CNVs may contribute to stillbirth risk and highlight the need for further investigation to improve genetic counseling and pregnancy management in cases with FSMs.[34]

Polyhydramnios 

Polyhydramnios complicates 1% to 2% of pregnancies. As assessed by abdominal ultrasound, polyhydramnios is defined as an amniotic fluid index of 24 cm or greater, or the deepest vertical pocket of fluid of 8 cm or greater. Fifty percent of the time, the cause of polyhydramnios is idiopathic.[35] A 2023 meta-analysis showed that pregnancies complicated by idiopathic polyhydramnios had significantly increased odds of stillbirth, with an odds ratio of 7.64 (95% CI: 2.50–23.38). The study also demonstrated increased odds of neonatal death, neonatal intensive care unit admissions, low Apgar score, cesarean delivery, macrosomia, and malpresentation.[36] 

Known causes of polyhydramnios include maternal diabetes mellitus, fetal anomalies, congenital infection, and alloimmunization.[37] Polyhydramnios is associated with a higher risk of preterm delivery, malpresentation, and cord prolapse, which may explain why it is associated with an increased risk of stillbirth. There is also a 3.2% risk of aneuploidy in pregnancies complicated by idiopathic polyhydramnios, which is significantly higher than the general population and may contribute to an increase in stillbirth risk.[38]

Polyhydramnios is also associated with congenital anomalies of the central nervous system, gastrointestinal system, cardiac system, hydrops, and aneuploidy, as well as maternal conditions such as diabetes, infection, and diabetes insipidus associated with the use of lithium. A study conducted in Ethiopia showed a 13.4-fold increased risk for stillbirth in pregnancies complicated by polyhydramnios.[39] Whether the fetal or maternal condition causing polyhydramnios leads to a higher risk for stillbirth or not is uncertain. The risk of adverse pregnancy outcomes increases with the degree of polyhydramnios in women with identified risk factors for polyhydramnios but not in idiopathic cases.[40] This risk is attributed to the comorbidities associated with nonidiopathic cases, excluding diabetes.[41] 

The relative risk for stillbirth is 7.7 for persistent polyhydramnios compared with pregnancies with resolved polyhydramnios. Compared with pregnancies unaffected by polyhydramnios, the risk of stillbirth for women with polyhydramnios increases with gestational age, with the lowest risk at 26 weeks' gestation, 7 times increased relative risk at 37 weeks, and 11 times increased relative risk at 40 weeks. The risk persists even after excluding confounding variables and sharply increases at term.[40][42]

Oligohydramnios

Oligohydramnios is an amniotic fluid index (AFI) less than or equal to 5 cm or a maximum vertical pocket under 2 cm. The deepest vertical pocket is the preferred measurement, as the AFI detects more cases of suspected oligohydramnios and polyhydramnios, which results in more labor inductions with no improvement in perinatal outcomes.[43] Oligohydramnios is associated with an increased risk for small for gestational age fetuses and stillbirth. For stillbirth, the risk is 11.54 (95% CI: 4.05–32.9).[44] Delivery for oligohydramnios may be indicated at 37 weeks' gestation when no other comorbidity is identified or sooner for nonreassuring fetal monitoring.[45]

Infectious and Autoimmune Causes

Infection as a cause of stillbirth may be underrepresented because signs and symptoms of infection are often undetected, and evaluation for infection is often not conducted.[46] Stillbirth related to infection varies from 5% to 22%.[47] In developed countries, infection accounts for 19% of stillbirths before 28 weeks but only 2% of stillbirths at term.[48] When an infection is the cause of stillbirth, spontaneous preterm delivery is common. A United States cohort study demonstrated infection as the probable or possible cause of stillbirth in 12.9% of cases.[46] The predominant bacteria cultured included Escherichia coli (29%), group B Streptococcus (GBS) (12%), Enterococcus species (12%), and Listeria monocytogenes (rarely). The placental evaluation found evidence of infection in 99% of culture-positive cases. Nonbacterial organisms causing stillbirth included cytomegalovirus (8%), parvovirus B19 (3%), Treponema pallidum (syphilis, 2%), and herpes simplex virus (2%).

Infection is unlikely to be the cause of stillbirth unless it results in significant autopsy or placental findings. Serologic screening for toxoplasmosis, chlamydia, rubella, or herpes is usually not indicated when these infections are not detected on placental or autopsy examination.[46] Malaria should be screened for in endemic areas. GBS infection is linked to the cause of stillbirth in 1% of stillbirths in developed countries and 4% in African countries. These estimates are poor, given the low quality of collected data. In Mozambique, the rate of BGS-associated stillbirth was 17%, which may be due to the high rate of screening performed there.[49] GBS must be isolated from a sterile body site, such as cerebrospinal fluid. Isolated detection from a surface or a placental swab would not qualify as a case related to GBS. Having a treated chlamydia infection before or during pregnancy does not increase the risk of preterm delivery, intrauterine growth restriction, or stillbirth.[50]

Antiphospholipid syndrome

Antiphospholipid syndrome (APS), in addition to thrombotic events, has been linked to stillbirth since 1984.[51][52] One clinical and 1 laboratory criterion must be met to diagnose antiphospholipid syndrome. The anticardiolipin antibodies, anti-beta2 glycoprotein 1 antibody, or the lupus anticoagulant must be above the 99th percentile and present at least 12 weeks apart on 2 occasions. In some cases, these antibodies may not be detected due to the limitations of current assays.[53] These antibodies may be found in 5% of people without clinical symptoms.[54]

Stillbirth risk is highest when all 3 lab criteria are positive and lowest when the lupus anticoagulant is negative.[55][56] Recently, anti-beta2 glycoprotein 1 domain-1 antibody has been linked to late pregnancy morbidity.[57] Lupus anticoagulant positivity at baseline was associated with an odds ratio of 8.3 (95% CI: 3.6–19.3) for adverse pregnancy outcomes.[58] An increased risk for pregnancy morbidity in women with APS is seen in women with a history of systemic lupus erythematosus, thromboses, previous adverse pregnancy outcomes, and low complement levels in the first trimester.[56][59][60][61] Patients with systemic lupus erythematosus have a 15% to 25% risk of stillbirth and need to be screened for antiphospholipid antibodies prenatally and offered treatment to reduce adverse pregnancy outcomes. Clinical criteria for the diagnosis of APS include a confirmed history of a thrombotic event without evidence of inflammation in the vessel wall, 1 or more unexplained fetal deaths after 10 weeks of gestational age, 3 or more deaths before the 10th week of gestation, or a preterm delivery due to eclampsia, preeclampsia with severe features or other placental insufficiencies. 

Currently, available treatment for APS remains associated with an unsuccessful pregnancy 20% to 30% of the time.[62] This syndrome is associated with growth restriction, preeclampsia, and preterm birth.[63] The exact mechanism of action leading to stillbirth is not known. The mechanism of obstetric APS appears to differ from that of thrombotic, nonobstetric APS.[64] Treatment at this time is heparin and aspirin. Newer agents being studied include pravastatin, which may improve outcomes in women with early preeclampsia attributed to the syndrome. Hydroxychloroquine may modulate the immune system and help to reduce pregnancy symptoms in women with APS.

Catastrophic APS is the loss of function of several vital organs attributed to this syndrome, and mortality is as high as 30% despite treatment.[65] This variant of APS affects less than 1% of patients with APS. Although rare, its potentially lethal outcome mandates the importance of its recognition. Lifelong anticoagulation is recommended for individuals with antiphospholipid syndrome and a history of prior thrombotic events. With a pregnancy diagnosis, warfarin must be stopped, and low molecular weight heparin (LMWH) must be started. Unlike warfarin, which crosses the placenta and increases the risk of fetal teratogenicity and hemorrhage, LMWH does not cross the placenta and is safe for the fetus.[66] A personal or family history of thromboembolism appears to increase the risk of stillbirth.[67]

Other Autoimmune Disorders

Women with systemic lupus erythematosus (SLE) have an increased risk of stillbirth compared to the general population (aOR 2.13, 95% CI: 1.02–4.45).[68] Compared to the general population, there is an increased risk of stillbirth in women with type 1 diabetes mellitus (OR 3.97, 95% CI: 3.44–4.58), rheumatoid arthritis (OR 1.99, 95% CI 1.17–2.06), celiac disease (OR 1.57, 95% CI: 1.17–2.10), and inflammatory bowel disease (OR 1.5, 95% CI:1.03–2.38).[69]

Intrahepatic Cholestasis

Intrahepatic cholestasis of pregnancy is a hepatic disorder characterized by elevated serum bile acids and pruritus, posing minimal risk to the mother but increasing the risk of fetal complications, including preterm delivery, meconium-stained amniotic fluid, and stillbirth.[70] A 2019 meta-analysis found that stillbirth was significantly associated with bile acid levels of 100 μmol/L or greater (hazard ratio [HR] 30.50, 95% CI: 8.83–105.3), whereas levels below this threshold carried a risk comparable to that of the general population.[71] Current recommendations emphasize the importance of bile acid monitoring, the use of ursodeoxycholic acid for symptom management, antenatal surveillance, and timing of delivery based on bile acid levels. Delivery is recommended at 36 weeks for those with bile acids of 100 μmol/L or greater and between 36 and 39 weeks for lower levels of bile acids.[70] 

Epidemiology

Understanding the epidemiology of stillbirth is essential to identifying populations at greatest risk and guiding prevention efforts. In the United States (US), stillbirth rates vary by race, maternal age, comorbidities, and gestational age. Persistent disparities—particularly among Black women—highlight the need for equity-focused strategies in obstetric care.

Age 

The risk of stillbirth is augmented by advanced maternal age due to an increased risk for aneuploidy and medical complications of pregnancy. Even after controlling for these risk factors, maternal age older than 35 has an increased risk for stillbirth, which is accentuated by nulliparity. At age 40, the risk is 1/116 for a nullipara and 1/304 for a multipara.[72][73] Stillbirth may be caused by lethal chromosomal abnormalities, which are more prevalent when the maternal age is older than 35.[74] Thirteen percent of stillbirths have an abnormal karyotype.[29] These abnormal karyotypes include Down syndrome (trisomy 21 in 23%), Edwards syndrome (trisomy 18 in 21%), and Patau syndrome (trisomy 13 in 8%).[75] A paternal age older than 40 also increases the risk of stillbirth.[76]

Race

Non-Hispanic Black women in the US have a 2-fold higher rate of stillbirth (11 per 1000 births) compared to other racial groups. A recent study performed a multivariate analysis comparing these populations; the results demonstrated that age younger than 20, obesity, hypertension (chronic and pregnancy-associated), nulliparity, and earlier gestational age are significant contributors to the risk of stillbirth in this population. Understanding risk factors and their interactions, listening respectfully to patients, and taking their concerns seriously are essential to providing appropriate care.[77]

Socioeconomic Status

 Addressing these disparities through targeted care and support is crucial to improving pregnancy outcomes.[78]

Late-Onset Prenatal Care

Late-onset prenatal care and prior home delivery are independent risk factors for subsequent adverse perinatal outcomes.[79] Women who do not attend antenatal care have 4 times the odds of stillbirth compared to those who attend the recommended visits (OR 4.1, 95% CI: 1.6–10). Women who attend 1 or 2 antenatal visits compared to 4 visits also show increased odds of stillbirth (OR 2.9, 95% CI: 1.7–5).[80] 

Gestational Age

The risk of stillbirth in low-risk pregnancies increases progressively as pregnancy progresses beyond 37 weeks. The relative risk [RR] of the chance of stillbirth if pregnancy continues versus delivery at the respective gestational age is as follows: 1.29 (95% CI: 1.18-1.40) at 37 weeks, 1.32 (95% CI: 1.22–1.44) at 38 weeks, 1.64 (95% CI: 1.51–1.79) at 39 weeks, 1.64 (95% CI: 1.51–1.77) at 40 weeks, 1.94 (95% CI: 1.72–2.19) at 41 weeks, 1.93 (95% CI: 1.50–2.36) at 42 weeks. These findings display the significantly increased risk of stillbirth in term pregnancies going beyond 41 weeks.[81] The American College of Obstetricians and Gynecologists recommends induction of labor by 42 weeks' gestation to reduce the risk of stillbirth and perinatal mortality, suggests antepartum monitoring beginning at 41 weeks, and supports elective induction starting at 39 weeks in low-risk, nulliparous patients to lower the risk of cesarean delivery and hypertensive disorders.[82]

Multiple Gestations

Multiple gestations are significantly associated with an increased risk of stillbirth. Compared to singleton pregnancies, twin pregnancies show more than double the stillbirth rate (1.15% vs 0.52%), with the highest risk seen in monochorionic twins. A global meta-analysis supports this finding, reporting an overall stillbirth prevalence of 1.4% in twin pregnancies, rising to 3.5% in monochorionic types. Fetal growth restriction, small for gestational age, and placental insufficiency are critical contributors to this risk, particularly when assessed using growth charts specific to twin gestations.[83][84] Stillbirth risk in multiple gestations rises steeply after 37 to 38 weeks, surpassing that of post-term singleton pregnancies. Therefore, current recommendations support considering elective delivery of uncomplicated multiple gestations at 37 to 38 weeks to reduce the likelihood of stillbirth.[85]

Pathophysiology

Stillbirth is primarily caused by fetal hypoxia. Since the fetus relies on the placenta to exchange oxygen with the mother, placental dysfunction is a key indicator of potential complications. Fetal growth depends on the delivery of oxygen and nutrients from the mother. The partial pressure of oxygen (PO2) in the maternal-fetal circulation is only a fraction of maternal PO2; therefore, even minor disruptions in PO2 can have significant effects. Fortunately, the fetal circulatory system has compensatory mechanisms that prioritize blood flow to the brain, heart, adrenal glands, and umbilical cord. When hypoxia is prolonged, however, it can lead to growth restriction.[86] 

Research results show that when uterine blood flow is experimentally reduced to 50% of baseline for 15 minutes, fetal circulation adapts by redistributing blood to critical organs. However, if blood flow drops to 25% of baseline, these compensatory mechanisms fail, leading to respiratory and metabolic acidosis, widespread vasoconstriction, and reduced blood flow to all vascular regions. This is followed by hypotension, bradycardia, decreased cardiac output, and ultimately fetal demise. Similarly, when the umbilical cord is completely occluded, circulatory centralization persists for approximately 5 minutes before vasoconstriction is lost, femoral blood flow increases, fetal heart rate declines further, and progressive hypotension develops due to depleted cardiac glycogen stores and impaired myocardial contractility.[86] Biomarkers such as elevated erythropoietin, glial fibrillary acidic protein, and cardiac troponin T can indicate fetal hypoxia and potential cerebral or myocardial ischemia.[86] 

Assessing placental pathology is crucial in evaluating fetal hypoxia. Delayed placental villous maturation, although subject to inter-observer variability among pathologists, can be more objectively analyzed using cluster of differentiation 15 (CD15) immunohistochemistry. This marker helps identify persistent villous immaturity and chronic placental dysfunction. Increased CD15 expression in both macrovascular and microvascular structures correlates with pathological placental villous immaturity. Therefore, placental pathology, including CD15 immunohistochemistry, should be considered in assessments of late fetal death.[86] 

Hypoxia resulting from placental dysfunction is the leading cause of death in structurally normal fetuses beyond 20 weeks' gestation. In 91% of hypoxic fetal deaths, evidence of brain, myocardial, or combined brain and myocardial injury is present. Circulatory failure and cardiac arrest, secondary to hypoxic myocardial injury, are the leading mechanisms of death in 70% of these cases. Placental dysfunction, confirmed through histopathological analysis, is identified in approximately 74% of stillbirths.[86] Several placental abnormalities are commonly associated with stillbirth, including placental abruption, maternal vascular malperfusion, and structural lesions such as infarctions or thrombi. Disruptions in umbilical cord blood flow, as seen in vasa previa, can also lead to fetal demise.[87][88]

Infections, particularly in early gestation, play a significant role in stillbirth. The most commonly implicated bacterial pathogens include Escherichia coli, (GBS), and Enterococcus species, while cytomegalovirus is the most frequently identified viral pathogen. These infections are often associated with chorioamnionitis and placental inflammation. [46] Although less common, fetal genetic and structural abnormalities can also contribute to stillbirth.[89]

History and Physical

A detailed history and physical examination are critical components of the evaluation following a stillbirth. These assessments help identify potential contributing factors, guide appropriate diagnostic testing, and support individualized care planning for the patient and family.

History

The history should always include details about abdominal pain, vaginal bleeding or discharge, pelvic pressure, and the last time fetal movement was noted.

Pertinent elements of the history include:

• Current pregnancy: Abnormal uterine bleeding, trauma, reproductive treatment, exposure to drugs or radiation, weight gain, infections, sexually transmitted diseases, hypertension, preeclampsia, diabetes, anemia, fetal anomaly, or growth restriction 
• Maternal history: Age, gravidity, parity, history of hypertension, diabetes, hypercoagulability, autoimmune disease, or cancer 
• Obstetrical history: Preterm delivery, stillbirth, or a fetus affected by growth restriction, as well as any pregnancy complicated by preeclampsia, diabetes, deep venous thrombosis, pulmonary embolism, or blood transfusion
• Exposure to infection: Zika, Parvovirus, cytomegalovirus, toxoplasmosis, syphilis, malaria 
• Immunization record: All completed immunizations
  • Testing for immune status may be indicated for endemic diseases such as measles. 
• Family history: Genetic disorders, recurrent miscarriages or stillbirth, paternal age, and history of genetic disorders
• Social history: Employment, nutrition, substance use, domestic violence, travel history, and exposure to animals or pets 
• Prenatal laboratory test results: Complete blood count, type and screen, hepatitis B surface antigen, syphilis, human immunodeficiency virus, rubella, prenatal testing for aneuploidy, urine toxicology, and diabetic screening

Physical Examination

Promptly evaluate patients with concerns for fetal well-being to facilitate timely intervention and alleviate anxiety. Attempt to auscultate fetal heart tones with the fetal Doppler and, if indicated, initiate electronic fetal monitoring. If unable to secure Doppler fetal heart tones, perform an abdominal ultrasound to confirm the presence or absence of fetal heart tones as soon as possible. The fetal examination should evaluate congenital anomalies, growth parameters, and signs of trauma. The maternal physical examination should include an assessment of vital signs, signs of infection, and any physical abnormalities that may be present. Additionally, a thorough inspection of the placenta, umbilical cord, and membranes is essential.

Evaluation

When stillbirth is diagnosed—either by the absence of cardiac activity on ultrasound or Apgar scores of 0 at both 1 and 5 minutes—a comprehensive evaluation is performed to determine the cause. A thorough history and physical examination are essential. Further assessment includes placental and umbilical pathology, fetal autopsy, genetic testing, maternal laboratory studies, and imaging.

The American College of Obstetricians and Gynecologists, the Royal College of Obstetricians and Gynecologists (RCOG), the Perinatal Society of Australia and New Zealand, and the Society of Obstetricians and Gynecologists of Canada summarized guidelines for stillbirth evaluation in 2020 (see Table. The 2020 Guidelines for Stillbirth Investigation).[90] Stillbirth definitions vary slightly among organizations. While all organizations recommend investigations, the extent of testing varies. Notably, RCOG uniquely emphasizes obtaining a second-opinion ultrasound for confirmation. The placental examination is universally recommended if an autopsy is declined, as it can provide valuable insights into the cause of stillbirth. Although an autopsy is the preferred method for determining cause, it requires parental consent, and imaging, such as magnetic resonance imaging, is considered a viable alternative when an autopsy is not performed. [De Gruyter. Investigation and management of stillbirth: a descriptive review of major guidelines. https://www.degruyter.com/document/doi/10.1515/jpm-2021-0403/html?lang=en] 

Table. The 2020 Guidelines for Stillbirth Investigation

ACOG, American College of Obstetricians and Gynecologists; HbA1c, hemoglobin A1c; MRI, magnetic resonance imaging; NZ, New Zealand; PSANZ, Perinatal Society of Australia and New Zealand; RCOG, Royal College of Obstetricians and Gynaecologists; SOGC, Society of Obstetricians and Gynaecologists of Canada; TSH, thyroid-stimulating hormone; UK, United Kingdom; US, United States

The Stillbirth Collaborative Research Network (SCRN) is a research initiative focused on identifying the causes, risk factors, and prevention strategies for stillbirth. Through its comprehensive and multidisciplinary approach, SCRN aims to improve both maternal and fetal health outcomes. This organization has developed standardized protocols for studying stillbirth, defining it as the birth of a baby with an Apgar score of 0 at both 1 and 5 minutes, and no signs of life observed at a gestational age of 20 weeks or more.[91]

Placental Evaluation

An evaluation of the causes of stillbirth using data from the 512 cases in the SCRN found that placental pathology was useful in determining the cause of death in 64.6% (95% CI: 57.9–72.0) of cases.[92] Gross examination of the placenta should include:

• Placental disc
• Size: Weight (kg), diameter (cm)
• Structure: Intact (yes/no), accessory lobes (yes/no)
• Lesions: Maternal surface (calcifications, hematoma, infarct), fetal surface (hemangioma)
• Amnion
• Color
• Lesions (amnion nodosa, bands)
• Umbilical cord
• Structure: Number of vessels, length (cm), coiling (normal, hypo, hyper), continuity (knots, torsion)
• Insertion site (central, velamentous, marginal, furcate)
• Multiple gestation
• Chorionicity
• Amnionicity

Obtaining a wedge sample for genetic testing should be considered. The placenta should then be sent to pathology in a 1- to 2-L container containing 100 to 200 mL of normal saline, along with pertinent maternal and fetal history. The placenta may be stored at 4 °C if pathological examination is delayed.[90]

Autopsy

A fetal autopsy is a detailed examination of the external and internal structures of the fetal body to identify any congenital anomalies, infections, or other pathological conditions.[93] An autopsy is useful in establishing a cause of death in 42.4% (95% CI: 36.9–48.4) of cases.[92] A comprehensive and detailed documentation of both positive and negative findings is crucial. Complete fetal autopsy components include: 

• Consent
• External gross examination: Photographs, radiographs, body measurements, document maceration, overall appearance, skin sample for cytogenetics
• Internal gross examination: Y-incision, routine cultures, in situ examination of abdomen/neck/thorax
• Removal of the organ block and brain, dissection of individual organs (all organs weighed and any abnormalities recorded)
• Brain gross and histological examination after fixation
• Histologic examination of tissues
• Review and recording of gross and histological findings
• Provisional anatomic diagnosis
• Review of all ancillary studies (genetic, metabolic, microbiology)
• Report including final anatomic diagnosis, summary of clinical history, gross description, microscopic description, and clinical pathologic correlation [93] 

A critical step in this list is consent; some patients and caregivers may find it difficult to address the topic of a stillborn autopsy. Discussing the autopsy with clear communication while respecting the parent or caregiver's values and addressing their concerns. Parents/caregivers may also request a limited autopsy (on a specific organ/system), external examination only, noninvasive autopsy, or minimally invasive autopsy is important. Additionally, fetal tissue is not considered part of the product of conception after 20 weeks of gestational age, and therefore, insurance may not cover its examination.

Genetic Testing

Genetic testing is helpful in the diagnosis of 11.9% (95% CI: 9.1–15.3) cases.[92] If fetal tissue is unavailable for genetic evaluation due to parental refusal, maceration, or poor tissue quality, amniocentesis can serve as an alternative method for obtaining genetic information. The primary techniques used for testing are chromosomal microarray analysis (CMA) and karyotyping, with CMA being preferred due to its higher diagnostic yield, ability to detect more minor genetic abnormalities, and flexibility in using nonviable tissue.[94] If CMA or karyotyping do not provide a diagnosis, exome or whole-genome sequencing may be able to identify causative single-nucleotide variants or small insertions/deletions.[95]

Laboratory Studies

Usefulness of routine laboratory evaluations for cause of stillbirth are as follows: antiphospholipid antibodies 11.1% (95% CI: 8.4–14.4), fetal-maternal hemorrhage 6.4% (95% CI: 4.4–9.1), glucose screen 1.6% (95% CI: 0.7–3.1), Parvovirus 0.4% (95% CI: 0.0–1.4), and syphilis 0.2% (95% CI: 0.0–1.1). Disseminated intravascular coagulation (DIC) is very rare in the context of stillbirth today due to early diagnosis and management. In cases of fetal demise undiagnosed for more than 3 weeks or in stillbirth cases complicated by placental abruption or sepsis, DIC may need to be ruled out.

Imaging 

Imaging studies such as postmortem MRI, ultrasound, and computed tomography (CT) scans serve as valuable tools for stillbirth evaluation, particularly when autopsy is declined. Postmortem MRI, the most studied method, provides high diagnostic accuracy (77%–94%), especially for fetuses beyond 20 weeks' gestation. In contrast, microfocus CT is highly effective for those with gestation of less than 20 weeks, achieving near-total agreement with autopsy findings. These imaging techniques, used alongside placental pathology and genetic testing, offer a noninvasive means of obtaining critical diagnostic information to better understand stillbirth causes.[96]

Treatment / Management

The management of stillbirth requires a compassionate, patient-centered approach that balances medical considerations with emotional support. Key aspects include confirming the diagnosis, discussing delivery options, and addressing the physical and psychological needs of the patient and family.

Communicating the Diagnosis of Stillbirth

Stillbirth should be confirmed by a second ultrasonographer if necessary. A healthcare professional should deliver the diagnosis promptly, with respect for privacy, empathy, and support. The approach depends on the situation:

• If the ultrasonographer identifies the stillbirth unexpectedly, they should notify a clinician for immediate consultation.
• If the clinician makes the diagnosis at the bedside, they should confirm and communicate the findings right away.
• Patients should be allowed to view the ultrasound if they wish to do so.

Empathy is key. Some patients may need to leave immediately as a coping mechanism, while others may appreciate a comforting presence until a support person arrives. Clinicians should acknowledge the patient's emotions, offer written resources, and schedule a follow-up visit based on the patient's readiness to do so. If urgent medical intervention is required, information should be provided calmly and clearly to obtain informed consent.

Meeting Emotional Needs

Patients experience a range of emotions, from shock and denial to grief and anger. Critical responses include the following:

• Validate the patient's emotions and stress that they are not to blame.
• Encourage bringing a support person to appointments.
• Allow the patient time and privacy to process the diagnosis.
• Offer clear explanations of the next steps, including management options.

If the patient needs to leave soon after receiving the news, they should be reassured that they can call back when they are ready. Printed information and contact details should be provided for future reference and follow-up.[97][98][99](B2)

Emotional Intelligence in Care

For parents, stillbirth is devastating, and the interprofessional healthcare team must ensure their communication is compassionate. Key considerations are as follows:

• Explain why vaginal delivery is preferred over cesarean when applicable.
• Discuss coping strategies and provide emotional support.
• Offer respectful counseling about autopsy, ensuring families understand the purpose and timeframe.[100]
• Address cultural or religious considerations regarding the baby's remains.
(B2)

Encouraging parents to spend quality time with their baby can aid in emotional processing. Some may prefer to see only certain features, and clinicians can offer appropriate clothing and wrapping. However, study results suggest that forced contact may lead to post-traumatic stress, so decisions should be respected.[99]

Memory-Making and Bereavement Support

Families may appreciate keepsakes such as:

• Photographs
• A lock of hair
• Hand or foot impressions

Parents should be informed about options for burial or hospital-handled arrangements, which vary by state law. In the US, a fetal death certificate is issued instead of a birth certificate, which may affect postpartum leave policies.[101]

Sensitive care includes the following:

• Housing away from families with newborns if requested.
• Avoiding triggering images or comments in patient care areas.
• Providing guidance on lactation suppression or milk donation.[102]
(B2)

Support for the family and planning for future pregnancies should be an integral part of post-loss care as follows:

• Siblings should be included in the grieving process.
• Clinicians should follow up regularly to assess for postpartum depression.
• Grief may last for months; dysfunctional grief should be identified and treated.
• Support groups and counseling resources should be offered.
• Future pregnancies can be discussed at an appropriate time. 

Management of Subsequent Pregnancies

The management of a pregnancy following stillbirth requires a comprehensive, individualized approach to optimize maternal and fetal outcomes. At the prepregnancy or initial prenatal visit, a detailed medical and obstetric history should be obtained, along with an evaluation of the previous stillbirth to determine recurrence risk. Smoking cessation and weight loss for obese individuals are encouraged before conception, while genetic counseling may be beneficial if a hereditary condition is suspected. Routine screening for diabetes and acquired thrombophilia, including lupus anticoagulant and immunoglobulin (Ig) IgG/IgM for anticardiolipin and β2-glycoprotein antibodies, is recommended. Emotional support and reassurance play a crucial role throughout the care process.

In the first trimester, dating ultrasonography is performed, and patients are offered first-trimester screening, which includes pregnancy-associated plasma protein A, human chorionic gonadotropin, nuchal translucency, and cell-free fetal deoxyribonucleic acid testing. The second trimester involves a detailed fetal anatomical survey at 18 to 20 weeks' gestation, with additional genetic screening or single-marker alpha-fetoprotein testing if indicated. The third trimester focuses on monitoring fetal growth via ultrasound after 28 weeks and initiating antepartum fetal surveillance at 32 weeks or earlier, depending on the gestational age of the previous stillbirth.

For delivery planning, induction is typically recommended at 39 weeks unless maternal or fetal conditions necessitate earlier intervention. In cases of severe parental anxiety, early-term delivery between 37 and 38 weeks may be considered, though this must be carefully weighed against the increased risk of neonatal complications.[ACOG. Management of Stillbirth. https://www.acog.org/clinical/clinical-guidance/obstetric-care-consensus/articles/2020/03/management-of-stillbirth]

Differential Diagnosis

The diagnosis of stillbirth must be carefully distinguished from other conditions that may present with similar clinical findings. Key indicators prompting concern for stillbirth include absent fetal heart tones, reduced or absent fetal movement, and uterine size discordant with gestational age. However, these findings may also be observed in conditions that do not indicate fetal demise, including:

• Maternal factors: Obesity (limiting Doppler assessment), incorrect gestational dating, or pseudocyesis
• Placental and fetal factors: Fetal malposition, anterior placenta, polyhydramnios/oligohydramnios, multiple gestation, fetal growth restriction, fetal macrosomia, or molar pregnancy
• Uterine pathology: Leiomyoma or structural abnormalities affecting fundal height assessment

Stillbirth is definitively diagnosed by ultrasound confirmation of absent fetal cardiac activity. If stillbirth is ruled out, but fetal well-being remains a concern, further evaluation is necessary to assess for other underlying pathologies that may compromise the pregnancy. This evaluation includes a nonstress test (NST) to evaluate fetal heart rate patterns and reactivity. If the NST is non-reassuring, a biophysical profile should be performed to assess fetal oxygenation and overall status. Additionally, a thorough maternal history and physical examination can help identify maternal conditions contributing to fetal distress or pregnancy complications. 

Pertinent Studies and Ongoing Trials

Several studies are investigating modifiable risk factors for stillbirth and early pregnancy loss to inform clinical practice and improve maternal care. A case-control study in São Paulo is analyzing risk factors for stillbirth across 14 hospitals, incorporating clinical data, placental pathology, environmental exposures, and evaluations of healthcare services to enhance prevention efforts and bereavement support. Similarly, a UK-based study is examining factors contributing to pregnancy loss between 20 and 28 weeks' gestation, focusing on exposures that could be addressed through public health initiatives and adaptations in antenatal care. Both studies aim to identify key risk factors, reduce disparities in pregnancy outcomes, and improve support for affected families.[103][104]

Micro-computed tomography has emerged as a valuable noninvasive tool for diagnosing stillbirth, particularly in early gestation fetuses, by providing high-resolution 3-dimensional imaging of small anatomical structures. Study results have demonstrated its high diagnostic accuracy, with a sensitivity of 93.8% (95% CI: 71.7%–98.9%) and a specificity of 100% (95% CI: 82.4%–100%), making it a reliable alternative to traditional autopsy for parents who decline invasive postmortem examinations.[105] Similarly, postmortem MRI has demonstrated diagnostic accuracy ranging from 77% to 94% for pregnancies beyond 20 weeks. Higher-field MRI scanners, such as the 9.4 Tesla, hold promise for improving diagnostic capabilities in earlier gestations. Additionally, postmortem ultrasound using high-frequency probes offers a more accessible and cost-effective alternative, with sensitivity and specificity ranging from 67% to 77% and 74% to 90%, respectively. These emerging imaging modalities provide valuable insights into stillbirth diagnosis while offering noninvasive options that are both parent-friendly and clinically informative.[96] 

Genetic research is investigating the role of channelopathy- and cardiomyopathy-related genes in stillbirth, aiming to uncover potential genetic contributions.[106] As sequencing technology becomes more accessible and cost-effective, whole-genome sequencing is expected to play an increasingly significant role in stillbirth evaluation, offering a 5.9% higher detection rate compared to comparative genomic analysis.[107] Additionally, ongoing studies are assessing the clinical utility and predictive value of biochemical markers, including human placental lactogen, placental growth factor, soluble fms-like tyrosine kinase 1, glycine, acetic acid, L-carnitine, creatine, and micro–ribonucleic acids, in identifying risk factors for stillbirth.

Prognosis

A 2024 systematic review found that patients with previous stillbirths, compared to women with previous live births, have increased risks of the following in subsequent pregnancies:

• Recurrent stillbirth (OR 2.68, 95% CI: 2.01–3.56)
• Preterm birth (OR 3.15, 95% CI: 2.07–4.80)
• Neonatal death (OR 4.24, 95% CI: 2.65–6.79)
• Small for gestational age/intrauterine growth restriction (OR 1.3, 95% CI: 1.0–1.8)
• Low birth weight (OR 3.32, 95% CI: 1.46–7.52)
• Placental abruption (OR 3.01, 95% CI: 1.01–8.98)
• Instrumental delivery (OR 2.29, 95% CI: 1.68–3.11)
• Labor induction (OR 4.09, 95% CI: 1.88–8.88)
• Cesarean delivery (OR 2.38, 95% CI: 1.20–4.73)
• Elective cesarean delivery (OR 2.42, 95% CI: 1.82–3.23)
• Emergency cesarean delivery (OR 2.35, 95% CI: 1.81–3.06) [23]

These risks may be influenced by multiple factors, including maternal health, gestational age, and identified causes for the stillbirth.[108] If a particular cause for stillbirth is found, then a literature review can estimate the risk of another stillbirth. There is no strict guideline for the time intervals between experiencing a stillbirth and attempting to conceive again. There is a general recommendation to wait until the patient feels emotionally, mentally, and physically ready to attempt again. An international cohort study reported that conception within 12 months following a stillbirth was a common occurrence and did not correlate with a higher risk of subsequent stillbirth, preterm birth, or small-for-gestational-age birth.[109] No evidence suggests that conceiving within 6 months increases risks.[109][110][111][112][113]

Complications

Psychosocial stressors after stillbirth may include the loss of employment or income, as well as the financial burden of healthcare costs incurred in treating the pregnancy complication. Depression, anxiety, and post-traumatic stress disorder may arise due to unresolved grief and guilt. Results from a study including 8292 women with stillborn singletons found that within 1 year of hospital discharge after stillbirth, 4% of women had an emergency department encounter or inpatient admission related to psychiatric morbidity—nearly 2.5 times higher than the 1.6% of women with live births (aOR 2.47, 95% CI: 2.20–2.77). Additionally, women who experienced stillbirth had a significantly higher risk of emergency or inpatient care for drug or alcohol use (aOR 2.41, 95% CI: 1.99–2.90). The highest risk for postpartum psychiatric illness occurred within the first 4 months following stillbirth (adjusted [a]HR 3.26, 95% CI: 2.63–4.04), but the risk remained elevated through 12 months after delivery (aHR 2.42, 95% CI: 2.13–2.76).[114] 

Relationship dysfunction may also be experienced, complicated by the stigma associated with being unable to deliver a healthy child. Incongruent coping mechanisms between the patient and her partner can lead to discord. The patient may develop a fear of future pregnancies, which may result in a decision to avoid them. Dysfunctional grief resolution can occur in other family members, including younger children in the home.