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The cause for intrauterine fetal demise (IUFD) occurring in early gestation in a high percentage of spontaneous abortions is unknown.
To determine the association, if any, of umbilical cord abnormalities with early IUFD.
All cases of IUFD occurring within 16 weeks of gestation that presented to our hospitals between August 1998 and July 2001 were prospectively studied. Once the fetal demise was diagnosed, pregnancy was terminated by medical induction, such that the products of conception were largely delivered intact. Cases with an intact umbilical cord connecting the fetus and placenta were considered in the study, whereas disrupted cord and curettage material was excluded from the study.
A total of 153 early IUFD cases were seen during the period of study. The medical induction yielded intact products of conception in 122 cases, whereas 31 cases had to be completed by curettage, as the expulsion of the conceptus was incomplete. Thirteen of the 122 IUFD cases showed abnormalities of the umbilical cord. The cord lesions most frequently encountered were constriction and coiling abnormalities. Other lesions seen included hemorrhage, thrombosis, edema, and amniotic band.
A significantly high number (10.7%) of IUFD in early gestation are associated with umbilical cord abnormalities. Routine assessment of umbilical cords in early pregnancy might help to detect pregnancies at risk.
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* Context-The cause for intrauterine fetal demise (IUFD) occurring in early gestation in a high percentage of spontaneous abortions is unknown.
Objective.-To determine the association, if any, of umbilical cord abnormalities with early IUFD.
Design-All cases of IUFD occurring within 16 weeks of gestation that presented to our hospitals between August 1998 and July 2001 were prospectively studied. Once the fetal demise was diagnosed, pregnancy was terminated by medical induction, such that the products of conception were largely delivered intact. Cases with an intact umbilical cord connecting the fetus and placenta were considered in the study, whereas disrupted cord and curettage material was excluded from the study.
Results-A total of 153 early IUFD cases were seen during the period of study. The medical induction yielded intact products of conception in 122 cases, whereas 31 cases had to be completed by curettage, as the expulsion of the conceptus was incomplete. Thirteen of the 122 IUFD cases showed abnormalities of the umbilical cord. The cord lesions most frequently encountered were constriction and coiling abnormalities. Other lesions seen included hemorrhage, thrombosis, edema, and amniotic band.
Conclusions-A significantly high number (10.7%) of IUFD in early gestation are associated with umbilical cord abnormalities. Routine assessment of umbilical cords in early pregnancy might help to detect pregnancies at risk.
(Arch Pathol Lab Med. 2003;127:850-853)
The role of umbilical cord abnormalities in causing intrauterine fetal demise (IUFD) has never received its due emphasis. Although there are many case reports and series studies that have identified cord anomalies as the direct cause of fetal death, exclusive prospective studies to evaluate the role of cord abnormalities in fetal death are rare. In part, the problem of studying the umbilical cord lies in the fact that it is difficult to procure an intact cord and still more difficult to obtain a gestational sac with the fetus and placenta connected by intact cord. More than 80% of all abortions occur in the first trimester, and 53% of these are attributable to chromosomal abnormalities.1 The cause of abortion in 45% of cases is unknown. Similarly, the cause of abortions in the early second trimester is unknown in a vast majority of cases. Therefore, we sought to evaluate the role of cord complications in IUFD during early pregnancy.
MATERIALS AND METHODS
During a 3-year period (August 1998-July 2001), all cases of IUFD in early pregnancy that were seen at 2 medical centers (Princess Durru Shehvar Children's & General Hospital and Vinaya Sree Nursing Home) were studied. Early pregnancy was defined as a period of amenorrhea in a pregnant woman not exceeding 16 weeks. Pregnant women who presented with clinical features and ultrasound evidence of IUFD were treated for uterine evacuation by medical induction of labor. The protocol for patient management at both the hospitals for IUFD in early pregnancy was essentially similar. Briefly, the procedure consisted of prior cervical softening and ripening by intravaginal Misoprostol (synthetic prostaglandin El analog). This was followed by intramuscular injections of Carboprost (15-methyl prostaglandin 2alpha) until onset of labor. Most patients went into labor after 3 to 4 injections of Carboprost (250 (mu)g). Although most patients tolerated the procedure well, in a few cases the expulsion of products of conception was incomplete. In such cases the uterine evacuation was completed by curettage. Thus, there was no alteration in the patient treatment for the sake of this study.
A total of 153 early IUFD were seen in the period of study. The gestational age ranged from 58 to 113 days, with a mean age of 83.1 days (12 weeks) and a median age of 80 days. The uterine evacuation by the medical procedure yielded largely intact gestational sac in 122 cases. In the remaining 31 cases in which curettage had to be employed to complete the evacuation, the products of conception were obtained as multiple shredded pieces of tissue. After evacuation of the uterus, the products of conception were immediately placed in 10% buffered formalin and sent for pathological examination. Of the 122 cases examined by the pathologist, 19 cases consisted of an empty sac. Thus, 103 cases consisted of a fetus attached to the placenta by an intact cord. External examination of the fetuses was performed, and the crown-heel length measure was used to determine the gestational age. The umbilical cords were carefully examined and appropriate sections for histology taken. Internal examination of the fetuses was not performed for various reasons that included institutional policy at one hospital and lack of consent for autopsy. All the cases studied were negative for Rh incompatibility and HIV infection. There were no cases of twin or multiple gestation.
RESULTS
The clinicopathologic features of the aborted fetuses with cord lesions are summarized in Table 1. All of the 13 cases that showed lesions in the umbilical cord were greater than 10 weeks' gestational age. All of the 19 cases that showed an empty sac with no fetus were less than 10 weeks' gestational age. The types and frequency of cord lesions that were encountered are listed in Table 2. One case of constriction with marked shortening of the cord is shown in the Figure, A. The constrictions were noted toward the fetal end in 4 of the 5 cases. One of the cases also had amniotic bands on his wrists. Three cases of hypercoiling were noted, with greater than 30 twists in each cord. One hypercoiled cord showed associated false knots (Figure, C) and another hypercoiled cord showed looping around the leg (Figure, B). One fetus showed disruption of the cord vasculature with significant intra-amniotic hemorrhage that formed a clot adherent to the cord close to the site of disruption (Figure, D). Amniotic bands that connected a hypocoiled cord to the fetal neck and strangulated the neck were seen in one case (Figure, E).
COMMENT
To our knowledge, this study is the first prospective study undertaken to specifically address the question of cord lesions associated with early (first-trimester and slightly beyond) IUFD. Most of the studies on umbilical cord abnormalities that are reported in literature are retrospective studies, and many do not mention the state of the examined cord. As will be apparent in the subsequent discussion, some of the subtle cord lesions can easily be missed if the cord is not intact or complete. In this study we have been unflinching in including only those cases in which the cord was complete and intact. The above caveat resulted in exclusion of 31 cases that comprised 20% of the total spontaneous abortion cases seen in the study period. The result of our study shows that 10.7% of IUFD occurring in early pregnancy are associated with abnormalities in the umbilical cord. This figure is close to the 9% association of IUFD with cord lesions reported by Karin et al.2 The study of Karin et al looked at IUFD occurring at or greater than 22 weeks of gestation. The cord complications seen in their study were thrombosis, cord prolapse, umbilical vessel rupture, true knot, and cord encirclement with strangulation.
Constriction or stricture of the cord consists of focal depletion of Wharton's jelly with narrowing of vessels. There may be torsion associated with the constriction. Several studies have shown the association between constriction and fetal death.3-5 The mechanism of death is postulated to be chronic ischemia superimposed by a catastrophic acute vascular event. In our series, constrictions were the most frequently encountered cord lesions.
Hypercoiling consists of increased number of twists in the cord. The normal cord shows 1 coil per 5 cm, and the coiling is established as early as 9 weeks of gestation.6 Hypercoiling may be associated with constriction and long cords. Frequently the hypercoiled cord becomes thin and whiplike, or sometimes the torsion is focal. Many studies have shown that hypercoiling can lead to fetal death.7-9 Machin et al,9 in studying the association of cord coiling with perinatal outcome, found that overcoiled cords were associated with a high incidence of fetal demise, intrauterine growth retardation, and fetal intolerance of labor. One case report10 documents the occurrence of torsion in a woman in 3 of her pregnancies, all of which ended in abortions. The 3 pregnancies were in the gestation periods of 15.5 to 19 weeks. We found 3 cases of hypercoiling in our study. At the other end of the coiling spectrum is acl-drality, or absence of coiling. There was one case of achiral cord and one case of hypocoiled cord in our study. Several studies have described the association of hypocoiling and achirality with high incidence of fetal distress, interventional delivery, and IUFD.11,12 The authors of these studies hypothesize that decreased coiling makes the cord less able to withstand external forces of compression. Some of these authors advocate routine antenatal assessment of umbilical cord coiling to monitor fetal wellbeing.
Disruption of vessels in the cord can lead to exsanguination of blood that, if confined to the cord, forms a hematoma. However, if the cord epithelium is breached, blood leaks into the amniotic cavity. Such an intra-amniotic cord hemorrhage might go unidentified if curettage or aspiration is employed to evacuate the products of conception. However, delivery of an intact gestational sac allows intra-amniotic hemorrhage and the focus of vascular disruption to be identified. In our study we encountered one case of umbilical cord rupture and intra-amniotic hemorrhage. Other authors have reported the association of cord hematoma with IUFD.13,14 Although rare, thrombosis can occur in the umbilical vessels. Thrombosis of the umbilical vein can result in lUFa 15-17 Factors that induce thrombosis are poorly understood. Over the last few years several markers have been identified that cause thrombophilia, which is characterized by increased risk for thrombosis. These markers include Protein C deficiency, Protein S deficiency, antithrombin-III deficiency, mutated methylenetetrahydrofolate reductase gene, mutated factor V Leiden, and mutated prothrombin gene (G20210A). Alonso et al18 in their study of women with unexplained fetal losses found that thrombophilia was associated with second- and third-trimester losses, but not with first-trimester IUFD. Maternal conditions such as diabetes mellitus,19 presence of lupus anticoagulant,20 and umbilical vein varix are known to enhance the risk of thrombus formation in the umbilical vein of the fetus. There was one case of umbilical vein thrombosis in our study; however, the mother had no identifiable risk factors.
A, Constriction in a short cord; arrow points to site of constriction. B, Hypercoiling whiplike hypercoiled segment between the arrows. C, Hypercoiling; arrow points to false knot. D, Arrow points to site of rupture, arrowhead points to large clot adherent to the cord. E, Amniotic band strangulating the cord and fetal neck. The face is covered by a veil of amniotic membranes. Arrows point to band.
We encountered one case of edematous cord in a nonhydrops fetus in our series. Edematous cords are usually associated with hydrops fetalis. However, in a nonhydrops setting, edema of the cord may be an harbinger of respiratory distress in the newborn.21 Edema in the cord can be identified by uniform, diffuse swelling of the cord that is moist and gelatinous on its cut surface. In the case of severe edema, fluid may ooze from the cut surface.
Rupture of the amniotic membranes can lead to formation of amniotic bands. When these amniotic bands encircle fetal parts or umbilical cord they can result in dysmorphogenesis, limb reduction defects, or fetal demise.22,23 We encountered one case in our study in which an amniotic band strangulated the neck of the fetus and the umbilical cord.
It is interesting to note that cord abnormalities such as true knots, nuchal cord, insertional abnormalities, tumors, and single umbilical artery were not seen in our study. Perusal of the literature on placental and cord pathology indicates that the aforementioned lesions in the cord occur more often in the second half of the pregnancy. Benirschke24 reported a higher incidence of cord constrictions in early IUFD. Perhaps different pathogenetic mechanisms underlie the lesions of the cord in early versus late pregnancy. Ultrasound evaluation of umbilical cord for cord length, diameter, coiling index, and vascular flow from early pregnancy can help identify patients at risk. Such an evaluation by ultrasound during the course of pregnancy will also help in identifying cases of cord lesions that may not develop distress and may survive the lesion. Some of the cord lesions, such as umbilical vein thrombosis, hypercoiling, or hypocoiling, are compatible with survival if the severity of the lesion is not extreme.
In summary, our study has found a significant association between early IUFD and lesions in the umbilical cord. Specifically, cord lesions like constriction, aberrations in coiling, hemorrhage, thrombosis, and amniotic bands appear to occur more frequently in early gestation. As fetal autopsy was not permitted, our study did not attempt to establish the cord lesions as the primary cause of fetal death. Nonetheless, the study has uncovered a significantly large number of lesions in the cord occurring during early gestation. From this and other studies it is apparent that cord abnormalities may account for as many as 9% to 11% of spontaneous abortions occurring in early gestation. However, comprehensive studies, perhaps multicentric ones, are needed to establish the exact incidence of cord lesions in early pregnancy.
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Vivekanand Singh, MD; Sufia Khanum, MBBS, DGO; Meenal Singh, MBBS
Accepted for publication January 27, 2003.
From the Departments of Pathology (Dr V Singh) and Obstetrics and Gynaecology (Dr Khanum), Princess Durru Shehvar Children's & General Hospital, Purani Haveli, Hyderabad, India 500002; and the Vinaya Sree Nursing Home, Vijayawada, AP-India (Dr M Singh).
Reprints: Vivekanand Singh, MD, FCAP, Children's Hospital, Anatomic Pathology, 700 Children's Dr, Columbus, OH 43205 (e-mail: [email protected]).
Copyright College of American Pathologists Jul 2003