• Author / Uploaded
• Christian Yzaguirre Abanto

• Categories
• Feto
• Desarrollo prenatal
• El embarazo
• Parto
• Placenta

Citation preview

Official reprint from UpToDate® www.uptodate.com ©2019 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Fetal death and stillbirth: Incidence, etiology, and prevention Authors: Ruth C Fretts, MD, MPH, Catherine Spong, MD Section Editor: Charles J Lockwood, MD, MHCM Deputy Editor: Vanessa A Barss, MD, FACOG

All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Dec 2018. | This topic last updated: Jan 08, 2019. INTRODUCTION — The terms fetal death, fetal demise, stillbirth, and stillborn all refer to the delivery of a fetus with no signs of life. The terms will be used interchangeably in this topic review. It should be noted that parent groups prefer the term stillbirth to the other terms. The ability to call a fetal loss a stillbirth is important to parents, in part because birth and death certificates are not generated after a miscarriage. In addition, parents report they receive less grief support after a miscarriage than after a stillbirth and less acknowledgment of the death of their child. The incidence and etiology of fetal death, as well as strategies for prevention, will be reviewed here. Diagnosis and management of fetal demise, pathological evaluation of stillborns, and parental support and counseling are discussed separately: ● (See "Evaluation of stillbirth".) ● (See "Fetal death and stillbirth: Maternal care".) DEFINITION Overview — Terminology regarding fetal death and stillbirth is complicated and confusing for several reasons, including: ● Differences in definitions among countries. ● Differences between medical definitions and regulatory criteria for reporting fetal deaths. ● Use of birth weight versus gestational age thresholds for reporting fetal death and interpretation when these values are discordant at the threshold distinguishing a fetal death from an abortus. ● Interpretation when there is a significant difference between the gestational age of fetal demise and the gestational age at delivery. This is particularly problematic in multiple gestations with a demised sibling before delivery of the live sibling. ● Inconsistent categorization as stillbirth of induced fetal demise and induced labor of previable fetuses (eg, multifetal reduction, fetal anomaly). ● Incomplete data from low-income countries where many births occur at home and in remote areas. Worldwide, the lower threshold for gestational age for defining stillbirth ranges from ≥16 weeks to ≥28 weeks of gestation and the lower threshold for birth weight ranges from ≥400 g to ≥1000 g [1].

Stillbirths can also be subclassified as early stillbirths, which occur at 20 to 27 weeks of gestation, or late stillbirths, which occur at ≥28 weeks of gestation. Although this division is somewhat arbitrary, the stratification allows for relatively reliable comparison of international data for late fetal losses and allows division of stillbirths into those that are early and difficult to prevent with any intervention from those that are late and potentially preventable by preterm delivery. World Health Organization definition — The World Health Organization (WHO) defines "fetal death" as death prior to complete expulsion from the mother, irrespective of the duration of pregnancy [2]. The diagnosis of death is based on absence of breathing or other evidence of life such as beating of the heart, pulsation of the umbilical cord, or definite movement of voluntary muscle. All fetal deaths ≥500 g should be reported; when weight is not available, gestational age ≥22 weeks is used as a criterion for reporting fetal death; if neither weight nor gestational age is available, crown-heel length ≥25 cm is used as a criterion for reporting fetal death and distinguishing a fetal death from an abortus. For international comparison purposes, the WHO defines "stillbirth" as a baby born with no signs of life at ≥28 weeks [3]. However, stillbirths from 22 weeks to 37 weeks) [5]. States have different reporting requirements; most report fetal deaths that are ≥20 weeks of gestation and/or ≥350 g birth weight and use 20 weeks of gestation as the gestational age threshold for distinguishing a stillbirth from the product of a miscarriage. The International Stillbirth Alliance also suggests this cutoff [6]. INCIDENCE AND EPIDEMIOLOGY Global — Worldwide, the stillbirth rate has been falling from approximately 35 deaths/1000 livebirths in 1980 to approximately 15 deaths/1000 livebirths in 2015 [7]. The reduction has been associated with improved access to and utilization of antenatal care and skilled birth attendants and attention to known maternal risks for stillbirth. When comparing stillbirth rates globally, the rates of late stillbirths are used (those 28 weeks of gestation or later). Approximately 98 percent of these stillbirths occur in low- and middle-income countries [8]. Rates of stillbirth in low-income countries have been substantially higher (approximately 21 deaths/1000 livebirths) than in high-income countries (approximately 3 deaths/1000 livebirths) [7]. However, declines in the past decade have been reported. A study in low- and middle-income countries (Zambia, Kenya, India, Pakistan, Guatemala) found a 3 percent decline in stillbirth from 2010 to 2016 (from 31.7 deaths per 1000 livebirths and fetal deaths to 26.4 deaths per 1000 livebirths and fetal deaths) [9]. At least half of the stillbirths in low-income countries occur during labor and birth, largely because of a lack of skilled birthing attendants and facilities for cesarean delivery [8]. Antepartum stillbirths are often related to maternal infection or fetal growth restriction. Pregnancy-induced hypertension that is not identified and appropriately managed with induction of labor is another common cause of both fetal and maternal death in these countries. United States — In the United States, the stillbirth rate is 2.84 per deaths per 1000 livebirths [7] and 5.96 deaths per 1000 livebirths and fetal deaths [10]. Approximately 50 percent of the fetal deaths occur between 20 and 27 weeks (primarily from 20 to 23 weeks of gestation), and the other 50 percent occur at ≥28 weeks [10]. The number of fetal deaths is higher than the number of neonatal deaths and the number of infant deaths. Sociodemographic factors affecting the fetal death rate:

● Black race – The fetal mortality rate was highest for non-Hispanic blacks (10.53 deaths per 1000 livebirths and fetal deaths) and lowest for non-Hispanic whites (4.88 deaths per 1000 livebirths and fetal deaths). While some of this increased risk can be attributed to access to, and quality of, medical care, other factors also contribute as black women experience a higher rate of stillbirth even when they have adequate access to prenatal care [11]. The increased risk in black women has been attributed to poorer preconception health, lower income, increased stress and racism, and a higher rate of infection. Genetic, behavioral, and environmental factors may be involved in the disparity as well as unknown factors. In addition, black women appear to be less likely than women of other races to be induced at term despite their higher rates of diabetes mellitus, hypertension, placental abruption, and term stillbirth [12], which also may account for some of the disparity. ● Younger and older age – The fetal mortality rate was lowest for women ages 25 to 34 and higher for teenagers and women ≥35 years of age. Older age appeared to be an independent risk factor for fetal death after adjusting for medical/obstetric conditions more common among older women (eg, hypertension, diabetes, multiple gestation) [13,14] (see "Effects of advanced maternal age on pregnancy"). Unexplained stillbirth is the only type of stillbirth that is statistically more common in older women. (See 'Unexplained stillbirth' below.) ● Unmarried status – The fetal mortality rate for unmarried non-Hispanic white women was 44 percent higher than for married non-Hispanic white women, whereas differences were smaller for non-Hispanic black women (14 percent difference) and Hispanic women (difference 11 percent). Marital status can affect availability of social, emotional, and financial resources. Effect of plurality and fetal sex on the fetal death rate: ● Multiple gestation – Fetal mortality increases with increasing number of fetuses: 2.5-fold higher for twins than singletons, fivefold higher for triplets or more. The increased rate in multiples is due to complications specific to multiple gestations (such as twin-twin transfusion syndrome and twin reverse arterial perfusion sequence) as well as complications, such as fetal anomalies and growth restriction, which can occur in any pregnancy. Monochorionic placentation accounts for most of the increased risk. (See "Twin pregnancy: Prenatal issues", section on 'Fetal complications'.) ● Male sex – Fetal mortality is higher for male fetuses than female fetuses among non-Hispanic white and black women. Prospective rate of fetal death — In clinical studies, researchers are increasingly citing the prospective fetal mortality rate, which represents the number of fetal deaths at a given gestational age per 1000 livebirths and fetal deaths at that gestational age or greater. In the United States in 2013, the prospective rate of fetal death at 20 to 22 weeks of gestation was high (0.52 to 0.56), declined at 29 to 33 weeks of gestation to its lowest level (0.18 to 0.19), remained relatively low until approximately 37 weeks of gestation, and then began to climb at 38 weeks, increasing to its highest level at 42 weeks of gestation (0.62) [10]. ETIOLOGY AND RISK FACTORS — Stillbirth is the end result of a variety of maternal, fetal, and placental disorders. The study of specific causes of stillbirth has been hindered by the lack of a uniform protocol for evaluating and classifying stillbirth [15] as well as declining autopsy rates. The relative frequencies of the various causes of stillbirth appear to differ between low- and high-income countries [16-20] and between early and late gestation [21]. Obstructed/prolonged labor, preeclampsia, and infection have been reported as common causes of stillbirth in low-income countries, whereas congenital or karyotype anomalies, placental problems associated with growth restriction, and maternal medical diseases appear to be common causes in high-income countries [19].

Early gestational fetal mortality appears to be related to congenital anomalies, infections, intrauterine growth restriction, and underlying maternal medical conditions, whereas late gestational fetal mortality appears to be due to both maternal medical disorders and obstetric disorders that generally evolve around the time of delivery, such as placental abruption and previa, cord prolapse, marginal insertion of the umbilical cord into the placenta, other labor and delivery complications, or unexplained. Unexplained stillbirth — An unexplained stillbirth is a fetal death that cannot be attributed to an identifiable fetal, placental, maternal, or obstetric etiology due to lack of sufficient information or because the cause cannot be determined at the current level of diagnostic ability [22]. It is reported to account for 25 to 60 percent of all fetal deaths [23-26]. Variation in the proportion of stillbirths reported as unexplained (or unknown or unclassified) generally reflects (1) whether the stillbirth has been fully evaluated (ie, detailed evaluation of the mother, stillborn, umbilical cord, placenta, and events leading up to stillbirth), (2) whether the classification system allows risk factors to be included as causes, (3) subjective interpretation (speculation regarding mechanisms of death), and (4) the population (a cause of death is more likely to be found in populations with generally high disease burdens) [22,27]. As an example, the cause of stillbirth in a small for gestational age stillborn may be fetal growth restriction in some systems but considered unexplained in others if the underlying etiology of the growth restriction is unknown [23-25,28]. In these systems, growth restriction may be considered a "contributing factor" rather than a cause. A systematic review of classification systems for stillbirths found that the percentage where the cause of death was unexplained ranged from 0.39 percent (Nordic-Baltic classification) to 46 percent (Keeling system) [22]. Stillbirths occurring near term are more likely to be unexplained than stillbirths occurring earlier in gestation. Two-thirds of unexplained fetal deaths occurred after 35 weeks of gestation in one series [23]. Fetal growth restriction — Death of a growth-restricted fetus is the second most common etiology of stillbirth [21]. Placental dysfunction is the presumed cause of both growth restriction and death. The estimated risk of stillbirth for growth-restricted fetuses is three to seven times that of the normally grown fetus [29-35]. In a multihospital study in the United States that included 527 stillbirths, the median gestational age at death of the growth restricted fetus was 28 weeks [35]. (See "Fetal growth restriction: Screening and diagnosis" and "Fetal growth restriction: Evaluation and management".) 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 [29,36]. The association between the birth of a small for gestational age infant in one pregnancy and stillbirth in a subsequent pregnancy has been reported in several studies [29,31,37]. The risk of stillbirth in a subsequent pregnancy is particularly high if the small for gestational age infant was born preterm. An analysis of data from the Swedish Birth Register is a representative example of these data (table 1) [29]. Placental dysfunction can be related to maternal vasculopathies or intrinsic placental disease. Abruptio placentae — Abruptio placentae occurs in approximately 1 percent of pregnancies but accounts for between 10 and 20 percent of all stillbirths [21]. 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 "Placental abruption: Pathophysiology, clinical features, diagnosis, and consequences".) Infection — Infection accounts for approximately 50 percent of stillbirths in low- and middle-income countries and 10 to 25 percent of stillbirths in high-income countries [38]. Infection may lead to fetal demise as a result of severe systemic maternal illness (eg, pneumonia), placental dysfunction due to placental infection (eg, malaria), or fetal systemic illness (eg, Escherichia coli, group B Streptococcus, cytomegalovirus, Zika virus).

Most studies report infection is the cause of more preterm than term stillbirths. In high-income countries, the majority of stillbirths related to infection occur in periviable fetuses following premature rupture of membranes [21]. 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. Viral pathogens are the most common source of hematogenous infection of the placenta, although bacteria, spirochetes, fungi, and protozoa can also cause transplacental infection. Almost any systemic infection that occurs during pregnancy can infect the placenta but usually does not lead to fetal death from infection. Malaria is a common cause of maternal infection leading to stillbirth in endemic areas. Parvovirus, cytomegalovirus (CMV), toxoplasmosis, listeria, and herpes simplex virus are other wellestablished maternal infections that can lead to stillbirth. Parvovirus and CMV infection are relatively common and should be considered in stillbirths of unknown etiology after autopsy [39,40]. In 2016, Zika virus was also associated with stillbirth [41], but the epidemic has subsided. Diagnostic criteria for determining whether a fetal death is due to infection are not well defined and are complicated by the relatively high frequency of asymptomatic maternal vaginal carriage of some potential pathogens [42]. Histological evidence of both placental and fetal infection should be documented when citing infection as the cause of fetal death. In some cases, however, an infected fetus may be unable to mount an immune response, resulting in the absence of this evidence [43,44]. Genetic abnormalities — Most aneuploidies are lethal in utero. Some aneuploidies, such as trisomy 21, 18, and 13 and monosomy X, confer an increased risk of fetal demise, but also can result in livebirth. Although death of a karyotypically abnormal embryo or fetus is most common in the first trimester, it can occur at all stages of pregnancy [45-47]. In one study that karyotyped 823 stillbirths and neonatal deaths, 6.3 percent had a major chromosomal abnormality [48]. The most common abnormalities were trisomies 18, 13, and 21; sex chromosome aneuploidy; and unbalanced translocations. The frequencies of abnormal karyotype in macerated stillbirths, nonmacerated stillbirths, and neonatal deaths were approximately 12, 4, and 6 percent, respectively, versus 0.7 percent in live borns [24]. A study of registry data reported stillbirth rates (after exclusion of pregnancy termination) for trisomy 21, 18 and 13 were 5, 37, and 22 percent, respectively [49]. The combination of a congenital anomaly and stillbirth increases the likelihood of a chromosomal abnormality. In one study of 750 stillbirths, chromosomal abnormalities were identified in 38 percent of anomalous stillborns versus 4.6 percent of stillborns that were morphologically normal [50]. Information on genetic causes of stillbirth other than aneuploidy is sparse. Single gene defects and microdeletions are examples of genetic causes of stillbirth that may be missed by a karyotype determined by conventional cytogenetic analysis. Microarray analysis has a higher diagnostic yield and is increasingly being utilized in the evaluation of stillbirth [51]. Ongoing research includes next-generation sequencing of cardiac channelopathies [52]. (See "Use of chromosomal microarray in obstetrics", section on 'Fetal demise'.) Congenital anomalies — Fifteen to 20 percent of stillbirths have a major malformation [21,45]. This rate varies from country to country and is greatly influenced by the availability of prenatal diagnosis and pregnancy termination. Fetal death can be attributed to a malformation if epidemiologic data support a relationship, the anomaly is rare in live borns, neonates with the anomaly often die, or there is biologic plausibility for an association [53]. Malformations associated with an increased risk of fetal demise, but unrelated to structural chromosomal abnormalities, include abdominal wall defects, neural tube defects, Potter syndrome, homozygous achondrogenesis, thanatophoric dysplasia, lethal multiple pterygium syndrome, and amniotic band sequence. In a study of registry data, the isolated anomalies with the highest rates of stillbirth after exclusion of pregnancy terminations were: anencephaly (51 percent), encephalocele (15 percent), arhinencephaly/holoprosencephaly (12 percent), hydrocephaly (9 percent), hypoplastic left or right heart (9 percent), single cardiac ventricle (9

percent), spina bifida (6 percent), gastroschisis or omphalocele (6 percent), common arterial truncus (4 percent), and diaphragmatic hernia (3 percent) [49]. Fetomaternal hemorrhage — Fetomaternal hemorrhage sufficiently large to cause fetal death has been reported in up to 5 percent of stillborns [54,55]. Usually there is no identifiable etiology; however, case reports have described associations with abruptio placentae, vasa previa, chorioangioma, choriocarcinoma, maternal trauma, cephalic version, and amniocentesis. (See "Spontaneous massive fetomaternal hemorrhage".) Diabetes — Women with diabetes are at increased risk of stillbirth, particularly at or near term. As an example, a multistate analysis from the United States reported that the term stillbirth rate among women with diabetes was 300/100,000 births, which was more than twice as high as the rate in the overall obstetric population of 130/100,000 births [56]. Hyperglycemia is one cause of stillbirth in diabetic pregnancies, but maternal obesity, maternal vasculopathy, advanced maternal age, congenital anomalies, fetal cardiomyopathy, and fetal growth restriction also can play a role [57]. The fetus of the diabetic mother is at risk for stillbirth primarily from two mechanisms: (1) fetal hyperglycemia and hyperinsulinemia increase fetal oxygen consumption, which may induce fetal hypoxemia and acidosis if the oxygen needs of the fetus are not met, and (2) maternal vasculopathy and hyperglycemia can lead to reduced uteroplacental perfusion, which may be associated with reduced fetal growth. Hypertensive disorders — Hypertensive disorders are associated with a significant number of stillbirths in lowincome countries [8] and in high-income countries if the worsening of maternal/fetal condition is not appreciated. Placental insufficiency and abruption are the major causes of fetal death in women with hypertension. The appropriate management of chronic hypertension, gestational hypertension, and preeclampsia can reduce the risk of stillbirth but preterm delivery is often necessary. (See "Gestational hypertension" and "Management of hypertension in pregnant and postpartum women".) Smoking, illicit drugs — A meta-analysis including 57 studies found that any active maternal smoking was associated with increased risks of stillbirth (summary relative risk 1.46, 95% CI 1.38-1.54) [58]. (See "Cigarette and tobacco products in pregnancy: Impact on pregnancy and the neonate", section on 'Stillbirth and neonatal death'.) In the United States Stillbirth Collaborative Research Network (SCRN), where the majority of cases and controls agreed to be tested for evidence of smoking and illicit drugs, there was a linear relationship between the number of cigarettes smoked and the risk of stillbirth, with a two- to threefold increased risk for women smoking ≥10 cigarettes/day [59]. In this study, passive smoking showed a similar pattern, with increasing risk with increasing exposure. Nicotine replacement therapy is useful for helping women to stop smoking and does not appear to increase the risk of stillbirth compared with nonsmoking women [60]. The role of illicit drug use in the risk of stillbirth has been difficult to estimate because most studies rely on selfreporting, and drug testing generally requires consent. In the SCRN study, 7 percent of women who had a stillbirth tested positive for an illicit drug compared with only 3.7 percent of women with livebirths (OR 1.9, 95% CI 1.2-3.3). The most common drug detected in this study was tetrahydrocannabinolic acid, which was detected in 3.8 percent of women with stillbirths versus 1.7 percent of women with livebirths. (See "Cigarette smoking in pregnancy: Cessation strategies and treatment options" and "Substance use by pregnant women", section on 'Impact of selected drugs on pregnancy'.) Umbilical cord abnormalities — Umbilical cord complications (eg, nuchal cord, knot, intrinsic cord abnormalities) are often cited as a cause of fetal death in the third trimester [61-65] and accounted for 10 percent of 500 fetal deaths in one population-based study [26]. Although nuchal cords and knots are relatively common (occurring in 15 to 34 percent of pregnancies at term) (see "Nuchal cord"), vascular constriction sufficiently severe to kill the fetus rarely occurs. A nuchal cord or knot may provide the clinician and the patient with an immediate potential

explanation for the fetal demise; however, the cause of death should be attributed to a cord complication only after a thorough search for other causes and when other findings support this diagnosis. (See "Gross examination of the placenta", section on 'Umbilical cord' and "Nuchal cord", section on 'Fetal demise'.) Placental abnormalities — Placental causes of stillbirth include abruptio placentae (see 'Abruptio placentae' above), ruptured vasa previa (see "Velamentous umbilical cord insertion and vasa previa"), infection, neoplasm, structural or vascular malformations, vasculopathy, and infarction. (See "The placental pathology report".) Small placentas are associated with growth restriction; pathological causes of large placentas include hydrops fetalis, maternal diabetes mellitus, and syphilis, which are also causes of stillbirth. For this reason, gross and microscopic examination of the placenta is an integral part of the evaluation of stillbirth. (See "Evaluation of stillbirth" and "Gross examination of the placenta".) Confined placental mosaicism is identified in 1 to 2 percent of chorionic villus biopsy samples; 15 to 20 percent of these pregnancies abort, develop fetal growth restriction, or end in stillbirth [53]. Outcome appears to be determined by the specific chromosome involved (2, 3, 9, 14, 15, 16, and 18 alter outcome), whether the abnormal line persists throughout pregnancy, the percentage of aneuploid cells, the cell line of the aneuploid cells, and whether uniparental disomy is present. (See "Chorionic villus sampling", section on 'Confined placental mosaicism'.) Uterine abnormalities — Uterine rupture is a rare but devastating cause of intrapartum stillbirth. (See "Uterine rupture: After previous cesarean delivery" and "Uterine rupture: Unscarred uterus".) Structural uterine abnormalities, such as a unicornuate uterus, can be associated with cervical insufficiency, which can lead to previable preterm birth. A pregnancy in a rudimentary horn may not develop to viability. Amniotic band sequence usually causes fetal deformation but may also result in stillbirth if the umbilical cord is constricted by a band. (See "Amniotic band sequence".) Hydrops fetalis — Hydrops fetalis may be due to immune or nonimmune etiologies and is often fatal. Causes, diagnosis, and management of these disorders are discussed separately. (See "Nonimmune hydrops fetalis" and "Management of pregnancy complicated by Rhesus (D) alloimmunization".) Arrhythmia — An unrecognized arrhythmia, such as long QT syndrome, may be a cause of unexplained fetal demise. (See "Overview of the general approach to diagnosis and treatment of fetal arrhythmias".) Platelet alloimmunization — Severe fetal alloimmune thrombocytopenia can result in intracranial hemorrhage and death in utero. (See "Fetal and neonatal alloimmune thrombocytopenia: Parental evaluation and pregnancy management".) Intrahepatic cholestasis of pregnancy — Intrahepatic cholestasis of pregnancy (ICP) causes pruritus without a rash, typically in the late second or the third trimester. The total bile acid level is elevated, and transaminases are often elevated. Fetal demise occurs in 2 standard deviations below the mean for gestational age [