Accepted Manuscript Comparison of placental pathology in preterm, late-preterm, near-term, and term births Jerzy Stanek, MD, PhD PII:
S0002-9378(13)01080-6
DOI:
10.1016/j.ajog.2013.10.015
Reference:
YMOB 9500
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 31 July 2013 Revised Date:
18 September 2013
Accepted Date: 16 October 2013
Please cite this article as: Stanek J, Comparison of placental pathology in preterm, late-preterm, near-term, and term births, American Journal of Obstetrics and Gynecology (2013), doi: 10.1016/ j.ajog.2013.10.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Comparison of placental pathology in preterm, late-preterm, near-term, and term births
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Jerzy STANEK, MD, PhD
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From the Department of Pathology and Laboratory Medicine and Department of Pediatrics,
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University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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The author reports no conflict of interest
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This research was orally presented at the 25 European Congress of Pathology, Lisbon, Portugal,
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August 31-September 4, 2013.
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Reprints not available from the author
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Address: Division of Pathology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet
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Avenue, Cincinnati, OH 45229-3026, tel. 513 636 8158 (work), 513 834 9956 (home), fax 513
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636 3924, email: [email protected]
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Word count: abstract 240, main text 2054
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Condensation: Varying of placental phenotypes support the division of the 3rd trimester in four
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gestational age intervals (25 words)
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Short version of the title: Placental pathology in 3rd trimester of high risk pregnancy
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Abstract
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OBJECTIVE: To study if placental pathology supports the recent suggestion of subcategorizing
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preterm and term births into smaller gestational age subgroups with different perinatal mortality
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and morbidity.
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STUDY DESIGN: 27 clinical and 43 placental phenotypes were retrospectively compared in
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4617 third trimester births: 1332 preterm pregnancies (28-33 weeks), 1066 late preterm
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pregnancies (34-36 weeks), 940 near term pregnancies (37-38 weeks), and 1279 term
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pregnancies (39+ weeks)
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RESULTS: Acute inflammatory pattern of placental injury was seen mostly at both gestational
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sides of the 3rd trimester, while the clinical conditions linked to in-utero hypoxia (preeclampsia,
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diabetes mellitus, fetal growth restriction) and their placental associations (atherosis, membrane
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chorionic microcysts, chorangiosis, intervillous thrombi) were statistically significantly
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associated with mid-3rd trimester. Acute fetal distress (abnormal fetal heart tracing, and clinical
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and histological meconium) were increasing with gestational age and were statistically
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significantly most common in full term pregnancies.
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CONCLUSION: Differences in placental pathology among the four subgroups of third trimester
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pregnancy not only challenge the use of an arbitrary cutoff point of 37 weeks separating the
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preterm birth and term birth, but also further support separation of late preterm births from
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preterm births, and term births from near term births. Based on placental pathology, chronic
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uteroplacental perfusion is the dominating etiopathogenetic factor in the mid 3rd trimester (late
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preterm and near term births), while acute fetal distress in full term births. This obscures relative
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frequencies of perinatal mortality and management modalities in the 3rd trimester.
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Key words: high risk pregnancy, placenta, preeclampsia, preterm birth, term birth
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Separation of third trimester births into preterm (up to 36 completes gestational weeks) and term
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(37+ gestational weeks) is time-honored.1 However, there is accumulating evidence that preterm
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and term births are not homogeneous groups with regard to maternal diagnoses and fetal
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morbidity and mortality profiles. It seems that prematurity by even a single week increases the
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risk of neonatal morbidity and mortality.2-4 Even at the 37 week, i.e. the first week of term
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gestation, the morbidity rates are twice those at 38 weeks.5 The prematurity rates increase even
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without increasing prevalence of maternal risk factors such as preeclampsia, umbilical cord
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accidents or chorioamnionitis.6 Others found a 23% decrease of adverse outcomes with each
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week of advancing gestational age between 32 and 39 completed weeks; therefore, more
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conservative approach was recommended for late preterm pregnancies.7 Therefore, the term birth
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previously considered a homogeneous group to which risks associated with preterm and postterm
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births are compared, forms a heterogeneous group and the children born earlier in the term
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period (early term) and those born later need to be considered as separate subgroups.8,9
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Placental examination is a well-recognized diary of pregnancy, its results included as one of
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the major phenotypes in assessment of preterm deliveries.10 Although the frequencies of various
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placental diagnoses vary with gestational age,11 the associations of various patterns of placental
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injury with the changing clinical phenotypes in the 3rd trimester gestational age intervals are
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largely unknown, assessment thereof is the goal of this retrospective analysis.
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Methods
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The project has been approved by the institutional review board. 27 clinical and 43 placental
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phenotypes were retrospectively analyzed in all consecutive 4617 third trimester births from
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which the placentas were examined by the author in years 1994-2012: 1332 preterm pregnancies
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(28-33 weeks), 1066 late preterm pregnancies (34-36 weeks), 940 near term (early term)
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pregnancies (37-38 weeks), and 1279 term pregnancies (39+ weeks). The gestational age
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determination for this study was determined based on combination of the 1st trimester ultrasound
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(where available), last menstrual period or obstetric estimate of gestational age. The data were
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extracted from the author’s clinicoplacental database built from clinical charts and placental
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reports. There were no exclusion criteria, therefore all types of perinatal mortality and morbidity,
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including stillbirths, were included. The post-term deliveries were included in the term group as
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the precise definitions of the post-term pregnancy are somewhat obscure.8 Placentas had been
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submitted for examination at discretion of obstetricians because of the high risk nature of
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pregnancy, fetal distress, poor condition of the neonate, operative delivery, or grossly abnormal
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placenta. Placental examination was performed according to generally accepted criteria;
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specifically, placental measurements and trimmed weights were recorded, at least 2 sections of
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placental membrane roll and umbilical cord, and at least two paracentral full thickness chorionic
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disc sections were routinely taken as a part of placental examination if no gross lesions were
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identified. All grossly seen lesions were additionally sampled. The samples were fixed in
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buffered formalin, followed by routine paraffin embedding, cutting, and staining with
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hematoxylin and eosin. Definitions of clinical conditions1 and placental diagnoses were either
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standard12-16 or same as reported by the author separately.17 The statistical analysis compared the
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clinical and placental phenotypes of the adjacent third trimester intervals using the Yates χ2 test
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followed by the Holm-Bonferroni correction for multiple comparisons.
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Results
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The analyzed clinical complications and outcomes and placental phenotypes were seen in all four
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gestational age intervals, thus indicating the continuity and overlapping of pathophysiology in
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the 3rd trimester of pregnancy (Table 1). However, the frequencies of particular clinical and
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placental phenotypes in the placentas from high-risk patients in four gestational age intervals
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varied.
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Of clinical variables, the frequency of all types of preeclampsia sharply dropped in term pregnancies, while that of mild preeclampsia nearly doubled between preterm and late preterm
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births. There were no statistically significant differences in, gestational hypertension, severe
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preeclampsia, HELLP, eclampsia, or chronic hypertension without superimposed preeclampsia.
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The frequency of premature rupture of membranes was twice as high in preterm then in late
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preterm births, and then decreased twice in nearly term and term births. The frequency of
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induction of labor doubled between preterm and late preterm births, and the frequencies of
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multiple pregnancy dropped between late preterm and near term, and again between near term
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and term pregnancies, while fetal malformations diminished by half between near term and term
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pregnancies. Frequencies of clinical abnormal fetal heart tracing were stable in the first three
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gestational age intervals, but increased sharply in term pregnancies. This was paralleled by
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clinical meconium (both thin and thick meconium). The fetal growth restriction was most
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common in the middle of the 3rd trimester (an inverted U-shape curve), with the frequencies
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significantly rising between preterm and late preterm pregnancies, and decreasing between near
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term and term births. The perinatal mortality rate halved between preterm and late preterm
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pregnancies and then leveled in the remaining three groups. On the contrary, complications of
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the 3rd stage of labor were least common in association with preterm placentas in comparison to
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the remaining 3rd trimester. There were no statistically significant differences in the remaining
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clinical variables studied: poor or absent prenatal care, maternal substance abuse,
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oligohydramnios, polyhydramnios, antepartum hemorrhage, cesarean section rate, nonmacerated
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stillbirth, and umbilical cord compromise (variable decelerations, entanglement, true knot,
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prolapse). Of placental phenotypes, the acute inflammatory pattern of placental injury was seen mostly at
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both gestational ends of the 3rd trimester and less commonly in the mid-3rd trimester (almost U-
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shaped frequency curve). The histological features of acute in-utero hypoxia (deep meconium
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penetration and placental infarction)17 showed more linear gestational age relationship in the 3rd
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trimester, the first one increasing and the second one decreasing, although the latter
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insignificantly. The pattern of the chronic uterine type of chronic hypoxic placental injury with
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its associated placental features (chorionic microcysts, chorangiosis)17 were statistically
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significantly more commonly seen in the mid-3rd trimester placentas, preceded by atherosis of
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maternal spiral arterioles in preterm placentas. The intervillous thrombi were the least common
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in preterm placentas. There were no statistically significant differences in features of fetal
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thrombotic vasculopathy, hydrops-related changes, chronic villitis of unknown etiology, plasma
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cell deciduitis, erythroblasts in fetal blood, villous infarction, hypertrophic decidual
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arteriolopathy, laminar necrosis of placental membranes, preuterine or postuterine patterns of
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chronic hypoxic patterns of placental injury, chorionic microcysts of chorionic disc, maternal
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floor multinucleate trophoblastic giant cells, excessive amount of extravillous trophoblasts,
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massive perivillous fibrinoid deposition, stem obliterative endarteritis, retroplacental hematoma,
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intravillous hemorrhage, choriodecidual hemosiderosis, or other, mostly gross, placental
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abnormalities among the studied 3rd trimester intervals placentas.
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Overall, for clinical and placental phenotypes, statistically significant differences (not
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including subcategories) were seen in 6, 3 and 7, and 5, 2, and 3 pairs of preterm-late preterm,
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later preterm-near term, and near term-term births, respectively (Fig. 1), i.e. the placental
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differences were less common than the clinical differences in this material. The only phenotype
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that consistently showed statistically significant differences between all adjacent intervals was
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the histological meconium, i.e. a placental phenotype.
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Conclusion and discussion
The impact of such factors as infection, inflammation, and abnormal implantation and
placentation on perinatal morbidity/mortality is not same throughout the gestation in general,18
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and throughout the third trimester in particular, as this analysis has shown. Usually, the preterm
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birth and hypertensive disorders are the most commonly discussed clinical phenotypes, and
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inflammation, decidual arteriolopathy and infarctions the most commonly discussed placental
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phenotypes. It is understandable that in preterm pregnancies, both neonatal and fetal mortality
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were statistically significantly the highest in the analyzed material, the former most likely related
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to consequences of prematurity and the latter to poor uteroplacental perfusion. It has been
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reported that the preterm birth rate has increased by 33% in the last 25 years, almost entirely due
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to the rise in the late preterm births (34-36 weeks gestation). The possible reasons are improved
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risk assessment, more elective inductions and cesarean sections, increasing maternal age and
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increasing rates of multiple gestations.5 The plateauing of perinatal mortality/morbidity starting
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with late preterm pregnancies by this analysis may result from overlapping of various etiologies
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which confirms observations of others19 and from the fact that not all placentas were examined.
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The cesarean section rate remained relatively constant throughout the third trimester, but in
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preterm gestations cesarean sections were most likely to be indicated while later they were could
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be also elective, including the repeat cesarean sections,20 or performed due to either abnormal
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fetal heart rate or due to failure to progress in labor.
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Placental examination can retrospectively shed light on the pathomechanisms of perinatal morbidity/mortality.
Recently, by a different statistical method, we have found the preterm
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delivery in a cluster with placental abruption, severe preeclampsia, severe ascending infection,
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premature rupture of membranes, acute in-utero hypoxia, with hypertrophic decidual
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arteriolopathy and atherosis of spiral arterioles,21 i.e. the “great obstetrical syndromes”.22 The
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current analysis confirmed the highest frequency of decidual arteriolopathy in the preterm group,
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preceding the occurrence of preeclampsia in the mid-3rd trimester groups, the association also
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observed by us previously in the early 3rd trimester.23 The preterm placentas and even more the
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late preterm placentas, were more likely to show the uterine type of chronic hypoxic placental
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injury, which is a developmental hypoxic placental pattern in women with pregnancies
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complicated by poor uteroplacental perfusion.17 On the other hand, the full term placentas were
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more likely to develop acute in utero hypoxia clinically manifesting with abnormal fetal heart
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rate tracing and thick meconium and histologically with deep membrane meconium penetration
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(possibly due to unrecognized umbilical cord compromise). It appears that, based on placental
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examination, in early 3rd trimester ascending infection, in mid-3rd trimester preeclampsia-
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associated poor uteroplacental perfusion, and at term acute fetal distress, possibly due to
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umbilical cord compromise contributed by the ascending infection have major impact on the
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curve od perinatal morbidity/mortality.
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The strength of this study is that it analyzes both clinical and placental phenotypes in the same
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cases, and that the placentas were signed out by same pathologist using consistently same
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criteria. At the same time, this can be regarded as a limitation as the study has a definite
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placental bias as not all delivered placentas, but only those sent by obstetricians, were examined.
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Therefore, this study does not reflect the prevalence of clinical and placental phenotypes in the
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general obstetrical population, only in high-risk or complicated pregnancies, e.g. mainly
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hypertension or maternal diabetes mellitus, fetal distress, stillbirths or grossly abnormal
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placentas. This analysis has only been intended only to assess the mutual relationships of the
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placental and clinical phenotypes in the selected four gestational age intervals, i.e. to discuss
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relative variations in frequencies of placental pathology. Therefore, the study has value when
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considering high risk pregnancies but should not be generalized to the population at large. Also,
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various management modalities (induced labor/elective cesarean section) could have potentially
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prevented the development of more advanced or severe placental lesions had the pregnancies
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were allowed to run their natural course. The author believes, however, that those modalities
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have smaller impact on the placenta than the underlying pathophysiological processes as more
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time is usually needed for the development, particularly the chronic/developmental patterns of
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hypoxic placental injury, but this issue could not have been resolved by this analysis. In summary, various 3rd trimester morphologic patterns of placental injury can be seen in all
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four 3rd trimester intervals, but statistically significant differences in occurrence thereof as well
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as of that of clinical phenotypes and outcomes are more common between the two subgroups of
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preterm placentas and between two subgroups of term placentas than between late preterm and
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near term placentas, thus challenging the use of an arbitrary cutoff point of 37 weeks separating
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the preterm birth and term birth. The results therefore further support the separation of late
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preterm births from preterm births, and near term births form term births9,10 which are not
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homogeneous groups. Determination of any strict cutoff points could be challenged along these
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lines. While the clinical and placental features of chronic uteroplacental perfusion dominated the
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two preterm subcategories, the frequencies of clinical and placental features of acute in-utero
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hypoxia were increasing in the two subgroups of the traditionally term cohort. The clinical
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differences among the four gestational age intervals were more common than the placental
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differences indicating that that the placental pathology, while important, cannot be the only and
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perhaps not even the most decisive in explaining the various pathomechanisms of the third
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trimester high-risk pregnancy.
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References
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1. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap III LC, Wenstrom KD. Williams
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obstetrics, 22nd edition, McGraw-Hill, New York 2005.
4
2. Kramer MS, Demissie K, Yang H, Platt RW, Sauvé R, Liston R. The contribution of mild and
5
moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian
6
Perinatal Surveillance System. JAMA 200;284:843-849.
7
3. Raju TNK, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late preterm
8
(near term) infants: a summary of the workshop sponsored by the National Institute of Child
9
Health and Human Development. Pediatrics 2006;118:1207-1214.
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4. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants.
11
Pediatrics 2004;114:372-6.
12
5. Shapiro-Mendoza CK, Lackritz EM. Epidemiology of late and moderate preterm birth. Sem
13
Fetal Neonat Med 2012;120-125.
14
6. Raju TNK. Late-preterm births: challenges and opportunities. Pediatrics 2008;121:402-403.
15
7. Bastek JA, Sammel MD, Paré E, Srinivas SK, Posencheg MA, Elovitz MA. Adverse neonatal
16
outcomes: examining the risks between preterm, late preterm, and term infants. Am J Obstet
17
Gynecol 2008;199:367.e1-367.e8.
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8. Fleischman AR, Oinuma M, Clark SL. Rethinking the definition of “term pregnancy”. Obstet
19
Gynecol 2010;116:136-139.
20
9. Reddy UM, Bettegowda VR, Dias T, Yamada-Kushnir T, Ko CW, Willinger M. Term
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pregnancy. A period of heterogeneous risk for infant mortality. Obstet Gynecol 2011;117:1279-
22
1287.
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10. Villar J, Papageorghiou AT, Knight HE, et al. The preterm birth syndrome: a prototype
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phenotypic classification. Am J Obstet Gynecol 2012;206:119-123.
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11. Stanek J, Biesiada J. 2011. Gestational age correlation of clinical conditions and placental
4
lesions. Placenta 2011;32:A15.
5
12. Baergen RN. Manual of Benirschke and Kaufmann’s Pathology of the Human Placenta. New
6
York, NY: Springer; 2005.
7
13. Benirschke K, Kaufmann P, Baergen RN. Pathology of the Human Placenta. New York:
8
Springer; 2006.
9
14. Fox H, Sebire NJ. Pathology of the Placenta. London: Saunders, 2007.
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RI PT
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15. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Placental pathology.
11
Washington, DC: American Registry of Pathology; 2004.
12
16. Langston C, Kaplan C, Macpherson T, et al. Practice guideline for examination of the
13
placenta. Arch Pathol Lab Med. 1997;121:449-476.
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17. Stanek, J. Hypoxic patterns of placental injury: A review. Arch Pathol Lab Med
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2013;137:706-720.
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18. Ashton DM, Lawrence III HC, Adams III NL, Fleischman AR. Surgeon general’s conference
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on the prevention of preterm birth. Obstet Gynecol 2009;113:925-930.
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19. Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, et al. Effect of late-preterm birth and
19
maternal medical conditions on newborn morbidity risk. Pediatrics 2008;121:e223-e232.
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20. Tita ATN, Landon MB, Spong CY, et al. Timing of elective repeat cesarean delivery at term
21
and neonatal outcomes. N Engl J Med 2009;360:111-120.
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21. Stanek J, Biesiada J. Clustering of maternal/fetal clinical conditions and outcomes and
23
placental lesions. Am J Obstet Gynecol 2012;206;493.a1-9.
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22. Brosens I, Pijnenborg R, Vecruysse L, Romero R. The “great obstetrical syndromes” are
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associated with disorders of deep placentation. Am J Obstet Gynecol 2011;204:193-201.
3
23. Moldenhauer JS, Stanek J, Warshak C, Khoury J, Sibai B. The frequency and severity of
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placental findings in women with preeclampsia are gestational age dependent. Am J Obstet
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Gynecol. 2003;189:1173-1177.
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Caption to Figure 1
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The statistically significant differences in 3rd trimester clinical (A) and placental (B) phenotypes.
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The connected points illustrate the statistically significant differences between the adjacent
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gestational age intervals, e.g. the differences in acute chorioamnionitis between the preterm and
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late preterm, and near term and term births were statistically significant but not those between
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the late preterm and near term births. The bimodal (V-shape) distribution of frequencies of
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statistically significant differences is obvious, with a dip between the late preterm and near term
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births.
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Table 1. Clinical and placental differences among four 3rd trimester gestational age intervals
208 15.6 171 12.8 37 2.8
38.8 37.0
93 7.0 100 7.5 93 7.0 157 11.8 89 6.7
11.9
S0002-9378(13)01080-6
DOI:
10.1016/j.ajog.2013.10.015
Reference:
YMOB 9500
To appear in:
American Journal of Obstetrics and Gynecology
Received Date: 31 July 2013 Revised Date:
18 September 2013
Accepted Date: 16 October 2013
Please cite this article as: Stanek J, Comparison of placental pathology in preterm, late-preterm, near-term, and term births, American Journal of Obstetrics and Gynecology (2013), doi: 10.1016/ j.ajog.2013.10.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 1
Comparison of placental pathology in preterm, late-preterm, near-term, and term births
2
Jerzy STANEK, MD, PhD
3
From the Department of Pathology and Laboratory Medicine and Department of Pediatrics,
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University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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The author reports no conflict of interest
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This research was orally presented at the 25 European Congress of Pathology, Lisbon, Portugal,
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August 31-September 4, 2013.
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Reprints not available from the author
11
Address: Division of Pathology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet
12
Avenue, Cincinnati, OH 45229-3026, tel. 513 636 8158 (work), 513 834 9956 (home), fax 513
13
636 3924, email: [email protected]
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Word count: abstract 240, main text 2054
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Condensation: Varying of placental phenotypes support the division of the 3rd trimester in four
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gestational age intervals (25 words)
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Short version of the title: Placental pathology in 3rd trimester of high risk pregnancy
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Abstract
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OBJECTIVE: To study if placental pathology supports the recent suggestion of subcategorizing
3
preterm and term births into smaller gestational age subgroups with different perinatal mortality
4
and morbidity.
5
STUDY DESIGN: 27 clinical and 43 placental phenotypes were retrospectively compared in
6
4617 third trimester births: 1332 preterm pregnancies (28-33 weeks), 1066 late preterm
7
pregnancies (34-36 weeks), 940 near term pregnancies (37-38 weeks), and 1279 term
8
pregnancies (39+ weeks)
9
RESULTS: Acute inflammatory pattern of placental injury was seen mostly at both gestational
10
sides of the 3rd trimester, while the clinical conditions linked to in-utero hypoxia (preeclampsia,
11
diabetes mellitus, fetal growth restriction) and their placental associations (atherosis, membrane
12
chorionic microcysts, chorangiosis, intervillous thrombi) were statistically significantly
13
associated with mid-3rd trimester. Acute fetal distress (abnormal fetal heart tracing, and clinical
14
and histological meconium) were increasing with gestational age and were statistically
15
significantly most common in full term pregnancies.
16
CONCLUSION: Differences in placental pathology among the four subgroups of third trimester
17
pregnancy not only challenge the use of an arbitrary cutoff point of 37 weeks separating the
18
preterm birth and term birth, but also further support separation of late preterm births from
19
preterm births, and term births from near term births. Based on placental pathology, chronic
20
uteroplacental perfusion is the dominating etiopathogenetic factor in the mid 3rd trimester (late
21
preterm and near term births), while acute fetal distress in full term births. This obscures relative
22
frequencies of perinatal mortality and management modalities in the 3rd trimester.
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Key words: high risk pregnancy, placenta, preeclampsia, preterm birth, term birth
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Separation of third trimester births into preterm (up to 36 completes gestational weeks) and term
2
(37+ gestational weeks) is time-honored.1 However, there is accumulating evidence that preterm
3
and term births are not homogeneous groups with regard to maternal diagnoses and fetal
4
morbidity and mortality profiles. It seems that prematurity by even a single week increases the
5
risk of neonatal morbidity and mortality.2-4 Even at the 37 week, i.e. the first week of term
6
gestation, the morbidity rates are twice those at 38 weeks.5 The prematurity rates increase even
7
without increasing prevalence of maternal risk factors such as preeclampsia, umbilical cord
8
accidents or chorioamnionitis.6 Others found a 23% decrease of adverse outcomes with each
9
week of advancing gestational age between 32 and 39 completed weeks; therefore, more
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conservative approach was recommended for late preterm pregnancies.7 Therefore, the term birth
11
previously considered a homogeneous group to which risks associated with preterm and postterm
12
births are compared, forms a heterogeneous group and the children born earlier in the term
13
period (early term) and those born later need to be considered as separate subgroups.8,9
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Placental examination is a well-recognized diary of pregnancy, its results included as one of
15
the major phenotypes in assessment of preterm deliveries.10 Although the frequencies of various
16
placental diagnoses vary with gestational age,11 the associations of various patterns of placental
17
injury with the changing clinical phenotypes in the 3rd trimester gestational age intervals are
18
largely unknown, assessment thereof is the goal of this retrospective analysis.
19
Methods
20
The project has been approved by the institutional review board. 27 clinical and 43 placental
21
phenotypes were retrospectively analyzed in all consecutive 4617 third trimester births from
22
which the placentas were examined by the author in years 1994-2012: 1332 preterm pregnancies
23
(28-33 weeks), 1066 late preterm pregnancies (34-36 weeks), 940 near term (early term)
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pregnancies (37-38 weeks), and 1279 term pregnancies (39+ weeks). The gestational age
2
determination for this study was determined based on combination of the 1st trimester ultrasound
3
(where available), last menstrual period or obstetric estimate of gestational age. The data were
4
extracted from the author’s clinicoplacental database built from clinical charts and placental
5
reports. There were no exclusion criteria, therefore all types of perinatal mortality and morbidity,
6
including stillbirths, were included. The post-term deliveries were included in the term group as
7
the precise definitions of the post-term pregnancy are somewhat obscure.8 Placentas had been
8
submitted for examination at discretion of obstetricians because of the high risk nature of
9
pregnancy, fetal distress, poor condition of the neonate, operative delivery, or grossly abnormal
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placenta. Placental examination was performed according to generally accepted criteria;
11
specifically, placental measurements and trimmed weights were recorded, at least 2 sections of
12
placental membrane roll and umbilical cord, and at least two paracentral full thickness chorionic
13
disc sections were routinely taken as a part of placental examination if no gross lesions were
14
identified. All grossly seen lesions were additionally sampled. The samples were fixed in
15
buffered formalin, followed by routine paraffin embedding, cutting, and staining with
16
hematoxylin and eosin. Definitions of clinical conditions1 and placental diagnoses were either
17
standard12-16 or same as reported by the author separately.17 The statistical analysis compared the
18
clinical and placental phenotypes of the adjacent third trimester intervals using the Yates χ2 test
19
followed by the Holm-Bonferroni correction for multiple comparisons.
20
Results
21
The analyzed clinical complications and outcomes and placental phenotypes were seen in all four
22
gestational age intervals, thus indicating the continuity and overlapping of pathophysiology in
23
the 3rd trimester of pregnancy (Table 1). However, the frequencies of particular clinical and
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1
placental phenotypes in the placentas from high-risk patients in four gestational age intervals
2
varied.
3
Of clinical variables, the frequency of all types of preeclampsia sharply dropped in term pregnancies, while that of mild preeclampsia nearly doubled between preterm and late preterm
5
births. There were no statistically significant differences in, gestational hypertension, severe
6
preeclampsia, HELLP, eclampsia, or chronic hypertension without superimposed preeclampsia.
7
The frequency of premature rupture of membranes was twice as high in preterm then in late
8
preterm births, and then decreased twice in nearly term and term births. The frequency of
9
induction of labor doubled between preterm and late preterm births, and the frequencies of
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multiple pregnancy dropped between late preterm and near term, and again between near term
11
and term pregnancies, while fetal malformations diminished by half between near term and term
12
pregnancies. Frequencies of clinical abnormal fetal heart tracing were stable in the first three
13
gestational age intervals, but increased sharply in term pregnancies. This was paralleled by
14
clinical meconium (both thin and thick meconium). The fetal growth restriction was most
15
common in the middle of the 3rd trimester (an inverted U-shape curve), with the frequencies
16
significantly rising between preterm and late preterm pregnancies, and decreasing between near
17
term and term births. The perinatal mortality rate halved between preterm and late preterm
18
pregnancies and then leveled in the remaining three groups. On the contrary, complications of
19
the 3rd stage of labor were least common in association with preterm placentas in comparison to
20
the remaining 3rd trimester. There were no statistically significant differences in the remaining
21
clinical variables studied: poor or absent prenatal care, maternal substance abuse,
22
oligohydramnios, polyhydramnios, antepartum hemorrhage, cesarean section rate, nonmacerated
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1
stillbirth, and umbilical cord compromise (variable decelerations, entanglement, true knot,
2
prolapse). Of placental phenotypes, the acute inflammatory pattern of placental injury was seen mostly at
4
both gestational ends of the 3rd trimester and less commonly in the mid-3rd trimester (almost U-
5
shaped frequency curve). The histological features of acute in-utero hypoxia (deep meconium
6
penetration and placental infarction)17 showed more linear gestational age relationship in the 3rd
7
trimester, the first one increasing and the second one decreasing, although the latter
8
insignificantly. The pattern of the chronic uterine type of chronic hypoxic placental injury with
9
its associated placental features (chorionic microcysts, chorangiosis)17 were statistically
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significantly more commonly seen in the mid-3rd trimester placentas, preceded by atherosis of
11
maternal spiral arterioles in preterm placentas. The intervillous thrombi were the least common
12
in preterm placentas. There were no statistically significant differences in features of fetal
13
thrombotic vasculopathy, hydrops-related changes, chronic villitis of unknown etiology, plasma
14
cell deciduitis, erythroblasts in fetal blood, villous infarction, hypertrophic decidual
15
arteriolopathy, laminar necrosis of placental membranes, preuterine or postuterine patterns of
16
chronic hypoxic patterns of placental injury, chorionic microcysts of chorionic disc, maternal
17
floor multinucleate trophoblastic giant cells, excessive amount of extravillous trophoblasts,
18
massive perivillous fibrinoid deposition, stem obliterative endarteritis, retroplacental hematoma,
19
intravillous hemorrhage, choriodecidual hemosiderosis, or other, mostly gross, placental
20
abnormalities among the studied 3rd trimester intervals placentas.
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Overall, for clinical and placental phenotypes, statistically significant differences (not
22
including subcategories) were seen in 6, 3 and 7, and 5, 2, and 3 pairs of preterm-late preterm,
23
later preterm-near term, and near term-term births, respectively (Fig. 1), i.e. the placental
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1
differences were less common than the clinical differences in this material. The only phenotype
2
that consistently showed statistically significant differences between all adjacent intervals was
3
the histological meconium, i.e. a placental phenotype.
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Conclusion and discussion
The impact of such factors as infection, inflammation, and abnormal implantation and
placentation on perinatal morbidity/mortality is not same throughout the gestation in general,18
8
and throughout the third trimester in particular, as this analysis has shown. Usually, the preterm
9
birth and hypertensive disorders are the most commonly discussed clinical phenotypes, and
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inflammation, decidual arteriolopathy and infarctions the most commonly discussed placental
11
phenotypes. It is understandable that in preterm pregnancies, both neonatal and fetal mortality
12
were statistically significantly the highest in the analyzed material, the former most likely related
13
to consequences of prematurity and the latter to poor uteroplacental perfusion. It has been
14
reported that the preterm birth rate has increased by 33% in the last 25 years, almost entirely due
15
to the rise in the late preterm births (34-36 weeks gestation). The possible reasons are improved
16
risk assessment, more elective inductions and cesarean sections, increasing maternal age and
17
increasing rates of multiple gestations.5 The plateauing of perinatal mortality/morbidity starting
18
with late preterm pregnancies by this analysis may result from overlapping of various etiologies
19
which confirms observations of others19 and from the fact that not all placentas were examined.
20
The cesarean section rate remained relatively constant throughout the third trimester, but in
21
preterm gestations cesarean sections were most likely to be indicated while later they were could
22
be also elective, including the repeat cesarean sections,20 or performed due to either abnormal
23
fetal heart rate or due to failure to progress in labor.
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Placental examination can retrospectively shed light on the pathomechanisms of perinatal morbidity/mortality.
Recently, by a different statistical method, we have found the preterm
3
delivery in a cluster with placental abruption, severe preeclampsia, severe ascending infection,
4
premature rupture of membranes, acute in-utero hypoxia, with hypertrophic decidual
5
arteriolopathy and atherosis of spiral arterioles,21 i.e. the “great obstetrical syndromes”.22 The
6
current analysis confirmed the highest frequency of decidual arteriolopathy in the preterm group,
7
preceding the occurrence of preeclampsia in the mid-3rd trimester groups, the association also
8
observed by us previously in the early 3rd trimester.23 The preterm placentas and even more the
9
late preterm placentas, were more likely to show the uterine type of chronic hypoxic placental
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injury, which is a developmental hypoxic placental pattern in women with pregnancies
11
complicated by poor uteroplacental perfusion.17 On the other hand, the full term placentas were
12
more likely to develop acute in utero hypoxia clinically manifesting with abnormal fetal heart
13
rate tracing and thick meconium and histologically with deep membrane meconium penetration
14
(possibly due to unrecognized umbilical cord compromise). It appears that, based on placental
15
examination, in early 3rd trimester ascending infection, in mid-3rd trimester preeclampsia-
16
associated poor uteroplacental perfusion, and at term acute fetal distress, possibly due to
17
umbilical cord compromise contributed by the ascending infection have major impact on the
18
curve od perinatal morbidity/mortality.
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The strength of this study is that it analyzes both clinical and placental phenotypes in the same
20
cases, and that the placentas were signed out by same pathologist using consistently same
21
criteria. At the same time, this can be regarded as a limitation as the study has a definite
22
placental bias as not all delivered placentas, but only those sent by obstetricians, were examined.
23
Therefore, this study does not reflect the prevalence of clinical and placental phenotypes in the
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general obstetrical population, only in high-risk or complicated pregnancies, e.g. mainly
2
hypertension or maternal diabetes mellitus, fetal distress, stillbirths or grossly abnormal
3
placentas. This analysis has only been intended only to assess the mutual relationships of the
4
placental and clinical phenotypes in the selected four gestational age intervals, i.e. to discuss
5
relative variations in frequencies of placental pathology. Therefore, the study has value when
6
considering high risk pregnancies but should not be generalized to the population at large. Also,
7
various management modalities (induced labor/elective cesarean section) could have potentially
8
prevented the development of more advanced or severe placental lesions had the pregnancies
9
were allowed to run their natural course. The author believes, however, that those modalities
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10
have smaller impact on the placenta than the underlying pathophysiological processes as more
11
time is usually needed for the development, particularly the chronic/developmental patterns of
12
hypoxic placental injury, but this issue could not have been resolved by this analysis. In summary, various 3rd trimester morphologic patterns of placental injury can be seen in all
14
four 3rd trimester intervals, but statistically significant differences in occurrence thereof as well
15
as of that of clinical phenotypes and outcomes are more common between the two subgroups of
16
preterm placentas and between two subgroups of term placentas than between late preterm and
17
near term placentas, thus challenging the use of an arbitrary cutoff point of 37 weeks separating
18
the preterm birth and term birth. The results therefore further support the separation of late
19
preterm births from preterm births, and near term births form term births9,10 which are not
20
homogeneous groups. Determination of any strict cutoff points could be challenged along these
21
lines. While the clinical and placental features of chronic uteroplacental perfusion dominated the
22
two preterm subcategories, the frequencies of clinical and placental features of acute in-utero
23
hypoxia were increasing in the two subgroups of the traditionally term cohort. The clinical
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differences among the four gestational age intervals were more common than the placental
2
differences indicating that that the placental pathology, while important, cannot be the only and
3
perhaps not even the most decisive in explaining the various pathomechanisms of the third
4
trimester high-risk pregnancy.
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References
2
1. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Gilstrap III LC, Wenstrom KD. Williams
3
obstetrics, 22nd edition, McGraw-Hill, New York 2005.
4
2. Kramer MS, Demissie K, Yang H, Platt RW, Sauvé R, Liston R. The contribution of mild and
5
moderate preterm birth to infant mortality. Fetal and Infant Health Study Group of the Canadian
6
Perinatal Surveillance System. JAMA 200;284:843-849.
7
3. Raju TNK, Higgins RD, Stark AR, Leveno KJ. Optimizing care and outcome for late preterm
8
(near term) infants: a summary of the workshop sponsored by the National Institute of Child
9
Health and Human Development. Pediatrics 2006;118:1207-1214.
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4. Wang ML, Dorer DJ, Fleming MP, Catlin EA. Clinical outcomes of near-term infants.
11
Pediatrics 2004;114:372-6.
12
5. Shapiro-Mendoza CK, Lackritz EM. Epidemiology of late and moderate preterm birth. Sem
13
Fetal Neonat Med 2012;120-125.
14
6. Raju TNK. Late-preterm births: challenges and opportunities. Pediatrics 2008;121:402-403.
15
7. Bastek JA, Sammel MD, Paré E, Srinivas SK, Posencheg MA, Elovitz MA. Adverse neonatal
16
outcomes: examining the risks between preterm, late preterm, and term infants. Am J Obstet
17
Gynecol 2008;199:367.e1-367.e8.
18
8. Fleischman AR, Oinuma M, Clark SL. Rethinking the definition of “term pregnancy”. Obstet
19
Gynecol 2010;116:136-139.
20
9. Reddy UM, Bettegowda VR, Dias T, Yamada-Kushnir T, Ko CW, Willinger M. Term
21
pregnancy. A period of heterogeneous risk for infant mortality. Obstet Gynecol 2011;117:1279-
22
1287.
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10. Villar J, Papageorghiou AT, Knight HE, et al. The preterm birth syndrome: a prototype
2
phenotypic classification. Am J Obstet Gynecol 2012;206:119-123.
3
11. Stanek J, Biesiada J. 2011. Gestational age correlation of clinical conditions and placental
4
lesions. Placenta 2011;32:A15.
5
12. Baergen RN. Manual of Benirschke and Kaufmann’s Pathology of the Human Placenta. New
6
York, NY: Springer; 2005.
7
13. Benirschke K, Kaufmann P, Baergen RN. Pathology of the Human Placenta. New York:
8
Springer; 2006.
9
14. Fox H, Sebire NJ. Pathology of the Placenta. London: Saunders, 2007.
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15. Kraus FT, Redline RW, Gersell DJ, Nelson DM, Dicke JM. Placental pathology.
11
Washington, DC: American Registry of Pathology; 2004.
12
16. Langston C, Kaplan C, Macpherson T, et al. Practice guideline for examination of the
13
placenta. Arch Pathol Lab Med. 1997;121:449-476.
14
17. Stanek, J. Hypoxic patterns of placental injury: A review. Arch Pathol Lab Med
15
2013;137:706-720.
16
18. Ashton DM, Lawrence III HC, Adams III NL, Fleischman AR. Surgeon general’s conference
17
on the prevention of preterm birth. Obstet Gynecol 2009;113:925-930.
18
19. Shapiro-Mendoza CK, Tomashek KM, Kotelchuck M, et al. Effect of late-preterm birth and
19
maternal medical conditions on newborn morbidity risk. Pediatrics 2008;121:e223-e232.
20
20. Tita ATN, Landon MB, Spong CY, et al. Timing of elective repeat cesarean delivery at term
21
and neonatal outcomes. N Engl J Med 2009;360:111-120.
22
21. Stanek J, Biesiada J. Clustering of maternal/fetal clinical conditions and outcomes and
23
placental lesions. Am J Obstet Gynecol 2012;206;493.a1-9.
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22. Brosens I, Pijnenborg R, Vecruysse L, Romero R. The “great obstetrical syndromes” are
2
associated with disorders of deep placentation. Am J Obstet Gynecol 2011;204:193-201.
3
23. Moldenhauer JS, Stanek J, Warshak C, Khoury J, Sibai B. The frequency and severity of
4
placental findings in women with preeclampsia are gestational age dependent. Am J Obstet
5
Gynecol. 2003;189:1173-1177.
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Caption to Figure 1
2
The statistically significant differences in 3rd trimester clinical (A) and placental (B) phenotypes.
3
The connected points illustrate the statistically significant differences between the adjacent
4
gestational age intervals, e.g. the differences in acute chorioamnionitis between the preterm and
5
late preterm, and near term and term births were statistically significant but not those between
6
the late preterm and near term births. The bimodal (V-shape) distribution of frequencies of
7
statistically significant differences is obvious, with a dip between the late preterm and near term
8
births.
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Table 1. Clinical and placental differences among four 3rd trimester gestational age intervals
208 15.6 171 12.8 37 2.8
38.8 37.0
93 7.0 100 7.5 93 7.0 157 11.8 89 6.7
11.9
