Number 10 (Replaces Practice Bulletin Number 102, March 2009)
This document was developed jointly by the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine in collaboration with Torri D. Metz, MD, MS; Rana Snipe Berry, MD; Ruth C. Fretts, MD; Uma M. Reddy, MD, MPH; and Mark A. Turrentine, MD.
ABSTRACT: Stillbirth is one of the most common adverse pregnancy outcomes, occurring in 1 in 160 deliveries in the United States. In developed countries, the most prevalent risk factors associated with stillbirth are non-Hispanic black race, nulliparity, advanced maternal age, obesity, preexisting diabetes, chronic hypertension, smoking, alcohol use, having a pregnancy using assisted reproductive technology, multiple gestation, male fetal sex, unmarried status, and past obstetric history. Although some of these factors may be modifiable (such as smoking), many are not. The study of specific causes of stillbirth has been hampered by the lack of uniform protocols to evaluate and classify stillbirths and by decreasing autopsy rates. In any specific case, it may be difficult to assign a definite cause to a stillbirth. A significant proportion of stillbirths remains unexplained even after a thorough evaluation. Evaluation of a stillbirth should include fetal autopsy; gross and histologic examination of the placenta, umbilical cord, and membranes; and genetic evaluation. The method and timing of delivery after a stillbirth depend on the gestational age at which the death occurred, maternal obstetric history (eg, previous hysterotomy), and maternal preference. Health care providers should weigh the risks and benefits of each strategy in a given clinical scenario and consider available institutional expertise. Patient support should include emotional support and clear communication of test results. Referral to a bereavement counselor, peer support group, or mental health professional may be advisable for management of grief and depression.
Stillbirth is one of the most common adverse pregnancy outcomes, occurring in 1 in 160 deliveries in the United States. Approximately 23,600 stillbirths at 20 weeks or greater of gestation are reported annually 1. The purpose of this document is to review the current information on stillbirth, including definitions and management, the evaluation of a stillbirth, and strategies for prevention.
The U.S. National Center for Health Statistics defines fetal death as the delivery of a fetus showing no signs of life as indicated by the absence of breathing, heartbeats, pulsation of the umbilical cord, or definite movements of voluntary muscles 1. There is not complete uniformity among states with regard to birth weight and gestational age criteria for reporting fetal deaths. However, the suggested requirement is to report fetal deaths at 20 weeks or greater of gestation (if the gestational age is known), or a weight greater than or equal to 350 grams if the gestational age is not known 2. The cutoff of 350 grams is the 50th percentile for weight at 20 weeks of gestation.
To promote the comparability of national data by year and state, U.S. vital statistics data are collected for fetal deaths with a stated or presumed period of gestation of 20 weeks or more 1. Terminations of pregnancy for life-limiting fetal anomalies and inductions of labor for previable premature rupture of membranes are specifically excluded from the stillbirth statistics and are classified as terminations of pregnancy 1.
The term stillbirth is preferred among parent groups, and more recent research efforts have begun using this term in place of fetal death. Therefore, in this document, the term stillbirth is used.
Frequency of Occurrence
In 2013, the stillbirth rate in the United States was 5.96 per 1,000 live births, a decrease from 6.61 in 2006 and 6.05 per 1,000 births in 2012 1. Between 2006 and 2012, the rate of early stillbirth (20–27 weeks) remained essentially unchanged, but between 2012 and 2013, the rate decreased from 3.11 to 3.01 per 1,000 births. The rate of late stillbirth (28 weeks or greater) has been relatively stable since 2006 and did not change significantly between 2012 and 2013 at 2.96 and 2.97 per 1,000 births, respectively 1. There is ongoing discussion regarding the most useful calculation for analysis of stillbirth occurrences. Currently, fetal mortality rates are widely calculated using a birth-based approach: the number of stillbirths per 1,000 live births and stillbirths 1.
There may be some utility in changing the denominator to better capture the population at risk, that is, all women who are still pregnant at a given gestational age. Using a denominator of women who are still pregnant at a given gestational age allows for calculation of a prospective fetal mortality rate defined as the number of stillbirths at a given gestational age (in single weeks) per 1,000 live births and stillbirths at that gestational age or greater 3. This approach produces the prospective risk of stillbirth, which can be clinically valuable to make predictions for individual pregnancies and to help health care providers balance the risks of expectant management with those of intervention 1 Figure 1.
In developed countries, the most prevalent risk factors associated with stillbirth are non-Hispanic black race, nulliparity, advanced maternal age, obesity, preexisting diabetes, chronic hypertension, smoking, alcohol use, having a pregnancy using assisted reproductive technology, multiple gestation, male fetal sex, unmarried status, and past obstetric history 4 5. Although some of these factors may be modifiable (such as smoking), many are not.
Social Demographic Factors Affecting Stillbirth
Non-Hispanic black women have a stillbirth rate that is more than twice the rate of other racial groups (10.53 deaths per 1,000 livebirths and stillbirths) 1. In the United States, the stillbirth rates for other groups were 4.88 for non-Hispanic white women, 5.22 for Hispanic women, 6.22 for American Indian or Alaska Native, and 4.68 for Asian or Pacific Islanders 1.
The reason for this health care disparity in stillbirth rates is multifactorial and the subject of ongoing research 6. Higher rates of stillbirth persist among non-Hispanic black women with adequate prenatal care; this has been attributed to higher rates of diabetes mellitus, hypertension, placental abruption, and premature rupture of membranes 7 8. The educational level for Hispanic and non-Hispanic black women does not appear to be protective as compared with white women, with the widest disparities observed between white and non-Hispanic black stillbirths at 20–27 weeks of gestation, regardless of educational attainment 9. Implicit and explicit bias and racism are implicated in many health disparities including perinatal morbidity and mortality 10. It remains to be better characterized how biologic and modifiable risk factors, including care disparities and environmental stressors, biases, and racism further contribute to the risk for non-Hispanic black women 11.
The stillbirth rate among twin pregnancies is approximately 2.5 times higher than that of singletons (14.07 versus 5.65 per 1,000 live births and stillbirths) 1. The risk of stillbirth increases in all twins with advancing gestational age, and it is significantly greater in monochorionic as compared with dichorionic twins 12. The stillbirth rate for triplet pregnancies and higher order multiples is reported as 30.53 per 1,000 live births and stillbirths. Higher rates are due to complications specific to multiple gestation (such as twin–twin transfusion syndrome), as well as to increased risks of common complications such as aneuploidy, congenital anomalies, and growth restriction 1 13.
Past Obstetric History
Women with a previous stillbirth are at increased risk of recurrence. Compared with women with no history of stillbirth, women who had a stillbirth in an index pregnancy had an increased risk in subsequent pregnancies (pooled odds ratio, 4.83; 95% CI, 3.77–6.18), which remained significant after adjustment for confounding factors 14.
Women with previous adverse pregnancy outcomes, such as preterm delivery, growth restriction, or preeclampsia, are at increased risk of stillbirth in subsequent pregnancies 15. The relationship between previous adverse pregnancy outcomes and stillbirth is strongest in the case of explained stillbirth. However, there remains a persistent 1.7-fold to 2-fold increase in unexplained stillbirth associated with a history of adverse pregnancy outcomes. In a study that examined previous preterm and small for gestational age (SGA) births and the risk of stillbirth in a subsequent pregnancy, the risk of stillbirth was increased in the setting of a prior SGA infant; the highest risk was for a prior SGA infant born at less than 32 weeks (OR, 8.0; 95% CI, 4.7–13.7) 16.
The relationship between previous cesarean delivery and subsequent stillbirth remains controversial. In two large studies from the United Kingdom, previous cesarean delivery was associated with an increased rate of explained 17 and unexplained stillbirth 15 with an adjusted hazard ratio ranging from 2.08 (95% CI, 1.00–4.31) and 1.75 (95% CI, 1.30–2.37), respectively, for all causes of subsequent stillbirth. A Danish analysis showed a slight increase in the rate of stillbirth after cesarean in explained and unexplained stillbirths, but neither reached statistical significance 18. In addition, three large observational studies from the United States 19 20 21 and one from Canada 22 found no association between history of cesarean and stillbirth. In the largest of these studies, the unexplained stillbirth rates at term for women with and without a previous cesarean delivery were 0.8 and 0.7 per 1,000 births, respectively (relative risk [RR] 0.90; 95% CI, 0.76–1.06) 20.
The extremes of parity have also been associated with stillbirth. Higher rates of stillbirth are observed in nulliparous women as well as multiparas women with greater than three previous pregnancies when compared to women with one or two previous births 23.
Male sex of the fetus has been observed as a risk factor for stillbirth. In a recent review of data from more than 30 million births, in a wide range of high-income and low-income countries, the crude mean rate (stillbirths per 1,000 total births) was 6.23 for males and 5.74 for females. The pooled RR was 1.10 (95% CI, 1.07–1.13), which indicates that a male fetus has approximately a 10% higher risk for stillbirth 24. Although this meta-analysis identifies fetal sex as an important risk factor for stillbirth, the reason why males are at higher risk is unknown.
Younger and Older Maternal Age
Maternal age at either end of the reproductive age spectrum (less than 15 years and greater than 35 years) is an independent risk factor for stillbirth. Maternal age greater than or equal to 35 years of age is associated with an increased risk of stillbirth in nulliparous and multiparous women 25 26. A significant proportion of perinatal deaths seen in older women are related to lethal congenital and chromosomal anomalies. The introduction of population-based screening for chromosomal abnormalities has contributed to lower rates of explained stillbirth or neonatal death resulting from chromosomal abnormalities 27. Large observational studies demonstrate that advanced maternal age is an independent risk factor for stillbirth even after controlling for risk factors such as hypertension, diabetes, placenta previa, and multiple gestation 26 28 29. In addition, there appears to be an interaction between first birth and increasing maternal age that places nulliparous older women at higher risk 27. Based on one study, the estimated risk of stillbirth is 1 in 116 in a 40-year-old nulliparous woman after 37 weeks of gestation, compared with 1 in 304 in a multiparous woman of the same age 27.
The stillbirth rate for teenagers younger than 15 years of age is 15.88 per 1,000 live births. This is nearly three times the rate of the lowest risk group, aged 25–29 years, with a rate of 5.34 per 1,000 live births. The rate for teenagers aged 15–17 years was 7.03 per 1,000, and the rate for 18–19-year olds was 6.52 per 1,000 live births. These were 32% and 22% higher than the lowest risk age group 1. This bimodal peak at extremes of reproductive age has been observed in several studies as well as confirmed in a large population-based cohort study using the Centers for Disease Control and Prevention's “Linked Birth-Infant Death” and “Fetal Death” data files of 37,504,230 births 30.
Comorbid Medical Conditions
Many maternal medical conditions are associated with an increased risk of stillbirth Table 1. Hypertension and diabetes are two of the most common comorbid pregnancy conditions 4 31. Population-based studies demonstrated almost a twofold to fivefold increase in the risk of stillbirth among women with pregestational diabetes and gestational diabetes 4 32 33 34. There appears to be a joint effect of pregestational diabetes and obesity that is stronger than the individual effects of each risk factor 35. However, with prepregnancy strict glycemic control aiming for HgbA1C values less than 7% and maintenance of maternal euglycemia during pregnancy, the risk of stillbirth may be reduced 36 37. The perinatal mortality rate reported with maternal chronic hypertension is 2–4 times higher than that of the general population 38, and the increased risk of stillbirth or neonatal death appears to be independent of other possible contributors such as superimposed preeclampsia or fetal growth restriction. The precise blood pressure level at which antihypertensive therapy is indicated during pregnancy in women with chronic hypertension continues to be debated; similarly, it is unknown if strict blood pressure control reduces the risk of stillbirth 38. There also appears to be interaction between chronic hypertension and pregestational diabetes on having a stillbirth and in women with both comorbidities, an even higher risk has been reported 39.
Numerous other medical conditions including systemic lupus erythematosus, renal disease, uncontrolled thyroid disease, and cholestasis of pregnancy have been associated with stillbirth Table 1. For guidance regarding antenatal fetal surveillance based on anticipated risk of stillbirth, refer to ACOG Practice Bulletin No. 145, Antepartum Fetal Surveillance.
Acquired and Inherited Thrombophilias
Antiphospholipid syndrome (APS) is an acquired thrombophilia that has been associated with stillbirth. The diagnosis of APS depends on women meeting laboratory and clinical criteria for the disorder. One of the clinical criteria for APS is history of stillbirth. As such, women with a stillbirth are typically tested for APS (see ACOG Practice Bulletin No. 132, Antiphospholipid Syndrome, for details of testing and management). In contrast, inherited thrombophilias have not been associated with stillbirth, and testing for them as part of a stillbirth evaluation is not recommended 40 Table 2.
Obesity and Gestational Weight Gain
Obesity is defined as a prepregnancy BMI (defined as weight in kilograms divided by height in meters squared) of 30 or greater and is the fastest growing health problem in the United States 41. Obesity in pregnancy is associated with an increased risk of early fetal loss and stillbirth 42. A comprehensive study of five high-income countries found that maternal overweight and obesity (BMI greater than 25) was the most common modifiable risk factor for stillbirth 43. A meta-analysis of 38 studies that included 16,274 stillbirths found that even small increases in maternal BMI were associated with an increased risk of stillbirth. For BMI levels of 20, 25, and 30, absolute risks per 1,000 pregnancies were 4.0 (reference standard), 4.8 (95% CI, 46–51), and 5.9 (95% CI, 55–63), respectively 44. Further, excessive weight gain was associated with higher risk of stillbirth among obese and morbidly obese women 45. There is some evidence that the obesity-related stillbirth risk increases with gestational age. In one study, the hazard ratio for stillbirth increased from 2.1 at 28–36 weeks to 4.6 at 40 weeks of gestation 46. The reason for this association is likely multifactorial, but obesity is associated with a fivefold increased risk of stillbirth resulting from placental dysfunction. Obesity remains an independent risk factor for stillbirth even after controlling for smoking, gestational diabetes, and preeclampsia 47 48 49; however, the optimal BMI to minimize stillbirth risk remains unknown 44.
Maternal cocaine, methamphetamine, other illicit drug use, and smoking tobacco, are all significant contributors to abruption and stillbirth 50 51 52 53 54. In a secondary analysis of a case–control study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Stillbirth Collaborative Research Network, any illicit drug use as detected by biological sampling of the umbilical cord homogenate was associated with an increased risk of stillbirth (OR, 1.94; 95% CI, 1.16–3.27) 55. Smoking is a particularly common risk factor, especially and increasingly in high-income countries. In a recent large systematic review, smoking during pregnancy was significantly associated with a 47% increase in the odds of stillbirth (OR, 1.47; 95% CI, 1.37–1.57, P<.0001) 56. The causal relationship of smoking and stillbirth has been established through many studies that demonstrated differential effects based on timing and amount of tobacco exposure.
Exposure to secondhand smoke also increases risk. Women with exposure to secondhand smoke were also at higher risk of stillbirth than never smokers with lower or no secondhand exposure and had comparable risks to some active smokers 57. Timing of exposure is also relevant; smoking during the first trimester is associated with increased risk of stillbirth (adjusted hazard ratio, 2.4; 95% CI, 1.2–4.9) 58. There is also a clear dose-response effect of maternal smoking in pregnancy on risk of stillbirth. Smoking one to nine cigarettes per day was associated with a 9% increased odds of having a stillbirth compared with women who do not smoke in pregnancy (OR, 1.09, 95% CI, 1.09–1.24, P=.55, six studies), and smoking 10 or more cigarettes per day was associated with a 52% increase in odds of stillbirth (OR, 1.52; 95% CI, 1.30–1.78, P<.0001, seven studies) 56. Quitting smoking between pregnancies is protective. Women who smoked during the first pregnancy but not during the second do not have an increased risk of recurrent stillbirth (OR, 1.02; 95% CI, 0.79–1.30), compared with woman who did not smoke in either pregnancy. The risk among women who smoked during both pregnancies was 1.35 (95% CI, 1.15–1.58) 59.
Assisted Reproductive Technology
Pregnancies achieved by in vitro fertilization (IVF) appear to be associated with an elevated risk (twofold to threefold increase) of stillbirth even after controlling for age, parity, and multifetal gestations 60 61 62 63. A more recent study from California for the years 2009–2011 confirms that the stillbirth risk is elevated at 5.5 per 1,000 64. Whether this is related to the procedures themselves or to unmeasured confounding variables associated with underlying causes of infertility is less clear. Couples with a waiting time to pregnancy of 1 year or more and women who became pregnant after non-IVF assisted reproductive technology had a risk for stillbirth similar to that of fertile couples and a lower risk than women who became pregnant after IVF or intracytoplasmic sperm injection, which indicates that the increased rate of stillbirth risk may be a result of the IVF or intracytoplasmic sperm injection and not the underlying infertility 62.
Late-Term and Postterm Pregnancies
In a Cochrane review of 30 RCTs of 12,479 women that compared expectant management with induction of labor in term and postterm pregnancies, induction of labor was associated with a decreased risk of perinatal death and cesarean delivery 65. Based on these and other observational data, induction of labor for an indication of late-term and postterm pregnancy is recommended after 42 0/7 weeks of gestation and can be considered at or after 41 weeks 0/7 days of gestation 66. Estimates of the risk of stillbirth after 41 weeks differ by race and ethnicity and range from 14–40 per 1,000 live births 67. For the California population overall from 1997–2006, mortality risks of stillbirth and neonatal death were equivalent at 38 weeks of gestation, but at later gestational ages the mortality risk of expectant management exceeded that of delivery with a mortality risk of 17.6 per 10,000 compared with 10.8 per 10,000 ongoing pregnancies at 42 weeks of gestation 68. The RR of stillbirth in this cohort was 2.9 (95% CI, 2.6–3.2) at 41 weeks and 5.1 (95% CI, 4.4–6.0) at 42 weeks, when compared with a referent stillbirth rate at 37 weeks 68.
Potential Causes of Stillbirth
The study of specific causes of stillbirth has been hampered by the lack of uniform protocols to evaluate and classify stillbirths and by decreasing autopsy rates. In most cases, stillbirth certificates are filled out before a full postnatal investigation has been completed and amended death certificates are rarely filed when additional information from the stillbirth evaluation emerges. In any specific case, it may be difficult to assign a definite cause to a stillbirth. A significant proportion of stillbirths remains unexplained even after a thorough evaluation 69.
Fetal Growth Restriction
Fetal growth restriction is associated with a significant increase in the risk of stillbirth. The most severely affected fetuses (weight less than the 2.5th percentile) are at greatest risk 70 71. The cumulative risk of stillbirth is approximately 1.5% at fetal weights less than the 10th percentile, and the risk increases to 2.5% at less than the 5th percentile for gestational age 72 73. Similarly, using data from all births in the United States, investigators demonstrated increased risk of stillbirth with increasing severity of growth restriction. The risk of stillbirth was highest among fetuses estimated to be less than the 3rd percentile for growth (58.0 per 10,000 at risk), decreased for those less than the 5th percentile (43.9 per 10,000 at risk) and was the lowest for those less than the 10th percentile (26.3 per 10,000 at risk) 71. Fetal growth restriction is associated with some fetal aneuploidies, fetal infection, maternal smoking, hypertension, autoimmune disease, obesity, and diabetes, which also modify the risk of stillbirth.
Placental abruption is identified as the cause of stillbirth in 5–10% of cases 69. Maternal cocaine and other illicit drug use, and smoking tobacco, are all significant contributors to abruption and stillbirth 50 51 52 53. If abruption occurs in the preterm fetus or involves a larger surface area of the placenta 74, it is more likely to cause stillbirth. The rates of abruption appear to be increasing 75. Hemodynamically significant fetomaternal hemorrhage in the absence of placental abruption is a rare cause of stillbirth and occurs mainly in unusual scenarios, such as chorioangioma or choriocarcinoma 76 77.
Chromosomal and Genetic Abnormalities
An abnormal karyotype can be found in approximately 6–13% of stillbirths 69 78 79 80. The rate of karyotypic abnormalities exceeds 20% in fetuses with anatomic abnormalities or in those with growth restriction, but the rate of chromosomal anomalies found in normally formed fetuses was found to be 4.6% in one large series 80. If an abnormal karyotype is found in association with stillbirth, the most common abnormalities are trisomy 21 (31%), monosomy X (22%), trisomy 18 (22%), and trisomy 13 (8%) 80.
Karyotypic analysis underestimates the contribution of genetic abnormalities to stillbirth because in up to 50% of karyotype attempts, cell culture is unsuccessful 79. One strategy to increase the yield of cell culture is to perform chorionic villi sampling or amniocentesis before the delivery. In a large study in the Netherlands, invasive testing had a much greater tissue culture rate (85%) than fetal tissue sampling after birth (28%) 80. In women who decline invasive testing, a portion of the placenta, an umbilical cord segment, or internal fetal tissue can be sent for genetic analysis Figure 2.
Microarray analysis not only detects aneuploidy but also detects copy number variants (smaller deletions and duplications) that are not detectable by karyotype. As compared to karyotype analysis, microarray analysis increased the diagnosis of a genetic cause to 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies 81. Microarray analysis was more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and it was especially valuable in analyses of stillbirths with congenital anomalies or when karyotype results could not be obtained. Thus, microarray analysis, incorporated into the stillbirth workup, improves the test success rate and the detection of genetic anomalies compared with conventional karyotyping 82. Microarrray is the preferred method of evaluation for these reasons but, due to cost and logistic concerns, karyotype may be the only method readily available for some patients. In the future, whole exome sequencing or whole genome sequencing may be part of the stillbirth workup, but it is not currently part of the standard evaluation.
Confined placental mosaicism in which the karyotype of the fetus is euploid despite an abnormal cell line in the placenta also has been associated with an increased risk of stillbirth, but currently it is not part of standard testing 83. Autosomal dominant disorders caused by spontaneous mutations (eg, skeletal dysplasias) or inherited parental mutations leading to long QT syndrome may contribute to stillbirth 84 85. However, routine assessments for single gene defects and microdeletions currently are limited because it is unlikely that any single gene defect will be responsible for a significant proportion of stillbirths. Genetic evaluation for specific abnormalities should be guided by the clinical history and detected fetal abnormalities. Approximately 20% of stillborn fetuses have dysmorphic features or skeletal abnormalities and 15–20% have a major malformation 78 86.
Infection is associated with approximately 10–20% of stillbirths in developed countries and a greater percentage in developing countries 69 87. In developed countries, infection accounts for a greater percentage of preterm stillbirths than of term stillbirths 69 88. Infectious pathogens may result in stillbirth by producing direct fetal infection, placental dysfunction, severe maternal illness, or by stimulating spontaneous preterm birth.
Placental and fetal infections originate from either ascending (eg, group B streptococcus or Escherichia coli) or hematogenous spread of agents such as Listeria monocytogenes or syphilis. Viral infections associated with stillbirth include cytomegalovirus, parvovirus, and Zika. Serology for toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus are not included because they are of unproven benefit and not recommended 89.
Umbilical Cord Events
Umbilical cord abnormalities account for approximately 10% of stillbirths but this diagnosis should be made with caution 69. In a cohort–control study of almost 14,000 deliveries, single nuchal cords were present at birth in 23.6% of deliveries and multiple nuchal cords in 3.7%. Single or multiple nuchal cords were not associated with an increased risk of stillbirth in this cohort 90. The criteria for considering a cord abnormality to be a cause of death were rigorous in the Stillbirth Collaborative Research Network and included vasa previa, cord entrapment, and evidence of occlusion and fetal hypoxia, prolapse, or stricture with thrombi 69. Nuchal cord alone was not considered a cause of death. In addition, other causes of stillbirth should be excluded.
Clinical Considerations and Management
What are the essential components of a stillbirth evaluation?
Evaluation of a stillbirth should include fetal autopsy; gross and histologic examination of the placenta, umbilical cord, and membranes; and genetic evaluation 91. An algorithm for evaluation is provided in Figure 2. Specific aspects of the evaluation are outlined as follows and in Figure 3.
Examination of the Placenta
Gross and microscopic examination of the placenta, umbilical cord, and fetal membranes by a trained pathologist is the single most useful aspect of the evaluation of stillbirth and is an essential component of the evaluation 91 92. Gross evaluation may reveal conditions such as abruption, umbilical cord thrombosis, velamentous cord insertion, and vasa previa. Placental evaluation may also provide information regarding infection, genetic abnormalities, and anemia. Examination of the placental vasculature and membranes can be particularly revealing in stillbirths that occur as part of a multifetal gestation. Chorionicity should be established and vascular anastomoses identified.
Umbilical cord knots or tangling should be noted but interpreted with caution, as cord entanglement occurs in approximately 25% of normal pregnancies and most true knots are found after live births. Corroborating evidence should be sought before concluding that a cord accident is the likely cause of death (eg, evidence of cord occlusion and hypoxia on perinatal postmortem examination and histologic examination of the placenta and umbilical cord). The minimal histologic criteria for considering a diagnosis of cord accident should include vascular ectasia and thrombosis in the umbilical cord, chorionic plate, and stem villi. In addition to the previous findings, for a probable diagnosis, a regional distribution of avascular villi or villi showing stromal karyorrhexis is suggested 93.
Examination of the Stillborn Fetus
The general examination of the stillborn fetus should be done promptly, noting any dysmorphic features and obtaining measurements of weight, length, and head circumference 94 95 96. Foot length may be especially useful before 23 weeks of gestation to ascertain gestational age. Photographs of the whole body (unclothed); frontal and profile views of the face, extremities, and palms; and close-up photographs of specific abnormalities are vital for subsequent review and consultation with a specialist, particularly if no geneticist is available at the institution.
Fetal autopsy should be offered because it is one of the most useful diagnostic tests in determining the cause of death. The yield is increased when dysmorphic features, inconsistent growth measurements, anomalies, hydrops, or growth restriction are present. If families are uncomfortable with a complete autopsy, other options such as partial autopsy, gross examination by a trained pathologist, ultrasonography and especially magnetic resonance imaging are particularly useful. Parents should be given the opportunity to hold the baby and perform cultural or religious activities before the autopsy. Whole-body X-ray with anterior–posterior and lateral views may reveal an unrecognized skeletal abnormality or further define a grossly apparent deformity.
When a full autopsy is performed, it should follow published guidelines and protocols for perinatal autopsy 97 98. These include measurements to establish gestational age, such as foot length and body weight. Recommendations also include an estimation of the interval between death and delivery, identification of intrinsic abnormalities and developmental disorders, and investigation for evidence of infection. It is preferable to use a pathologist who is experienced in perinatal autopsy and to have a physician who is experienced in genetics and dysmorphology examine the fetus. The clinician should communicate the obstetric and pertinent medical history to the pathology team and request any tissue collection that may be needed for additional analysis.
Fetal Laboratory Studies
Genetic analyses are of sufficient yield that they should be performed in all cases of stillbirth after appropriate parental permission is obtained 80. Karyotype or microarray are of higher yield if the fetus displays dysmorphic features, inconsistent growth measurements, anomalies, hydrops, or growth restriction 81. Comparative genomic hybridization or single nucleotide probe and copy number probe microarrays provide almost the same information as karyotype plus they detect abnormalities in smaller regions of chromosomes that are missed by traditional karyotyping. Single nucleotide probe arrays also can detect uniparental disomy and consanguinity. Fetal karyotype is important if a parent carries a balanced chromosomal rearrangement (eg, translocation or inversion) or has a mosaic karyotype.
Acceptable cytogenetic specimens include amniotic fluid and a placental block taken from below the cord insertion site that includes the chorionic plate, an umbilical cord segment, or an internal fetal tissue specimen that thrives under low-oxygen tension such as costochondral or patellar tissue. Fetal skin is suboptimal Figure 1 99 100 101. Amniocentesis for fetal karyotyping has the highest yield and is particularly valuable if delivery is not expected imminently 80. Appropriate history and physical findings should be included in the requisition sent to the laboratory to assist the laboratory personnel to interpret cytogenetic tests. Cost of various genetic analyses may affect patient decision making at the time of stillbirth evaluation, and efforts should be made to communicate information about anticipated cost whenever possible.
A thorough maternal history should be taken to look for known conditions or symptoms suggestive of those that have been associated with stillbirth Table 3. In addition to the medical and obstetric history, including exposures (eg, medications and viral infections), a family history with a three-generation pedigree including stillborn infants should be reviewed. Any pertinent information in the maternal or paternal pedigree should be documented and investigated further. Recurrent pregnancy losses and the presence of live born individuals with developmental delay or structural anomalies may be clues to single-gene disorders. Consanguinity should be identified because of the increased possibility of severe autosomal recessive disorders. A detailed history of arrhythmias and sudden death (including sudden infant death syndrome) should be ascertained, because prolonged QT syndrome may be associated with stillbirth.
Relevant original medical records and documentation should be obtained whenever possible. The gestational age by last menstrual period, maternal examinations, laboratory data, and ultrasound examination should be recorded for correlation with the physical examination of the neonate. Possible nongenetic causes, such as infection, placental abruption, and umbilical cord abnormality also should be considered.
Although fetomaternal hemorrhage is an uncommon cause of stillbirth, Kleihaur-Betke testing could be falsely elevated after delivery; therefore, testing for significant fetomaternal hemorrhage either with a Kleihaur-Betke or flow cytometry test should be conducted as soon as possible after the diagnosis of stillbirth 102.
Antiphospholipid syndrome testing is recommended in many stillbirths, especially when accompanied by fetal growth restriction, severe preeclampsia, or other evidence of placental insufficiency. Laboratory testing is performed by testing for lupus anticoagulant as well as immunoglobulin G and immunoglobulin M for both anticardiolipin and β2-glycoprotein antibodies. A moderate to high immunoglobulin G phospholipid or immunoglobulin M phospholipid titer (greater than 40 immunoglobulin M phospholipid or immunoglobulin G phospholipid, or greater than 99th percentile) is considered positive but must be confirmed with repeat testing after 12 weeks. Elevated levels of anticardiolipin and anti-β2-glycoprotein-I antibodies are associated with a threefold to fivefold increased odds of stillbirth, which supports testing for antiphospholipid antibodies in cases of otherwise unexplained stillbirth 103. However, testing for inherited thrombophilias is not recommended 40.
The percentage of cases in which the various components of the stillbirth evaluation were considered useful to establish a cause of stillbirth in the Stillbirth Collaborative Research Network study of 512 stillbirths that underwent a complete evaluation was as follows: 64.6% placental pathology (95% CI, 57.9–72.0), 42.4% fetal autopsy (95% CI, 36.9–48.4), 11.9% genetic testing by karyotype or microarray (95% CI, 9.1–15.3), 11.1% testing for antiphospholipid antibodies (95% CI, 8.4–14.4), 6.4% fetal–maternal hemorrhage (95% CI, 4.4–9.1), 1.6% glucose screen (95% CI, 0.7–3.1), 0.4% parvovirus (95% CI, 0.0–1.4), and 0.2% syphilis (95% CI, 0.0–1.1). The utility of the tests varied by clinical presentation, which suggests a customized approach for each patient. The most useful tests were placental pathology and fetal autopsy followed by genetic testing and testing for antiphospholipid antibodies. Further testing is indicated based on the results of the postmortem examination and placental histology, as well as the clinical circumstances accompanying the stillbirth 91 Figure 3, Evaluation of Stillbirth).
What are the options for management of the current pregnancy after confirmation of a diagnosis of stillbirth?
Methods of Delivery
The method and timing of delivery after a stillbirth depend on the gestational age at which the death occurred, maternal obstetric history (eg, previous hysterotomy), and maternal preference. Although most patients desire prompt delivery, the timing of delivery is not critical; coagulopathies associated with prolonged fetal retention are uncommon.
Options for delivery of the stillborn fetus typically include dilation and evacuation or induction of labor. In the second trimester, dilation and evacuation can be offered if an experienced health care provider is available, although patients should be counseled that dilation and evacuation may limit efficacy of autopsy for the detection of macroscopic fetal abnormalities, and often precludes seeing or holding the fetus after removal. On the other hand, women undergoing induction of labor, especially early in the second trimester, are at high risk of requiring a dilation and curettage for removal of the placenta after delivery of the fetus. In addition, induction of labor for pregnancies with a fetal demise between 14 weeks and 24 weeks of gestation has been associated with an increased risk of maternal morbidity (predominantly infection morbidity that requires intravenous antibiotics) when compared with surgical uterine evacuation 104. Induction of labor has also been demonstrated to be less effective and to have higher complication rates than dilation and evacuation between 13 weeks and 24 weeks of gestation with an adjusted risk ratio of 8.5 (95% CI, 3.7–19.8) 105. Health care providers should weigh the risks and benefits of each strategy in a given clinical scenario and consider available institutional expertise. Shared decision making plays an important role in determining the optimal method for delivery in the setting of fetal demise.
Appropriate methods for labor induction vary based on gestational age at the time of fetal demise. Much of the data for management of fetal demise are extrapolated from randomized trials that evaluated optimal methods for second trimester pregnancy termination. Before 28 weeks of gestation, vaginal misoprostol appears to be the most efficient method of induction, regardless of cervical Bishop score 106 107, although high-dose oxytocin infusion also is an acceptable choice 108 109 110 111. A meta-analysis of 14 randomized controlled trials that evaluated methods of induction for second and third trimester stillbirth demonstrated that both vaginal and oral misoprostol regimens were 100% effective in achieving uterine evacuation within 48 hours 112. Dose regimens and frequency of administration differed in the included trials, which makes direct comparisons of dose strategy challenging. Based on limited evidence, before 28 weeks of gestation, typical dosages for misoprostol are 400–600 micrograms vaginally every 3–6 hours. Doses less than 400 micrograms have decreased efficacy 113. After 28 weeks of gestation, induction of labor should be managed according to usual obstetric protocols.
There is high-quality evidence to support the use of mifepristone plus misoprostol for management of pregnancy loss before 20 weeks when compared to misoprostol alone 114. Data regarding the use of mifepristone as an adjunct to misoprostol for pregnancy loss from 24–28 weeks are more limited 115 116 117. Mifepristone (either 200 or 600 mg orally) can be used as an adjunct to misoprostol for induction of labor in the setting of stillbirth and reduces the time to delivery when compared with misoprostol alone. However, it does not appear to increase overall efficacy of induction 115. When available, mifepristone can be administered 24–48 hours before initiation of induction with misoprostol.
Both induction of labor and dilation and evacuation remain options for women with a previous hysterotomy. In a population-based case–control study of 611 stillbirths, induction of labor resulted in vaginal delivery for 91% (41 of 45) of women with a history of cesarean delivery with two cases of uterine rupture 118. Although induction of labor is preferred rather than cesarean delivery in the setting of fetal demise, the presence of a previous hysterotomy modifies management. Several studies have evaluated the use of misoprostol at a dosage of 400 micrograms every 6 hours in women with a stillbirth between 24 and 28 weeks of gestation and a previous uterine scar 119 120. Available evidence from randomized trials supports the use of vaginal misoprostol as a medical treatment to terminate nonviable pregnancies before 24 weeks of gestation 110. Further research is required to assess effectiveness and safety, optimal route of administration, and dose, especially in women between 24 weeks and 28 weeks of gestation in whom lower doses of misoprostol (200 micrograms per dose) may be preferred 113. Women with a previous hysterotomy and fetal demise after 28 weeks of gestation should undergo induction of labor per standard obstetric protocols for trial of labor after cesarean (see ACOG Practice Bulletin No. 205, Vaginal Birth After Cesarean Delivery) rather than misoprostol administration.
In patients after 28 weeks of gestation with a previous hysterotomy, cervical ripening with a transcervical Foley catheter has been associated with uterine rupture rates comparable to spontaneous labor 121, and this may be a helpful adjunct in patients with an unfavorable cervical examination. Therefore, based on limited data in patients with one previous low transverse cesarean delivery, trial of labor remains a favorable option. There are limited data to guide clinical practice in a patient with a previous classical cesarean delivery or multiple previous cesarean deliveries, and the delivery plan should be individualized based on individual circumstances and patient preference. In general, cesarean delivery for fetal demise should be reserved for unusual circumstances because it is associated with potential maternal morbidity without any fetal benefit. In women with an increased risk of uterine rupture (eg, history of classical hysterotomy or transfundal surgery), repeat cesarean delivery is a reasonable option. Women with an increased risk of uterine rupture who opt for induction of labor should do so with an understanding of the increased risk, and health care providers need to be attuned to signs and symptoms of uterine rupture throughout the labor course.
What support services and clinical counseling should be offered to the patient with a stillbirth?
Patient support should include emotional support and clear communication of test results. Bereavement care should be individualized to recognize bereaved parents’ personal, cultural, or religious needs. Other components of bereavement care after a stillbirth include good communication; shared decision making; recognition of parenthood; acknowledgement of a partners’ and families’ grief; acknowledgement that grief is individual; awareness of burials, cremation, and funerals; ongoing emotional and practical support; health professionals trained in bereavement care; and health professionals with access to self-care 122 Table 4. Referral to a bereavement counselor, peer support group, or mental health professional may be advisable for management of grief and depression. Feelings of guilt or anger in parents who have experienced a stillbirth are common and may be magnified when there is an abnormal child or a genetic defect. However, some parents may welcome discussion and find relief in autopsy results. The results of the tests are important even when no specific diagnosis is identified 123. The results of the autopsy, placental examination, laboratory tests, and cytogenetic studies should be communicated to the involved clinicians and to the family of the deceased infant in a timely manner. If there was no growth of the fetal chromosomes (or these were not obtained), further consultation with a genetic or maternal–fetal medicine subspecialist is advised to discuss the need for parental chromosomal testing. A copy of the results of the tests and a list of diagnoses excluded should be provided to the patients if desired.
For the patient with a history of an unexplained stillbirth in a previous pregnancy, how should clinical management be altered in subsequent pregnancies?
Data on management of pregnancies after an unexplained stillbirth are scarce. Women should be encouraged to minimize the risk of stillbirth attributable to modifiable risk factors (eg, optimize glycemic control in the setting of diabetes). However, a 2018 Cochrane review found insufficient evidence to inform clinical practice regarding effective interventions to improve care for women with a history of stillbirth 124.
Risk of Stillbirth Recurrence Counseling
The evidence surrounding the recurrence risk of stillbirth remains controversial and limited 14. Counseling can be hampered by insufficient information regarding the etiology of the previous stillbirth. In many cases, the previous stillbirth may be unexplained despite a thorough evaluation. In a systematic review and meta-analysis of 13 cohort and three case–control studies, increased risk of stillbirth was found among women with a history of any stillbirth (2.5%) compared with those with a history of live birth (0.4%) (pooled OR, 4.83; 95% CI, 3.77–6.18). In this meta-analysis, the authors were unable to pool the studies that specifically evaluated the risk of stillbirth in the setting of previous unexplained stillbirth. Two studies included in the systematic review reported adjusted risks for stillbirth in a subsequent pregnancy after previous unexplained stillbirth of 3.11 (95% CI, 0.72–13.50) and 1.00 (95% CI, 0.23–4.30) 125 126. A retrospective analysis reported adjusted risks for unexplained stillbirth after one previous stillbirth of 4.18 (95% CI, 1.36–12.89) 127.
When specific risks for stillbirth are identified, the risk of recurrence may be better quantified Table 1. Rates of recurrent fetal loss are higher in women with medical complications such as diabetes or hypertension or in those with obstetric problems with a significant recurrence risk, such as placental abruption. Despite reassurances, the patient is likely to be anxious and to require extra support 128.
There are little data to guide the treating clinician in the antepartum surveillance of a patient who had a previous unexplained stillbirth. Compared with women whose first infant was live born, those with a previous stillborn infant are 2.5 times (95% CI, 1.4–4.7) more likely to have a subsequent stillbirth 16. The risk of recurrent stillbirth may be increased as high as 10-fold depending on maternal race and characteristics of the previous stillbirth, such as etiology, gestational age, and presence of fetal growth restriction 129. Using maternal linked cohort data, stillbirth occurred in 22.7 per 1,000 women with a previous stillbirth compared with 4.7 per 1,000 for those without such a history 130. The etiology of a previous stillbirth also affects the ability of antenatal testing to prevent recurrences. However, for many cases of stillbirth the etiology is unknown 131.
For stillbirths associated with specific conditions, such as hypertension or diabetes, the fetal surveillance should be part of the recommended management guidelines for such conditions. For patients with a previous stillbirth at or after 32 0/7 weeks, once or twice weekly antenatal surveillance is recommended at 32 0/7 weeks or starting at 1–2 weeks before the gestational age of the previous stillbirth. For prior stillbirth that occurred before 32 0/7 weeks of gestation, individualized timing of antenatal surveillance may be considered. However, this approach is associated with potential morbidity and cost: rates of delivery for abnormal or equivocal testing were 16.3% at or before 39 weeks of gestation and 1% before 36 weeks of gestation. Similarly, the authors of one study estimate that antenatal testing before 37 weeks of gestation results in a 1.5% rate of iatrogenic prematurity for intervention based on false-positive test results 132. The excess risk of infant mortality because of late preterm birth is 8.8 per 1,000 live births at 32–33 weeks of gestation and 3 per 1,000 at 34–36 weeks of gestation 133, and this must be considered in any strategy that may lead to iatrogenic late preterm birth.
Fetal Kick Counting for Women with History of Unexplained Stillbirth
Multiple studies have demonstrated that women who report decreased fetal movement are at increased risk for adverse perinatal outcomes 134. Although fetal kick counting is an inexpensive test of fetal well-being, evidence of its effectiveness in preventing stillbirth remains uncertain 135 136. One study demonstrated that a combination of providing uniform information to patients and improving standardized guidelines for health care providers in the management of decreased fetal movement was associated with a reduction in stillbirth rates 137. However, a large randomized study of fetal movement awareness with a primary outcome of stillbirth did not demonstrate a reduction in stillbirth rates, and there was an observed increase in interventions such as inductions and hospital admissions 138. There are insufficient data to make specific recommendations regarding fetal kick counts. Best practices regarding fetal kick counting seems to involve encouragement of awareness of fetal movement patterns, being attentive to the complaint of reduced fetal movements, addressing the complaint in a systematic way, and the use of shared decision making to employ interventions safely 139.
Timing of Delivery
The decision to proceed with early delivery to prevent stillbirth must incorporate an understanding of the increased risks of maternal and neonatal complications compared with the potential benefits. Risks of pregnancy continuation will be variable and largely dependent on underlying maternal and fetal comorbidities in the current pregnancy. Deliveries before 39 weeks of gestation are associated with an increased risk of admission to neonatal special care units for respiratory complications and other neonatal morbidities; however, maternal anxiety with a history of stillbirth should be considered and may warrant an early term delivery (37 0/7 weeks to 38 6/7 weeks) in women who are educated regarding, and accept, the associated neonatal risks. Ultimately, actual care and delivery interventions should be based on all potential aspects of the maternal and fetal conditions, as well as the risks and benefits associated with the suggested timing of delivery. When the suggested timing of delivery occurs during early term periods, timing of delivery must balance the maternal and newborn risk of early term delivery with the risks of further continuation of pregnancy. Amniocentesis for the determination of fetal lung maturity generally should not be used to guide the timing of delivery. Details of pregnancy management recommendations for women with a previous stillbirth are listed in Box 1.
Management of Subsequent Pregnancy After Stillbirth
Prepregnancy or Initial Prenatal Visit
Detailed medical and obstetric history
Evaluation and workup of previous stillbirth
Determination of recurrence risk
Weight loss in obese women (prepregnancy only)
Genetic counseling if family genetic condition exists
Acquired thrombophilia testing: lupus anticoagulant as well as IgG and IgM for both anticardiolipin and β2-glycoprotein antibodies
Support and reassurance
First-trimester screen: pregnancy-associated plasma protein A, human chorionic gonadotropin, and nuchal translucency* or cell-free fetal DNA testing
Support and reassurance
Fetal sonographic anatomic survey at 18–20 weeks
Offer genetic screening if not performed in the first trimester or single marker alpha fetoprotein if first trimester screening already performed
Support and reassurance
Sonographic screening for fetal growth restriction after 28 weeks
Antepartum fetal surveillance starting at 32 weeks of gestation or 1–2 weeks earlier than previous stillbirth
Support and reassurance
Planned delivery at 39 0/7 weeks of gestation or as dictated by other maternal or fetal comorbid conditions. In cases of severe patient anxiety, where there is a preference to proceed with early term delivery (37 0/7 weeks to 38 6/7 weeks) to prevent recurrent stillbirth, such decisions must incorporate the understanding of the increased risks of neonatal complications with early term delivery compared with the potential benefit.
*Provides risk modification but does not alter management.
(Adapted from Reddy UM. Prediction and prevention of recurrent stillbirth. Obstet Gynecol 2007;110:1151–64.)