Measures of Placental Growth in Relation to Birth Weight and Gestational Age
Carolyn M. Salafia1,2,
Elizabeth Maas2,
John M. Thorp3,
Barbara Eucker3,
John C. Pezzullo2 and
David A. Savitz4
1 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY
2 EarlyPath Clinical and Research Diagnostics, Larchmont, NY
3 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, School of Medicine, University of North Carolina, Chapel Hill, NC
4 Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, NC
Correspondence to Dr. Carolyn M. Salafia, EarlyPath Clinical and Research Diagnostics, 86 Edgewood Avenue, Larchmont, NY 10538 (e-mail: salafiacm{at}aol.com).
Received for publication December 1, 2004.
Accepted for publication June 14, 2005.
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ABSTRACT
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Fetal growth depends in part on placental growth. The authors tested placental measures derived from digital images for reliability and to evaluate their association with birth weight and gestational age. A total of 628 women recruited into the Pregnancy, Infection, and Nutrition Study, a prospective cohort study of preterm birth in central North Carolina between 2002 and 2004, delivered singleton liveborn infants after 24 completed weeks' gestation. Novel chorionic plate morphometric parameters captured off digital images of the gross placenta were analyzed as estimators of gestational age and birth weight. Without acknowledgment to placental weight, digitally obtained lateral chorionic plate growth measures accounted for 17 percent of gestational age variance and 35 percent of birth weight variance, overall. Chorionic plate measures accounted for 10 percent of birth weight variance beyond that accounted for by placental weight alone. Among preterm births, 34 percent of gestational age variance and 63 percent of birth weight variance were accounted for by lateral chorionic plate growth measures. Intraclass correlation coefficients for the novel digital measures ranged from 0.96 to 0.98. Reliable digital measures of lateral chorionic plate growth estimate birth weight variance more strongly than gestational age, project variance that is not accounted for by placental weight, and project these outcomes to a greater degree in preterm births than at term.
birth weight; gestational age; infant, premature; placenta
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INTRODUCTION
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The placenta cannot be measured directly until after birth, but the dimensions of the delivered placenta reveal the cumulative development of the placenta from conception to delivery. Placental weight is one of several standard placental measures by which placental growth can be characterized. Weight is a summary of different dimensions of growth, including the laterally expanding growth of the chorionic plate (measured by chorionic plate shape, the distance from the cord insertion site to the nearest chorionic plate margin, chorionic plate diameters) and arborization of the villous and vascular nutrient exchange surface, reflected in increasing thickness of the chorionic disk. These standard placental measures have been a routine part of gross placental pathologic examinations since the large perinatal cohort studies in the 1960s (1
3
). However, these simple measures may have limitations in capturing the often much more variable chorionic plate growth of placentas from complicated pregnancies (4
6
). One pair of larger and smaller diameters may be excellent measures of round and/or oval chorionic plates but poorer for irregular or multilobate chorionic plate shapes. A measurement method that may not measure the same feature as well in all cases is not ideal. Furthermore, these variable placentas with irregular chorionic plate outlines and/or variable placental arborization may be the placentas most germane to the "fetal origins" hypothesis that posits a wide variety of lifelong health risks to be influenced by the fetal experience. Measures that capture the subtle variations in placental growth may be most responsive to a recent call for "other more biologically grounded ways of characterizing inter-individual difference in placental function" (7
, p. 1170).
Better measurement would not only improve our ability to detect interindividual differences in intrauterine experience but also provide a biologically grounded method to capture the physiology of the fetal experience. The growth of the placenta is directly related to its functional efficiency as the sole fetal source of both nutrients and oxygen. For example, laterally expanding chorionic plate growth marks two functional aspects of the placenta. First, the umbilical-chorionic vessels bear the burden of rapid transfer of large volumes of fetal blood to and from the villous capillary bed. Chorionic plate shape, distance from cord insertion to margin, and the larger and smaller chorionic plate diameters are each measures that capture aspects of this high capacitance/low resistance flow system. Second, the chorionic plate area measures the area of the uterine lining covered by the placenta and, in effect, how many maternal spiral arteries are potential suppliers of the placenta. Placental disk thickness, by contrast, marks the extent of arborization of the villous capillary bed, the actual locus of maternal fetal exchange; however, a simple correlation of arborization with functional efficiency should not be assumed. Fetal stem arterioles are also principal sites of placental vascular resistance. Thus, they contribute to total fetal peripheral resistance and fetal heart work.
There is also a time order implicit in these measures, as recently summarized (8
). Of course, placental weight is the culmination of placental growth in the lateral chorionic plate expansion and in disk thickness. However, chorionic plate lateral expansion generally plateaus by the middle of the third trimester (6
). Abnormal chorionic plate shape generally reflects either pathologic villous atrophy, dating from the end of the first trimester, or placental infarct (5
). At 3032 weeks' gestation, the principal placental growth dimension thereafter, by arborization of the villous tree, is thickness (9
). Thus, the aspects of placental growth captured in lateral chorionic plate expansion may be considered necessary antecedents or essential foundations of the actual achieved placental weight at delivery.
We designed this study to evaluate the reliability of digital morphometry of the chorionic plate and to test the ability of novel measures to account for variance in gestational age and birth weight. Predictors of infant health are of increasing interest in relation to adult health outcomes (10
). Digital image analysis might offer an opportunity to develop additional indices to more accurately reflect irregularly shaped placentas and might facilitate field research using on-site photography of placentas with centralized image analysis. Nevertheless, an irregular shape may reflect to varying degrees both successful accommodation of the placenta and compromise to the fetus.
In addition, the standard method of weighing the placenta, after trimming the placental disk of membranes and umbilical cord, may also merit simplification. Leary et al. (11
) suggested that the fetal weight/placental weight correlation does not change when placentas are weighed trimmed compared when they are weighed untrimmed. If true, this would also facilitate on-site gross placental examination by less specialized personnel.
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MATERIALS AND METHODS
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The sample
The Pregnancy, Infection, and Nutrition Study is a cohort study of pregnant women recruited at mid pregnancy from an academic health center in central North Carolina. Our study population and recruitment techniques are described in detail elsewhere (12
). Beginning in March 2002, all women recruited into the Pregnancy, Infection, and Nutrition Study were requested to consent to detailed placental examination. As of October 1, 2004, 1,159 women (94.6 percent) consented to such examination. Of those women who consented, 1,014 (87.4 percent) had placentas collected and photographed for image analysis. This report details the analyses of consecutive specimens archived into the pathology database. Of the 642 consecutive placentas collected, nine (1.4 percent) were delivered from stillborn fetuses and were excluded from this analysis. Two cases were excluded because the trimmed placental weight was not recorded, and three cases were delivered in fragments, such that measurement of chorionic plate landmarks was not possible. This left 628 cases for analysis, 98 percent of the available placental sample. Placental gross examinations, histology review, and image analyses were performed at EarlyPath Clinical and Research Diagnostics, a New York State-licensed histopathology facility under the direct supervision of Dr. Salafia.
The institutional review board from the University of North Carolina at Chapel Hill approved this protocol.
Image capture and analysis
One digital image was captured of the fetal surface of the chorionic plate. The fresh placenta was patted dry and placed on a clean surface. The umbilical cord was trimmed to within 1 cm of its insertion, and extraplacental membranes were trimmed from the chorionic plate perimeter. The placentas were weighed both before and after trimming, and the length of the cord received with the placenta was measured in centimeters. The distance from the site of rupture to the nearest placental chorionic plate margin was recorded in centimeters. The placenta was oriented so that the chorionic plate margin nearest to the membrane rupture site was positioned at 6 o'clock. If the site of rupture could not be identified or the distance was equal around the perimeter of the chorionic plate, the chorionic plate orientation was noted as "arbitrary." The image was captured with a centimeter ruler in the field of view, for calibrating pixels to centimeter. The digital images were captured in *.tif format, as high-resolution images of 2.3 MB size. The morphometrist and the data analyst were blinded to the clinical characteristics of the pregnancy.
Measures obtained from placental plate images
A 1-pixel (high-resolution) outline of the whole chorionic plate was traced manually on a graphics tablet and analyzed with Scanalytics software (Scanalytics, Inc., Fairfax, Virginia). The umbilical cord insertion site was marked, and the edge of the chorionic plate closest to the membrane edge (at the site of rupture) was marked if it could be determined. Measures included equivalents of standard placental measures and digital features of the chorionic plate and umbilical cord insertion site (table 1).
Reliability analysis of digital measures
To determine the reliability of the placental measures, the morphometrist remeasured a random sample of 55 cases. The second measure was performed at least 3 months from the initial measurement to reduce the potential for recognition or familiarity that might affect the second measure; the intraclass correlation coefficients ranged between 0.96 and 0.98.
Statistical analysis
The digital measures were entered into regression equations in the following order: 1) variables related to the umbilical cord insertion on the chorionic plate, 2) variables related to laterally expanding chorionic plate growth, and 3) placental weight. Placental weight served as an indicator of placental thickness, a digital measure of which was not available for this analysis. Placental weight also represented the accumulated placental "growth experience."
We questioned whether the strength of association of lateral chorionic plate growth with gestational age and birth weight would vary between preterm and term cases, since the relation of fetal weight to placental weight changes rapidly in the third trimester (9
). We hypothesized that lateral chorionic plate growth measures would be more strongly associated with gestational age and birth weight when their growth was most dynamic, that is, prior to term. To test the relations of lateral chorionic plate measures to birth weight and gestational age in preterm compared with term infants, we split the data set into the 89 cases delivered between 24 and under 37 completed gestational weeks and the remaining 539 cases delivered at 37 completed weeks or greater.
In all analyses, we focused on the F change and adjusted r2 rather than on the magnitude of the regression beta coefficients. We expected the lateral chorionic plate growth measures to be highly collinear, which would inflate standard errors of the point estimates of beta coefficients, while the r2 change would be unaffected by collinearity. We did check the p values of individual measures in the different model steps; while we expected the p values to be inflated because of collinearity, we considered this a conservative estimate of "persisting direct effects" after additional variables were added to the model.
Regressions were performed with SPSS software, version 12.0 (SPSS, Inc., Chicago, Illinois). The adjusted r2 and F change were evaluated in models of lateral chorionic plate growth measures in relation to gestational age and birth weight.
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RESULTS
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The analysis includes 628 placentas from 89 preterm and 539 term deliveries. Tables 2 and 3 describe this sample and provide distributions of the placental variables. The study participants were predominantly Caucasian (72 percent) and well educated (80 percent had at least some college education), and they had a moderately high proportion of preterm (delivered at <37 completed gestational weeks (14 percent)) and low birth weight (<2,500 g (9 percent)) births. In 78 (12 percent) of the cases, the chorionic plate edge closest to the site of membrane rupture could not be determined, and the chorionic plate orientation was therefore arbitrary.
As expected, the placental weight alone correlated significantly with both gestational age and birth weight (r2 = 0.07 and r2 = 0.36, respectively). Our models are presented, however, beginning with the novel lateral chorionic plate growth measures and then adding placental weight. We then detail the shared and unique portions of the gestational age and birth weight variances associated with our novel chorionic plate measures and with placental weight. Both chorionic plate parameters and placental weight are measured at term, but lateral expansion of the chorionic plate is generally considered to be most dynamic prior to term (6
) and, thus, may be antecedent to the total mass accumulation of the placenta measured at term.
The digital measures of the placental lateral chorionic plate, shown by models 1 and 2 of table 4, accounted for a total of 17 percent of gestational age variance. Trimmed placental weight accounted for a nonsignificant 0.3 percent additional gestational age variance, as shown by model 3 of table 4 (p = 0.13). By contrast, the weight of the membranes and the trimmed umbilical cord accounted for an additional 5.4 percent of gestational age variance, as shown by model 4 of table 4 (p < 0.0001). Thus, these novel digital chorionic plate measures captured all of the gestational age variance accounted for by placental weight (9 percent in univariate analysis) plus 8 percent of the unique gestational age variance not accounted for by placental weight alone.
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TABLE 4. Digital placental measures as predictors of gestational age, Pregnancy, Infection, and Nutrition Study, 20022004
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With regard to birth weight, digital measures of the placental lateral chorionic plate, shown by models 1 and 2 of table 5, accounted for a total of 35 percent of birth weight variance, similar to that of placental weight alone (37 percent). Approximately two thirds of the birth weight variance was shared between chorionic plate measures and placental weight; one third of birth weight variance was unique to each measure set. As shown by model 3 of table 5, trimmed placental weight accounted for an additional 10 percent of birth weight variance unique from that shared with the novel digital plate measures (r2 change = 0.103, p < 0.0001). Chorionic plate measures and placental weight are therefore complementary measures that account for significant unique portions of birth weight vraiance. As shown by model 4 (table 5), the trimmed membranes and umbilical cord accounted for an additional 5 percent of birth weight variance (p < 0.0001).
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TABLE 5. Digital placental measures as predictors of birth weight, Pregnancy, Infection, and Nutrition Study, 20022004
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The orientation of site of rupture to placental edge did not contribute independently to either gestational age or birth weight variance; modeling of "arbitrary" orientation as a dummy variable and omission of the arbitrarily oriented cases did not affect the strength of the associations of the models.
The population was split into preterm (n = 89, <37 completed gestational weeks) and term (n = 539,
37 completed gestational weeks) and reanalyzed. Lateral chorionic plate growth measures accounted for 34 percent of gestational age variance among preterm births but 1.7 percent among term births (table 6). Placental weight and the weight of the trimmed membranes and umbilical cord accounted for an additional 0.9 percent and 3 percent of preterm gestational age variance, respectively. In the term sample, placental weight and the weight of the trimmed membranes and umbilical cord accounted for an additional 0.2 percent and 1 percent of preterm gestational age variance, respectively.
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TABLE 6. Digital placental measures as predictors of gestational age, in preterm versus term births, Pregnancy, Infection, and Nutrition Study, 20022004
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Lateral chorionic plate growth measures accounted for 63 percent of birth weight variance preterm and for 20 percent of birth weight variance at term (table 7). Placental weight independently accounted for only 3 percent of additional unique birth weight variance preterm but 15 percent of unique birth weight variance at term.
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TABLE 7. Digital placental measures as predictors of birth weight, in preterm versus term births, Pregnancy, Infection, and Nutrition Study, 20022004
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We also explored the relation between the trimmed membranes and umbilical cord ("trimmings") and the trimmed placental weight. The range for the trimmings of extraplacental membranes and umbilical cord was 10240 g. The length in centimeters of the umbilical cord did not affect the estimated effect of the trimmings on birth weight. The correlation between the trimmed placental weight and the total placental weight (trimmed placental disk plus "trimmings") was 0.97. However, the correlation between trimmed placental weight and its trimmings was only 0.42.
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DISCUSSION
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Digital measures of lateral chorionic plate growth account for sizable proportions of variance of both gestational age and birth weight and for substantially more gestational age and birth weight variance preterm than at term. The difference in r2 in preterm versus term, denoting different abilities of chorionic plate growth measures to account for outcome variances, suggests that lateral chorionic plate growth measures are more powerful at gestational ages when they are considered to be more dynamic, which occurs prior to the late third trimester (3
5
). Placental weight, in this analysis a proxy for disk thickness, for which our digital measures are not yet operative, was more strongly associated with gestational age and birth weight variance in term births than among preterm births; the principal dimension of late gestational placental growth is in disk thickness via elaboration of the villous surface exchange area. Again, placental growth measures will have their strongest associations with birth weight variance when they themselves are changing. Our analysis demonstrates that chorionic plate growth measures and placental weight are correlated (as one would expect of two measures of a single placenta) but that each measure type accounts for approximately one quarter of birth weight variance that is unique. Chorionic plate measures complement the ability of placental weight to account for birth weight variance.
Our digital measures capture more subtle patterns of abnormal laterally expanding chorionic plate growth than does a pair of larger and smaller diameters, and they capture greater birth weight variance than do the comparable standard placental chorionic plate growth measures (chorionic plate shape, distance from cord insertion to the nearest margin, and the larger and smaller chorionic plate diameters) in the National Collaborative Perinatal Project. Our disk measures account for 35 percent of birth weight variance compared with 21 percent of birth weight variance for standard placental growth measures in the Collaborative Perinatal Project (C. M. Salafia, Columbia University Mailman School of Public Health, unpublished manuscript). Irregular placentas may be those of most interest for epidemiologic studies, since they may reflect the effects of early intrauterine environmental pathology.
These novel lateral chorionic plate measures are related to both gestational age and birth weight at delivery, but their relations are not identical. For example, the chorionic plate variables account for 17 percent of gestational age variance but 35 percent of birth weight variance. One explanation might be that growth parameters naturally change across gestation, independent of any environmental effectors. However, we speculate that, for example, in the case of preterm birth, chronic intrauterine pathology modifies normal chorionic plate growth. In such a scenario, altered chorionic plate growth would be antecedent to the initiation of parturition physiology. Altered chorionic plate growth may mediate the pathophysiology that ends in preterm birth. In this case, chorionic plate growth pathology is part of the pathway from environmental pathology to preterm birth. Altered chorionic plate growth may only be a marker of an abnormal intrauterine environment that can result in preterm birth, but one that our findings suggest can be reliably measured.
These measures are highly reproducible. The measures in this report were performed by a dedicated morphometrist who had measured 400 placentas before this series. However, we expect the intraclass correlation coefficients reported here would be achievable generally. Simple measures of tracing the chorionic plate perimeter (as opposed to determining a pair of larger and smaller diameters) and maintaining the relative orientation of different chorionic plate landmarks (such as noting the orientation of the umbilical cord relative to the site of membrane rupture and to the weighted center of the disk area) account for 35 percent of birth weight variance. The use of digital photography in fieldwork would obviate need for trained examiners to accurately describe a placenta; after photography, tissue sampling protocols could be reliably performed by less-specialized personnel.
An important limitation of this study is that the current set of novel measures leaves the story incomplete. A placental measure that was not included in this analysis is placental thickness. Thickness can vary strikingly within placentas and may affect placental functional efficiency. Tissue density has also been observed to vary notably within and between specimens representing underlying structural variation. We have also not included such pathology processes as maternal or fetal vascular pathology or acute or chronic infection/inflammation that has long been correlated with shortened gestational length, reduced birth weight, or both (13
17
).
Additional limitations of this study must also be highlighted. The strength of association of our digital measures for birth weight and gestational age and their minimal intermeasure variability require confirmation in a second sample. The value of our digital measures may be greater in selected populations of high-risk infants, in which our digital placental measures themselves have greater variability. Samples with higher frequency of placental histology lesions than our population sample may allow a correlation between pathology type and pattern of placental gross growth. Finally, our highly collinear measures produced large standard errors and rather large p values. The reliance on r2 is sufficient to demonstrate the power of these novel digital measures. However, we plan to use latent variable analysis and classification and regression trees to evaluate measurement scales and thresholds that may be clinically and/or epidemiologically germane and to better quantify the utility of placental measures.
The placenta can be weighed with membranes and cord attached, but the standard approach since its proposal by Benirschke (2
) in the early 1960s has been to weigh the placenta after the extraplacental membranes and the umbilical cord are trimmed from the disk. This limits the measurement to the weight of the placental disk, the actual nutrient exchange mass of the placenta. Leary et al. (11
) recently have suggested that trimmed and untrimmed placental weights are exchangeable, based on their high correlation. Correlations between trimmed placental weight (weighing in the hundredths of grams) and the total weight before trimming (equal to the trimmed weight plus trimmings, weighing in the tenths of grams) would be expected to be high, since both variables have the preponderant contribution coming from the same measure, the trimmed placental weight. However, we found low correlations between placental weights and trimmings. Trimmed and untrimmed placental weights may not be exchangeable, although untrimmed placental weights may be adequate proxies when trimmed weights are not available. We suggest that, if it is confirmed that trimmings may account for gestational age variance separately from the placental weight, further study may be prudent before standard protocols are changed. While cord length did not affect the association of trimmings, we did not weigh the cord; it is possible that cord diameter, which varies in the thickness of Wharton's jelly, also varies with birth weight and accounts for our findings. Second, it is possible that the weight of the membranes that make up the amniotic sac may vary with birth weight. Increased fetal size may increase amnion epithelium injury and increase membrane permeability causing membrane edema. Maturational changes in the membranes should result in reduced membrane thickness; mitotic activity of the amnion epithelium is low after the sixth month (18
), and there is a net loss of extracellular matrix during the last weeks of gestation (19
).
We could not analyze by principal indication for delivery, such as preeclampsia versus spontaneous preterm labor or preterm membrane rupture because of the small numbers of preterm cases. We speculate that placental relations to both gestational age and birth weight variance might differ between spontaneous and indicated prematurity, especially when spontaneous preterm birth due to an acute ascending infection is compared with a case of preterm preeclampsia with chronic fetal and placental growth pathology. The excellent reproducibility of our measures is likely to yield valid estimates of placental associations with gestational age and birth weight that may clarify the complex interrelations among mother, placenta, and fetus to maintain pregnancy and support fetal growth.
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ACKNOWLEDGMENTS
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Supported in part by grant RR00046 from the General Clinical Research Centers program of the Division of Research Resources, National Institutes of Health; by grant 1 K23 MH067857-01, a Mid Career Development Award from the National Institute of Mental Health to C. M. S.; and by a grant from the Dische-Hime Fund for Placental Research to E. M.
Conflict of interest: none declared.
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