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Abstract
Objective. To compare pathological findings of placentas from term and preterm pregnancies complicated by intrauterine
fetal death (IUFD).
Study design. A retrospective cohort study was conducted including deliveries complicated by IUFD. A comparison was
For personal use only.
made between placentas from term and preterm (537 weeks gestation) pregnancies complicated by IUFD. A second
analysis was undertaken comparing IUFD placentas delivered before and after 34 weeks gestation. Uteroplacental
insufficiency was defined when one or more of the following pathological features were found: placental infarct, poor
vascularity of the chorionic villi, intravascular thrombi and vascular occlusion.
Results. During the study period, 849 placentas of IUFD were examined. Gross and microscopic pathological finding were
noted. When comparing gross and microscopic findings in term and preterm (537 weeks) IUFD placentas, higher rates of
calcifications, tissue congestion and cellular metaplasia were found in term vs. preterm placentas. Significantly increased
rates of poor tissue vascularity, placental vascular occlusion and uteroplacental insufficiency were demonstrated in preterm
IUFD placentas. When comparing pathological findings in IUFD placentas delivered before and after 34 weeks gestation,
higher rates of abnormal cord insertion, calcifications, tissue congestion, infarcts and intravascular thrombi as well as poor
tissue vascularity and placental vascular occlusion were demonstrated in IUFD placentas delivered before 34 weeks.
Regardless of gestational age at the time of IUFD in more than 90% of placentas vascular wall thickening was found. A third
of both term and preterm placentas demonstrated histological chorioamionitis.
Conclusions. A vast majority of IUFD placentas reveal numerous pathological findings that reflect uteroplacental
insufficiency and abnormal blood supply. Different characteristics were noted in term and preterm placentas of pregnancies
complicated by IUFD. Better definition of causes and associated placental pathological findings of IUFD might aid
clinicians in counseling such patients regarding the reason and risk of recurrence in subsequent pregnancies.
Keywords: Intrauterine fetal death, placenta, uteroplacental insufficiency, poor vascularity, vascular occlusion, intravascular
thrombi, infarct
Correspondence: Adi Weintraub, MD, Department of Obstetrics and Gynecology, Soroka University Medical Center, POB 151 Beer-Sheva 84101, Israel.
Tel: 972-8-640-0774. Fax: 972-8-627-5338. E-mail: adiyehud@bgu.ac.il
ISSN 1476-7058 print/ISSN 1476-4954 online 2009 Informa UK Ltd.
DOI: 10.3109/14767050902929396
760 H. Amir et al.
after 22 complete gestational weeks or a fetus been well defined. More accurate definitions for the
weighing more than 500 g. subgroup of infants born near-term are important
In the United States, the incidence of fetal death is because of the rapid increase in rate of births
6.4/1000 births (2002), whereas among Afro-Amer- attributed to this group. Replacing near-term with
ican population it was 12.1/1000, and among late preterm would better reflect the higher risk for
Caucasians 5.5/1000 births. Fetal death consists of complications of prematurity experienced by this
60% of all perinatal death [1]. In Israel, at our center, subgroup of infants. Late preterm has been defined
the incidence of IUFD was found to be 3.6 per 1000 as beginning on the 239th day (34 0/7 weeks
births [7]. Less then one percent (0.9%) suffered gestation) and ending on the 259th day (36 6/7
recurrent perinatal mortality [3]. weeks gestation) since the first day of the last
Many causes and risk factors for IUFD have been menstrual period [14].
elaborately described in the literature [13,79]. The literature regarding placental pathologies in
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They can be classified to etiologies related to the cases of IUFD according to the time of occurrence is
fetus, the mother and the pregnancy. In the absence of scarce. Little is known about different placental
a definite cause, many of these cases are defined as features in cases of IUFD at term and preterm. The
unknown or idiopathic. Furthermore, the causes and purpose of this study was to compare pathological
risk factors for fetal death change according to the time findings in placentas from term and preterm preg-
of death. According to Kunzel and Misselwitz [10], nancies complicated by IUFD and to assess weather
40% of all cases of fetal death occur during week 37 of different pathological features of IUFD placentas
gestation or more and 27% occur between weeks 32 delivered before and after 34 weeks are noted.
and 36. They also found that out of all pregnancies,
the chance of fetal death declines as the pregnancy
Materials and methods
continues. In the same study, the main risk factors
found for fetal loss before 36 weeks of gestation were A retrospective cohort study was conducted includ-
bleeding because of placenta previa and placental ing all singleton deliveries complicated by IUFD,
For personal use only.
abruption. The main risk factors for fetal death beyond defined as pregnancy loss after 22 complete gestation
36 weeks of gestation were placental insufficiency, weeks or 500 g. Deliveries occurred between the
proteinuria, and diabetes [10]. years 1995 and 2004 at the Soroka University
Comprehensive IUFD assessment is important, Medical Center. This is the sole hospital in the
cost-effective and justified for recurrence risk estima- Negev, the southern part of Israel, serving the entire
tion, prenatal diagnosis recommendations, or pre- obstetrical population in this region. The local ethics
conceptual, prenatal, perinatal or neonatal institutional review board approved the study.
treatment. Michalski et al. [11] found that when Data were collected from the computerised
comprehensive, nonselective analysis is performed, perinatal database, which includes information pro-
new and relevant information arises in 51% of IUFD vided immediately after delivery by the attending
infants [11]. Upon investigating possible explana- obstetrician. Specialist medical secretaries examine
tions for IUFD, an autopsy is considered the best the information routinely before entering it into the
possible method. An autopsy can provide informa- database. Coding is done after assessing the medical
tion regarding the risk factors and offer explanations prenatal care records as well as the regular hospital
for the fetal death, such as chromosomal abnormal- documents. These procedures ensure the complete-
ities, structural abnormalities, metabolic abnormal- ness and accuracy of the database.
ities, signs of hypoxia, infection and other Pathology data were collected from the compu-
abnormalities. The autopsy result can also aid in terised pathology database. The placentas at the
consulting the parents and assessing the odds of pathology department are grossly examined by a
recurrence in 2651% of the cases [12]. resident in surgical pathology, who routinely takes
Unfortunately, an autopsy is preformed in less two samples from the placental tissue, one sample of
than 50% of the cases mainly because of religious umbilical cord, and one sample of the extra-placental
and cultural reasons in Israel as well as in other membranes for each case. Additional tissue is taken
countries in the world. After an autopsy, the most from each gross lesion.
informative investigation is an examination of the The following clinical characteristics were evalu-
placenta by a trained pathologist. A macroscopic and ated: Maternal age, gravidity, parity, ethnicity (Jew-
microscopic examination could reveal many patho- ish vs. Bedouin Arabs), nulliparity, gestational age,
logical findings including structural abnormalities, placental weight. In addition, fetal gender, birth
infections and evidence of uteroplacental insuffi- weight [grouped into small for gestational age
ciency [1,13]. (SGA), appropriate for gestational age (AGA) and
Definitions for preterm, term and post term have large for gestational age (LAG)], maternal blood type
been specifically classified. However, definitions for and Rhesus (Rh) status and maternal serum hemo-
subgroups of infants within these categories have not globin level were recorded.
Placental findings in IUFD pregnancies 761
The following macroscopic pathological features Term IUFD were of higher parity compared with
have been inspected: Placental size and weight, preterm IUFD. There were no significant differences
umbilical cord length and color, number of blood between groups neither in maternal age, maternal
vessels in the cord, placental tissue engorgement, blood type and Rh status nor in fetal gender.
infarcts, calcifications and signs of hemorrhage. The Table III presents gross pathological findings in
following microscopic features have been examined: term and preterm IUFD placentas. Higher rates of
Degree of vascularity, infarcts, placental calcifica- calcifications and tissue congestion were noted in
tions, changes in blood vessel walls and lumen, term as compared with preterm IUFD placentas.
thromboses, metaplasia, syncitial knots, hemorrhage, Microscopic pathological findings in term and
chorioamnionitis and funisitis. preterm IUFD placentas are presented in Table IV.
We defined uteroplacental insufficiency when one A significant difference in cellular metaplasia was
or more of the following pathological features were found between the groups (70.8% of term IUFD vs.
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found: placental infarct, poor vascularity of the 55.5% of preterm IUFD, p 0.014). An increased
chorionic villi, intravascular thrombi and vascular rate of poor tissue vascularity (86.5% vs. 65.9%,
occlusion (described elsewhere [15]). p 5 0.001), vascular occlusion (25.5% vs. 13.5%,
Statistical analysis was performed using the SPSS p 0.022) and uteroplacental insufficiency 83.1% vs.
package (SPSS, Chicago, IL). Statistical significance 92.0%, p 0.025) was demonstrated in preterm
was ascertained using the Chi-square test for IUFD placentas.
differences in qualitative variables and the Student Regardless of gestational age at the time of IUFD
t-test for differences in continuous variables. A p- in more than 90% of placentas vascular wall
value of 50.05 was accepted as statistically signifi- thickening was found. A third of both term and
cant. preterm (537 weeks) placentas demonstrated histo-
logical chorioamionitis.
Table V presents gross pathological findings in
Results
IUFD placentas delivered before and after 34 weeks.
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During the study period, 849 placentas of IUFD Higher rates of calcifications and tissue congestion
were examined, macroscopic and microscopic patho- were noted in IUFD placentas delivered after 34
logical finding were noted. Demographic and clinical weeks (29.2% vs. 14.0%, p 5 0.001 and 74.4% vs.
characteristics of patients with term and preterm
IUFD are presented in Table I. Patients were more
likely to be of Bedouin than of Jewish ethnicity Table II. Maternal, fetal and placental characteristics in preterm
and term IUFD.
(62.9% vs. 37.1%). More than 20% of the patients
were nulliparas. Preterm Term
Maternal, fetal and placental characteristics in Characteristics IUFD IUFD p
term and preterm IUFD are presented in Table II.
Maternal age (years + SD) 16.2 + 12.9 29.9 + 0.5 0.52
Biophysical characteristics such as birth-weight for
Gravidity 4.4 + 0.1 4.8 + 0.2 0.89
gestational age, placental volume (ml), placental Parity 3.7 + 0.1 4.3 + 0.2 0.012
weight (g) and length of the placental portion of Maternal blood type 0.57
the cord (cm) are gestational age related and A 30.4 31.6
therefore, were significantly different between B 24.2 23.6
AB 4.8 7.1
groups. A significant higher level of maternal
O 40.5 37.8
hemoglobin was noted in term vs. preterm IUFD Rhesus status 0.29
(11.5 + 0.1 g/dl vs. 11.1 + 0.07 g/dl, p 0.004). Positive Rh 88.5 85.8
Negative Rh 11.5 14.2
Table I. Demographic and clinical characteristics of patients with Maternal serum 11.1 + 0.07 11.5 + 0.1 0.004
IUFD. hemoglobin level (g/dl)
Fetal gender 0.72
Characteristic Study group (n) Male 49.9 51.3
Female 50.1 48.7
Maternal age 29 + 6.87 (849) Birth-weight for gestational age 50.001
Gravidity 4.49 + 3.40 (849) SGA 27.9 35.1
Parity 3.85 + 3.00 (849) AGA 67.9 54.1
Ethnicity LGA 4.2 10.8
Jewish 37.1% (315) Placental volume (ml) 379 + 12 567 + 6 50.001
Bedouins 62.9% (534) Placental weight (g) 413 + 14 831 + 60 50.001
Nulliparity 21.2% (180) Cord length (cm) 26.3 + 0.5 34.6 + 1.0 50.001
Gestational age 31.67 + 5.68 (849)
Placental weight 547.57 + 586.688 (749) SGA, small for gestational age; AGA, appropriate for gestational
age; LGA, large for gestational age.
IUFD, intrauterine fetal demise. Data are expressed as means + standard deviation (SD) or
Data are expressed as mean + standard deviation (SD). percentages.
762 H. Amir et al.
Table III. Gross pathological findings from preterm and term Table V. Gross pathological findings from IUFD placentas
IUFD placentas. delivered before and after 34 weeks gestation.
Abnormal cord insertion 1.9% (9) 4.1% (7) 0.148 Abnormal cord 1.1% (4) 4.5% (12) 0.006
Calcifications 15.8% (81) 33.5% (59) 50.001 insertion
SUA 5.5% (27) 4.1% (7) 0.455 Calcifications 14% (57) 29.2% (83) 50.001
Meconium 40.4% (21) 36.4% (8) 0.746 SUA 5.2% (20) 5.1% (14) 0.997
Congestion 51.6% (210) 77.3% (116) 50.001 Meconium 55% (22) 67.6% (23) 0.267
Hemorrhage 5.4% (28) 5.7% (10) 0.906 Congestion 47.6% (157) 74.4% (169) 50.001
Infarcts 15.2% (78) 13.6% (24) 0.620 Hemorrhage 5.7% (23) 5.3% (15) 0.828
Infarcts 14% (57) 15.8% (45) 0.511
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Vascular occlusion 25.5% (51) 13.5% (12) 0.022 Infarcts 41% (64) 54.1% (72) 0.026
Intravascular thrombi 4.5% (9) 9% (8) 0.134 Vascular occlusion 28.8% (45) 13.5% (18) 0.005
Knots 4.5% (9) 3.4% (3) 0.657 Intravascular thrombi 3.2% (5) 9% (12) 0.036
Wall thickening 91% (182) 91% (81) 0.998 Knots 3.8% (6) 4.5% (6) 0.778
Hemorrhage 12.5% (25) 16.9% (15) 0.322 Wall thickening 91% (142) 91% (121) 0.989
Calcifications 12.5% (25) 10.1% (9) 0.561 Hemorrhage 12.2% (19) 15.8% (21) 0.376
Histological 33% (66) 30.3% (27) 0.655 Calcifications 12.8% (20) 10.5% (14) 0.546
chorioamnionitis Histological 33.3% (52) 30.8% (41) 0.649
Funisitis 6% (12) 6.7% (6) 0.810 chorioamnionitis
Uteroplacental 92.0% (184) 83.1% (74) 0.025 Funisitis 5.8% (9) 6.8% (9) 0.726
insufficiency* Uteroplacental 91.7% (143) 86.5% (115) 0.154
insufficiency*
IUFD, intrauterine fetal demise.
Data are presented as percentages and p values for statistical IUFD, intrauterine fetal demise.
significance. Data are presented as percentages or means + SD and p values for
*Uteroplacental insufficiency was defined as one or more of the statistical significance.
following: vascular occlusion, poor vascularity, intravascular *Uteroplacental insufficiency was defined as one or more of the
thrombi and placental infarcts. following: vascular occlusion, poor vascularity, intravascular
thrombi and placental infarcts.
Although similar rates of uteroplacental insufficiency adverse outcomes in most studies [23]. Redline [24]
were noted in placentas delivered before and after 34 found that histological evidence of chorioamnionitis
weeks gestation, this difference was not statistically decreases with gestational age reaching 1015% at
significant. Perhaps, this indicates a late insult, which term. Histological chorioamnionitis was documented
occurs more frequently during the period of late in 3033% of all IUFD placentas in the current
prematurity. study, regardless of gestational age. This high and
The maternal and fetal placental vascular trees are constant incidence of histological chorioamnionitis
dynamic structures which can be significantly altered could be the cause of IUFD in some cases, whereas
by abnormal development, luminal obstruction and in others, it could be the result of a prolonged
physical loss of integrity. Inflammatory responses can induced labour.
develop at the maternalfetal interfaces of the Higher rates of calcifications and tissue congestion
placenta where organisms enter the placental envir- were noted in placentas from term IUFD placentas
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onment, fetal antigens are presented to the adaptive compared with preterm (537 weeks) placentas. This
maternal immune system and ischemic processes was also true while comparing IUFD before and after
release mediators that can activate the innate 34 weeks gestation. Calcifications are common in
immune system [17]. human placentas and are widely recognised as a
Different placental lesions were associated with normal part of maturation and aging of this organ
uteroplacental insufficiency [15,18,19]. In this study, [25]. Tissue congestion may be a result of stasis and
we defined uteroplacental insufficiency when one or therefore reflects a consequence rather than a cause
more of the following pathological features were of IUFD. Placental tissue congestion can be a result
found: placental infarct, poor vascularity of the of increased resistance to flow through the umbilical
chorionic villi, intravascular thrombi and vascular and placental vessels, therefore decreased flow,
occlusion. Unfortunately, no pathological guidelines venous stasis, villous congestion, and distension of
regarding autopsy and placental examination after the fetal vessels, predisposing the placenta to the
IUFD exist [16]. development of thrombi and congestion. Lack of
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Placental lesions leading to obstruction of the fetal blood flow through fetal vessels could lead to
circulation are an important cause of adverse decreased oxygen to the placenta and fetus, poten-
pregnancy outcomes [20]. When sufficiently exten- tially causing intrauterine hypoxia [26].
sive thrombosis may in some cases, be the conse- The lesion of acute atherosis is characterised by
quence of stasis or vascular wall damage. In our thickening of the vascular intima and necrosis of the
study, we found that poor vascularisation was more media. Intimal thickening is because of deposition of
frequent in early compared with late IUFD placen- fibrin and other plasma constituents and migration of
tas, both when 37 weeks gestation (65.9% term vs. macrophages and myointimal cells which accumulate
86.5% preterm, p 5 0.001), and 34 weeks gestation fat in their cytoplasm to become foam cells. Clinical
(72.8% 434 weeks vs. 86.2% 5 34 weeks, and experimental studies indicate that these lesions
p 0.006), were used as cutoffs. can be initiated by several factors which cause
The most common cause of stasis is compromised endothelial injury [27]. Placental vascular wall
umbilical blood flow secondary to chronic partial or thickening was found in over 90% of placentas
recurrent intermittent umbilical cord compression examined in the current study. Because we could not
[21, 22]. We found abnormal cord insertion in 4.5% differentiate between cases in which endothelial
placentas of IUFD 434 weeks, and only 1.1% when injury was the cause of IUFD from those in which
IUFD occurred before 34 weeks. It is possible that it was the result of IUFD we did not include this
abnormal cord insertion predisposes the cord to variable in the definition of placental insufficiency.
chronic or acute compression. Five cases were noted Cellular metaplasia occurs because of abnormal
between 34 and 37 weeks, it is possible that the rate stimulus, such as fetal stress or inflammation, and
and severity of cord compression increases with includes a replacement of one differentiated cell type
gestational age. to another, to survive the changing environment
The most common placental inflammatory lesion [28]. Such metaplasia was more frequent in term
is acute chorioamnionitis caused by micro-organisms placentas, which might reflect fetal stress occurring
gaining access to the placental membranes and/or late in gestation, causing cellular metaplasia and
amniotic fluid [22], Chorioamnionitis per se is a eventually fetal death.
maternal inflammatory response beginning near In conclusion, a vast majority of IUFD placentas
venules in the decidua capsularis and in the reveal pathological findings that reflect uteroplacen-
subchorionic fibrin above the intervillous space and tal insufficiency and abnormal blood supply. Differ-
subsequently spreading into the adjacent chorion ent characteristic findings were noted in term and
and amnion. This maternal response is usually preterm placentas of pregnancies complicated by
clinically silent and has not been associated with IUFD. In future studies, a better definition of IUFD
764 H. Amir et al.
causes and associated placental pathological findings 14. Engle WA. A recommendation for the definition of late
might aid clinicians in counseling, assessing the risk preterm (near-term) and the birth weight-gestational age
classification system. Semin Perinatol 2006;30:27.
of recurrence and even preventing IUFD in sub- 15. Salafia CM, Pezzullo JC, Minior VK, Divon MY.
sequent pregnancies. Placental pathology of absent and reversed end-diastolic flow
in growth-restricted fetuses. Obstet Gynecol 1997;90:830
Declaration of interest: The authors report no 836.
16. Korteweg FJ, Gordijn SJ, Timmer A, Holm JP, Ravise JM,
conflicts of interest. The authors alone are respon-
Erwich JJ. A placental cause of intra-uterine fetal death
sible for the content and writing of the paper. depends on the perinatal mortality classification system used.
Placenta 2008;29:7180.
17. Redline RW. Placental pathology: a systematic approach with
References clinical correlations. Placenta 2008;29:S86S91.
1. Silver RM. Fetal death. Obstet Gynecol 2007;109:153167. 18. Salafia CM, Ernst LM, Pezzullo JC, Wolf EJ,
Rosenkrantz TS, Vintzileos AM. The very low birthweight
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