Etiology and management of antepartum fetal death

Author

Ruth C Fretts, MD, MPH Section Editor

Charles J Lockwood, MD Deputy Editor

Vanessa A Barss, MD

Last literature review version 16.3: September 2008 | This topic last updated: September 12, 2008 (More)

INTRODUCTION — The terms fetal death, fetal demise, stillbirth, and stillborn all refer to the delivery of a fetus showing no signs of life. The terms will be used interchangeably in this topic review; however, it \should be noted that parent groups prefer the term stillbirth to the other terms.

The incidence, etiology, prevention, and management of antepartum fetal death will be reviewed here. Pathological evaluation of stillborns and counseling parents after stillbirth are discussed separately. (See "Evaluation of stillbirth" and see "Counseling parents after stillbirth").

DEFINITION — The terminology defining fetal, neonatal, perinatal, and infant death is described in detail separately. A brief synopsis of the definition of stillbirth is provided below. All fetal deaths are not stillbirths, as embryologists define the fetal period as beginning at the end of embryonic period (ie, the eight weeks after conception). (See "Perinatal mortality", section on Terminology). World Health Organization definition — The World Health Organization (WHO) defines stillbirth as a "fetal death late in pregnancy" and allows each country to define the gestational age at which a fetal death is considered a stillbirth for reporting purposes [1] . As a result, some countries define stillbirth as early as 16 weeks of gestation, whereas others use a threshold as late as 28 weeks [2-4] . Fetal deaths under the threshold are considered products of miscarriage (abortuses). United States National Center for Health Statistics

definition — The standardized definition for fetal mortality used by the United States National Center for Health Statistics (NCHS) is similar to the WHO definition and adds that stillbirth is indicated by the absence of breathing, heart beats, pulsation of the umbilical cord, or definite movements of voluntary muscles [5] . The majority of individual states in the United States use 20 weeks of gestation as the threshold for distinguishing a stillbirth from a miscarriage; the International Stillbirth Alliance also suggests this cut-off [6] . The use of this threshold results in a more reliable estimate of the stillbirth rate than estimates using earlier gestational age thresholds because of the difficulty of reliably capturing data on early gestational losses.

If the gestational age is not known, fetal weight may be used to distinguish a stillbirth from a miscarriage. The threshold weight used varies from ≥ 350 to ≥ 500 g.

Stillbirths can be subclassified according to the gestational age at delivery. Early stillbirths are typically defined as those occurring at 20 to 27 weeks of gestation, while late stillbirths occur at or after 28 weeks of gestation. Although the division is somewhat arbitrary, this stratification allows for relatively reliable international comparison of late fetal losses, and allows division of stillbirths into those that are more difficult to prevent (early losses) from the losses that might potentially be preventable (late losses).

Despite these definitions, comparison of stillbirth rates between different countries should be done with caution. Obtaining reliable estimates of the number of stillbirths in developing countries is difficult since most births occur in the home and, in some remote areas, data are completely lacking [7] . In developed countries, there is an inconsistent approach as to whether induced pregnancy terminations for prenatally diagnosed fetal anomalies and induced labor for previable infants due to premature rupture of membranes are categorized as stillbirths.

In addition, the ability to call a fetal loss a stillbirth is important as birth and death certificates are not generated after a miscarriage, and parents have reported that they feel less grief support is provided after a miscarriage than after a stillbirth.

INCIDENCE AND EPIDEMIOLOGY — Over three million stillbirths occur each year worldwide [8-10] . In the United States, the stillbirth rate is higher than the neonatal death rate and slightly lower than the infant mortality rate [11] . Antepartum fetal death is much more common than intrapartum fetal death [12] and unexplained fetal death occurs far more commonly than unexplained infant death [11,13] . (See "Perinatal mortality" and see "Sudden infant death syndrome").

In 2004, the stillbirth rate in the United States was 6.20/1000 live births and fetal deaths (ie, total births), down from 6.41/1000 in 2002 [14] . Since 1990, the rate of early fetal loss (20 to 27 weeks of gestation) has remained stable at about 3.2 per 1000, while the rate of late fetal loss (greater than or equal to 28 weeks of gestation) has decreased by 29 percent such that the current rates of early and late fetal death are about the same. About one-half of late fetal deaths occur at term (show figure 1A).

In the United States, it is important to note that black women have twice the rate of stillbirth compared to white women [14] , and while some of this increased risk can be attributed to access to, and quality of, medical care, other factors contribute, as well [13,15-20] . Even in the setting where black women have adequate access to prenatal care, they experience a higher rate of stillbirth. This increased risk has been attributed to higher rates of diabetes mellitus, hypertension, placental abruption, and premature rupture of membranes in these women [19] .

The frequencies of the various etiologies of stillbirth differ among racial groups. This may be related to genetic, as well as behavioral and environmental, factors. A study from the United Kingdom observed that the most important factor associated with antepartum stillbirth among white women was placental abruption, but among South Asian and black women it was birth weight below 2000 g [21] .

Rates of stillbirth in developing countries are substantially higher (9-34/1000 births) than in developed countries [22] .

CLASSIFICATION SYSTEMS — The study of specific causes of stillbirth has been hindered by the lack of a uniform protocol for evaluating and classifying stillbirths, and from declining autopsy rates. In most cases, fetal death certificates are completed before all results from post-mortem evaluations become available.

A system for classifying specific causes of fetal death could serve many purposes. As an example, parents obviously want to know why their baby died, and whether they are at an increased risk for similar losses in the future. Researchers want to understand the pathogenetic mechanisms for stillbirth so they can develop prevention strategies. This information could also be useful for compiling a perinatal database and as a tool for quality improvement.

There are more than 30 published systems for classifying perinatal deaths [23] . The rate of unexplained stillbirth depends, in part, on the system used. In one study including 154 stillbirths, the rate of unexplained stillbirth by classification system was RoDeCo (14.3 percent), Wigglesworth (47.4 percent), de Galan-Roosen (18.2 percent), and Tulip (16.2 percent) [24] . Mean gestational age at stillbirth in unexplained and explained stillbirth was similar for all four protocols.

Early classification systems included only a small number of subtypes stratified into normally formed stillbirths, congenital malformations, immaturity, asphyxia, and "others" (show table 1) [25] . Subsequent systems attempted to capture more information, including aberrations of fetal growth, placental pathology, and maternal conditions [23,26] . There is considerable debate over whether hierarchical systems should be used, and if conditions such as growth restriction and hypertension are causes, or merely risk factors, for stillbirth. Nevertheless, a systematic approach to classifying stillbirth would be a critical step in designing prevention strategies [27] .

Efforts are underway to adopt an international classification system which would indicate maternal conditions and fetal growth status; capture late fetal deaths versus intrapartum deaths; and classify deaths in multiple gestations in a useful way, in addition to usual perinatal data (eg, birth weight, gestational age, maternal marital status). However, this is not expected for several years. Currently, the most useful information about the specific causes of stillbirth comes from hospitals or regions that systematically review and classify these deaths over time (show table 5).

ETIOLOGY — The frequencies of the various etiologies of stillbirth differ between developing and developed countries [27-29] . For example, in developing countries obstructed/prolonged labor, preeclampsia, and infection are common causes of stillbirth, whereas in developed countries congenital or karyotypic anomalies, growth restriction, and maternal medical diseases are the most common causes [8] . The following discussion refers primarily to stillbirth occurring in developed countries.

The frequencies of the various etiologies of stillbirth also vary in relation to gestational age. In this review, the most common causes of stillbirth between 24 and 27 weeks of gestation were infection (19 percent), abruption (14 percent), and fetal anomalies (14 percent) [30] . After 28 weeks of gestation, the most frequent cause of stillbirth was unexplained fetal loss, which included stillbirths associated with growth restriction and placental abruption.

Unexplained stillbirth — An unexplained stillbirth is a fetal death that cannot be attributed to an identifiable fetal, placental, maternal, or obstetrical etiology. It accounts for 25 to 60 percent of all fetal

deaths [31-33] . Variation in the proportion of stillbirths reported as unexplained generally reflects whether the stillbirth has been fully evaluated, and if the classification system allows risk factors to be included as causes. As an example, the cause of stillbirth in an infant who is small for gestational age may be attributed to fetal growth restriction in some systems, but is considered unexplained in others if the underlying cause of the growth restriction is unknown [31-34] .

Stillbirths occurring near term are more likely to be unexplained than stillbirths that occur earlier in gestation. As an example, in one series, two thirds of unexplained fetal deaths occurred after 35 weeks of gestation [31] . In another series, the rate of unexplained fetal death in pregnancies over 40 weeks of gestation was more than double the rate earlier in pregnancy [33] .

The largest study of unexplained stillbirth (n = 196 cases) reported the following characteristics were independent risk factors: maternal prepregnancy weight greater than 68 kg (OR 2.9; 95% CI 1.85-4.68), birth weight ratio (defined as ratio of birth weight to mean weight for gestational age) between 0.75 and 0.85 (OR 2.77, 95% CI 1.48-5.18) or over 1.15 (OR 2.36, 95% CI 1.26-4.44), parity of three or more (OR 2.01, 95% CI 1.26-3.20), primiparity (OR 1.74, 95% CI 1.26-2.40), cord loops (OR 1.75, 95% CI 1.04-2.97), low socioeconomic status (OR 1.59, 95% CI 1.14-2.22), and, for the 1978 to 1996 period only, maternal age 40 years or more (OR 3.69, 95% CI 1.28-0.58) [31] . Trimester of first antenatal visit, low maternal weight, postdate pregnancy, fetal-to-placental weight ratio, fetal sex, previous fetal death, previous abortion, cigarette smoking, and alcohol use were not significantly associated with unexplained fetal death in this series.

Fetal growth restriction — Fetal death of a growth-restricted fetus is the second most common type of stillbirth [30] . Placental dysfunction is the presumed cause of both the growth restriction and the fetal death. The estimated risk of stillbirth for growth restricted fetuses is five to seven times that of the normally grown fetus [35-39] . A large Norwegian study determined that mean gestational age at death was 35 weeks of gestation [36] . (See "Diagnosis of fetal growth restriction" and see "Overview of causes of and risk factors for fetal growth restriction").

Conditions resulting in placental dysfunction can be recurrent, but the placental complications may manifest in different ways in different pregnancies. Growth restriction, preterm delivery, and stillbirth can all be sequelae of impaired placental function [35,40] . The association between the birth of a small for gestational age (SGA) infant in one pregnancy and stillbirth in a subsequent pregnancy was illustrated by analysis of data from the Swedish Birth Register (show table 6) [35] .

Abruptio placenta — Abruptio placenta occurs in approximately 1 percent of pregnancies, but accounts for 10 and 20 percent of all stillbirths [30] . The risk of fetal death is highest when more than 50 percent of the placental surface becomes separated or when the abruption involves the central aspect of the placenta. (See "Clinical features and diagnosis of placental abruption").

Infection — Infection accounts for approximately one-half of all stillbirths globally [41] . Infection may lead to fetal demise as a result of severe systemic maternal illness (eg, influenza), placental dysfunction due to placental infection (eg, malaria), or fetal systemic illness (eg, Escherichia coli). Fetal infection can be acquired transplacentally (hematogenous dissemination of infectious agents) or transcervically (ascending infection from colonization of the lower genital tract).

Viral pathogens are the most common source of hematogenous infection of the placenta, although bacteria, spirochetes, fungi, and protozoa can also cause infection via this route. Almost any systemic infection that occurs during pregnancy can infect the placenta, but fetal death as a result of maternal infection is rare. The diagnostic criteria for determining if a fetal death is due to infection are not well-defined, and complicated by the relatively high frequency of asymptomatic maternal vaginal colonization of some potential pathogens [41] .

In developed countries, the majority of stillbirths related to infection occur in periviable fetuses following premature rupture of membranes [30] . The usual mechanism is ascending infection from the lower genital tract. The rate of these losses has been relatively stable over the past 30 years. (See "Midtrimester preterm premature rupture of membranes").

Malaria is a common infectious cause of stillbirth in endemic areas. Parvovirus, cytomegalovirus, toxoplasmosis, listeria, and herpes simplex virus are other well-established infectious causes of stillbirth. (See "Placental infections" and see individual topic reviews on specific infections).

Studies have found that women who have had an unexplained stillbirth have a higher number of "memory T cells" (CD45RO) than "naive T cells" (CD45RA) compared to mothers of live born controls [42] . This finding suggests that, in spite of the absence of any overt evidence of clinically significant infection, these women had had prior exposure to infectious agents or other unidentified antigens, which may have played a role in the fetal demise.

In addition, the absence of a fetal inflammatory response in the presence of chorioamnionitis in an unexplained stillbirth may reflect the inability of the fetus to mount an immune response sufficient to trigger the onset of labor [43] . This could result in intrauterine death. A large study including 428 stillbirths found histologic chorioamnionitis in 158 (36.9 percent) [44] . A fetal inflammatory response was also present in 57/158 (36 percent) and was most likely in cases with intrapartum death after spontaneous onset of labor or after spontaneous rupture of membranes. There was no fetal inflammatory response in 101/158 (64 percent) and these cases were more likely to be associated with unexplained fetal death prior to the onset of labor. These findings support a pathophysiologic relationship between fetal inflammation and initiation of parturition. (See "Intraamniotic infection", section on Fetal and neonatal complications).

Chromosomal and genetic abnormalities — Death of a karyotypically abnormal embryo or fetus occurs at all stages of pregnancy, but is most common in the first trimester [45-47] . (See "Spontaneous abortion: Risk factors; etiology; clinical manifestations; and diagnostic evaluation").

One large series that karyotyped a combined group of 823 stillbirths and neonatal deaths reported 6.3 percent had a major chromosomal abnormality [48] . The frequency of abnormal karyotype in macerated stillbirths, nonmacerated stillbirths, and neonatal deaths was approximately 12, 4, and 6 percent, respectively [32] . The abnormalities reported were mostly comprised of trisomies 18, 13, and 21; sex chromosome aneuploidy; and unbalanced translocations. By comparison, the frequency of chromosomal abnormality in the total population of live born infants was 0.7 percent.

Single gene defects, confined placental mosaicism, and microdeletions are examples of genetic causes of stillbirth that may be present even though a karyotype determined by conventional cytogenetic analysis is normal. Molecular genetic technology may help to identify these cases. (See "Cytogenetic and molecular genetic diagnostic tools").

Congenital anomalies — Fifteen to 20 percent of stillbirths have a major malformation [30,45] . Malformations associated with fetal demise, but unrelated to structural chromosomal abnormalities, include abdominal wall defects, neural tube defects, Potter syndrome, achondrogenesis, and amniotic band syndrome.

Fetomaternal hemorrhage — Fetomaternal hemorrhage (FMH) sufficiently large to cause fetal death has been reported in up to 5 percent of stillborns [49,50] . Usually there is no identifiable etiology; however,

some cases have been associated with abruptio placenta, vasa previa, chorioangioma, choriocarcinoma, maternal trauma, cephalic version, and amniocentesis [50] .

Umbilical cord complications — Umbilical cord complications (eg, nuchal cord, knot, intrinsic cord abnormalities) are often cited as a cause of fetal death in the third trimester [51-55] . Although nuchal cords and knots are relatively common, vascular constriction severe enough to kill the fetus rarely occurs. The presence of a nuchal cord or knot may provide the clinician and the patient with an immediate potential explanation for the fetal demise; however, attributing the cause of death to a cord complication should occur only after a thorough search for other causes and when there are other findings supporting this diagnosis. (See "Gross examination of the placenta", section on Umbilical cord).

Hydrops fetalis — Hydrops fetalis may be due to immune or nonimmune etiologies and is often fatal. Diagnosis and management of these disorders are discussed separately. (See "Nonimmune hydrops fetalis" and see "Management of Rhesus (Rh) alloimmunization in pregnancy").

RISK FACTORS

Biologic markers — No good screening tests are available for clinical assessment of risk of stillbirth in the general obstetrical population. (See "Evidence-based approach to prevention", section on Criteria for a good screening test).

Two laboratory tests commonly obtained in pregnant women have shown some predictive value: Biochemical tests obtained as part of population-based screening programs for Down syndrome, if abnormal, are predictive of adverse pregnancy outcome, including fetal death. The utility of these tests for predicting or preventing stillbirth is low, and is discussed in detail separately. (See "Pregnancy complications predicted by maternal serum analyte screening", section on Adverse pregnancy outcome). Hemoconcentration has been associated with an elevated risk of stillbirth. Plasma volume expansion and lowered hemoglobin concentration are normal physiologic responses to pregnancy. Plasma volume expansion appears to be important for fetal growth and failure of sufficient hemodilution is associated with an increased risk of stillbirth, even if the fetus is not growth-restricted. This was illustrated in an analysis of a Swedish database that found both an elevated hemoglobin at initial prenatal examination (initial hemoglobin ≥ 14.6 g/dL) and failure of significant hemodilution over the course of pregnancy significantly increased the risk of nonanomalous antepartum stillbirth (OR 2.0, 95% C, 1.1-3.8), even after women with preeclampsia and eclampsia were excluded [56] . However, only 5.6 percent of women with stillbirth had an elevated hemoglobin level early in pregnancy.

Other risk factors — Common risk factors and medical conditions associated with stillbirth are listed in the table (show table 7). The prevalence of some risk factors is increasing. As an example, in developed countries, primiparity, advanced maternal age, obesity, and multiple gestation are becoming more common. Globally, cigarette smoking is the major modifiable risk factor associated with fetal death.

Race and socioeconomic factors — In the United States, studies have consistently shown that black women have twice the risk of stillbirth as white women, even when only women who received adequate prenatal care were evaluated [17-20,57] . The increased risk of stillbirth in black women has been attributed to higher rates of diabetes mellitus, hypertension, placental abruption, and premature rupture of membranes in these women [19] .

Advanced maternal age — Advanced maternal age is an independent risk factor for stillbirth, even after accounting for medical conditions that are more likely to occur in older women, such as multiple gestation, hypertension, diabetes, previous abortion, and abruptio placenta, all of which are associated with higher rates of stillbirth [58,59] . (See "Effect of advanced age on fertility and pregnancy in women").

Historically, stillbirth related to fetal anomalies occurred more often in women 35 years of age or older than in younger women [60] . However, after the introduction of routine prenatal screening for fetal anomalies, this risk declined to that observed in their younger counterparts. Currently, the only type of stillbirth that is statistically significantly more common in older women is unexplained fetal demise (see "Unexplained stillbirth" below).

Obesity — Obese gravidas (body mass index over 30 kg/m2) are at increased risk of fetal death, especially late fetal death [61] . The reasons for this association are unknown, but are thought to be due to behavioral, socioeconomic, and obstetrical factors. As an example, obese women are more likely to smoke and to have pregnancies complicated by gestational diabetes and preeclampsia. However, even after controlling for these factors, obesity remains a significant risk factor for stillbirth. (See "The impact of obesity on fertility and pregnancy").

Multiple gestation — The stillbirth rate from all causes is higher in fetuses of a multiple gestation than in singletons (19.6 versus 4.7 per 1000 births) [62] . The increased rate is due to complications specific to twin pregnancy (such as twin-twin transfusion syndrome) as well as complications, such as fetal

anomalies and growth restriction, that can occur in any pregnancy. (See "Pathogenesis and diagnosis of twin-twin transfusion syndrome").

Limiting the number of embryos transferred during in vitro fertilization or multifetal pregnancy reduction could reduce the number of stillbirths related to multiple gestation. (See "Strategies to control the rate of high order multiple gestation" and see "Multifetal pregnancy reduction and selective termination").

Smoking — Large case control and cohort studies have shown a relative risk of stillbirth in smokers ranging from 1.2 to 1.4. (See "Smoking and pregnancy", section on Stillbirth).

Maternal medical disorders — Hypertension and diabetes mellitus are among the most common medical conditions that complicate pregnancy [63] . In the past, these conditions accounted for a significant proportion of fetal deaths due to inadequate medical control of maternal disease. (See "Prepregnancy counseling and evaluation of women with diabetes mellitus" and see "Obstetrical management of pregnancy complicated by diabetes mellitus" and see "Management of hypertension in pregnancy").

Other important medical conditions associated with an increased risk of stillbirth are listed in the table (show table 7). These conditions are discussed in separate topic reviews on each disorder (see individual topic reviews on pregnancy and renal disease, systemic lupus erythematosus, inherited and acquired thrombophilias, thyroid disease, cardiac disease, specific infections, asthma, cholestasis, hemoglobinopathies, etc).

Past obstetrical history — As discussed above, growth restriction, preterm delivery, and stillbirth can all be sequelae of impaired placental function and there is an association between the birth of a SGA infant in one pregnancy and stillbirth in a subsequent pregnancy (show table 6). (See "Fetal growth restriction" above).

There is a two- to ten-fold risk of recurrent stillbirth, which is affected by multiple factors, including characteristics of the stillbirth and race [64] . The risk of recurrent stillbirth is discussed separately. (See "Counseling parents after stillbirth" section on Recurrence risk).

PREVENTION STRATEGIES — Effective interventions for stillbirth prevention are possible in the developing world, where the risk of stillbirth is high and resources are low [8,65-67] . A detailed discussion of these interventions is beyond the scope of this review.

There are no randomised-controlled trials demonstrating an effective method of reducing stillbirth in the general population of developed countries. Stillbirth prevention is possible in some pregnancies at high-risk of stillbirth (eg, anomalous fetuses, fetal growth restriction), if these pregnancies are identified.

There is no evidence that intensive monitoring in future pregnancies will make a significant difference in preventing stillbirth, especially when the cause was unknown. Nevertheless, many practitioners offer frequent prenatal visits and frequent testing, such as nonstress tests and ultrasound examinations, as well as early delivery (eg, 38 weeks) to provide the couple with some psychological reassurance and a measure of control over the pregnancy [68,69] . (See "Counseling parents after stillbirth" section on Planning future pregnancies).

Medical and obstetrical care — Appropriate medical and obstetrical care can reduce the risk of stillbirth in women with some medical disorders which carry an increased risk of stillbirth, such as poorly controlled pregestational diabetes mellitus or hyperthyroidism (see "Maternal medical disorders" above and see "Preconception evaluation and counseling").

Prenatal diagnosis of fetal anomalies — Prenatal screening, diagnostic testing, and elective termination of pregnancies with major congenital anomalies could reduce the proportion of stillbirths related to this etiology [70] . However, pregnancy termination merely results in some potential stillbirths and neonatal deaths to be classified as abortuses, which may not be captured by national vital statistics. As an example, 7 percent of anencephalics in ongoing pregnancies are stillborn [71] , but pregnancy termination for this diagnosis is common (20 to 70 percent of cases) [72] . Routine prenatal screening of low-risk populations has only been proven cost-effective for some abnormalities (eg, Down syndrome, neural tube defects). (See individual topic reviews on prenatal diagnosis and see "Routine prenatal ultrasonography as a screening tool").

Antepartum fetal monitoring — Theoretically, antepartum fetal monitoring should reduce the risk of stillbirth by identifying fetuses in whom timely intervention will prevent death. The best evidence that antepartum fetal monitoring can play a role in reducing stillbirth rates involves the use of Doppler velocimetry for monitoring the growth restricted fetus. The value of this approach is discussed in detail separately. (See "Fetal growth restriction: Evaluation and management"). The rationale for and the

efficacy of various antepartum fetal monitoring techniques are also reviewed elsewhere. (See "Antepartum fetal heart rate assessment" and see "The fetal biophysical profile" and see "Doppler ultrasound of the umbilical artery for fetal surveillance").

The challenge for the clinician is to assess the a priori risk of stillbirth and use antepartum fetal testing wisely. Given that many factors influence the risk of stillbirth, it would be helpful to have an evidence-based interactive model that would estimate the risk of fetal demise in a specific pregnancy. However, no such model exists due to the relatively low-risk of stillbirth and the fact that our tools for assessing fetal well-being are far from perfect. Therefore, the obstetrical care provider uses her/his clinical judgment to decide on the appropriate type and frequency of antepartum monitoring, and to determine when the maternal/fetal risks of ongoing pregnancy warrant intervention for delivery, even though delivery may result in the birth of a preterm infant or require cesarean delivery [63] .

The complexity of these decisions was illustrated in a decision-analysis of the risks and benefits of antepartum testing late in pregnancy for women 35 years of age or older using the McGill Obstetrical Neonatal Database to obtain risk estimates [73] . This decision analysis considered only late unexplained stillbirth, which comprise the majority of late stillbirths. The model assumed that there was no measurable long-term adverse effect of being born at 36 weeks of gestation or later, so the analysis was begun during the 37th week. It also assumed that the major risk of antepartum testing after 36 weeks was induction of labor and its associated down-stream effects (eg, increased potential for cesarean delivery, morbidity associated with induction and surgery) [74] .

Sensitivity analysis was used to estimate the effects of this strategy late in pregnancy and found that antepartum testing was successful in reducing the number of unexplained stillbirths, but was also associated with a high risk of labor induction. For nulliparous women 35 years of age or older with an estimated risk of late stillbirth of 5.2/1000 pregnancies, the number of fetal deaths averted late in pregnancy was 3.9 per 1000 pregnancies. It would take 863 antepartum tests, 71 additional inductions, and 14 additional cesarean deliveries to prevent one unexplained stillbirth. By comparison, if the estimated risk of late stillbirth was 1 to 2/1000 pregnancies, then a strategy of antepartum testing would be expected to avert 1.2 late fetal deaths per 1000 pregnancies, at a cost of 2862 antepartum tests, 233 additional inductions, and 44 additional cesareans per fetal death averted.

Monitoring fetal movement — Patients who report decreased fetal movement are at increased risk of having an adverse pregnancy outcome, including stillbirth. Monitoring fetal movement has been suggested as a means of identifying fetuses in whom timely intervention will prevent death. Trials comparing fetal/neonatal outcome in mixed risk populations of women randomly assigned to follow a

formal program of fetal movement counting or to routine care have not yielded conclusive results [75] . Observational studies suggest monitoring fetal movement and promptly evaluating women with decreased fetal activity may improve pregnancy outcome. (See "Evaluation of decreased fetal movements").

Perinatal audit — Developing strategies for stillbirth reduction requires an ongoing audit process to evaluate the specific causes of stillbirth and the results of intervention programs. As an example, perinatal audits have identified stillbirths resulting from deficiencies in intrapartum care, and quality improvement processes have been initiated to prevent recurrence [67,76] . An audit by the Confidential Inquiry into Stillbirths and Infant Death of Northern Ireland found that failure to diagnose and appropriately manage fetal growth restriction was the most common error leading to stillbirth, followed by failure to recognize additional maternal medical risk factors [77] . As discussed above, there is some evidence that antepartum identification and optimal management of these disorders might lower stillbirth rates.

Elective delivery — Studies consistently show that the risk of stillbirth increases late in pregnancy, especially after 38 weeks of gestation [33,78-83] . A life-table analysis found that the risk of antepartum stillbirth increased from 1 in 2000 women per week at 37 weeks of gestation, to 1 in 500 at 42 weeks, and 1 in 200 by 43 weeks [84] . Theoretically, elective delivery of women at term should prevent some stillbirths since fetal demise can only occur in an ongoing pregnancy. This theory is supported by indirect evidence from an analysis of management of postterm pregnancy over time in Canada [85] . Between 1980 and 1995 there was a marked decrease in pregnancies reaching 42 or more weeks of gestation and a decrease in the rate of stillbirth, presumably related, at least in part, to the increased prevalence of inducing labor at 41 weeks of gestation.

There are insufficient data to support a policy of routine elective induction of labor at term. Large, randomized trials with emphasis on maternal and neonatal safety, determination of neonatal benefit as a reflection of reduced unexplained fetal death, and cost-effectiveness/cost-benefit analyses are needed. (See "Induction of labor", section on Elective induction at term).

However, a strategy of elective induction might be useful in situations associated with an increased risk of stillbirth, such as monoamniotic twin pregnancy, poor glycemic control in a pregnancy complicated by diabetes mellitus, or postterm pregnancy. (See "Delivery of twin gestations" and see "Obstetrical management of pregnancy complicated by diabetes mellitus" and see "Postterm pregnancy").

Issues relating to antepartum monitoring and elective delivery of women with a prior stillbirth are reviewed separately. (See "Counseling parents after stillbirth", section on Planning future pregnancies).

DIAGNOSIS — Clinical signs and symptoms that may be associated with fetal death include cessation of previously perceived fetal movements, a decrease in pregnancy-related symptoms (eg, nausea, breast tenderness), and uterine bleeding or contractions. The diagnosis must be confirmed with an ultrasound examination documenting absence of fetal cardiac activity.

MANAGEMENT — If a fetal karyotype has not been obtained but is now desired as part of the evaluation of stillbirth, an amniocentesis prior to delivery should be considered because it is more likely to yield viable cells for analysis than tissue obtained at a later date.

Maternal laboratory evaluation — Laboratory studies might provide information as to the cause of stillbirth. These are discussed in detail separately. (See "Evaluation of stillbirth" section on Maternal laboratory evaluation).

Delivery decisions — We suggest offering induction of labor soon after diagnosis of fetal death because of the emotional distress associated with this event and the prospect of carrying a dead baby. Furthermore, the patient is at risk of developing chronic consumptive coagulopathy. However, some couples may choose to delay induction or even wait for spontaneous labor; prompt induction is not medically necessary.

Risk of coagulopathy — If no intervention is taken, most women (80 to 90 percent) will enter labor spontaneously within two weeks of a fetal demise. Retention of a dead fetus can cause chronic consumptive coagulopathy due to gradual release of tissue factor (also called thromboplastin) from the placenta into the maternal circulation [86,87] . This usually occurs after four weeks, but may occur earlier, and has been reported in 25 percent of women who retain a dead fetus for more than a month.

Testing for coagulopathy is typically performed as this information is important prior to administration of neuraxial anesthesia, as well as other invasive procedures [87] . A fibrinogen concentration and platelet count should be obtained; a prothrombin time and activated partial thromboplastin time are optional as long as the patient has no obvious signs of bleeding.

Treatment of disseminated intravascular coagulation (DIC) consists of replacement of volume, blood products, and coagulation components and cardiovascular and respiratory support. Administration of low dose heparin in women with an intact circulation may correct hypofibrinogenemia (fibrinogen less than 100 mg/dL) prior to induction [88] . (See "Clinical features, diagnosis, and treatment of disseminated intravascular coagulation in adults").

Induction — The method of induction for a fetal death depends on the probability of success in specific clinical settings. Third trimester — In the third trimester, we suggest induction of labor with oxytocin in standard doses, with use of cervical ripening agents when the cervix is unfavorable. We use misoprostol in usual doses for cervical ripening (eg, 25 mcg per vaginam every three to six hours) if the woman does not have a previous uterine scar. (See "Techniques for cervical ripening prior to labor induction").

Misoprostol can also be used to induce labor and will result in successful expulsion in almost all cases. The optimal dose of misoprostol in the third trimester in the setting of fetal death has not been determined. A World Health Organization expert panel suggested misoprostol 25 to 50 mcg vaginally repeated every four hours (if fewer than 2 contractions in 10 minutes) for a maximum of six doses; the second dose can be doubled if the first dose isn't effective [89] . Second trimester (18 to 28 weeks of gestation) — In the late second trimester, we use 200 to 400 mcg of misoprostol per vaginam, repeating the dose every three hours to a maximum cumulative dose of 1400 mcg. A wide variety of doses (100 to 400 mcg or more), routes of administration (oral, vaginal, sublingual), and frequencies of administration (every three to 12 hours) of misoprostol have been reported to be successful; the optimum regimen has not been established. A World Health Organization expert panel suggested misoprostol 100 mcg per vaginam repeated every six hours for a maximum of four doses; if the first dose isn't effective, the second dose can be doubled [89] .

If use of misoprostol is contraindicated, we suggest intravenous infusion of high dose oxytocin (200 units in 500 mL saline at 50 mL per hour) [90] . The mother should be observed for signs of water intoxication and maternal electrolyte concentrations should be monitored at least every 24 hours. Nausea and malaise are the earliest findings of hyponatremia, and may be seen when the plasma sodium concentration falls below 125 to 130 meq/L. This may be followed by headache, lethargy, obtundation and eventually seizures, coma and respiratory arrest.

Another option is to use PGE2 suppositories; however, the dose is reduced to 5 to 10 mg inserted vaginally every four hours until active labor ensues because uterine sensitivity and the risk of uterine rupture increase with gestational age [91] . In earlier gestations, the dose of prostaglandin E2 may need to be increased to achieve delivery. Prostaglandin E2 (PGE2) suppositories (20 mg) inserted vaginally

every four hours until active labor ensues are effective. Pretreatment with acetaminophen, compazine, and diphenoxylate is useful to minimize fever, nausea, vomiting, and diarrhea, which invariably occur. Gestations less than 18 weeks — We suggest early second trimester losses be managed as a second trimester termination of pregnancy. Maternal morbidity is similar to that observed in pregnancies without a fetal demise [92] . (See "Termination of pregnancy: Second trimester").

Options for women with a previous cesarean delivery — Women who have had a previous cesarean delivery are at higher risk of intrapartum uterine rupture than women with an unscarred uterus, and the risk is even higher if they are induced than if they enter labor spontaneously [93-95] . For this reason, prostaglandins for cervical ripening and labor induction should be used judiciously or, preferably, not at all in the setting of vaginal birth after a previous cesarean delivery. If the cervix is unfavorable, cervical ripening may be performed using mechanical means (Foley balloon or laminara). (See "Induction of labor in women with prior cesarean delivery").

We encourage women with antepartum fetal demise and previous cesarean delivery to attempt vaginal birth. However, it has been our practice to perform a repeat cesarean delivery if the patient so chooses after being counseled about the risks and benefits of both approaches. (See "Trial of labor after cesarean delivery").

Evaluation of the stillborn — One of the most important aspects of a woman's care after a stillbirth is an appropriate and comprehensive stillbirth assessment. A worksheet for both parents and providers is useful to ensure a complete investigation of the cause of death and organizing the information obtained. A sample of a placental worksheet is shown in the figure (show figure 2). (See "Evaluation of stillbirth").

Counseling — Most hospitals have instituted a program to help bereaved parents cope with their loss. These issues, as well issues related to future pregnancy, are reviewed separately. (See "Counseling parents after stillbirth").

SUMMARY AND RECOMMENDATIONS The definition of stillbirth varies around the world. In the United States, the most common gestational age threshold for distinguishing a stillbirth from a miscarriage is 20 weeks of gestation. Early stillbirths are defined as those occurring at 20 to 27 weeks of gestation, while late stillbirths occur at or after 28 weeks of gestation. (See "Definition" above). The stillbirth rate in the United States in 2003 was 6.23/1000 live births and fetal deaths. (See "Incidence and epidemiology" above). Causes of stillbirth include growth restriction, infection, placental abruption, fetal anomalies

(with and without chromosomal abnormalities), fetomaternal hemorrhage, constriction of the umbilical cord, and hydrops fetalis, but a large proportion are unexplained, especially late in gestation. Variation in the proportion of stillbirths reported as unexplained generally reflects whether the stillbirth has been fully evaluated, and if the classification system allows risk factors to be included as causes. (See "Etiology" above). Risk factors for stillbirth include black race, older maternal age, obesity, multiple gestation, concurrent medical disorders, and pregnancy complications. (See "Risk factors" above). No intervention has been proven to significantly reduce the rate of stillbirth in the general obstetrical population. Interventions such as achieving good glycemic control, induction of labor, and Doppler velocimetry are useful in selected high risk populations. (See "Prevention strategies" above). The diagnosis of fetal death must be confirmed with an ultrasound examination to document absence of fetal cardiac activity. (See "Diagnosis" above). Given the emotional burden of continuing pregnancy in which the fetus has died and the risk of coagulopathy, we suggest offering induction of labor soon after diagnosis of fetal death (Grade 2C). (See "Management" above).

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EB, MYERS, ER, HEFFNER, LJ. Should older women have antepartum testing to prevent unexplained stillbirth? Obstet Gynecol 2004; 104:56. HEFFNER, LJ, ELKIN, E, FRETTS, RC. Impact of labor induction, gestational age, and maternal age on cesarean delivery rates. Obstet Gynecol 2003; 102:287. Mangesi, L, Hofmeyr, G. Fetal movement counting for assessment of fetal wellbeing. Cochrane Database Syst Rev 2007; :CD004909. Sachs, BP. A 38-year-old woman with fetal loss and hysterectomy. JAMA 2005; 294:833. Confidential Enquiry into Maternal and Child Health. Perinatal Mortality Surveillance, 2004: England, Wales and Northern Ireland. London: CEMACH, 2006. COTZIAS, CS, PATERSON-BROWN, S, FISK, NM. Prospective risk of unexplained stillbirth in singleton pregnancies at term: population based analysis. Bmj 1999; 319:287. HILDER, L, COSTELOE, K, THILAGANATHAN, B. Prolonged pregnancy: evaluating gestation-specific risks of fetal and infant mortality. Br J Obstet Gynaecol 1998; 105:169. CAUGHEY, AB, MUSCI, TJ. Complications of term pregnancies beyond 37 weeks of gestation. Obstet Gynecol 2004; 103:57. STALLMACH, T, HEBISCH, G, MEIER, K, DUDENHAUSEN, JW, VOGEL, M. Rescue by birth: defective placental maturation and late fetal mortality. Obstet Gynecol 2001; 97:505. Divon, MY, Haglund, B, Nisell, H, et al. Fetal and neonatal mortality in the postterm pregnancy: the impact of gestational age and fetal growth restriction. Am J Obstet Gynecol 1998; 178:726. CAMPBELL, MK, OSTBYE, T, IRGENS, LM. Post-term birth: risk factors and outcomes in a 10-year cohort of Norwegian births. Obstet Gynecol 1997; 89:543. SMITH, GC, et al. Life table analysis of the risk of perinatal death at term and post-term in singleton pregnanies. AM J OBSTET GYNECOL 2001; 184:489. Sue-A-Quan, AK, Hannah, ME, Cohen, MM, et al. Effect of labour induction on rates of stillbirth and cesarean section in post-term pregnancies. CMAJ 1999; 160:1145. Pritchard, JA. Fetal death in utero. Obstet Gynecol 1959; 14:573. Maslow, AD, Breen, TW, Sarna, MC, et al. Prevalence of coagulation abnormalities associated with intrauterine fetal death. Can J Anaesth 1996; 43:1237. Lurie, S, Feinstein, M, Mamet, Y. Disseminated intravascular coagulopathy in pregnancy: thorough comprehension of etiology and management reduces obstetricians' stress. Arch Gynecol Obstet 2000; 263:126. Gomez Ponce, de Leon R, Wing, D, Fiala, C. Misoprostol for intrauterine fetal death. Int J Gynaecol Obstet 2007; 99 Suppl 2:S190. Toaff, R, Ayalon, D, Gogol, G. Clinical use of high concentration oxytocin drip. Obstet Gynecol 1971; 37:112. Kent, DR, Goldstein, AI, Linzey, EM. Safety and efficacy of vaginal prostaglandin E2 suppositories in the management of third-trimester fetal demise. J Reprod Med 1984; 29:101. Magann, EF, Chauhan, SP, Bofill, JA, et al. Maternal morbidity and mortality associated with intrauterine fetal demise: five-year experience in a tertiary referral hospital. South Med J 2001; 94:493. Lydon-Rochelle, M, Holt, VL, Easterling, TR, Martin, DP. Risk of uterine rupture during labor among women with a prior cesarean delivery. N Engl J Med 2001; 345:3. American College of Obstetricians and Gynecologists. Induction of labor with misoprostol. ACOG Committee Opinioin #228, American College of Obstetricians and Gynecologists, Washington, DC 2000. Wing, DA, Lovett, K, Paul, RH. Disruption of prior uterine incision following misoprostol for labor induction in women with previous cesarean delivery. Obstet Gynecol 1998; 91:828.

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Evaluation of stillbirth

Author

Drucilla J Roberts, MD Section Editor

Charles J Lockwood, MD Deputy Editor

Vanessa A Barss, MD

Last literature review version 16.3: September 2008 | This topic last updated: July 8, 2008 (More)

INTRODUCTION — The postmortem examination is a useful and necessary tool for helping to determine the cause of stillbirth. Despite a comprehensive examination, however, some parents will still be left without a definitive reason for their baby's demise.

Procedures for evaluation of the stillborn infant will be reviewed here. The incidence, etiology, prevention, and management of antepartum fetal death and counseling parents after stillbirth are discussed separately. (See "Etiology and management of antepartum fetal death" and see "Counseling parents after stillbirth").

MATERNAL LABORATORY EVALUATION — The optimal laboratory evaluation of women who have had a stillbirth is controversial. Many lists have been proposed, but the most cost-effective approach has not been determined [1-8] . Our approach is guided by clinical, sonographic, and histopathologic findings. We order or review recent tests results for: Fetomaternal hemorrhage (eg, Kleihauer-Betke test, flow cytometry) in all women who have an unexplained stillbirth since detection of a large fetomaternal

hemorrhage may explain the cause of an otherwise unexplained fetal demise. Urine toxicology Complete blood count to look for anemia or leukocytosis Serological testing for syphilis in women with a history of sexually transmitted infections and those who live in areas of high prevalence, or if this test has not been performed earlier in pregnancy A fasting glucose concentration or glycosylated hemoglobin level, which can be useful for excluding poor glycemic control as a cause of stillbirth in women who have not been evaluated for gestational diabetes and in those known to have diabetes mellitus Blood antibody screen to exclude red blood cell alloimmunization Thyroid function tests, lupus anticoagulant and anticardiolipin antibody titers, liver function tests, fibrinogen concentration, and thrombophilia evaluation are obtained in selected patients (those in whom there is a clinical suspicion of a specific underlying disorder) or to further evaluate unexplained stillbirths (stillborns with no gross or microscopic abnormalities).

Routine serologic testing for infection is unlikely to be useful because many women have positive serologies from prior infections, which are unrelated to the stillbirth [3] . Culture of the fetus or placenta also may be misleading because of contamination during delivery, although culture of the area between the amnion and chorion may be more reliable. Cytomegalovirus titer (IgM, acute and convalescent IgG), toxoplasmosis titer (IgM, acute and convalescent IgG), parvovirus B19 titer (IgM), and a Listeria culture are obtained if indicated by maternal clinical, prenatal sonographic, or histopathologic findings. (See "Placental infections" and see individual topic reviews on these infections).

OVERVIEW OF THE AUTOPSY AND PLACENTAL EXAMINATION

Clinical value — The cause of fetal death can often be determined through gross and histopathologic examination of the fetus and placenta [9-14] . Determining the cause of death is important because sooner or later parents will want to know "Why did this happen?" and "Will it happen again?" Answers to these questions are often impossible without information gained from pathologic examination [15-19] .

Findings at perinatal autopsy have been reported to change the clinical diagnosis of the cause of fetal death or yield additional findings in 22 to 76 percent of cases [19] . This new information often influences management of future pregnancies. As an example, a study including 1477 stillbirths reported that autopsy findings identified the cause of death in 46 percent of cases and yielded new information in 51 percent [17] . This new information changed the estimated recurrence risk in 40 percent of cases, and changed recommendations for preconceptional care in 9 percent, prenatal diagnostic procedures in 21 percent, prenatal management in 7 percent, and neonatal management in 3 percent.

Examples of histological findings of diagnostic importance are shown in the micrographs (show histology 1A-1F).

Role of the pathologist — Compassionate parental counseling is important to obtain informed consent before the pathologic examination and when communicating the findings afterwards.

Ideally, the autopsy should be performed by an experienced perinatal pathologist. If a perinatal pathologist is not available at the hospital where the stillbirth occurred, specimens may be sent for evaluation at a medical center with appropriate personnel and facilities. The fetus can be transferred to another institution intact or after evisceration. If questions persist or if the pathologist wishes, an experienced perinatal pathologist can be consulted and sent all of the slides and other materials (eg, photographs, radiographs) developed for the case.

Good documentation and careful dissection is essential. Photographs of any malformations or suspected malformations (especially if an anomaly was diagnosed by imaging and not verified at autopsy), results of laboratory and imaging studies, unusual findings, and pertinent negative findings are extremely important.

Completion of the autopsy needs to be timely, as the family and clinician's concerns and grieving period grow with delays. Autopsy reports should be completed promptly so that a family meeting with the clinicians can be timely. We believe that including the pathologist in these meetings is very helpful for explaining the autopsy report and answering questions (see "Autopsy report" below). The pathologist is often thought of as an impartial specialist since she was not involved in the patient's antepartum or intrapartum management.

Components of the perinatal autopsy — The Autopsy Committee of the College of American Pathologists, with representatives of other interested organizations, prepared a guideline to assist pathologists in reporting perinatal autopsies [1] . The judgment of the pathologist performing a specific case should guide the evaluation since there is no high quality evidence establishing the optimum combination of tests that should be performed routinely on all stillbirths. The following examinations are commonly performed: Review of the complete medical record to obtain the clinical history, with attention to medical, obstetrical (past and present), and genetic conditions potentially associated with stillbirth (show table 1A-1C). Informational gaps may be provided by the patient or her clinician. (See "Etiology and management of antepartum fetal death", sections on Etiology and risk factors). Birth weight and external measurements (eg, foot length, head and chest circumference, crown-to-foot length). Gross external examination of the stillborn, with detailed description and photographs of abnormalities, dysmorphic features, and pertinent negative findings. Detailed photographs of the entire

fetus from several views (anterior, posterior and lateral) and a facial photograph provide good documentation for future reference. Photographs of normal findings and pertinent negative findings can also be useful (as an example, a directed photograph of the fingers with nails can exclude many syndromes if the nail formation is normal). The facial photograph may be given to the parents, if requested. Gross and microscopic examination of the placenta and cord. Obtaining the placenta is critical, as often the placental findings are the most informative in determining the etiology of the stillbirth. The placenta is the best tissue for obtaining special studies (eg, karyotype) when autolysis is present. Umibilical cord or chorionic plate is the best tissue to send for karyotype as maternal contamination is avoided. (See "Gross examination of the placenta").

Evaluation of the true complete cord length and number of vessels is essential. A short cord can be a sign of neuromuscular compromise, a long cord can be a sign of heart failure or that a cord accident may have played a pivotal role in the demise, while a single umbilical artery can be associated with genitourinary anomalies (eg, renal agenesis, horseshoe kidney). (See "Histopathology of placental disorders"). Bacterial cultures perfomed on the placenta are an especially useful tool if autopsy permission is declined. The placenta, although contaminated by the birthing procedures and handling after delivery, can be cultured by peeling off the amnion from the chorion and swabbing this newly exposed chorionic surface. We have often found pathogens responsible for the fetal death (eg, Group B Streptococcus) using these techniques and have not had any contamination. Cultures of the placenta are sent for aerobic and anaerobic microbiologic studies. We do not feel viral or mycoplasma/ureoplasma specialized cultures of the placenta are necessary or cost effective. Gross and microscopic examination of major organs, including the weight of each organ. We typically open the thorax and then take a small portion of fetal lung using sterile utensils (a suture removal kit works well) and place it in a sterile container for further testing, if indicated, based on the clinical information and the autopsy findings (as an example, hydrops fetalis increases suspicion for a viral infection, preterm rupture of membranes increases suspicion for a bacterial infection). There is no consensus as to when cytogenetic, biochemical, and molecular genetic studies and viral cultures of the fetus are indicated [2] . One study evaluating a protocol for postmortem examination of stillbirths concluded that gross examination, photography, radiography, and bacterial cultures should be performed in all cases, while karyotyping and microscopy could be reserved for stillborns that are abnormal on gross examination [20] . This approach was less costly than performing these studies routinely, but still provided adequate information for genetic counseling since the prevalence of karyotype abnormalities is low (<2 percent) in the absence of dysmorphic features, growth abnormalities, structural anomalies, or hydrops. However, this protocol might fail to detect some chromosomal abnormalities and some nongenetic disorders, such as viral infection [21] . (See "Histopathology of placental disorders" and see "Placental infections" and see "Cytogenetic abnormalities in the embryo; fetus; and infant").

We follow a decision tree to decide if we will obtain tissue for karyotype or tissues for other special studies (show table 3A-3B). In our opinion, fetal lung tissue should be taken, using sterile techniques, for

microbiologic studies in all cases and for virology if indicated or requested. In general, anaerobic and aerobic studies are necessary if a bacterial process is suspected. Viral cultures are rarely indicated, as the histopathology of the placental and fetal organs is diagnostic in most cases (eg, CMV, parvovirus, herpes simplex virus). Coxsackie virus can be passed across the placenta and should be suspected if myocarditis is found on histopathology; molecular studies can confirm this infection. X-rays may reveal unrecognized skeletal malformations, or can be obtained to further evaluate suspected skeletal abnormalities. Plain whole body anteroposterior and lateral radiographs are taken with the infant's head "straight" (use cellophane tape to hold the head straight, nose in line with umbilicus, arms and legs in anatomic position) and the extremities extended (the legs are placed as if jogging, with one leg flexed above the other and with extended arms slightly separated). Magnetic resonance imaging may be useful and acceptable to parents who refuse autopsy [22] . Fetal radiographs should be examined carefully by the autopsy pathologist for specific findings:

- Appropriate ossification of bones for gestational age

- Documentation and timing of fractures (which should be sampled histologically)

- Presence of ectopic mineralization/ossification of nonboney tissues (eg, heart, arteries, bowel lumen), which can be associated with a variety of in-utero disorders (eg, TORCH infections, bowel abnormalities, hypoxic-ischemic encephalopathy, metabolic diseases). Tissue may be frozen (at 4º Celsius) for future examination and laboratory studies (show table 2).

Specimen collection and processing — Amniocentesis or chorionic villus sampling performed upon diagnosis of fetal demise appears to yield a higher rate of viable cells for successful culture and karyotyping than studies performed on the stillborn after delivery [23,24] . In one study, successful karyotyping was possible in 90 percent of cases in which amniocentesis was performed, 100 percent of those who had chorionic villus sampling, but only 13.5 percent of those who had skin biopsies of the stillborn [23] . One-half of the skin biopsies were unsuitable for analysis, while all of the CVS and amniocentesis could be utilized. In another study including 750 intrauterine fetal deaths, successful cytogenetic analysis was possible in 84 percent of fetuses evaluated antepartum, but only 20 to 30 percent of those evaluated after birth [24] .

Cytogenetic studies may be performed on the stillborn's blood, tissue, or body fluids (eg, bile, urine, vitreous humor), as long as the cells are viable. Blood can be collected from the umbilical cord; at least 3 mL should be placed in a heparinized tube. Skin samples are obtained by washing the skin with alcohol or sterile saline, drying the area with sterile gauze, and removing one square centimeter of tissue with underlying dermis. A specimen of adequate size and depth is important for successful culture. Fascia samples are usually taken from the Achilles tendon or thigh, using sterile technique. Fresh tissue samples should be placed in sterile medium (eg, Hanks balanced salt solution) from the cytogenetics laboratory, or sterile saline solution, and kept at room temperature (do not use fixatives such as formaldehyde).

In cases of moderate or marked autolysis (retention of a stillbirth), the umbilical cord or chorionic plate vessel can be sampled for karyotype analysis. We suggest that in these cases, two separate samples be obtained and sent for cytogenetics: one from fetal skin and the other from umbilical cord. If culture fails and, therefore, karyotype analysis cannot be performed, directed FISH studies (eg, for Trisomy 13, 18, or 21) can be done on the paraffin embedded blocks of fetal or placental tissues [25] .

Microbiologic studies can be performed on fetal blood taken from the heart or umbilical cord; however, fetal blood is more easily obtained from the fetal lung at autopsy. After the chest wall is opened and before any evaluation of the contents is performed or organs handled, using a sterile suture removal kit, lift up the right lower lobe of the lung and snip off a small portion (5 mm3 is sufficient) and place it in a sterile jar or in sterile medium for transport to the microbiology lab.

Sections from the fetal and placental tissues should be processed for histological examination in all cases, even when severely autolyzed or structurally normal. Important pathologic findings that have clinical relevance beyond that of identifying a cause of death can still be diagnosed in severely autolyzed tissues.

Other special studies may be indicated and can be performed at evisceration.

AUTOPSY PROTOCOL — Fetal autopsies should be performed with the care and respect that all autopsies are given. Also, it is not uncommon for a family to decide to view the body after the postmortem examination has been done; therefore; careful dissection to avoid any disfigurement is important. In our experience, even the smallest, youngest (in gestational age), and most autolyzed cases can receive a thorough post-mortem examination and be returned in a condition suitable for viewing.

Performance of the fetal autopsy is nearly identical to that of the adult or pediatric autopsy, but the focus on the dissection is modified. Since one major goal is to detect and/or verify congenital malformations, it is important that the dissection be careful with attention to detail, despite the fetus' size and level of autolysis (show table 4).

We obtain the following measurements: Body weight Crown-to-rump length (crown to ischial tuberosities, "sitting height") Crown-to-heel length (crown to heel of extended leg) Foot length Hand length Head circumference (ie, occipitofrontal circumference - above ears, as if wearing glasses) Chest circumference (around nipples) Abdominal circumference (at umbilical insertion) Inner canthal distance Outer canthal distance Any other potentially anomalous measurement (eg, finger, lip, ear)

Body weight, placental weight (trimmed of cord and membranes), and organ weights are very important, as are the body measurements as outlined in the protocol. A good 0 to 500 g (in at least 1 gram increments) table top scale, and hanging 100 to 5000 g scale (in 10 gram increments), is essential. Paired organs are weighed together. Many good standards for weights and measurements are available [26-30] and should be posted at the bench where the autopsy is performed for quick consultation. If a weight significantly deviates from the norm, additional tests or sampling may be indicated. Brain weight is often facilitated by weighing a vessel of fixative, then allowing the brain to "slip" into the fixative while dissecting, then reweighing the vessel (with brain and fixative) and subtracting out the first weight. We do not open the GI tract (you need to preserve the contents), nor do we inflate the lungs (retain the in utero lung contents).

Dissection of the fetal heart can be difficult, especially in autolyzed cases. Fixing the heart-lung block can be very helpful. The dissection of the fetal heart starts with a good in situ examination looking at situs, pulmonary venous return, persistence of the left superior vena cava, and caliber of the aortic arch and the brachiocephalic vein. Any anomalies in these structures should warrant careful dissection, and consideration of consultation with a cardiac surgeon or a pathologist with expertise; such consultation should be performed before continuing the dissection. Removing the heart and great vessels from the lungs and dissection along lines of flow (being careful to cut away from the septa, see below), observation of normal fetal structures (patent and competent foramen ovale, patent ductus arteriosis), and documentation of all valves should be completed before the great vessels are removed and the heart weighed. If possible, photographic documentation of findings and pertinent negatives should always be performed.

We always obtain tissue for microscopy and sample all tissues; many samples can often be placed in a single cassette.

The entire autopsy generally takes about 10 to 20 cassettes, including the placenta. A detailed procedure is provided in the table (show table 4).

AUTOPSY REPORT — The following template for autopsy reports is simple and provides the key information for the clinician and family:

(Male/Female) fetus of estimated gestational age ____ weeks based on autopsy measurements of _____grams, _____cm crown-to-rump length, _____ cm foot length. The fetus is appropriate/small/large for clinical estimation of gestational age of ____ weeks based on (1st trimester sonogram, LMP, other).

Pertinent maternal data:

Cause of death:

Congenital anomalies: no or yes (list)

Other pertinent fetal findings:

Placenta: full surgical pathology report

Microbiology results:

Radiographic findings:

Pertinent negative findings:

We follow this information with a comment stating whether or not an anatomic cause of death was determined by the autopsy. If no anatomic cause of death was identified, we state this and then provide a description and interpretation of all findings.

Families usually read these reports; therefore, they should be carefully worded.

SUMMARY AND RECOMMENDATIONS Perinatal autopsy may provide information about the cause of fetal death that is different from that derived from other clinical examinations. This information often changes the estimated risk of stillbirth recurrence and frequently influences recommendations for management of future pregnancies. For these reasons, we suggest perinatal autopsy of stillborn infants (Grade 2C). (See "Clinical value" above). Perinatal autopsy can include review of clinical records and patient interview, gross and microscopic examination of the infant and placenta, photographs and x-rays, bacterial and viral cultures, and chromosome analysis. (See "Components of the perinatal autopsy" above). Amniocentesis or chorionic villus sampling performed upon diagnosis of fetal demise may yield a higher rate of viable cells for successful culture and karyotyping than studies on the stillborn's blood, tissue, or body fluids performed after delivery. (See "Specimen collection and processing" above). The optimal laboratory evaluation of women who have had a stillbirth is controversial. We suggest that the evaluation be guided by clinical, sonographic, and histopathologic findings. (See "Maternal laboratory evaluation" above).

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES

Bove, KE. Practice guidelines for autopsy pathology: the perinatal and pediatric autopsy. Autopsy Committee of the College of American Pathologists. Arch Pathol Lab Med 1997; 121:368. American College of Obstetricians and Gynecologists. Genetic evaluation of stillbirths and neonatal deaths. ACOG Committee Opinion No 257. American College of Obstetricians and Gynecologists, Washington, DC 2001. Incerpi, MH, Miller, DA, Samadi, R, et al. Stillbirth evaluation: what tests are needed?. Am J Obstet Gynecol 1998; 178:1121. Froen, JF, Vege, A, Ormerod, E, Stray-Pedersen, B. [Finding the cause of death in intrauterine death--which examination should be done?]. Tidsskr Nor Laegeforen 2001; 121:326. Martinek, IE, Vial, Y, Hohlfeld, P. [Management of in utero foetal death: Which assessment to undertake?]. J Gynecol Obstet Biol Reprod (Paris) 2006; 35:594. Eller, AG, Branch, DW, Byrne, JL. Stillbirth at term. Obstet Gynecol 2006; 108:442. Silver, RM, Varner, MW, Reddy, U, et al. Work-up of stillbirth: a review of the evidence. Am J Obstet Gynecol 2007; 196:433. ACOG Committee Opinion No. 383: Evaluation of stillbirths and neonatal deaths. Obstet Gynecol 2007; 110:963. Kliman, HJ. The placenta revealed [comment]. Am J Pathol 1993; 143:332. Redline, RW. Placental pathology: a neglected link between basic disease mechanisms and untoward pregnancy outcome. Curr Opin Obstet Gynecol 1995; 7:10. Redline, RW, Patterson, P. Villitis of unknown etiology is associated with major infiltration of fetal tissue by maternal inflammatory cells. Am J Pathol 1993; 143:473. Kovalovszki, L, Villanyi, E, Benko, G. Placental villous edema: a possible cause of antenatal hypoxia. Acta Paediatr Hung 1990; 30:209. Redline, RW, Wilson-Costello, D, Borawski, E, et al. The relationship between placental and other perinatal risk factors for neurologic impairment in very low birth weight children. Pediatr Res 2000; 47:721. Redline, RW, Wilson-Costello, D, Borawski, E, et al. Placental lesions associated with neurologic impairment and cerebral palsy in very low-birth-weight infants. Arch Pathol Lab Med 1998; 122:1091.

Saller, DN Jr, Lesser, KB, Harrel, U, et al. The clinical utility of the perinatal autopsy. JAMA 1995; 273:663. Faye-Petersen, OM, Guinn, DA, Wenstrom, KD. Value of perinatal autopsy. Obstet Gynecol 1999; 94:915. Michalski, ST, Porter, J, Pauli, RM. Costs and consequences of comprehensive stillbirth assessment. Am J Obstet Gynecol 2002; 186:1027. Sankar, VH, Phadke, SR. Clinical utility of fetal autopsy and comparison with prenatal ultrasound findings. J Perinatol 2006; 26:224. Gordijn, SJ, Erwich, JJ, Khong, TY. Value of the perinatal autopsy: critique. Pediatr Dev Pathol 2002; 5:480. Mueller, RF, Sybert, VP, Johnson, J, et al. Evaluation of a protocol for post-mortem examination of stillbirths. N Engl J Med 1983; 309:586. Naeye, RL. The investigation of perinatal deaths [editorial]. N Engl J Med 1983; 309:611. Woodward, PJ, Sohaey, R, Harris, DP, et al. Postmortem fetal MR imaging: comparison with findings at autopsy. AJR Am J Roentgenol 1997; 168:41. Khare, M, Howarth, E, Sadler, J, et al. A comparison of prenatal versus postnatal karyotyping for the investigation of intrauterine fetal death after the first trimester of pregnancy. Prenat Diagn 2005; 25:1192. Korteweg, FJ, Bouman, K, Erwich, JJ, et al. Cytogenetic analysis after evaluation of 750 fetal deaths: proposal for diagnostic workup. Obstet Gynecol 2008; 111:865. Wolfe, KQ, Herrington, CS. Interphase cytogenetics and pathology: a tool for diagnosis and research. J Pathol 1997; 181:359. De Paepe, ME, Friedman, RM, Gundogan, F, Pinar, H. Postmortem lung weight/body weight standards for term and preterm infants. Pediatr Pulmonol 2005; 40:445. Guihard-Costa, AM, Menez, F, Delezoide, AL. Organ weights in human fetuses after formalin fixation: standards by gestational age and body weight. Pediatr Dev Pathol 2002; 5:559. Maroun, LL, Graem, N. Autopsy standards of body parameters and fresh organ weights in nonmacerated and macerated human fetuses. Pediatr Dev Pathol 2005; 8:204. Shepard, TH, Shi, M, Fellingham, GW, et al. Organ weight standards for human fetuses. Pediatr Pathol 1988; 8:513. Wigglesworth, JS, Singer, DB. Textbook of fetal and perinatal pathology: Blackwell Science, 2nd ed, Wigglesworth, JS, Singer, DB (Eds), Backwell Publishers 1998.

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Sudden infant death syndrome

Author

Michael J Corwin, MD Section Editors

George B Mallory, MD

Teresa K Duryea, MD Deputy Editor

Alison G Hoppin, MD

Last literature review version 16.3: September 2008 | This topic last updated: October 8, 2008 (More)

DEFINITION — Sudden infant death syndrome (SIDS), also called crib or cot death, is the leading cause of infant mortality between 1 month and 1 year of age in the United States. It is defined as the sudden death of an infant younger than 1 year of age, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history [1] . The cause of SIDS cannot be identified in most cases. Since the 1990s, however, new studies in pathology and epidemiology have provided the basis for an important evolution in the understanding of SIDS.

In 1991, the definition of SIDS was revised by an expert panel convened by the National Institute of Child Health and Human Development. The new definition differs from the previous description (from 1969) in several important ways: It omits the phrase that the death was "unexpected by history." This change reflects one of the most significant lessons of SIDS research in the 1990s: SIDS victims were not entirely normal before death. The new definition emphasizes the necessity of autopsy, death scene investigation, and review of the clinical history to provide accurate counseling to parents.

Development and implementation of death scene [2] and autopsy [3] protocols have led to standardized approaches to unexpected infant deaths with increasing diagnoses of accidental asphyxia. Specific steps (external examination, radiology, internal examination, histology, microbiology, toxicology, electric, metabolic, and genetic studies) in the evaluation of unexpected infant deaths have contributed to increased accuracy in the diagnosis of SIDS, a diagnosis of exclusion [4] . A known cause of death is identified by the postmortem examination in approximately 15 percent of suspected SIDS cases, even when the clinical history and circumstances of death are consistent with SIDS (show table 1) [5] . It is impossible, for example, to detect some congenital abnormalities, injuries, infections, or metabolic defects without an autopsy. Similarly, the death scene investigation is essential to exclude accidental, environmental, and unnatural mechanisms of death [6-9] .

The diagnosis of SIDS must be consistent with the child's medical and family history: A family history of a previous SIDS death, the presence of undiagnosed neurologic problems, or a past history of failure to thrive or hypotonia warrants further investigation to exclude inherited metabolic diseases. A prior history of multiple dramatic episodes of unexplained apnea, cyanosis, or seizure may suggest deliberate asphyxiation, so-called Munchausen syndrome by proxy, an insidious form of child abuse [10] . (See "Munchausen syndrome by proxy").

Due in part to potential inconsistencies in the diagnosis of SIDS, the term "sudden unexpected death in infancy" (SUDI) is often used to describe all unexpected infant deaths. The SUDI designation can then be sub-divided into explained SUDI and unexplained SUDI. Unexplained SUDI generally includes those cases considered SIDS by the medical examiner, as well as some cases that are not considered SIDS, but lack a clear explanation due to uncertain circumstances. Reports in the literature increasingly use the term "unexplained SUDI" instead of "SIDS" to avoid inconsistencies between medical examiners in reporting SIDS as a cause of death.

EPIDEMIOLOGY — SIDS is the leading cause of infant mortality between 1 month and 1 year of age in the United States. The risk of SIDS in the United States is <1 per 1000 live births [11-13] . Higher rates (two to three times the national average) are found in black and American Indian/Alaskan native children [14,15] . A disproportionately high rate (15 to 20 percent) of SIDS cases occur in child care settings [15-17] . The risk of SIDS is slightly increased in boys (multivariate OR 1.49 (95%CI 1.14-1.83) in one large European case-control study) [18] .

The incidence of SIDS in the United States has declined by more than 50 percent since the mid-1980s. The greatest reduction has occurred since 1992, when the American Academy of Pediatrics (AAP) issued a recommendation to reduce the risk of SIDS by placing infants in a supine position for sleep [19-23] . Between 1992 and 2001, the SIDS rate in the United States fell from 1.2 to 0.56 per 1000 live births [24,25] . Similar declines have occurred in other countries following Back to Sleep campaigns [26,27] .

Data from the National Institute of Child Health and Human Development (NICHD) Collaborative SIDS Study have helped to define the epidemiologic features of SIDS (show table 2) [28] . This landmark study was a multicenter, population-based, case-controlled project that included 10 percent of the live births in the United States. The pathologic diagnoses were confirmed by an independent panel of forensic pathologists.

The median age for SIDS deaths was 11 weeks, the peak incidence was between 2 and 4 months, and 90 percent occurred before 6 months of age [28] . This unique distribution strongly suggests that critical stages of development or maturation affect the risk of SIDS. The most important conclusion from the NICHD study was that no strong predictive and/or diagnostic characteristics of mothers or infants can be identified in most SIDS victims that would permit clinically useful screening for high-risk infants.

RISK FACTORS — Numerous risk factors for SIDS have been identified in observational and case control studies. Those that are consistently identified as independent risk factors include [15] : Young maternal age Maternal smoking during pregnancy Late or no prenatal care Preterm birth and/or low birth weight Prone sleeping position Sleeping on a soft surface Overheating

Risk factors for SIDS are discussed below. Those that can be modified to decrease the risk of SIDS are also discussed in the section on Prevention. (See "Prevention" below).

Maternal risk factors — There are two major maternal risk factors for SIDS that are independent of birth weight [18,28] Maternal smoking Age of the mother under 20 years

These factors increased the risk of SIDS two to four-fold in the NICHD Collaborative SIDS Study [28] . Maternal smoking usually occurs both prenatally and postnatally, and it is unclear whether smoking during a specific developmental period is particularly harmful [29] . SIDS rates increase with the amount smoked [30,31] . Smoking is one of the most important preventable risk factors for SIDS, and smoking prevention/intervention programs have the potential to substantially lower SIDS rates [30,32] .

Drug abuse and all its associated phenomena are also associated with an excessive number of SIDS deaths. In one report, a five-fold increase in SIDS risk was reported for infants of substance-abusing mothers in the Los Angeles area [33] . It is not known if this association is related primarily to the biologic effect of drugs in utero, an increased risk of prematurity and low birth weight, and/or other postnatal conditions (socioeconomic, environmental, or parenting behavior).

In some populations, maternal alcohol use is an important risk factor. In a population-based case-control study among Northern Plains American Indians, SIDS was significantly associated with periconceptional maternal alcohol use (adjusted odds ratio 6.2, 95% CI 1.6-23.3) and first trimester binge drinking (adjusted OR 8.2, 95% CI 1.9-35.3) [34] .

Pregnancy complications associated with an increased risk of SIDS include placenta previa, abruptio placenta, premature rupture of membranes, and elevated maternal alpha-fetoprotein [13,35-37] . The increased risk associated with these complications appears to be independent of their relationship with preterm birth.

Prematurity — Preterm infants are at a higher risk for SIDS than term infants [38-41] . Among low and very low birth weight infants, the SIDS rate has consistently been three- to fourfold higher than in term infants [41] . The postmenstrual age of peak vulnerability for SIDS appears to occur four to six weeks earlier among preterm than term infants [38] .

It is unclear whether the population of low birth weight infants is experiencing a decline in the rate of SIDS similar to that in the general population. A similar decline was noted in New Zealand [40] , but not in Sweden [42] . Preterm infants are subject to the same risk factors for SIDS as term infants, as discussed in greater detail below [40,43,44] .

Supine positioning for sleep substantially reduces the risk for SIDS among premature infants. Although there are some concerns that supine positioning may reduce oxygenation in premature infants, a small study suggested that this was not the case in infants older than 32 weeks postmenstrual age who are not oxygen dependent [45] . The importance of supine sleep position for premature infants was demonstrated in a population based case-control study in England, in which the parents of 325 SIDS cases and 1300 age-matched control infants were interviewed [43] . In multivariate analysis, infants who were small at birth (<37 weeks and/or <2500 g) were five times more likely to die of SIDS than infants who were born at term or >2500 g. However, when infants who were small at birth were placed to sleep on their side or prone, they were 15 and 24 times more likely, respectively, to die of SIDS than infants who were not small at birth who were placed on their backs to sleep.

Apnea — Apnea is a marker of prematurity, but is not specifically increased in SIDS victims [28] . There is no prior history of apnea in the great majority of SIDS victims. In the NICHD Collaborative SIDS Study, approximately 5 percent of mothers of SIDS victims recalled a previous cyanotic episode in their child before death, compared to three percent of mothers of control infants. A large series of infants with and without SIDS risk factors provides further evidence that apneas are not causally associated with SIDS risk [46] . Neither "conventional" (apnea 20 to 30 seconds) nor "extreme" events (apnea >30 seconds) correlate with the primary epidemiologic risk factors for SIDS, including time of night of the apnea and the infant's age. (See "Clinical features and management of apnea of prematurity").

Low birthweight — Infants born small for gestational age (SGA) have an increased risk for SIDS [13,43,47] . Low birthweight has a weak but significant association with SIDS risk even after adjustment for gestational age and several other factors known to be associated with low birthweight, including maternal tobacco use and hypertension.

Sleep position — The prone sleeping position has been found to be associated with an increased risk of SIDS in a number of observational and case-control studies [18,48-53] . Additional support for this association comes from the decreased rate of SIDS in various countries following recommendations to place infants on their back or side to sleep [20,24,25,54-56] . Increasing evidence also suggests that avoidance of side positioning is important, perhaps because the probability of rolling from the side to the prone position is greater than that of rolling from the supine to the prone position [57-59] . (See "Epidemiology" above).

As the proportion of infants placed to sleep in the prone position has decreased, the relative contribution of side-sleeping to SIDS risk has increased [43,57,60-63] , as suggested by the following studies: In a population-based case-control study, the risk of SIDS was increased for infants placed on the side and found in the prone position (adjusted odds ratio 8.7) [61] . In the same study, the risk of SIDS was also increased among infants who were usually placed supine but were placed on their sides or prone for the last sleep (OR 6.9 and 8.2, respectively) [61] . Other case-control studies have demonstrated an increased risk of SIDS when infants unaccustomed to the prone position are placed in the prone position [64,65] . A population-based study noted decreases in SIDS mortality associated with non-prone sleep positioning, and documented further decreases associated with specifically supine positioning of infants for sleep [66] .

The increased risk among infants unaccustomed to the side or prone position highlights the importance of supine positioning for every sleep [15] .

Sleep environment — Various aspects of the sleep environment, including the sleep surface, sleepwear, bedding, room temperature, and whether or not the bed or room are shared with parents also appear to affect the risk of SIDS, as illustrated below. In a case-control study, soft cot mattresses were associated with a twofold increased risk of SIDS that was independent of the prone position [67] . Other forms of soft bedding (eg, polystyrene beads, natural fiber mattresses) also have been associated with an increased risk of SIDS [68,69] . Sheepskin bedding has been associated with an increased risk for SIDS when infants are placed in the prone position [70] . The risk sheepskin bedding presents to infants sleeping in the supine or lateral positions is less clear. There are reports of deaths by "suffocation"

attributed to crib bumper pads [71] , prompting the Canadian Pediatric Society to caution against their use [72] . In a population-based case-control study performed in California, fan use was associated with a 72 percent reduction in SIDS risk (adjusted odds ratio 0.28, 95% CI 0.10 - 0.77) [73] . The effect was greater for infants with other environmental SIDS risk factors, including prone or side sleeping, bed sharing, and warmer room temperature. The study was limited by low participation rates and recall bias, and needs confirmation by prospective studies. In a population-based case-control study among Northern Plains American Indians, SIDS was significantly associated with two or more layers of clothing on the infant (adjusted OR 6.2, 95% CI 1.4-26.5) [34] . Another study noted an increased risk with swaddling or in heated rooms [69] . A reported association between SIDS risk and infants sharing a bed with their parents has proven controversial [23,74-76] . However, there does appear to be an association at least for younger infants (eg, younger than 4 months of age) [18,77-81] , or if the mother smokes [15,18,57,79] . There is a consistent association between increased risk of SIDS and sharing a couch or sofa with parents [15,26,77,78,82,83] . Based on these findings, the AAP suggests that bed-sharing be avoided, although room-sharing is encouraged [15] . Room sharing, without bedsharing, between parents and infants appears to reduce the risk of SIDS [18,77,78,82,83] . In addition, the risk associated with sleeping in the prone position appears to be mitigated if the child is sharing a room with an adult. In a case-control study from New Zealand in which 393 infants who died from SIDS were compared to 1592 controls, the relative risk associated with sleeping in the prone position was reduced by approximately 80 percent if the infant slept in the same room as an adult [84] . A similar reduction in the risk of SIDS was not seen if the infant shared a room with another child.

Pacifier use — A meta-analysis of seven studies of the effects of pacifier (dummy, soother) use on the risk of SIDS found a protective effect (multivariate summary odds ratio 0.71 [95% CI 0.59-0.85] and 0.39 [95% CI 0.31-0.50] for usual pacifier use and pacifier use during last sleep, respectively) [85] . The mechanism for this association is unclear; it may be related to the lowered arousal threshold during pacifier use [86,87] . (See "Pathology and pathogenesis" below). Because of this apparent reduction in risk, the AAP suggests offering a pacifier during sleep, provided that it does not interfere with establishment of breast feeding [15] .

Breastfeeding — The association between breastfeeding and risk of SIDS is inconsistent [62,82,88-92] and is complicated by confounding factors (eg, maternal age, smoking) [93-97] .

Immunizations — SIDS is not associated with diphtheria-tetanus-pertussis (DTP) vaccine or other vaccines [98-100] . In fact, immunization may lower the risk of SIDS [101-103] .

Sibling of SIDS victim — Siblings of SIDS victims have a five- to six-fold increase in risk for SIDS [104-107] . However, assuming a SIDS rate of 0.56 per 1000 live births (0.06 percent) [24,25] , the risk in subsequent siblings for most families remains less than 1 percent.

The small, but increased risk of SIDS in siblings of SIDS victims is probably due to a combination of biologic and/or epidemiologic factors.

However, it has not been possible to identify the relative importance of these factors because many of the risk factors for SIDS are the same as those for other causes of infant mortality [104] . In some cases, for example, deaths from inborn errors of metabolism may have been mistaken for SIDS. In other cases, the deaths may have resulted from child abuse or were in some way related to severe deprivation and poverty [108] . (See "Differential diagnosis" below).

Twins — In cohort studies, linking data from birth and death records, the crude risk of SIDS among twins is approximately twice that of singletons [11,12,109] . The increased risk is in part attributable to the higher proportion of twins that are preterm and/or of low birth weight [11,12] . However, in subset analyses of some studies, the risk of SIDS among twins born at ≥ 37 weeks gestation [109] or with birth weight ≥ 3000 gm [12] , remained increased compared to singletons as described below: 37 to 38 weeks: Relative risk (RR) 1.31 39 to 40 weeks: RR 1.47 ≥ 41 weeks: RR 2.09 Birthweight ≥ 3000 g: RR 2.98

PATHOLOGY AND PATHOGENESIS — SIDS is characterized by several gross and microscopic autopsy features, even though none of these abnormalities is sufficiently grave to explain the infant's death (show table 3) [4] . External findings include a well-developed, well-nourished child with frothy, blood-tinged fluid at the nares. Internal findings include intrathoracic petechiae, pulmonary congestion and edema, upper respiratory tract inflammation, and hepatic hematopoiesis.

A triple-risk model has been proposed, suggesting that SIDS occurs in infants with underlying vulnerability (eg, genetic pattern, brainstem abnormality) who experience a trigger event (eg, maternal smoking, infection), at a vulnerable developmental stage of the central nervous or immune system [110-112] .

Underlying vulnerability

Brain abnormalities — Emerging evidence suggests that underlying abnormalities in serotonin (5HT) signaling in the brain play a role in the pathogenesis of SIDS. These abnormalities could be either genetic in origin, or acquired from exposures in utero.

Several studies have shown subtle alterations or "delayed maturation" in the arcuate nucleus and other regions of the brain that participate in ventilatory and blood pressure responses to hypoxia and hypercarbia [113-116] . More recently, specific abnormalities of serotonin signaling have been shown, including decreased 5-HT(1A) receptor binding in the medullary areas of infants who succumbed to SIDS [117] . In addition, male infants had particularly low binding, consistent with the clinical observation of a male predominance in SIDS cases. Because serotonin is known to influence a broad range of autonomic processes, these findings are consistent with the hypothesis that SIDS is related to serotonin-mediated dysregulation of the autonomic nervous system.

All of the studies relying on brain tissue from autopsies are limited by small sample size and underrepresentation of some racial or ethnic groups in the sample. Similar studies in other populations will be necessary to confirm these findings and to determine if similar abnormalities are found in other populations with high risks for SIDS, such as African American infants.

Several other brain abnormalities have been reported in some SIDS victims. These include delayed maturation of the central nervous system, periventricular and subcortical leukomalacia, brain stem gliosis, increased brain weight, and alteration in the density of dendritic spines [118] . In autopsy studies, the density of kainate and muscarinic receptors in the arcuate nucleus (which mediate ventilatory responses in animal models) were decreased in more than one-half of SIDS victims studied versus controls [113,119] .

Together, these findings support the concept that a brainstem abnormality or maturational delay related to neuroregulation or cardiorespiratory control is a critical contributor to the pathogenesis of SIDS. This hypothesis is supported by two additional findings: Maternal and antenatal risk factors indicating a less than optimal intrauterine environment have been described for infants who later died of SIDS [28,120,121] . These observations suggest that the presumed brain disorder may originate before birth (See "Maternal risk factors" above). Subtle abnormalities in the regulation of cardiac, respiratory, and sleep arousal patterns have been observed in infants who subsequently succumbed to SIDS [122,123] .

Genetic factors — The role that genetic factors play in susceptibility to SIDS is not clear. On the one hand, the overall low rate of SIDS in siblings, the lack of concordance in twins, and the finding that like-sex twins are at no greater risk than unlike-sex twins [11,12] suggest that SIDS is not a genetic disorder. On the other hand, the identification of gene polymorphisms in SIDS victims suggests that specific genetic polymorphisms may interact with specific environmental risk factors to increase the susceptibility to SIDS in critical situations [124,125] . Specific genetic polymorphisms in the following genes have been proposed to play a role in SIDS [124,125] : Genes encoding cardiac ion channels [126-128] Partial deletions of complement component C4 [129] Interleuken-10 promoter gene [130,131] Serotonin transporter gene [132-135] Testis-specific Y like gene [136] , which is expressed in the fetal brain [137] Genes encoding heat shock proteins [134] Genes involved in the development of the autonomic nervous system [138]

Environmental triggers — Little is known about the mechanism of death in SIDS. One report described heart rate and respiratory effort wave form data recorded by memory monitors in three children who died while being monitored and whose autopsies reported SIDS as the cause of death [139] . Bradycardia, not apnea, was the predominant feature in these infants' deaths. One major caveat to interpreting this report is that the home monitors could not have detected obstructive apnea and did not record oxyhemoglobin saturation data.

Prone position — The mechanism for the apparent increase in risk with the prone position is not known. Some studies have suggested a role for suffocation associated with several factors, such as decreased arousal [140,141] , hyperthermia, and the type of bedding [57,67-69,142,143] . In one study of Belgian infants, prone sleep position was associated with longer duration of sleep, longer obstructive events, decreased behavioral arousal, longer interval between obstruction and arousal, and overall decreased reaction (arousal or sigh) to obstructive events [140] . In another study, arousal thresholds during both active and quiet sleep, were higher in infants younger than 5 to 6 months of age [141] . In another study of 25 infant deaths that occurred during sleep in the prone position on cushions filled with polystyrene beads, accidental suffocation by rebreathing was found to be the most likely cause of death in most of the infants [68] . The cushion was thought to allow limited movement of the infant's head to obtain fresh air, and the estimated amount of subsequent rebreathing was lethal in a rabbit model. In a study of 393 cases of SIDS in New Zealand, infants who were found in the prone position with their face down were more likely to be younger, have a low birthweight, and to have used sheepskin bedding or pillows as compared to infants found other positions (prone with face to side, supine, or side) [144] . This finding suggests that infants dying of SIDS in the face down prone position represent a distinct subgroup, and that the mechanism of SIDS may differ depending on specific circumstances related to the infant's sleeping position.

Cardiac dysfunction — Some studies have suggested the control of cardiac function may be abnormal in infants at risk for SIDS, but results have been inconsistent. One large, prospective study found mildly increased heart rates in infants who subsequently died of SIDS [145] . Others have described prolonged QT intervals on electrocardiographic analysis [146] or sodium channel mutations associated with long QT syndrome in post-mortem tissues [147,148] . However, given the limitations of small sample sizes in cross-sectional studies of rare conditions, the incidence and role of cardiac abnormalities in SIDS remains controversial. Based on a study of the prevalence of functionally significant genetic variants associated with Long-QT syndrome, such abnormalities appear to be present in fewer than 10 percent of SIDS cases. (See "Clinical features of congenital long QT syndrome", section on Sudden infant death syndrome).

Susceptibility to SIDS is complex, and identifying high-risk infants who may be particularly vulnerable to cardiac disturbances is important. Further understanding of individual susceptibility across a broad spectrum of infants is needed to clarify pathogenesis and to develop responsible public health initiatives for SIDS prevention.

Infection — Infection is clearly the cause in a sub-group of explained sudden unexpected deaths in infancy. There has not been convincing evidence of a role for infection as a cause of SIDS. However, similarities between the common autopsy findings and those of toxemic shock have raised the possibility for a role for infectious triggers in cases of SIDS even in the absence of a recognizable tissue reaction, which may lead to a toxic shock-like event [149,150] . Implicated organisms include enteric bacteria (enterotoxigenic S. aureus and E. coli), and mild viral infections [149,150] . Variations in the innate immune system, including polymorphisms that result in an exaggerated pro-inflammatory response, have been found in a higher proportion of SIDS cases than in controls [130,149,151] .

Distinguishing between autopsy findings that represent perimortem contamination and those that suggest infection as a trigger for SIDS is challenging and controversial. More than 70 percent of post-mortem bacteriological samples grow organisms when cultured, but this is not sufficient to attribute infection as a cause or trigger for death. However, one well-conducted study found that infants dying of SIDS were more likely to harbor organisms that are potentially pathogenic, as compared with infants dying from clearly non-infectious causes (eg, accidents or congenital heart disease) [152] . The bacterial colonization documented in this study could also be explained as an epiphenomenon, caused by another established epidemiological risk factor for SIDS such as prone sleeping, but not directly implicated as a cause of death.

Developmental timing — SIDS usually occurs between the second and fourth months of life, a period of remarkable developmental changes in cardiac, ventilatory, and sleep/wake patterns in otherwise normal infants. This coincidence of timing suggests that SIDS infants are vulnerable to sudden death during a critical period of autonomic maturation.

DIFFERENTIAL DIAGNOSIS — SIDS is a diagnosis of exclusion; other causes of sudden unexpected death in infancy (show table 1) must be considered and excluded before a diagnosis of SIDS can be established. Among these, fatal child abuse and metabolic disease are particularly important, because they have implications for other children in the family.

Fatal child abuse — Fatal child abuse (filicide) is fortunately uncommon, but should be considered when a child dies suddenly and unexpectedly. Although precise figures are lacking, estimates of the frequency of infanticide among cases designated as SIDS range from 1 to 5 percent of such deaths [7,9,153-155] .

Most deaths related to child abuse can be distinguished from SIDS by a complete autopsy, death scene investigation, and a review of the medical history [6,156] . However, the autopsy cannot distinguish between accidental or deliberate asphyxiation with a soft object and SIDS [5] . A report in 1990, for example, described 27 children who had been suffocated by their mothers [10] . Of the 33 children previously born into these families, 18 had died suddenly and unexpectedly between one and 36 months of age, including 13 who reportedly died from SIDS. In a chronicle of historical markers and clinical observations associated with life-threatening child abuse from intentional suffocation confirmed by covert video surveillance, one third of the abused infants had siblings whose deaths had been classified as SIDS [154] .

Data from The Care of Next Infant programme (CONI), which supports parents who have had an unexpected and apparently unexplained infant death and is available in 90 percent of health districts in England, Wales, and Northern Ireland, were used to estimate the probability that a second episode of sudden unexpected and unexplained death is natural versus unnatural [107] . The following results were noted: Among 6373 infants who completed the program between 1988 and 1999, there were 57 deaths (8.9 per 1000); nine were inevitable, and 48 were unexpected; 44 families lost one child and 2 families lost two children. Excluding the second death in two families with two deaths, 40 deaths were considered to be natural (including SIDS), five were ultimately considered to be filicide, and one homicide (at the hands of a babysitter). Recurrent unexpected deaths among siblings were more often natural (including SIDs) than unnatural (odds ratio 6.7, 95% CI 2.8-19.4). The relative risk of recurrence of SIDS in siblings was 5.9, similar to that in other large epidemiologic studies [104-106] (see "Sibling of SIDS victim" above").

Summary — Certain historical features, some of which overlap with inborn errors of metabolism, discussed below, should raise the suspicion of deliberate asphyxiation, but do not confirm it. These include [6] : Previous recurrent cyanosis, apnea, or ALTE while in the care of the same person Age at death older than 6 months Previously unexpected or unexplained deaths of one or more siblings Previous death of infants under the care of the same unrelated person [10] Simultaneous or near-simultaneous death of twins [157] Evidence of previous pulmonary hemorrhage (such as marked siderophages in the lung)

Even when suspected, this form of child abuse is extraordinarily difficult to prove. The emphasis on full death scene investigations by appropriately trained individuals and careful review of the clinical and family history will minimize mistakes in ascertainment of the cause and manner of death [107] .

Metabolic disease — Inborn errors of metabolism often present in early infancy with life-threatening episodes of metabolic decompensation. Metabolic disease has been shown to play a small (approximately 5 percent) but significant role in the cause of unexpected infant death [158] . In a report that included unexpected deaths in children up to 3 years old, previously undiagnosed metabolic diseases detected by postmortem screening were contributing factors in 1 percent [159] .

The most common disorders that can cause sudden death are defects in the metabolism of fatty acids. Since the initial case report of medium chain acyl-CoA dehydrogenase deficiency in a SIDS victim in 1984 [160] , more than 13 fatty acid oxidation disorders have been associated with sudden infant death. Some affected infants die during their first episode of fasting intolerance. Abnormal metabolites accumulate in the body tissues and can be identified in the liver, urine, or other body fluids. However, these deaths often meet the criteria for SIDS if appropriate investigations are not performed at the time of autopsy.

The autopsy finding of a fatty liver should raise the suspicion of a fatty acid oxidation disorder. (See "Presenting features of inborn errors of metabolism" and see "Overview of the evaluation of inborn errors of metabolism in children", section on SIDS and ALTE).

Other metabolic diseases associated with sudden death include those related to the degradation of branched chain amino acids, urea cycle disorders, and propionic and methylmalonic acidemias. (See "Overview of maple syrup urine disease", see "Clinical features and diagnosis of urea cycle disorders", and see "Organic acidemias").

Certain clinical features increase the probability of a metabolic disease as the cause of sudden infant death [161] : History of previous SIDS or unexpected death in a sibling (especially if the death occurred in the first weeks or after two years of life). Family history of a sibling or cousin with an apparent life-threatening event, Reye's syndrome, or myopathy. Symptoms or signs prior to death, such as neonatal hypoglycemia, an apparent life-threatening event, muscular hypotonia, vomiting, failure to thrive, hyperventilation, severe infections, or elevated aminotransferase levels.

Experts recommend that appropriate metabolic investigations be undertaken in all infants who die suddenly and unexpectedly, even if the diagnosis is initially considered to be SIDS [162] . The evaluation for metabolic disease in victims of SIDS is discussed separately. (See "Overview of the evaluation of inborn errors of metabolism in children" and see "Presenting features of inborn errors of metabolism", section on SIDS or ALTE).

MANAGEMENT — The appropriate professional response to the death of any infant is compassionate, empathic, supportive, and nonaccusatory [6,163] . At the same time, it is essential to discover the cause of death, if possible.

Personnel in first response teams should be trained to make observations at the scene such as the position of the infant, marks on the body, body temperature and rigor, type of bed or crib and any defects, amount and position of clothing and bedding, room temperature, type of ventilation and heating, and reactions of the caretakers [6] .

In the absence of evidence of injury or significant antecedent illness, the parents can be told that death appears to be due to SIDS. However, other causes can be excluded only after a thorough death scene investigation, postmortem examination, and review of the clinical history have been performed [6] . Parents should understand that these procedures will enable them and their physician to understand why their infant died and how other children in the family, including subsequent children, might be affected [6] .

The family is entitled to see and hold the infant once death has been pronounced, if permitted by local protocols and statutes [6] . Many issues including religious support, grief counseling, and reactions of surviving siblings will require attention [164,165] . All parents should be provided with information about SIDS and the telephone number of the local SIDS support group (show table 4). When appropriate, parents should be reassured that neither they nor a physician could have prevented their infant's death. It is important to maintain supportive contact with the parents during the time of the

investigation. A family's anxiety can be further increased if there is a delay in notification of the autopsy results. In most cases, the parents can be informed promptly of the gross autopsy results without waiting for the microscopic examination [163] .

PREVENTION — A number of epidemiologic and physiologic factors are associated with an increased risk for SIDS, but these factors cannot prospectively identify the infant at high risk for SIDS. There are, however, several interventions that can be effective in reducing the risk of SIDS [15,72,166,167] . The following recommendations are made by the American Academy of Pediatrics [15] , the Canadian Paediatric Society [72] , and/or the United Kingdom Department of Health [167,168] : All infants, including infants with a history of prematurity, should be placed to sleep on their backs for every sleep. Even though they may be able to roll from their backs to the prone position, infants should be placed on their back to sleep [167] . Although earlier AAP policy statements suggested that side sleeping was an acceptable alternative to supine sleeping [22,23] , side sleeping is no longer recommended. Prone positioning is encouraged when the infant is awake and observed. Prone positioning facilitates the development of shoulder girdle strength and avoidance of occipital plagiocephaly [23] . (See "Overview of craniosynostosis"). Maternal smoking during pregnancy and exposure of infants to tobacco smoke should be avoided. Infants should be placed to sleep on a firm surface; polystyrene filled cushions and sheepskin bedding should be avoided. Soft objects (eg, pillows, stuffed animals) and loose blankets should be kept out of the crib, bassinet, or cradle. The infant's head should remain uncovered. If blankets are used, the infant's feet should be placed at the bottom of the crib and the blankets tucked around the mattress to prevent the infant from moving into a position in which the head could be covered by the blanket. The safest place for an infant to sleep is in a crib (cradle, bassinet) in the parents' room for the first six months. Infants should not share a bed during sleep; they should not sleep on or share a sofa, recliner, armchair, or other type of cushioned chair. Overheating should be avoided; the infant should be lightly clothed for sleep; the bedroom temperature should be comfortable for a lightly clothed adult (approximately 65ºF [18ºC]); if the infant is dressed in a sleeper, no more than a thin blanket should be necessary. Infants should not sleep next to a radiator or heater or in direct sunshine. The use of a pacifier during sleep may reduce the risk of SIDS. The AAP suggests that the pacifier should be used when placing the infant to sleep, but not reinserted once the infant is asleep [15] . The AAP suggests delaying the introduction of the pacifier until 1 month of age for breastfed infants to ensure that breastfeeding is firmly established [169] . There is some concern that pacifier use may increase the risk of acute otitis media (AOM) [170] . However, the incidence of AOM is relatively low during the first six months of life when the risk of SIDS is greatest. (See "Breastfeeding in the perinatal period", see "Epidemiology, pathogenesis, clinical manifestations, and complications of acute otitis media", and see "Prevention of recurrent acute otitis media"). Commercial devices, marketed to reduce the risk of SIDS, have not been sufficiently tested for efficacy or safety.

Home monitors — There is no evidence to support the role of home monitors in SIDS prevention [171] . In 1972, a paper reported prolonged sleep apnea in five children from three different families who

subsequently died of SIDS [172] . Largely as a result of this observation, the "apnea hypothesis" became the leading explanation for SIDS, and home monitors became widely used for the prevention of SIDS. However, studies done over the past decade have failed to confirm the relationship between SIDS and apnea. As a final blow to this hypothesis, the mother of two of the children in the original report confessed to and was ultimately convicted of having suffocated them [173] . (See "Apparent life-threatening event in infants", section Lack of causal relationship between ALTE and SIDS).

There is no evidence that siblings of SIDS infants have increased episodes of apnea or bradycardia compared to control infants [174,175] . Although SIDS siblings have an increased risk of SIDS compared to control infants, the increased risk is probably due to a combination of biologic and/or epidemiologic factors, rather than an increased prevalence of apnea or bradycardia. (See "Sibling of SIDS victim" above).

There are no scientifically designed studies that have shown that monitors reduce the risk of SIDS [176] . One problem is that, in 50 percent of the infant deaths that occurred while babies were on home monitors, the monitor was not "in use" at the time of death. Home monitors are also plagued with problems including: high incidence of false alarms (>90 percent), failure of the parents to distinguish real alarms from false alarms, variable parent compliance, "real" alarms for clinically insignificant cardiorespiratory changes, and the inability to detect obstructive apnea or hypoxemia [177] . In addition, infants have died or have been unresuscitatable despite home monitor observation and prompt attempts at resuscitation [139,178] . Thus, home monitoring does not guarantee outcome.

At this time, there are insufficient data to support the routine use of home monitoring in siblings of SIDS victims. Management of the survivor of a twin pair is a psychologically difficult issue; no clinical studies have investigated home monitoring in this group of infants. The American Academy of Pediatrics recommends against prescribing home cardiorespiratory monitoring to prevent SIDS [15,171] .

INFORMATION FOR PATIENTS — Educational materials on this topic are available for patients. (See "Patient information: Sudden infant death syndrome (SIDS)"). We encourage you to print or e-mail this topic, or to refer patients to our public Web site www.uptodate.com/patients, which includes this and other topics.

SUMMARY AND RECOMMENDATIONS SIDS is defined as the sudden death of an infant under one year of age, which remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of the clinical history. It is the leading

cause of infant mortality between 1 month and 1 year of age in the United States. (See "Definition" above). The mechanism of sudden death is unknown. The most compelling hypothesis involves a brainstem abnormality or maturational delay related to neuroregulation or cardiorespiratory control. The mechanism most likely involves abnormalities of serotonin (5-HT) signaling. (See "Pathology and Pathogenesis" above). A number of risk factors for SIDS have been identified (show table 2). These include exposure to cigarette smoke, maternal age <20 years, prematurity, prone sleeping position, soft bedding, and overheating. Apnea of prematurity, although a marker for prematurity, is not a risk factor for SIDS. (See "Risk factors" above). The appropriate professional response to the death of any infant is compassionate, empathic, supportive, and nonaccusatory. At the same time, it is essential to discover the cause of death, if possible. (See "Management" above). The differential diagnosis of SIDS includes a number of disorders (show table 1). Inborn errors of metabolism and child abuse are two important causes to remember, since early recognition may prevent morbidity/mortality in siblings of the index case. (See "Differential diagnosis" above). Prevention of SIDS entails education of caregivers regarding modifiable risks: supine sleep position for every sleep, elimination of prenatal and postnatal exposure to tobacco smoke, safe sleep environment. The safest place for an infant to sleep during the first six months is in a crib (cradle, bassinet) in the parents' room. The sleep surface should be firm and free of soft objects, loose bedding, excessive clothing, and extreme room temperatures should be avoided. The AAP suggests using a pacifier when placing the infant to sleep. (See "Prevention" above). The use of home monitors has not been proven to reduce the incidence of SIDS and is not recommended for this purpose. (See "Home monitors" above).

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Williams, S. Changing infants' sleep position increases risk of sudden infant death syndrome. New Zealand Cot Death Study. Arch Pediatr Adolesc Med 1999; 153:1136. L'Hoir, MP, Engelberts, AC, van Well, GT, et al. Sudden unexpected death in infancy: epidemiologically determined risk factors related to pathological classification. Acta Paediatr 1998; 87:1279. Mitchell, EA, Hutchison, L, Stewart, AW. The continuing decline in SIDS mortality. Arch Dis Child 2007; 92:625. Mitchell, EA, Scragg, L, Clements, M. Soft cot mattresses and the sudden infant death syndrome. N Z Med J 1996; 109:206. Kemp, JS, Thach, BT. Sudden death in infants sleeping on polystyrene filled cushions. N Engl J Med 1991; 324:1858. Ponsonby, A-L, Dwyer, T, Gibbons, LE, et al. Factors potentiating the risk of sudden infant death syndrome associated with the prone position. N Engl J Med 1993; 329:377. Mitchell, EA, Thompson, JMD, Ford, RPK, Taylor, BJ. Sheepskin bedding and the sudden infant death syndrome. J Pediatr 1998; 133:701. Thach, BT, Rutherford, GW Jr, Harris, K. Deaths and injuries attributed to infant crib bumper pads. J Pediatr 2007; 151:271. Canadian Paediatric Society. Position statement (CP 2004-02) Recommendations for safe sleeping environments for infants and children. Paediatr Child Health 2004; 9:659. Coleman-Phox, K, Odouli, R, Li, DK. Use of a fan during sleep and the risk of sudden infant death syndrome. Arch Pediatr Adolesc Med 2008; 162:963. Mosko, S, Richard, C, McKenna, J. Infant arousals during mother-infant bed sharing: implications for infant sleep and sudden infant death syndrome research. Pediatrics 1997; 100:841. Does bed sharing affect the risk of SIDS? American Academy of Pediatrics. Task Force on Infant Positioning and SIDS. Pediatrics 1997; 100:272. McGarvey, C, McDonnell, M, Hamilton, K, et al. An 8 year study of risk factors for SIDS: bed-sharing versus non-bed-sharing. Arch Dis Child 2006; 91:318. Blair, PS, Fleming, PJ, Smith, IJ, et al. Babies sleeping with parents: Case-control study of factors influencing the risk of the sudden infant death syndrome. CESDI SUDI research group. BMJ 1999; 319:1457. Tappin, D, Ecob, R, Brooke, H. Bedsharing, roomsharing, and sudden infant death syndrome in Scotland: a case-control study. J Pediatr 2005; 147:32. Lahr, MB, Rosenberg, KD, Lapidus, JA. Bedsharing and maternal smoking in a population-based survey of new mothers. Pediatrics 2005; 116:e530. Horsley, T, Clifford, T, Barrowman, N, et al. Benefits and harms associated with the practice of bed sharing: a systematic review. Arch Pediatr Adolesc Med 2007; 161:237. Ruys, JH, de Jonge, GA, Brand, R, et al. Bed-sharing in the first four months of life: a risk factor for sudden infant death. Acta Paediatr 2007; 96:1399. Hauck, FR, Herman, SM, Donovan, M, et al. Sleep environment and the risk of sudden infant death syndrome in an urban population: the Chicago Infant Mortality Study. Pediatrics 2003; 111:1207. McGarvey, C, McDonnell, M, Chong, A, et al. Factors relating to the infant's last sleep environment in sudden infant death syndrome in the Republic of Ireland. Arch Dis Child 2003; 88:1058. Scragg, RKR, Mitchell, EA, Stewart, AW, et al. Infant room-sharing and prone sleep position in sudden infant death syndrome. Lancet 1996; 347:7. Hauck, FR, Omojokun, OO, Siadaty, MS. Do pacifiers reduce the risk of sudden infant death syndrome? A meta-analysis. Pediatrics 2005; 116:e716. Franco, P, Scaillet, S, Wermenbol, V, et al. The influence of a pacifier on infants' arousals from sleep. J Pediatr 2000; 136:775. Kahn, A, Sawaguchi, T, Sawaguchi, A, et al. Sudden infant deaths: from epidemiology to physiology. Forensic Sci Int 2002; 130 Suppl:S8. l'Hoir, MP, Engelberts, AC, van Well, GT, et al. Case-control study of current validity of previously described risk factors for SIDS in The Netherlands. Arch Dis Child 1998; 79:386. Wennergren, G, Alm, B, Oyen, N, et al. The decline in the incidence of SIDS in Scandinavia and its relation to risk-intervention campaigns. Nordic Epidemiological SIDS Study. Acta Paediatr 1997; 86:963. Kraus, JF, Greenland, S, Bulterys, M. Risk factors for sudden infant death syndrome in the US Collaborative Perinatal Project. Int J Epidemiol 1989; 18:113. Brooke, H, Gibson, A,

Tappin, D, Brown, H. Case-control study of sudden infant death syndrome in Scotland, 1992-5. BMJ 1997; 314:1516. Gilbert, RE, Wigfield, RE, Fleming, PJ, et al. Bottle feeding and the sudden infant death syndrome. BMJ 1995; 310:88. Bertini, G, Perugi, S, Dani, C, et al. Maternal education and the incidence and duration of breast feeding: a prospective study. J Pediatr Gastroenterol Nutr 2003; 37:447. Amir, LH, Donath, SM. Does maternal smoking have a negative physiological effect on breastfeeding? The epidemiological evidence. Breastfeed Rev 2003; 11:19. Donath, SM, Amir, LH. The relationship between maternal smoking and breastfeeding duration after adjustment for maternal infant feeding intention. Acta Paediatr 2004; 93:1514. Noble, L, Hand, I, Haynes, D, et al. Factors influencing initiation of breast-feeding among urban women. Am J Perinatol 2003; 20:477. Vingraite, J, Bartkeviciute, R, Michaelsen, KF. A cohort study of term infants from Vilnius, Lithuania: feeding patterns. Acta Paediatr 2004; 93:1349. Hoffman, HJ, Hunter, JC, Damus, K, et al. Diphtheria-tetanus-pertussis immunization and sudden infant death: Results of the National Institute of Child Health and Human Development Cooperative Epidemiological Study of Sudden Infant Death Syndrome Risk Factors. Pediatrics 1987; 79:598. Griffin, MR, Ray, WA, Livengood, JR, Schaffner, W. Risk of sudden infant death syndrome after immunization with the diphtheria-tetanus-pertussis vaccine. N Engl J Med 1988; 319:618. Jonville-Bera, AP, Autret-Leca, E, Barbeillon, F, Paris-Llado, J. Sudden unexpected death in infants under 3 months of age and vaccination status- -a case-control study. Br J Clin Pharmacol 2001; 51:271. Fleming, PJ, Blair, PS, Platt, MW, et al. The UK accelerated immunisation programme and sudden unexpected death in infancy: case-control study. BMJ 2001; 322:822. Mitchell, EA, Stewart, AW, Clements, M. Immunisation and the sudden infant death syndrome. New Zealand Cot Death Study Group. Arch Dis Child 1995; 73:498. MacIntyre, CR, Leask, J. Immunization myths and realities: responding to arguments against immunization. J Paediatr Child Health 2003; 39:487. Guntheroth, WG, Lohmann, R, Spiers, PS. Risk of sudden infant death syndrome in subsequent siblings. J Pediatr 1990; 116:520. Beal, SM, Blundell, HK. Recurrence incidence of sudden infant death syndrome. Arch Dis Child 1988; 63:924. Oyen, N, Skjaerven, R, Irgens, LM. Population-based recurrence risk of sudden infant death syndrome compared with other infant and fetal deaths. Am J Epidemiol 1996; 144:300. Carpenter, RG, Waite, A, Coombs, RC, et al. Repeat sudden unexpected and unexplained infant deaths: natural or unnatural?. Lancet 2005; 365:29. Beal, SM. Siblings of sudden infant death syndrome victims. Clin Perinatol 1992; 19:839. Getahun, D, Demissie, K, Lu, SE, Rhoads, GG. Sudden infant death syndrome among twin births: United States, 1995-1998. J Perinatol 2004; 24:544. Guntheroth, WG, Spiers, PS. The triple risk hypotheses in sudden infant death syndrome. Pediatrics 2002; 110:e64. Rognum, TO, Saugstad, OD. Biochemical and immunological studies in SIDS victims. Clues to understanding the death mechanism. Acta Paediatr Suppl 1993; 82 Suppl 389:82. Filiano, JJ, Kinney, HC. A perspective on neuropathologic findings in victims of the sudden infant death syndrome: the triple-risk model. Biol Neonate 1994; 65:194. Panigrahy, A, Filiano, JJ, Sleeper, LA, et al. Decreased kainate receptor binding in the arcuate nucleus of the sudden infant death syndrome. J Neuropathol Exp Neurol 1997; 56:1253. Biondo, B, Lavezzi, A, Tosi, D, et al. Delayed neuronal maturation of the medullary arcuate nucleus in sudden infant death syndrome. Acta Neuropathol (Berl) 2003; 106:545. Kinney, HC, McHugh, T, Miller, K, et al. Subtle developmental abnormalities in the inferior olive: an indicator of prenatal brainstem injury in the sudden infant death syndrome. J Neuropathol Exp Neurol 2002; 61:427. Filiano, JJ, Kinney, HC. Arcuate nucleus hypoplasia in the sudden infant death syndrome. J Neuropathol Exp Neurol 1992; 51:394. Paterson, DS, Trachtenberg, FL, Thompson, EG, et al. Multiple serotonergic brainstem abnormalities in sudden infant death

syndrome. JAMA 2006; 296:2124. Kinney, HC, Filiano, JJ, Harper, RM. The neuropathology of sudden infant death syndrome. A review. J Neuropathol Exp Neurol 1992; 51:115. Kinney, HC, Filiano, JJ, Sleeper, LA, et al. Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome. Science 1995; 269:1446. Hoffman, HJ, Hillman, LS. Epidemiology of the sudden infant death syndrome: Maternal, neonatal, and postneonatal risk factors. Clin Perinatol 1992; 19:717. Li, DK, Wi, S. Maternal placental abnormality and the risk of sudden infant death syndrome. Am J Epidemiol 1999; 149:608. Hunt, CE. Sudden infant death syndrome. In: Respiratory Control Disorders in Infants and Children, Beckerman, RC, Brouillette, RT, Hunt, CE, (Eds), Williams & Wilkins, Baltimore, 1992. Schechtman, VL, Lee, MY, Wilson, AJ, Harper, RM. Dynamics of respiratory patterning in normal infants and infants who subsequently died of the sudden infant death syndrome. Pediatr Res 1996; 40:571. Opdal, SH, Rognum, TO. The sudden infant death syndrome gene: does it exist?. Pediatrics 2004; 114:e506. Hunt, CE. Gene-environment interactions: implications for sudden unexpected deaths in infancy. Arch Dis Child 2005; 90:48. Wang, DW, Desai, RR, Crotti, L, et al. Cardiac sodium channel dysfunction in sudden infant death syndrome. Circulation 2007; 115:368. Arnestad, M, Crotti, L, Rognum, TO, et al. Prevalence of long-QT syndrome gene variants in sudden infant death syndrome. Circulation 2007; 115:361. Van Norstrand, DW, Valdivia, CR, Tester, DJ, et al. Molecular and functional characterization of novel glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) mutations in sudden infant death syndrome. Circulation 2007; 116:2253. Opdal, SH, Vege, A, Stave, AK, Rognum, TO. The complement component C4 in sudden infant death. Eur J Pediatr 1999; 158:210. Summers, AM, Summers, CW, Drucker, DB, et al. Association of IL-10 genotype with sudden infant death syndrome. Hum Immunol 2000; 61:1270. Opdal, SH, Opstad, A, Vege, A, Rognum, TO. IL-10 gene polymorphisms are associated with infectious cause of sudden infant death. Hum Immunol 2003; 64:1183. Narita, N, Narita, M, Takashima, S, et al. Serotonin transporter gene variation is a risk factor for sudden infant death syndrome in the Japanese population. Pediatrics 2001; 107:690. Weese-Mayer, DE, Zhou, L, Berry-Kravis, EM, et al. Association of the serotonin transporter gene with sudden infant death syndrome: a haplotype analysis. Am J Med Genet A 2003; 122:238. Rahim, RA, Boyd, PA, Ainslie Patrick, WJ, Burdon, RH. Human heat shock protein gene polymorphisms and sudden infant death syndrome. Arch Dis Child 1996; 75:451. Opdal, SH, Vege, A, Rognum, TO. Serotonin transporter gene variation in sudden infant death syndrome. Acta Paediatr 2008; 97:861. Puffenberger, EG, Hu-Lince, D, Parod, JM, et al. Mapping of sudden infant death with dysgenesis of the testes syndrome (SIDDT) by a SNP genome scan and identification of TSPYL loss of function. Proc Natl Acad Sci U S A 2004; 101:11689. Opdal, SH, Rognum, TO. New insight into sudden infant-death syndrome. Lancet 2004; 364:825. Weese-Mayer, DE, Berry-Kravis, EM, Zhou, L, et al. Sudden infant death syndrome: case-control frequency differences at genes pertinent to early autonomic nervous system embryologic development. Pediatr Res 2004; 56:391. Meny, RG, Carroll, JL, Carbone, MT, et al. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 1994; 93:44. Groswasser, J, Simon, T, Scaillet, S, et al. Reduced arousals following obstructive apneas in infants sleeping prone. Pediatr Res 2001; 49:402. Horne, RS, Ferens, D, Watts, AM, et al. The prone sleeping position impairs arousability in term infants. J Pediatr 2001; 138:811. Chiodini, BA, Thach, BT. Impaired ventilation in infants sleeping facedown: Potential significance for sudden infant death syndrome. J Pediatr 1993; 123:686. Guntheroth, WG, Spiers, PS. Thermal stress in sudden infant death: Is there an ambiguity with the rebreathing hypothesis?. Pediatrics 2001; 107:693. Thompson, JM, Thach, BT, Becroft, DM, Mitchell, EA. Sudden infant death

syndrome: risk factors for infants found face down differ from other SIDS cases. J Pediatr 2006; 149:630. Southall, DP, Stevens, V, Franks, CI, et al. Sinus tachycardia in term infants preceding sudden infant death. Eur J Pediatr 1988; 147:74. Schwartz, PF, Stramba-Badiale, M, Segantini, A. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998; 338:1709. Ackerman, MJ, Siu, BL, Sturner, WQ, et al. Postmortem molecular analysis of SCN5A defects in sudden infant death syndrome. JAMA 2001; 286:2264. Plant, LD, Bowers, PN, Liu, Q, et al. A common cardiac sodium channel variant associated with sudden infant death in African Americans, SCN5A S1103Y. J Clin Invest 2006; 116:430. Highet, AR. An infectious aetiology of sudden infant death syndrome. J Appl Microbiol 2008; :. Goldwater, PN. SIDS pathogenesis: pathological findings indicate infection and inflammatory responses are involved. FEMS Immunol Med Microbiol 2004; 42:11. Korachi, M, Pravica, V, Barson, AJ, et al. Interleukin 10 genotype as a risk factor for sudden infant death syndrome: determination of IL-10 genotype from wax-embedded postmortem samples. FEMS Immunol Med Microbiol 2004; 42:125. Weber, MA, Klein, NJ, Hartley, JC, et al. Infection and sudden unexpected death in infancy: a systematic retrospective case review. Lancet 2008; 371:1848. McClain, PW, Sacks, JJ, Froehlke, RG, et al. Estimates of fatal child abuse and neglect, United States, 1979 through 1988. Pediatrics 1993; 91:338. Southall, DP, Plunkett, MC, Banks, MW, et al. Covert video recordings of life-threatening child abuse: Lessons for child protection. Pediatrics 1997; 100:735. Kukull, WA, Peterson, DR. Sudden infant death and infanticide. Am J Epidemiol 1977; 106:485. Meadow, R. Unnatural sudden infant death. Arch Dis Child 1999; 80:7. 43. Bonham, JR, Downing, M. Metabolic deficiencies and SIDS. J Clin Pathol 1992; 45:33. Contribution of selected metabolic diseases to early childhood deaths--Virginia, 1996-2001. MMWR Morb Mortal Wkly Rep 2003; 52:677. Howat, AJ, Bennett, MJ, Variend, S, Shaw, L. Deficiency of medium chain fatty acylcoenzyme A dehydrogenase presenting as the sudden infant death syndrome. Br Med J (Clin Res Ed) 1984; 288:976. Seashore, MR, Rinaldo, P. Metabolic disease of the neonate and young infant. Semin Perinatol 1993; 17:318. Bennett, MJ, Powell, S. Metabolic disease and sudden, unexpected death in infancy. Hum Pathol 1994; 25:742. Goldberg, J. The counseling of SIDS parents. Clin Perinatol 1992; 19:927. Limerick, S. Family and health-professional interactions. Ann N Y Acad Sci 1988; 533:145. American Academy of Pediatrics Committee on Psychosocial Aspects of Child and Family Health: The pediatrician and childhood bereavement. Pediatrics 1992; 89:516. Creery, D, Mikrogianakis, A. Sudden infant death syndrome. Clin Evid 2005; :434. Reduce the risk of cot death (September 2005). United Kingdom Department of Health, Available at: www.dh.gov.uk/assetRoot/04/12/36/26/04123626.pdf, Accessed on March 8, 2006. Mitchell, EA. Recommendations for sudden infant death syndrome prevention: a discussion document. Arch Dis Child 2007; 92:155. Howard, CR, Howard, FM, Lanphear, B, et al. Randomized clinical trial of pacifier use and bottle-feeding or cupfeeding and their effect on breastfeeding. Pediatrics 2003; 111:511. Uhari, M, Mantysaari, K, Niemela, M. A meta-analytic review of the risk factors for acute otitis media. Clin Infect Dis 1996; 22:1079. Apnea, sudden infant death syndrome, and home monitoring. Pediatrics 2003; 111:914. Steinschneider, A. Prolonged apnea and sudden infant death syndrome. clinical and laboratory observations. Pediatrics 1972; 50:646. Pinholster, G. SIDS paper triggers a murder charge. Science 1994; 264:197. Krongrad, E. Infants at high risk for sudden infant death syndrome??? Have they been identified???--A commentary. Pediatrics 1991; 88:1274. Southall, DP, Alexander, JR, Stebbens, VA, et al. Cardiorespiratory patterns in siblings of babies with sudden infant death syndrome. Arch Dis Child 1987; 62:721. Brooks, J. Risk related intervention for SIDS prevention: Timely or premature. Paediatr Perinat Epidemiol 1994; 8:10. Weese-Mayer, DE,

Silvestri, JM. Documented monitoring: An alarming turn of events. Clin Perinatol 1992; 19:891. Poets, CF, Meny, RG, Chobanian, MR, et al. Gasping and other cardiorespiratory patterns during sudden infant deaths. Pediatr Res 1999; 45:350.

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Hazard (risk) of stillbirth for singleton births without congenital anomalies by gestational age, 2001-2002

Reproduced with permission from: Reddy, UM, Ko, CW, Willinger, M. Maternal age and the risk of stillbirth throughout pregnancy in the United States. Am J Obstet Gynecol 2006; 195:764. Copyright ©2006 Elsevier.

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Expanded Wigglesworth classification worksheet

Cause of death Subclassification

Congenital anomaly Chromosomal defect

Numerical

Structural

Microdeletion/uniparental disomy

Syndrome

Monogenic

Other

Central nervous system

Heart and circulatory system

Respiratory system

Digestive system

Urogenital system

Musculoskeletal system

Endocrine/metabolic system

Neoplasm

Other

Single organ

Multiple organ

Placenta Placental bed pathology

Placental pathology

Development

Parenchyma

Localization

Umbilical cord complication

NOS

Prematurity/immaturity PPROM

Preterm labor

Cervical dysfunction

Iatrogenic

NOS

Infection Transplacental

Ascending

Neonatal

NOS

Other Fetal hydrops of unknown origin

Maternal disease

Trauma

Maternal

Fetal

Out of the ordinary

Unknown Despite thorough investigation

Important information missing

Reproduced with permission from: Wigglesworth, JS. Monitoring perinatal mortality. A pathophysiological approach. Lancet 1980; 2:684. Copyright ©1980 Elsevier.

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Etiology of fetal death

Perinatal infection

Bacterial

Group B Streptococcus

E coli

Listeria monocytogenes

Spirochaetal

Other bacterial

Viral

Cytomegalovirus

Parvovirus

Herpes simplex virus

Rubella virus

Other viral

Protozoal, eg Toxoplasma

Fungal

Other specified organism

Hypertension or preeclampsia

Antepartum hemorrhage

Placental abruption

Placenta previa

Vasa previa

Other

Maternal conditions

Termination of pregnancy

Diabetes/gestational diabetes

Maternal injury

Accidental

Non-accidental

Maternal sepsis

Systemic lupus erythematosis

Obstetric cholestasis

Other

Perinatal conditions

Twin-twin transfusion

Fetomaternal hemorrhage

Antepartum cord complications

Uterine abnormalities

Birth trauma

Alloimmune disease

Nonimmune fetal hydrops

Other

Hypoxic peripartum death

With intrapartum complications

Uterine rupture

Cord prolapse

Shoulder dystocia

Other

Evidence of non-reassuring fetal status in a normally grown infant

No intrapartum complications and no evidence of non-reassuring fetal status.

Fetal growth restriction

Unspecified or not known whether placenta examined

Spontaneous preterm birth

Intact membranes

Ruptured membranes

Unexplained antepartum death

With evidence of reduced vascular perfusion on Doppler studies and/or placental histopathology (eg significant infarction, acute atherosis, maternal and/or fetal vascular thrombosis or maternal floor infarction)

With chronic villitis

No placental pathology

Other specified placental pathology

Data from: Chan, A, King, JF, Flenady, V, Haslam, RH, Tudehope DI. Classification of perinatal deaths: development of the Australian and New Zealand classifications. J Paediatr Child Health 2004; 40:340.

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Relationship between selected first and second pregnancy outcomes

Outcome of first pregnancy, live births only Odds ratio for stillbirth in second pregnancy (95 percent CI) Stillbirth rate per 1000 births

AGA, term 1.0 2.4

SGA, term 2.0 (1.5 to 2.6) 4.8

SGA, moderately preterm 4.0 (2.5 to 6.3) 9.5

SGA, very preterm 8.0 (4.7 to 13.7) 19.0

AGA: weight appropriate for gestational age; SGA: weight small for gestational age, ie birth weight >2 standard deviations below the mean for gestational age (<2.5th percentile); moderately preterm: 32 to 36 weeks of gestation; very preterm: <32 weeks of gestation.

Analysis adjusted for factors such as cigarette smoking, maternal age, interpregnancy interval, and presence of hypertension or antepartum bleeding.

Adapted from: Surkan, PS, Stephansson, O, Dickman, PW, Cnattingius, S. N Eng J Med 2004; 350:777.

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Estimates of maternal risk factors and risk of stillbirth

Condition Prevalence, percent Estimated rate of stillbirth, per 1000 women Odds ratio

All pregnancies 6.4 1.0

Low risk pregnancies 80 4.0-5.5 0.86

Nulliparity 40 7-8 1.2-3.0

Hypertensive disorder

Chronic hypertension 6-10 6-25 1.5-2.7

Pregnancy induced hypertension

Mild 5.8-7.7 9-51 1.2-4.0

Severe 1.3-3.3 12-29 1.8-4.4

Diabetes

Treated with diet 2.5-5 6-10 1.2-2.2

Treated with insulin 2.4 6-35 1.7-7.0

Systemic lupus erythematosus <1 40-150 6-20

Renal disease <1 15-200 2.2-30

Thyroid disorders 0.2-2 12-20 2.2-3.0

Thrombophilia 1-5 18-40 2.8-5.0

Cholestasis of pregnancy <0.1 12-30 1.8-4.4

Smoking >10 cigarettes 10-20 10-15 1.7-3.0

Obesity (prepregnancy)

BMI 25-29.9 kg/m2 21 12-15 1.9-2.7

BMI >30 20 13-18 2.1-2.8

Low educational attainment (<12 years vs. 12 years+) 30 10-13 1.6-2.0

Previous growth restricted infant (<10 percent) 6.7 12-30 2-4.6

Previous cesarean section 24-28 6-13 1.0-2.0

Previous stillbirth 0.5-1.0 9-20 1.4-3.2

Multiple gestation 2-3.5

Twins 2.7 12 1.0-2.8

Triplets 0.14 34 2.8-3.7

Advanced maternal age (reference <35)

35-39 15-18 11-14 1.8-2.2

40+ 2 11-21 1.8-3.3

Black compared to White 15 12-14 2.0-2.2

Adapted with permission from: Fretts RC. Etiology and prevention of stillbirth. Obstet Gynecol 2005; 193:1923. Copyright ©2005 Lippincott Williams and Wilkins.

Reproduced with permission from Lippincott Williams & Wilkins.

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