Williams Obstetrics, 24th Edition

CHAPTER 35. Stillbirth

DEFINITION OF FETAL MORTALITY

CAUSES OF FETAL DEATH

RISK FACTORS FOR FETAL DEATH

EVALUATION OF THE STILLBORN

PSYCHOLOGICAL ASPECTS

MANAGEMENT OF WOMEN WITH PRIOR STILLBIRTH

Fetal mortality—the intrauterine death of a fetus at any gestational age—is considered a major but often overlooked public health issue. It is estimated that there are more than 1 million fetal losses each year in the United States, and most occur before 20 weeks’ gestation. Fetal mortality data from the National Vital Statistics system are usually presented for fetal deaths at 20 weeks’ gestation or older (MacDorman, 2012). Using this definition, there are nearly as many fetal deaths as infant deaths (Fig. 35-1). As shown in Figure 35-2, fetal deaths rates at 20 weeks or more are gestational-age related, reaching a nadir that plateaus between approximately 27 and 33 weeks. Following this, there is a progressive rate increase.

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FIGURE 35-1 Percent distribution of fetal deaths at 20 weeks’ gestation or more, and infant deaths: United States 2006. (From MacDorman, 2012.)

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FIGURE 35-2 Fetal mortality rate per 1000 births by single weeks of gestation: United States, 2006. (From MacDorman, 2012.)

DEFINITION OF FETAL MORTALITY

The definition of fetal death adopted by the Centers for Disease Control and Prevention National Center for Health Statistics is based on the definitions recommended by the World Health Organization (MacDorman, 2012). This definition is as follows:

Fetal death means death prior to complete expulsion or extraction from the mother of a product of human conception irrespective of the duration of pregnancy and which is not an induced termination of pregnancy. The death is indicated by the fact that after such expulsion or extraction, the fetus does not breathe or show any other evidence of life such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscles. Heartbeats are to be distinguished from transient cardiac contractions; respirations are to be distinguished from fleeting respiratory efforts or gasps.

Reporting requirements for fetal deaths are determined by each state, and thus, requirements differ significantly (Chap. 1p. 2). Most states require reporting of fetal deaths at 20 weeks’ gestation or older or a minimum 350-g birthweight—roughly equivalent to 20 weeks—or some combination of these two. Seven states require fetal deaths before 20 weeks to be reported, and one state sets the threshold at 16 weeks. Three states require reporting of fetal deaths with birthweights 500 g or more—roughly equivalent to 22 weeks. There is substantial evidence that not all fetal deaths for which reporting is required are actually recorded (MacDorman, 2012). This is most likely at the earlier gestations of various state requirements.

The overall fetal mortality rate at 20 weeks or more for the United States has steadily declined since 1985 from 7.8 to 6.1 per 1000 total births in 2006 (MacDorman, 2012). Before this, declines were even more impressive and likely due to elimination of deaths of anomalous fetuses at later gestational ages that were “prevented” by early pregnancy terminations (Fretts, 1992).

Fetal mortality is generally divided into three periods: early, or < 20 completed weeks; intermediate, 20–27 weeks; and late, 28 weeks or more. The fetal death rate after 28 weeks has declined since 1990, whereas deaths from 20 to 27 weeks are largely unchanged (Fig. 35-3).

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FIGURE 35-3 Fetal mortality rates by period of gestation: United States, 1990–2006. (From MacDorman, 2012.)

CAUSES OF FETAL DEATH

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) created the Stillbirth Collaborative Research Network to ascertain stillbirth causes in a racially and geographically diverse population in the United States. From this, the Stillbirth Collaborative Research Writing Group (2011b) ascertained stillbirths at 20 weeks or later between 2006 and 2008 in 59 tertiary care and community hospitals in five states. Standardized evaluations that included autopsy, placental histology, and testing of maternal or fetal blood/tissues—including fetal karyotyping—were performed in 500 women with 512 stillbirths. Of these, 83 percent were before labor and were considered antepartum stillbirths. Causes of stillbirth were divided into eight categories shown in Table 35-1. These categories were then classified as probable, possible, or unknown. As an example, diabetes was considered a probable cause if the fetus had diabetic embryopathy with lethal anomalies or the mother had diabetic ketoacidosis, but it was a possible cause if the mother had poor glycemic control and the fetus had abnormal growth. Overall, a probable or possible source was identified in 76 percent of cases.

TABLE 35-1. Causes of 512 Stillbirths in the Stillbirth Collaborative Research Network Study

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This Network study of stillbirths is unprecedented in the United States for several reasons. It was a population-based cohort of stillbirths, all of which underwent systematic and thorough evaluation. Each cause of fetal death assigned is reasonably straightforward and comprehensible except for “placental abnormalities,” which includes “uteroplacental insufficiency” as well as a few other entities less clearly defined. This aside, the leading reasons for fetal death were obstetrical complications that primarily included abruption, multifetal gestation, and spontaneous labor or ruptured membranes before viability. The major contribution of this study was that systematic evaluation led to a likely cause in approximately three fourths of stillbirths. This rate is considerably higher then most analyses of stillbirth etiologies and serves to emphasize the importance of careful evaluations.

RISK FACTORS FOR FETAL DEATH

Factors that have been associated with an increased risk of antepartum stillbirth include advanced maternal age; African-American race; smoking; illicit drug use; maternal medical diseases—such as overt diabetes or chronic hypertension; assisted reproductive technology; nulliparity; obesity; and previous adverse pregnancy outcomes—such as prior preterm birth or growth-restricted newborn (Reddy, 2010; Varner, 2014). There have been two major recent studies in which the investigators assessed whether it was possible to identify stillbirth risk factors either before or shortly after confirmation of pregnancy. Reddy and colleagues (2010) analyzed data from the NICHD Consortium on Safe Labor. Briefly, the pregnancy outcomes of 206,969 women delivered between 2002 and 2008 at 19 hospitals in the United States were analyzed. Shown in Figure 35-4 is the distribution of stillbirths according to gestational age. Clearly, the tragedy of stillbirth occurs primarily in term pregnancies. Reddy and colleagues (2010) found individual risk factors that included race, parity, advanced maternal age, and obesity performed poorly as predictors of stillbirth at term. They concluded that these results did not support routine antenatal surveillance for any of these demographic risk factors. This is discussed further subsequently.

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FIGURE 35-4 Distribution of livebirths and stillbirths in the National Institute of Child Health and Development Safe Labor Consortium according to gestational age. (From Reddy, 2010.)

The second recent analysis of stillbirth risk factors was included in the Stillbirth Collaborative Research Network study described earlier. Investigators studied stillbirth prediction based on risks identified in early pregnancy. They found that pregnancy factors known at the start of pregnancy accounted for a small proportion of stillbirth risk. Except for prior stillbirth or pregnancy loss such as preterm birth or fetal-growth restriction, other risks had limited predictive value (Stillbirth Collaborative Research Network Writing Group, 2011a). The importance of prior stillbirth as a risk for recurrence has been emphasized by Sharma and associates (2006). Specifically, stillbirth risk was fivefold higher in women with a prior stillbirth, and this recurrence risk was almost tripled in African-American women. Rasmussen (2009) analyzed 864,531 births in Norway between 1967 and 2005 and reported that prior preterm birth, fetal-growth restriction, preeclampsia, and placental abruption were strongly associated with subsequent stillbirth. Shown in Table 35-2 are estimates of stillbirth risk according to maternal factors including prior loss.

TABLE 35-2. Estimated Maternal Risk Factors and Risk of Stillbirth

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EVALUATION OF THE STILLBORN

Determining the cause of fetal death aids maternal psychological adaptation to a significant loss, helps assuage the guilt that is part of grieving, permits more accurate counseling regarding recurrence risk, and may prompt therapy or intervention to prevent a similar outcome in the next pregnancy (American College of Obstetricians and Gynecologists, 2012). Identification of inherited syndromes also provides useful information for other family members.

image Clinical Examination

Important tests in stillbirth evaluation are neonatal autopsy and karyotyping and examination of the placenta, cord, and membranes (Pinar, 2014). An algorithm provided by the American College of Obstetricians and Gynecologists (2012) is shown in Figure 35-5. A thorough examination of the fetus, placenta, and membranes is recommended at delivery, with careful documentation in the medical record. The details of relevant prenatal events should be provided. Photographs should be taken whenever possible, and a full radiograph of the fetus—a fetogram—may be performed. Magnetic resonance (MR) imaging and sonography may be especially important in providing anatomical information if parents decline a full autopsy.

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FIGURE 35-5 Flow chart for fetal and placental evaluation. (From Management of stillbirth. ACOG Practice Bulletin No. 102. American College of Obstetricians and Gynecologists. Obstet Gynecol 2009;113:748-61.

image Laboratory Evaluation

If autopsy and chromosomal studies are performed, up to 35 percent of stillborns are discovered to have major structural anomalies (Faye-Petersen, 1999). Approximately 20 percent have dysmorphic features or skeletal abnormalities, and 8 percent have chromosomal abnormalities (Pauli, 1994; Saller, 1995). The American College of Obstetricians and Gynecologists (2012) recommends karyotyping all stillborns. Reddy and coworkers (2012) have recently reported that microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue. In the absence of morphological anomalies, up to 5 percent of stillborns will have a chromosomal abnormality (Korteweg, 2008).

Appropriate consent must be obtained to take fetal tissue samples, including fluid obtained postmortem by needle aspiration. A total of 3 mL of fetal blood, obtained from the umbilical cord or by cardiac puncture, is placed into a sterile, heparinized tube for cytogenetic studies. If blood cannot be obtained, the American College of Obstetricians and Gynecologists (2012) recommends at least one of the following samples: (1) a placental block measuring about 1 × 1 cm taken below the cord insertion site in the unfixed specimen; (2) umbilical cord segment approximately 1.5 cm long; or (3) internal fetal tissue specimen such as costochondral junction or patella. Importantly, skin is no longer recommended for a tissue sample. Tissue is washed with sterile saline before being placed in lactated Ringer solution or sterile cytogenetic medium. Placement in formalin or alcohol kills remaining viable cells and prevents cytogenetic analysis.

A full karyotype may not be possible in cases with prolonged fetal death. For example, Korteweg and associates (2008) reported that they successfully performed cytogenetic analysis in only a third of macerated fetuses. Fluorescence in situ hybridization might be used to exclude numerical abnormalities or to document certain common deletions such as that causing DiGeorge syndrome. Maternal blood should be obtained for Kleihauer-Betke staining; for antiphospholipid antibody and lupus anticoagulant testing if indicated; and for serum glucose measurement to exclude overt diabetes (Silver, 2013).

image Autopsy

Parents should be offered and encouraged to allow a full autopsy. However, valuable information can still be obtained from limited studies. Pinar and colleagues (2012) described the autopsy protocol used by the Stillbirth Collaborative Research Network. In the absence of an autopsy, a gross external examination combined with photography, radiography, MR imaging, bacterial cultures, and selective use of chromosomal and histopathological studies often can aid determination of the cause of death.

A complete autopsy is more likely to yield valuable information. An analysis of 400 consecutive fetal deaths in Wales found that autopsy altered the presumed cause of death in 13 percent and provided new information in another 26 percent (Cartlidge, 1995). Other investigators have shown that autopsy results changed the recurrence risk estimates and parental counseling in 25 to 50 percent of cases (Faye-Petersen, 1999; Silver, 2007).

According to the survey by Goldenberg and coworkers (2013), most hospitals do not audit stillbirths. In other centers, however, maternal records and autopsy findings are reviewed on a monthly basis by a stillbirth committee composed of obstetricians, maternal-fetal medicine specialists, neonatologists, clinical geneticists, and perinatal pathologists. If possible, the cause of death is assigned based on available evidence. Most importantly, parents should then be contacted and offered counseling regarding the reason for death, the recurrence risk if any, and possible strategies to avoid recurrence in future pregnancies.

PSYCHOLOGICAL ASPECTS

Fetal death is psychologically traumatic for the woman and her family. Further stress results from an interval of more than 24 hours between the diagnosis of fetal death and the induction of labor, not seeing her infant for as long as she desires, and having no tokens of remembrance (Radestad, 1996). As discussed in Chapter 61 (p. 1205), the woman experiencing a stillbirth or even an early miscarriage is at increased risk for postpartum depression and should be closely monitored (Nelson, 2013). This and other significant life events increase the risks for another subsequent stillborn (Hogue, 2013).

MANAGEMENT OF WOMEN WITH PRIOR STILLBIRTH

The American College of Obstetricians and Gynecologists (2012) has provided a management outline for women with prior stillbirth (Table 35-3). Importantly, these recommendations are based primarily on limited or inconsistent scientific evidence or on expert opinions. Unfortunately, few studies address management of such women. Those with modifiable risk factors for stillbirth such as hypertension or diabetes control require specific management strategies. According to Reddy (2007), because almost half of fetal deaths are associated with growth restriction, fetal sonographic anatomical assessment beginning at midpregnancy is recommended. This is followed by serial growth studies beginning at 28 weeks.

TABLE 35-3. Management of Subsequent Pregnancy after Stillbirth


Preconceptional or Initial Prenatal Visit

Detailed medical and obstetrical history

Evaluation and workup of previous stillbirth

Determination of recurrence risk

Smoking cessation

Weight loss in obese women (preconceptional only)

Genetic counseling if family genetic condition exists

Diabetes screen

Thrombophilia workup: antiphospholipid antibodies (only if specifically indicated)

Support and reassurance

First Trimester

Dating ultrasonography

First-trimester screen: pregnancy-associated plasma protein A, human chorionic gonadotropin, and nuchal translucencya

Support and reassurance

Second Trimester

Fetal ultrasonographic anatomic survey at 18–20 weeks of gestation

Maternal serum screening (quadruple) or single-marker alpha fetoprotein if first trimester screeninga

Support and reassurance

Third Trimester

Ultrasonographic screening for fetal-growth restriction after 28 weeks

Kick counts starting at 28 weeks

Antepartum fetal surveillance starting at 32 weeks or 1–2 weeks earlier than prior stillbirth

Support and reassurance

Delivery

Elective induction at 39 weeks

Delivery before 39 weeks only with documented fetal lung maturity by amniocentesis

aProvides risk modification but does not alter management.

Adapted from American College of Obstetricians and Gynecologists, 2012; Reddy, 2007.

Weeks and associates (1995) evaluated fetal biophysical testing in 300 women whose only indication was prior stillbirth. There was only one recurrent stillbirth, and only three fetuses had abnormal testing results before 32 weeks. There was no relationship between the gestational age of the previous stillborn and the incidence or timing of abnormal test results or fetal jeopardy in the subsequent pregnancy. These investigators concluded that antepartum surveillance should begin at 32 weeks or later in the otherwise healthy woman with a history of stillbirth. This recommendation is supported by the American College of Obstetricians and Gynecologists (2012) with the caveat that it increases the iatrogenic preterm delivery rate.

Delivery at 39 weeks is recommended by induction or by cesarean delivery for those with a contraindication to induction. This minimizes fetal mortality rates, although the degree of risk reduction may be greater for older women (Page, 2013).

REFERENCES

American College of Obstetricians and Gynecologists: Management of stillbirth. Practice Bulletin No.102, March 2009, Reaffirmed 2012

Cartlidge PHT, Stewart JH: Effect of changing the stillbirth definition on evaluation of perinatal mortality rates. Lancet 346:486, 1995

Faye-Petersen OM, Guinn DA, Wenstrom KD: Value of perinatal autopsy. Obstet Gynecol 94(6):915, 1999

Fretts RC: Etiology and prevention of stillbirth. Am J Obstet Gynecol 193(6):1923, 2005

Fretts RC, Boyd ME, Usher RH, et al: The changing pattern of fetal death, 1961–1988. Obstet Gynecol 79:35, 1992

Goldenberg RL, Farrow V, McClure EM, et al: Stillbirth: knowledge and practice among U.S. obstetrician-gynecologists. Am J Perinatol 30(10):813, 2013

Hogue CJR, Parker CB, Willinger M, et al: A population-based case-control study of stillbirth: the relationship of significant life events to the racial disparity for African Americans. Am J Epidemiol 177(8):755, 2013

Korteweg FJ, Bouman K, Erwich JJ, et al: Cytogenetic analysis after evaluation of 750 fetal deaths. Obstet Gynecol 111:865, 2008

MacDorman MF, Kirmeyer SE, Wilson EC: Fetal and perinatal mortality, United States, 2006. Natl Vital Stat Rep 60(8):1, 2012

Nelson DB, Freeman MP, Johnson, NL, et al: A prospective study of postpartum depression in 17,648 parturients. J Matern Fetal Neonatal Med 26(12):1155, 2013

Page JM, Snowden JM, Cheng YW, et al: The risk of stillbirth and infant death by each additional week of expectant management stratified by maternal age. Am J Obstet Gynecol 209(4):375.e1, 2013

Pauli RM, Reiser CA: Wisconsin Stillbirth Service Program: II. Analysis of diagnoses and diagnostic categories in the first 1,000 referrals. Am J Med Genet 50:135, 1994

Pinar H, Goldenberg RL, Koch MA, et al: Placental findings in singleton stillbirths. Obstet Gynecol 123:325, 2014

Pinar H, Koch MA, Hawkins H, et al: The Stillbirth Collaborative Research Network Postmortem Examination protocol. Am J Perinatol 29:187, 2012

Radestad I, Steineck G, Nordin C, et al: Psychological complications after stillbirth—influence of memories and immediate management: population based study. BMJ 312:1505, 1996

Rasmussen S, Irgens LM, Skjaerven R, et al: Prior adverse pregnancy outcome and the risk of stillbirth. Obstet Gynecol 114(6):1259, 2009

Reddy UM: Prediction and prevention of recurrent stillbirth. Obstet Gynecol 110:1151, 2007

Reddy UM, Laughon SK, Sun L, et al: Prepregnancy risk factors for antepartum stillbirth in the United States. Obstet Gynecol 116:1119, 2010

Reddy UM, Page GP, Saade GR, et al: Karyotype versus microarray testing for genetic abnormalities after stillbirth. N Engl J Med 367(23):2185, 2012

Saller DN Jr, Lesser KB, Harrel U, et al: The clinical utility of the perinatal autopsy. JAMA 273:663, 1995

Sharma PP, Salihu HM, Oyelese Y, et al: Is race a determinant of stillbirth recurrence? Obstet Gynecol 107(2 Pt 1):391, 2006

Silver RM: Fetal death. Obstet Gynecol 109:153, 2007

Silver RM, Parker CB, Reddy UM, et al: Antiphospholipid antibodies in stillbirth. Obstet Gynecol 122(3):641, 2013

Stillbirth Collaborative Research Network Writing Group: Association between stillbirth and risk factors known at pregnancy confirmation. JAMA 306(22):2469, 2011a

Stillbirth Collaborative Research Network Writing Group: Causes of death among stillbirths. JAMA 306(22):2459, 2011b

Varner JW, Silver RM, Rowland Hogue CJ, et al: Association between stillbirth and illicit drug use and smoking during pregnancy. Obstet Gynecol 123:113, 2014

Weeks JW, Asrat T, Morgan MA, et al: Antepartum surveillance for a history of stillbirth: when to begin? Am J Obstet Gynecol 172:486, 1995