Fetal death: etiology and pathological findings

 

EPIDEMIOLOGY

FIRST TRIMESTER LOSSES

Chromosomal abnormalities

Frequencies of chromosomal abnormalities

SECOND AND THIRD TRIMESTER LOSSES

Infection

Diabetes

Prepregnancy weight

IUFD due to umbilical cord complications

Utility of placental pathology

Unexplained fetal deaths

Fetal death: etiology and pathological findings

 

Harvey J. Kliman, MD, PhD.

Juliette C. McSweet

Yifat A. Levin

December 1, 2000

 

When considering the fact that in any given menstrual cycle, healthy couples who have intercourse regularly without the use of contraception only have a 25 to 30 percent chance of beginning a pregnancy [1], that only 70 to 75 percent of blastocysts created are able to implant and that only 58 percent of the blastocysts that implant survive past the second week of gestation [2], one comes to understand the miracle of reproduction. Even after these hurtles are overcome, there are still many variables that can affect the likelihood of a successful pregnancy and delivery.

 

The majority of pregnancies have no complications and result in the birth of a healthy child. Some pregnancies end prematurely and some even develop normally to term and end tragically during the birthing process. A pregnancy loss can be extremely devastating at any stage for the expectant parents and these tragic events have lead many researchers to investigate the causes of specific pregnancy associated complications and the possible etiologies of these poor pregnancy outcome.

 

This card will review the major causes and pathologic findings of fetal demise throughout gestation.

 

 

EPIDEMIOLOGY Early pregnancy loss has been estimated to occur in at least 75 percent of all women trying to conceive [3]. Perinatal death (the number of stillbirths and neonatal deaths) occurs in the United States at a rate of 1 percent. Early studies reported that about 2 percent of pregnancies end in perinatal death after 28 weeks gestation, while 10-25 percent of recognized pregnancies end before 28 weeks [4]. Today, an estimated 10-15 percent of all recognized pregnancies end in unexpected loss [5].

 

The timing of the losses varies, and is related to the cause of death. Table 1 shows the incidence of fetal death as it varies by gestational age [6].

 

Table 1

 

Gestation (weeks)	Mean incidence fetal death (percent)
5-7	17.5
8-11	50.6
12-15	47.0
16-19	32.8
20-27	10.7
Total 5-27	33.0

 

 

FIRST TRIMESTER LOSSES The first trimester of pregnancy, usually defined as the period from fertilization until the 13^th week of gestation, is the most sensitive time of development for the conceptus. Therefore, there is a very high incidence of first trimester spontaneous abortion reported in the literature.

 

Although maternal exposure to certain teratogens, and possible immune rejection of the conceptus does occur, the most common cause of first trimester spontaneous abortion is chromosomal abnormality.

 

Chromosomal abnormalities The estimate of the incidence of chromosomal anomalies causing early fetal demise has typically been cited as 30-60 percent[7-9]. With the advent of preimplantation genetic diagnosis (PGD), it has been estimated that this number may in fact be higher, especially as maternal age at time of conception increases [10-12]. Since only about 7 percent of fetuses that survive to term have chromosomal abnormalities it is believed that the chromosomal abnormalities that do occur in early losses are the most severe and prevent the normal development of the embryo [9]. Byrne et al. investigated the morphologic features of 3472 spontaneous abortuses , finding 27.9 percent consisted of an empty sac, 34.2 percent consisted only of fetal membranes and the remainder consisted of different embryonic forms [9].

 

Frequencies of chromosomal abnormalities Kajii et al. karyotyped 447 abortuses and found that 54 percent of them had an abnormal karyotype [8]. The most common abnormalities were autosomal trisomies, one fifth were 45,X and almost one-seventh were polyploid. This study found that the most common trisomy was trisomy 16, with a frequency of 28 percent, and that the second most common was trisomy 22 at 14 percent. In another study, Byrne et al. also found trisomy 16 to be the most common and trisomy 22 to be the next most common autosomal trisomy among first trimester losses, and that the morphology of these abortuses were so often disorganized that a fetus never developed [9].

 

Genetic anomalies may not only affect the development of the fetus, but the placenta as well. One recent study found an increase in apoptosis and a decrease in cell proliferation in chromosomally abnormal placentae compared to chromosomally normal placentae of spontaneous abortion specimens, which suggests that genetic abnormalities can lead to changes that affect trophoblast development and proliferation [13].

 

 

SECOND AND THIRD TRIMESTER LOSSES Second and third trimester fetal demise can be attributed to many different single causes, or to a combination of causes. There are acute etiologies such as abruption or umbilical cord complications; subacute etiologies, such as infections or uteroplacental insufficiency; and chronic etiologies such as longstanding uteroplacental insufficiency, diabetes or immunologic rejection [14-16]. According to Naeye, the majority of deaths between 14 and 20 weeks gestation are caused by acute chorioamnionitis, chronic low uteroplacental blood flow, or developmental disorders [17].

 

Infection Infection is a significant risk for the fetus [18-23]. Romero and colleagues over the last 15 years have demonstrated the severe repercussions of intrauterine bacterial infections. They have postulated that ascending bacterial infections (where bacteria migrate from the vagina through the cervix into the amniotic cavity) trigger a cytokine cascade that ultimately leads to fetal damage, preterm delivery, and in severe cases, intrauterine fetal demise (IUFD) [18, 21-24]. Moyo et al. examining stillbirths in Zimbabwe directly confirmed the consequences of ascending infections by finding different strains of E. coli in internal organs of stillborns. Among the 104 stillborns studied, moderate bacterial growth occurred in 17-33 percent of specimens obtained from lung, liver and cardiac fluid, while bacterial growth was significantly more prevalent in cultures from the throat, umbilical cord and placenta [25]. Not all intrauterine infections are caused by bacteria. For example, a recent study done in Sweden showed that Parovirus B19, which is found in 50-70 percent adults and is often asymptomatic in this population, in pregnancy is associated with fetal anemia, fetal hydrops, spontaneous abortion and IUFD [26].

 

Diabetes Diabetes is often the cause of complications during pregnancy for the fetus as well as the mother. Cundy et al. found that compared to the non-diabetic population, the rate of fetal death or fetal demise occurring between 20 and 28 weeks increases 2.5 fold in women with Type 2 diabetes [27].

 

Prepregnancy weight Prepregnancy body mass index has been studied in correlation with poor pregnancy outcome. In a 1998 study, it was determined that nulliparous women with a prepregnancy body mass index of 25.0 or more had a quadrupled risk of late fetal death when compared to women with a body mass index of 20 or less. This study also documented that nulliparous women with a high body mass index had a higher rate of hypertensive disorders [28].

 

IUFD due to umbilical cord complications The most common cause of IUFD in the third trimester is due to umbilical cord accidents [15, 29, 30]. Carey and Rayburn reported that over a five year period in their institution a single nuchal cord was observed in 23.6 percent of all deliveries, both live and stillborn, and multiple nuchal cords were found in 3.7 percent of the stillborns [31]. In another study Sornes [32] determined an incidence of umbilical cord knots to be 1 percent, and a knot associated mortality rate of 2.7 percent. This was in contrast to the 0.48 percent rate of mortality in unknotted population. However, mere presence of a knot does not predict death. If the knot is loose and fetal circulation is maintained the fetus can survive, but if the knot is tightened, then there can be constriction of the blood vessels and fetal circulation can not be maintained. Furthermore, decreased Wharton’s jelly in certain areas of the cord, most notably the fetal and placental insertions, can result in occlusion of fetal blood flow if the vessels are twisted sufficiently [33].

 

Insertion abnormalities such as marginal insertion and velamentous insertion can also cause fetal death. Marginal insertions only occur 5 to 7 percent of the time, but may be more prone to vessel rupture or compression, thereby resulting in fetal demise [34, 35]. Velamentous insertion, which occurs in about 1 percent of singleton births, is the insertion of the umbilical cord vessels into the external membranes prior to their penetration into the placenta. These vessels are not surrounded by the protective Wharton’s and are therefore susceptible to folding, torsion rupture and exposure to inflammation if they traverse the internal cervical os [33]. Recent advances in ultrasound technology can help identify cord problemsincluding velamentous insertion, vasa previa, short cords, long cords, two vessel cords, true knots and nuchal cordsthereby potentiating the ability of the obstetrician to intervene when possible [36].

 

Utility of placental pathology The cause of fetal death can often be determined through pathologic examination of the placenta [14, 37-41]. The major pathologic processes observable in the placenta that can adversely affect pregnancy outcome include intrauterine bacterial infections [42, 43], decreased blood flow to the placenta from the mother [44, 45] and immunologic attack of the placenta by the mother’s immune system [38].

 

Unexplained fetal deaths Even with all of the advances made to date it has been estimated that there are as many as 12-50 percent of stillbirths with no identifiable etiology [46].

 

 

 

The causes of fetal death are often complex and sometimes even unknown, however, certain causes of fetal demise have higher incidences during specific periods of gestation. The major causes of fetal loss in each of the trimesters can be summarized as follows:

 

      First trimester: genetic

      Second trimester: infection

      Third trimester: cord accident

 

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