Matern Child Health J DOI 10.1007/s10995-014-1662-1
Effects of Advanced Maternal Age and Race/Ethnicity on Placental Weight and Placental Weight/Birthweight Ratio in Very Low Birthweight Infants B. E. de Jongh • A. Mackley • N. Jain R. Locke • D. A. Paul
•
Ó Springer Science+Business Media New York 2015
Abstract To study the association of advanced maternal age (AMA) and race/ethnicity on placental pathology in very low birthweight (VLBW) infants. Retrospective analysis of placental pathology of inborn singleton VLBW infants from a regional level 3 NICU between July, 2002 and June, 2009. Subjects were stratified by age and race/ ethnicity. Statistical analysis included One-way ANOVA, Chi Square and multivariable analyses. A total of 739 mother/infant dyads were included. AMA was associated with a decrease in placental weight and placental weight/ birthweight ratio. Black/Non-Hispanic mothers C35 had a lower placental weight (p = 0.01) and lower placental weight/birth weight ratio (z-score, -0.45 ± 0.71 vs -0.04 ± 1.1, p = 0.01) compared to Black/Non-Hispanic mothers \35 years of age. After controlling for gestational age, race/ethnicity, maternal diabetes, maternal smoking, maternal hypertension and clinical chorioamnionitis, AMA, but not race/ethnicity, remained independently B. E. de Jongh, R. Locke and D. A. Paul contributed equally to this article. B. E. de Jongh (&) Division of Neonatal-Perinatal Medicine, St. Christopher’s Hospital for Children, 3601 A Street, Philadelphia, PA 19134, USA e-mail: [email protected] B. E. de Jongh Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA A. Mackley R. Locke D. A. Paul Department of Neonatology, Christiana Care Health System, Newark, DE, USA e-mail: [email protected]
associated with placental weight/birthweight ratio z score (full model r2 = 0.22, p \ 0.01). In our study sample of VLBW infants, placental weight and placental weight/ birthweight ratio were lower in mothers of advanced maternal age compared to mothers \35 years of age. Our data suggest that maternal age affects placentation in VLBW infants, which could influence maternal and neonatal outcomes. Keywords Placenta Prematurity Maternal age Race/ethnicity
Introduction The placenta, as the vector for all maternal-fetal oxygen and nutrient exchange, has a principal influence on birthweight and thus necessary for a successful pregnancy outcome [1]. Placental weight is the most common way to characterize placental growth, which relates to placental function [1]. The placenta weight/birthweight ratio has D. A. Paul e-mail: [email protected] N. Jain Department of Pediatrics, Children’s National Medical Center, Washington, DC, USA e-mail: [email protected] R. Locke D. A. Paul Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA
R. Locke e-mail: [email protected]
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been used as an indicator of neonatal outcomes; both high and low placental weight/birthweight ratios have been associated with an increased risk of stillbirth and adverse neonatal outcomes [2]. Advanced maternal age, C35 years, is an increasing clinical occurrence and has been associated with numerous adverse maternal and perinatal outcomes [3–6]. Few studies have looked at the association between advanced maternal age, maternal race/ethnicity and placental weight and placental histology/pathology [7]. The aim of our study was to explore the relationship of advanced maternal age and maternal race/ethnicity on placental pathology in very low birthweight (VLBW) infants. We hypothesized that among VLBW infants born to mothers of AMA, there would be a lower placental weight/birthweight ratio when compared to VLBW infants born to mothers \35 years old. We also hypothesized that there would be differences in placental weight/birthweight ratio, along with differences in placental histology, based on race/ethnicity and maternal age.
Methods Our study design was a retrospective cohort analysis of all singleton very low birthweight (VLBW) infants (\1,500 g) born at Christiana Care Health System between July 2002 and June 2009 (n = 739). This study was approved by the Institutional Review Board at Christiana Care Health System. Multiple gestation births were excluded as were any outborn infants. Standard placental histology was reviewed. Subjects were divided into two groups: (1) maternal age \35 years; and (2) maternal age C35 years or advanced maternal age (AMA). Placental weight and birthweight were measured in grams. Mean placental weights and birth weights for each maternal age group, in addition to the placental weight/ birthweight ratios were calculated. In our study, placental weight was normalized to birthweight to account for the relationship between fetal growth and placental growth. Placentation is defined as the series of events following implantation of the embryo and leading to development of the placenta. Maternal race/ethnicity was identified by selfreport. Maternal clinical data including fever, premature rupture of membranes, prolonged rupture of membranes, maternal chronic hypertension, maternal preeclampsia, maternal diabetes and maternal chorioamnionitis were obtained from the medical record. We also obtained data on routine clinical placental histology including histologic chorioamnionitis, infarction, meconium staining, calcifications, funisitis, vasculopathy, presence of fibrin and placenta previa.
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A temperature greater than 100.4 °F while in active labor determined maternal fever. Premature rupture of membranes refers to rupture of the fetal membranes prior to the onset of labor irrespective of gestational age [8]. Prolonged rupture of membranes was defined as rupture of membranes greater than 18 h in duration. Maternal chronic hypertension is defined as blood pressure exceeding 140/90 mmHg before pregnancy or before 20 weeks gestation [9]. Maternal diabetes, pre-gestational and gestational, was included. The diagnosis of clinical chorioamnionitis was made by the attending obstetrician. The diagnosis of preeclampsia was made by the attending obstetrician based on ACOG guidelines. The placentas were sent for routine clinical evaluation and were examined by one of the attending pathologists at Christiana Care Health System. The placentas were systematically reviewed according to the Placental Pathology Practice Guideline Development Task Force [10]. Histologic chorioamnionitis was defined by subchorionic margination of inflammatory cells; infiltration in and through chorionic plate to amniotic epithelium; amniotic basement membrane thickening and hyalinization; and fetal vasculitis/micro-abscesses [10]. Placental infarction is defined by obliteration of intervillous space with villous crowding [10]. Meconium staining of the placenta is defined by a variety of changes including vacuolation of amniotic epithelium, pseudo stratification, epithelial disorganization, cell degeneration, and even epithelial necrosis with finely granular brown pigment in macrophages of amnion, chorion and decidua [10]. White granular lesions, irregularly scattered over maternal surface, defined the presence of calcifications [10]. Funisitis refers to neutrophils penetrating through the vessel wall into Wharton’s jelly [10]. Placental vasculopathy is the alteration of decidual vessels with fibrinoid change and foamy intimal cells and thrombosis [10]. Presence of fibrin can be divided into parenchymal and subchorionic. For the purpose of this study, any degree of fibrin deposition was reported [10]. Placenta previa is classified in marginal and complete. Marginal placenta previa is hemorrhage and blood at edge of the placental disc. Marginal cord insertion is often present. Complete placenta previa is hemorrhage and blood clot over maternal surface of placental disc [10]. Statistical analysis included both unadjusted and adjusted multivariable analyses. Unadjusted analyses included ANOVA and Chi square. Both multiple linear regression and logistic regression were used for multivariable analyses. Variables added into the models included those variables with p \ 0.2 on adjusted analyses and known potential confounders for the dependent variable. The data analysis included multiple comparisons, p B 0.01 was considered significant. Data are presented as mean ± SD and percentages for categorical variables.
Matern Child Health J
Results A total of 795 VLBW inborn, singleton infants were eligible for study inclusion. Placental pathology was not obtained on 56 infants leaving 739 singleton mother/infant dyads in the final study sample. No differences were seen in gestation, birthweight, maternal race/ethnicity or maternal age in the 56 mother/infant dyads in which placental pathology was not obtained compared to the final study sample. Study demographics and maternal/infant dyad characteristics are presented in Table 1. Of the 739 dyads included in the study, 629 (85 %) mothers were \35 years, and 110 (15 %) mothers were of AMA (C35 years). The two age groups had no differences in mean birthweight or gestational age (Table 1). Similarly, no differences were appreciated in the presence of maternal fever, premature rupture of membranes, prolonged rupture of membranes, maternal chronic hypertension and maternal pre-eclampsia in mothers \35 compared to mothers C35. We did see differences in the rates of maternal diabetes, with a higher rate (17 %) in the AMA group when compared to the group of mothers \35 years old (8 %) (p \ 0.01,Table 1). Clinical chorioamnionitis had an increase rate in the younger age group of mothers (11 %) compared to the AMA group (5 %) (p = 0.05, Table 1). No differences were observed between the two age groups in regards to histologic chorioamnionitis, placental infarction, the presence of fibrin, meconium staining, funisitis, placental vasculopathy or placenta previa (Table 1). Babies born to White/Non-Hispanic (n = 299) and Black/Non-Hispanic Mothers (n = 353) had similar placental weight/birthweight Z score (-0.09 ± 0.87 vs -0.02 ± 1.4, p = .38). No comparison was done with
babies born to mothers of Hispanic (n = 64) or other (n = 23) ethnicity due to relatively small numbers of infants in these categories. An overall difference was seen in the placental weight/birthweight ratio based on maternal age, with mothers of advanced maternal age having a lower ratio (p \ 0.01) compared to mothers \35 years (Table 2). When analyzing the effect of age within a race/ethnicity group, no difference in placental weight/birthweight in White/Non-Hispanic mothers (p = 0.22) was observed. However, when looking at placental weight/birthweight ratio in Black/Non-Hispanic mothers, we did see a difference, with results of 0.23 in AMA mothers and 0.26 in younger mothers (\35 years old) (p = 0.01, Table 2). Infants who died before hospital discharge, had a higher placental weight/birthweight and placental weight/birthweight z score compared to the infants who survived to hospital discharge (Table 3). Multivariable Analysis After adjusting for gestational age, placental weight/birthweight z score was no longer independently associated with death before discharge (odds ratio 0.92, 95 % CI 0.73–1.12). After controlling for gestational age, maternal diabetes, maternal smoking, preeclampsia, IVF, clinical chorioamnionitis, and race/ethnicity, AMA remained independently associated with placental weight/birthweight ratio z score (full model r2 = 0.22, p \ 0.01). In this model, maternal race/ethnicity did not remain independently associated with placental weight/birthweight ratio z score. An interaction term of maternal race/ethnicity and AMA was added to the models and did not remain independently associated with
Table 1 Study demographics and maternal/infant dyad characteristics Demographic parameter
All mothers
Age C 35 (n = 110)
Age \ 35 (n = 629)
p
Gestational age (weeks) (mean ± SD)
27.9 ± 2.9
27.9 ± 2.9
27.9 ± 2.9
0.99
Birthweight (g) (mean ± SD)
1,014 ± 296
1,006.3 ± 292
1,011.5 ± 297.2
0.86
Maternal age (years) Infant gender (% male)
27.2 ± 6.6 49
38.5 ± 2.2 59
25.6 ± 5.2 49
Maternal fever (%)
6
5
7
0.40
Premature rupture of membranes (%)
30
25
30
0.34
Prolonged rupture of membranes (PROM) (%)
19
15
20
0.20
Chronic hypertension (%)
39
45
39
0.18
Pre-eclampsia (%)
36
38
35
0.54
Clinical chorioamnionitis (%)
9
5
11
Diabetes (pre-gestational and gestational) (%)
9
17
8
Maternal smoking (%)
19
13
19
In vitro fertilization (%)
3
11
2
Antenatal steroid administration (%)
78
69
79
0.02
Cesarean section delivery (%)
65
77
64
0.01
\0.01 0.05
0.05 \0.01 0.09 \0.01
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Matern Child Health J Table 2 Placental pathology in all mothers, Black/Non-Hispanic and White/Non-Hispanic Mothers Placenta
All mothers Age C 35 (n = 110)
p
Black/Non-Hispanic Mothers
Age \ 35 (n = 629)
Age C 35 (n = 51)
p
Age \ 35 (n = 300)
White/Non-Hispanic Mothers Age C 35 (n = 46)
p
Age \ 35 (n = 250)
Weight (g)
231 ± 74
254 ± 85
\0.01
216 ± 64
246 ± 91
0.03
244 ± 79
262 ± 76
0.15
Placental weight/ birthweight
0.24 ± 0.06
0.26 ± 0.08
\0.01
0.23 ± 0.05
0.26 ± 0.09
0.01
0.24 ± 0.07
0.25 ± 0.07
0.22
Placental weight/ birthweight Z score
-0.32 ± 0.84
0.004 ± 1.05 \0.01
-0.45 ± 0.71
-0.04 ± 1.1
0.01
-0.23 ± 0.84
-0.08 ± 0.87
0.27
Histologic chorioamnionitis
43 %
45 %
0.59
35 %
51 %
0.03
50 %
38 %
0.14
Meconium staining
13 %
15 %
0.60
11 %
13 %
0.63
19 %
19 %
0.95
Infarction Calcification
22 % 5%
24 % 11 %
0.57 0.08
22 % 4%
24 % 9%
0.71 0.22
20 % 4%
26 % 13 %
0.38 0.09
Funisitis
19 %
24 %
0.28
22 %
29 %
0.29
15 %
20 %
0.48
Vasculopathy
5%
11 %
0.06
6%
11 %
0.32
5%
13 %
0.13
Fibrin
20 %
26 %
0.18
24 %
29 %
0.45
17 %
24 %
0.36
Previa
2%
2%
0.95
0%
1%
0.47
4%
4%
0.80
Table 3 Placental weight/birthweight and neonatal mortality Died (n = 96)
Survived (n = 699)
p
Placental weight/birthweight (SD)
0.30 (0.10)
0.25 (0.08)
\0.01
Placental weight/birthweight z score (SD)
0.41 (1.30)
-0.11 (0.96)
\0.01
placental weight/birthweight z score. The models were also analyzed with absolute placental weight and placental weight/birthweight as dependent variables. In both cases, AMA remained independently associated with placental weight or placental weight/birth weight. After controlling for gestational age, race/ethnicity, smoking, preeclampsia, diabetes, IVF and clinical chorioamnionitis, AMA mothers had an increased odds of having a placental weight/birthweight ratio z score in the lowest quartile (z score \ -0.71) for the cohort; odds ratio 2.1 (95 % CI 1.3–3.5). In this model, Black/Non-Hispanic maternal race/ethnicity did not remain independently associated with a placental weight/birthweight ratio z score in the lowest quartile, odds ratio 1.02 (95 % CI 0.68–1.53). An interaction term of maternal race and AMA was added to the models and did not remain independently associated with placental weight/birthweight z score.
Discussion The main finding of our study was that placental weight and placental weight/birthweight ratio were lower in
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mothers of advanced maternal age. After controlling for gestational age, race/ethnicity, maternal diabetes, maternal smoking, maternal hypertension and clinical chorioamnionitis, AMA, but not race/ethnicity, remained independently associated with placental weight/birthweight ratio z score. Our study provides important information relating to the biology of pregnancy of older Black/Non-Hispanic mothers delivering VLBW infants. Our data suggests differences in placentation based on maternal age. Placental weight/birthweight ratio has been previously associated with adverse newborn outcomes. In a population of term neonates, a high placental weight/birthweight ratio was associated with an increased risk of NICU admission [11]. In contrast, a low placental weight/birthweight ratio was associated with comparable outcomes when compared to a normal placental weight/birthweight ratio [11]. Our study found no association of placental weight/birthweight with mortality in VLBW infants. In a large population cohort of all singleton births in Norway, in which the mean maternal age at delivery was 29.4 years, and 16.4 % of the population was 35 years or older, the mean placental weight was 673.1 g and increased with maternal age. Mothers of advanced maternal age also had a higher
Matern Child Health J
placental weight relative to birthweight as compared with younger mothers [12]. In contrast to the homogenous study population from Norway, in our more heterogeneous population of VLBW infants, the offspring of mothers of advanced maternal age had a lower placental weight and a lower placental weight/ birthweight ratio. The reasons for the differing findings are likely related to the specific maternal and infant populations studied. Our study sample included a diverse racial ethnic population and was limited to VLBW infants. The study of Haalvaldsen included all gestational ages and was more population based. In the United States, Black/NonHispanic mothers are known to have a higher rate of premature and low birthweight births compared to White/NonHispanic mothers. The reasons behind these disparities remain an important topic of ongoing investigation. Black/ Non-Hispanic mothers of advanced maternal age represent a group at particularly high risk for premature birth [13– 15]. In our population of VLBW infants, AMA, but not race negatively affected placental weight. Our data show few differences in placental histology based on maternal age, and race/ethnicity. One of these differences was the reduced occurrence of histologic chorioamnionitis in Black/Non-Hispanic mothers of advanced maternal age. This difference was not significant based on an a priori set p value cutoff of B0.01. Few studies have looked at different placental pathology stratified by race/ethnicity and maternal age. Racial disparities in intrauterine infection during pregnancy have previously been shown and may result from a constellation of environmental and intergenerational risk factors including psychosocial stress, diet, intrauterine growth and genes [16]. The rate of histologic chorioamnionitis was previously investigated by race and by gestation in a cross-sectional study involving 1,843 deliveries. The severity of chorioamnionitis was graded histologically and the conclusion was that overall rates of histologic chorioamnionitis did not contribute to racial disparities in low birthweight despite black women having twice the rate of severe histologic chorioamnionitis [17]. Only severe histologic chorioamnionitis predicted preterm delivery [17]. This study did not subdivide the women by maternal age. To our knowledge, this study is the first to explore the interaction between maternal race/ethnicity, maternal age and histologic chorioamnionitis. Our data suggest that larger population based studies are needed to further interrogate this association. Our study has a number of limitations. First, our population sample was limited to VLBW infants and with each step of our analysis the numbers of our subpopulations became smaller. Due to this fact, we did not include the Hispanic and Asian populations or stratify further the maternal age categories. Although the exclusion of Hispanic patients is a potential limitation, we also consider it a
strength because the study population is more homogenous and is influenced less by factors related to gestational age. Second, the procedure used to weigh the placentas was not standardized in the data set. Third, the degree of severity of histologic chorioamnionitis was not reported. Fourth, the possibility of interobserver variability when making the different diagnosis of the placental pathology or weighing placentas does exist. However, because all patients are from a single institution and adhering to the same standard definition and similar clinical practices, the influence of this potential variability is diminished. As this study is limited to single center’s catchment population, it will need to be reproduced in order to be more generalizable. Additionally, our study sample was limited to VLBW infants and may not apply to term infants or other populations of preterm infants.
Conclusions To our knowledge, this study is the first to evaluate the effect of maternal age and maternal race/ethnicity on placental weight, placental weight/birthweight ratio and placental pathology in a very low birthweight infant population. In our population of VLBW infants, advanced maternal age was associated with a decrease in placental weight and placental weight/birthweight ratio. From our data we cannot determine if older maternal age is causal for reduced placental weight/birthweight or representative of unmeasured confounding variables. Further research is needed to explore possible causal mechanisms, which may explain the relationship between AMA and reduced placental weight in VLBW infants. Conflict of interest The authors of this paper have nothing to disclose. No financial or non-financial interests to declare.
References 1. Salafia, C. M. M. M., Charles, A. K. M., & Maas, E. M. B. (2006). Placenta and fetal growth restriction. Clinical Obstetrics and Gynecology, 49(2), 236–256. 2. McNamara, H., Platt, R., Kramer, M., et al. (1998) The fetoplacental ratio: useful predictor of neonatal outcome in preterm infants? [Report]. American Journal of Obstetrics and Gynecology 178(1S)(Supplement):123S. 3. Yaniv, S. S., Levy, A., Wiznitzer, A., et al. (2011). A significant linear association exists between advanced maternal age and adverse perinatal outcome. Archives of Gynecology and Obstetrics, 283(4), 755–759. 4. Jacobsson, B. M. D. P., Ladfors, L. M. D. P., & Milsom, I. M. D. P. (2004). Advanced maternal age and adverse perinatal outcome. Obstetrics and Gynecology, 104(4), 727–733. 5. Carolan, M., & Frankowska, D. (2011). Advanced maternal age and adverse perinatal outcome: A review of the evidence. Midwifery, 27(6), 793–801.
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Matern Child Health J 6. Hsieh, T. -T., Liou, J. -D., Hsu, J. -J., et al. (2010). Advanced maternal age and adverse perinatal outcomes in an Asian population. European Journal of Obstetrics, Gynecology, and Reproductive Biology, 148(1), 21–26. 7. Anum, E. A., Springel, E. H., Shriver, M. D., et al. (2009). Genetic contributions to disparities in preterm birth. Pediatric research, 65(1), 1–9. doi:10.1203/PDR.0b013e31818912e7. 8. Caughey, A. B. R. J., & Norwitz, E. R. (2008). Contemporary diagnosis and management of preterm premature rupture of membranes. Reviews in Obstetrics and Gynecology, 1(1), 11–22. 9. Hypertension and Pregnancy. Medscape 2012. Accessed Febraury 06, 2012. 10. Langston, C., Kaplan, C., Macpherson, T., et al. (1997). Practice guideline for examination of the placenta: Developed by the placental pathology practice guideline development task force of the college of American pathologists. Archives of Pathology and Laboratory Medicine, 121(5), 449–476. 11. Shehata, F., Levin, I., Shrim, A., et al. (2011). Placenta/birthweight ratio and perinatal outcome: a retrospective cohort analysis. BJOG: An International Journal of Obstetrics and Gynaecology, 118(6), 741–747.
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12. Haavaldsen, C., Samuelsen, S. O., & Eskild, A. (2011). The association of maternal age with placental weight: A populationbased study of 536 954 pregnancies. BJOG: An International Journal of Obstetrics and Gynaecology, 118(12), 1470–1476. 13. Spong, C. Y. M. D., Iams, J. M. D., Goldenberg, R. M. D., et al. (2011). Disparities in perinatal medicine: Preterm birth, stillbirth, and infant mortality. Obstetrics and Gynecology, 117(4), 948–955. 14. Kramer, M. R., & Hogue, C. R. (2009). What causes racial disparities in very preterm birth? A biosocial perspective. Epidemiologic Reviews, 31(1), 84–98. 15. de Jongh, B. E., Locke, R., Paul, D. A., et al. (2012). The differential effects of maternal age, race/ethnicity and insurance on neonatal intensive care unit admission rates. BMC Pregnancy Childbirth, 12, 97. doi:10.1186/1471-2393-12-97. 16. Fiscella, K. M. D. M. P. H. (2004). Racial disparity in infant and maternal mortality: Confluence of infection, and microvascular dysfunction. Maternal and Child Health Journal, 8(2), 45–54. 17. Mueller-Heubach, E. M., Rubinstein, D. N. M., & Schwarz, S. S. M. B. (1990). Histologic chorioamnionitis and preterm delivery in different patient populations. Obstetrics and Gynecology, 75(4), 622–626.
Effects of Advanced Maternal Age and Race/Ethnicity on Placental Weight and Placental Weight/Birthweight Ratio in Very Low Birthweight Infants B. E. de Jongh • A. Mackley • N. Jain R. Locke • D. A. Paul
•
Ó Springer Science+Business Media New York 2015
Abstract To study the association of advanced maternal age (AMA) and race/ethnicity on placental pathology in very low birthweight (VLBW) infants. Retrospective analysis of placental pathology of inborn singleton VLBW infants from a regional level 3 NICU between July, 2002 and June, 2009. Subjects were stratified by age and race/ ethnicity. Statistical analysis included One-way ANOVA, Chi Square and multivariable analyses. A total of 739 mother/infant dyads were included. AMA was associated with a decrease in placental weight and placental weight/ birthweight ratio. Black/Non-Hispanic mothers C35 had a lower placental weight (p = 0.01) and lower placental weight/birth weight ratio (z-score, -0.45 ± 0.71 vs -0.04 ± 1.1, p = 0.01) compared to Black/Non-Hispanic mothers \35 years of age. After controlling for gestational age, race/ethnicity, maternal diabetes, maternal smoking, maternal hypertension and clinical chorioamnionitis, AMA, but not race/ethnicity, remained independently B. E. de Jongh, R. Locke and D. A. Paul contributed equally to this article. B. E. de Jongh (&) Division of Neonatal-Perinatal Medicine, St. Christopher’s Hospital for Children, 3601 A Street, Philadelphia, PA 19134, USA e-mail: [email protected] B. E. de Jongh Department of Pediatrics, Drexel University College of Medicine, Philadelphia, PA, USA A. Mackley R. Locke D. A. Paul Department of Neonatology, Christiana Care Health System, Newark, DE, USA e-mail: [email protected]
associated with placental weight/birthweight ratio z score (full model r2 = 0.22, p \ 0.01). In our study sample of VLBW infants, placental weight and placental weight/ birthweight ratio were lower in mothers of advanced maternal age compared to mothers \35 years of age. Our data suggest that maternal age affects placentation in VLBW infants, which could influence maternal and neonatal outcomes. Keywords Placenta Prematurity Maternal age Race/ethnicity
Introduction The placenta, as the vector for all maternal-fetal oxygen and nutrient exchange, has a principal influence on birthweight and thus necessary for a successful pregnancy outcome [1]. Placental weight is the most common way to characterize placental growth, which relates to placental function [1]. The placenta weight/birthweight ratio has D. A. Paul e-mail: [email protected] N. Jain Department of Pediatrics, Children’s National Medical Center, Washington, DC, USA e-mail: [email protected] R. Locke D. A. Paul Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA, USA
R. Locke e-mail: [email protected]
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been used as an indicator of neonatal outcomes; both high and low placental weight/birthweight ratios have been associated with an increased risk of stillbirth and adverse neonatal outcomes [2]. Advanced maternal age, C35 years, is an increasing clinical occurrence and has been associated with numerous adverse maternal and perinatal outcomes [3–6]. Few studies have looked at the association between advanced maternal age, maternal race/ethnicity and placental weight and placental histology/pathology [7]. The aim of our study was to explore the relationship of advanced maternal age and maternal race/ethnicity on placental pathology in very low birthweight (VLBW) infants. We hypothesized that among VLBW infants born to mothers of AMA, there would be a lower placental weight/birthweight ratio when compared to VLBW infants born to mothers \35 years old. We also hypothesized that there would be differences in placental weight/birthweight ratio, along with differences in placental histology, based on race/ethnicity and maternal age.
Methods Our study design was a retrospective cohort analysis of all singleton very low birthweight (VLBW) infants (\1,500 g) born at Christiana Care Health System between July 2002 and June 2009 (n = 739). This study was approved by the Institutional Review Board at Christiana Care Health System. Multiple gestation births were excluded as were any outborn infants. Standard placental histology was reviewed. Subjects were divided into two groups: (1) maternal age \35 years; and (2) maternal age C35 years or advanced maternal age (AMA). Placental weight and birthweight were measured in grams. Mean placental weights and birth weights for each maternal age group, in addition to the placental weight/ birthweight ratios were calculated. In our study, placental weight was normalized to birthweight to account for the relationship between fetal growth and placental growth. Placentation is defined as the series of events following implantation of the embryo and leading to development of the placenta. Maternal race/ethnicity was identified by selfreport. Maternal clinical data including fever, premature rupture of membranes, prolonged rupture of membranes, maternal chronic hypertension, maternal preeclampsia, maternal diabetes and maternal chorioamnionitis were obtained from the medical record. We also obtained data on routine clinical placental histology including histologic chorioamnionitis, infarction, meconium staining, calcifications, funisitis, vasculopathy, presence of fibrin and placenta previa.
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A temperature greater than 100.4 °F while in active labor determined maternal fever. Premature rupture of membranes refers to rupture of the fetal membranes prior to the onset of labor irrespective of gestational age [8]. Prolonged rupture of membranes was defined as rupture of membranes greater than 18 h in duration. Maternal chronic hypertension is defined as blood pressure exceeding 140/90 mmHg before pregnancy or before 20 weeks gestation [9]. Maternal diabetes, pre-gestational and gestational, was included. The diagnosis of clinical chorioamnionitis was made by the attending obstetrician. The diagnosis of preeclampsia was made by the attending obstetrician based on ACOG guidelines. The placentas were sent for routine clinical evaluation and were examined by one of the attending pathologists at Christiana Care Health System. The placentas were systematically reviewed according to the Placental Pathology Practice Guideline Development Task Force [10]. Histologic chorioamnionitis was defined by subchorionic margination of inflammatory cells; infiltration in and through chorionic plate to amniotic epithelium; amniotic basement membrane thickening and hyalinization; and fetal vasculitis/micro-abscesses [10]. Placental infarction is defined by obliteration of intervillous space with villous crowding [10]. Meconium staining of the placenta is defined by a variety of changes including vacuolation of amniotic epithelium, pseudo stratification, epithelial disorganization, cell degeneration, and even epithelial necrosis with finely granular brown pigment in macrophages of amnion, chorion and decidua [10]. White granular lesions, irregularly scattered over maternal surface, defined the presence of calcifications [10]. Funisitis refers to neutrophils penetrating through the vessel wall into Wharton’s jelly [10]. Placental vasculopathy is the alteration of decidual vessels with fibrinoid change and foamy intimal cells and thrombosis [10]. Presence of fibrin can be divided into parenchymal and subchorionic. For the purpose of this study, any degree of fibrin deposition was reported [10]. Placenta previa is classified in marginal and complete. Marginal placenta previa is hemorrhage and blood at edge of the placental disc. Marginal cord insertion is often present. Complete placenta previa is hemorrhage and blood clot over maternal surface of placental disc [10]. Statistical analysis included both unadjusted and adjusted multivariable analyses. Unadjusted analyses included ANOVA and Chi square. Both multiple linear regression and logistic regression were used for multivariable analyses. Variables added into the models included those variables with p \ 0.2 on adjusted analyses and known potential confounders for the dependent variable. The data analysis included multiple comparisons, p B 0.01 was considered significant. Data are presented as mean ± SD and percentages for categorical variables.
Matern Child Health J
Results A total of 795 VLBW inborn, singleton infants were eligible for study inclusion. Placental pathology was not obtained on 56 infants leaving 739 singleton mother/infant dyads in the final study sample. No differences were seen in gestation, birthweight, maternal race/ethnicity or maternal age in the 56 mother/infant dyads in which placental pathology was not obtained compared to the final study sample. Study demographics and maternal/infant dyad characteristics are presented in Table 1. Of the 739 dyads included in the study, 629 (85 %) mothers were \35 years, and 110 (15 %) mothers were of AMA (C35 years). The two age groups had no differences in mean birthweight or gestational age (Table 1). Similarly, no differences were appreciated in the presence of maternal fever, premature rupture of membranes, prolonged rupture of membranes, maternal chronic hypertension and maternal pre-eclampsia in mothers \35 compared to mothers C35. We did see differences in the rates of maternal diabetes, with a higher rate (17 %) in the AMA group when compared to the group of mothers \35 years old (8 %) (p \ 0.01,Table 1). Clinical chorioamnionitis had an increase rate in the younger age group of mothers (11 %) compared to the AMA group (5 %) (p = 0.05, Table 1). No differences were observed between the two age groups in regards to histologic chorioamnionitis, placental infarction, the presence of fibrin, meconium staining, funisitis, placental vasculopathy or placenta previa (Table 1). Babies born to White/Non-Hispanic (n = 299) and Black/Non-Hispanic Mothers (n = 353) had similar placental weight/birthweight Z score (-0.09 ± 0.87 vs -0.02 ± 1.4, p = .38). No comparison was done with
babies born to mothers of Hispanic (n = 64) or other (n = 23) ethnicity due to relatively small numbers of infants in these categories. An overall difference was seen in the placental weight/birthweight ratio based on maternal age, with mothers of advanced maternal age having a lower ratio (p \ 0.01) compared to mothers \35 years (Table 2). When analyzing the effect of age within a race/ethnicity group, no difference in placental weight/birthweight in White/Non-Hispanic mothers (p = 0.22) was observed. However, when looking at placental weight/birthweight ratio in Black/Non-Hispanic mothers, we did see a difference, with results of 0.23 in AMA mothers and 0.26 in younger mothers (\35 years old) (p = 0.01, Table 2). Infants who died before hospital discharge, had a higher placental weight/birthweight and placental weight/birthweight z score compared to the infants who survived to hospital discharge (Table 3). Multivariable Analysis After adjusting for gestational age, placental weight/birthweight z score was no longer independently associated with death before discharge (odds ratio 0.92, 95 % CI 0.73–1.12). After controlling for gestational age, maternal diabetes, maternal smoking, preeclampsia, IVF, clinical chorioamnionitis, and race/ethnicity, AMA remained independently associated with placental weight/birthweight ratio z score (full model r2 = 0.22, p \ 0.01). In this model, maternal race/ethnicity did not remain independently associated with placental weight/birthweight ratio z score. An interaction term of maternal race/ethnicity and AMA was added to the models and did not remain independently associated with
Table 1 Study demographics and maternal/infant dyad characteristics Demographic parameter
All mothers
Age C 35 (n = 110)
Age \ 35 (n = 629)
p
Gestational age (weeks) (mean ± SD)
27.9 ± 2.9
27.9 ± 2.9
27.9 ± 2.9
0.99
Birthweight (g) (mean ± SD)
1,014 ± 296
1,006.3 ± 292
1,011.5 ± 297.2
0.86
Maternal age (years) Infant gender (% male)
27.2 ± 6.6 49
38.5 ± 2.2 59
25.6 ± 5.2 49
Maternal fever (%)
6
5
7
0.40
Premature rupture of membranes (%)
30
25
30
0.34
Prolonged rupture of membranes (PROM) (%)
19
15
20
0.20
Chronic hypertension (%)
39
45
39
0.18
Pre-eclampsia (%)
36
38
35
0.54
Clinical chorioamnionitis (%)
9
5
11
Diabetes (pre-gestational and gestational) (%)
9
17
8
Maternal smoking (%)
19
13
19
In vitro fertilization (%)
3
11
2
Antenatal steroid administration (%)
78
69
79
0.02
Cesarean section delivery (%)
65
77
64
0.01
\0.01 0.05
0.05 \0.01 0.09 \0.01
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Matern Child Health J Table 2 Placental pathology in all mothers, Black/Non-Hispanic and White/Non-Hispanic Mothers Placenta
All mothers Age C 35 (n = 110)
p
Black/Non-Hispanic Mothers
Age \ 35 (n = 629)
Age C 35 (n = 51)
p
Age \ 35 (n = 300)
White/Non-Hispanic Mothers Age C 35 (n = 46)
p
Age \ 35 (n = 250)
Weight (g)
231 ± 74
254 ± 85
\0.01
216 ± 64
246 ± 91
0.03
244 ± 79
262 ± 76
0.15
Placental weight/ birthweight
0.24 ± 0.06
0.26 ± 0.08
\0.01
0.23 ± 0.05
0.26 ± 0.09
0.01
0.24 ± 0.07
0.25 ± 0.07
0.22
Placental weight/ birthweight Z score
-0.32 ± 0.84
0.004 ± 1.05 \0.01
-0.45 ± 0.71
-0.04 ± 1.1
0.01
-0.23 ± 0.84
-0.08 ± 0.87
0.27
Histologic chorioamnionitis
43 %
45 %
0.59
35 %
51 %
0.03
50 %
38 %
0.14
Meconium staining
13 %
15 %
0.60
11 %
13 %
0.63
19 %
19 %
0.95
Infarction Calcification
22 % 5%
24 % 11 %
0.57 0.08
22 % 4%
24 % 9%
0.71 0.22
20 % 4%
26 % 13 %
0.38 0.09
Funisitis
19 %
24 %
0.28
22 %
29 %
0.29
15 %
20 %
0.48
Vasculopathy
5%
11 %
0.06
6%
11 %
0.32
5%
13 %
0.13
Fibrin
20 %
26 %
0.18
24 %
29 %
0.45
17 %
24 %
0.36
Previa
2%
2%
0.95
0%
1%
0.47
4%
4%
0.80
Table 3 Placental weight/birthweight and neonatal mortality Died (n = 96)
Survived (n = 699)
p
Placental weight/birthweight (SD)
0.30 (0.10)
0.25 (0.08)
\0.01
Placental weight/birthweight z score (SD)
0.41 (1.30)
-0.11 (0.96)
\0.01
placental weight/birthweight z score. The models were also analyzed with absolute placental weight and placental weight/birthweight as dependent variables. In both cases, AMA remained independently associated with placental weight or placental weight/birth weight. After controlling for gestational age, race/ethnicity, smoking, preeclampsia, diabetes, IVF and clinical chorioamnionitis, AMA mothers had an increased odds of having a placental weight/birthweight ratio z score in the lowest quartile (z score \ -0.71) for the cohort; odds ratio 2.1 (95 % CI 1.3–3.5). In this model, Black/Non-Hispanic maternal race/ethnicity did not remain independently associated with a placental weight/birthweight ratio z score in the lowest quartile, odds ratio 1.02 (95 % CI 0.68–1.53). An interaction term of maternal race and AMA was added to the models and did not remain independently associated with placental weight/birthweight z score.
Discussion The main finding of our study was that placental weight and placental weight/birthweight ratio were lower in
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mothers of advanced maternal age. After controlling for gestational age, race/ethnicity, maternal diabetes, maternal smoking, maternal hypertension and clinical chorioamnionitis, AMA, but not race/ethnicity, remained independently associated with placental weight/birthweight ratio z score. Our study provides important information relating to the biology of pregnancy of older Black/Non-Hispanic mothers delivering VLBW infants. Our data suggests differences in placentation based on maternal age. Placental weight/birthweight ratio has been previously associated with adverse newborn outcomes. In a population of term neonates, a high placental weight/birthweight ratio was associated with an increased risk of NICU admission [11]. In contrast, a low placental weight/birthweight ratio was associated with comparable outcomes when compared to a normal placental weight/birthweight ratio [11]. Our study found no association of placental weight/birthweight with mortality in VLBW infants. In a large population cohort of all singleton births in Norway, in which the mean maternal age at delivery was 29.4 years, and 16.4 % of the population was 35 years or older, the mean placental weight was 673.1 g and increased with maternal age. Mothers of advanced maternal age also had a higher
Matern Child Health J
placental weight relative to birthweight as compared with younger mothers [12]. In contrast to the homogenous study population from Norway, in our more heterogeneous population of VLBW infants, the offspring of mothers of advanced maternal age had a lower placental weight and a lower placental weight/ birthweight ratio. The reasons for the differing findings are likely related to the specific maternal and infant populations studied. Our study sample included a diverse racial ethnic population and was limited to VLBW infants. The study of Haalvaldsen included all gestational ages and was more population based. In the United States, Black/NonHispanic mothers are known to have a higher rate of premature and low birthweight births compared to White/NonHispanic mothers. The reasons behind these disparities remain an important topic of ongoing investigation. Black/ Non-Hispanic mothers of advanced maternal age represent a group at particularly high risk for premature birth [13– 15]. In our population of VLBW infants, AMA, but not race negatively affected placental weight. Our data show few differences in placental histology based on maternal age, and race/ethnicity. One of these differences was the reduced occurrence of histologic chorioamnionitis in Black/Non-Hispanic mothers of advanced maternal age. This difference was not significant based on an a priori set p value cutoff of B0.01. Few studies have looked at different placental pathology stratified by race/ethnicity and maternal age. Racial disparities in intrauterine infection during pregnancy have previously been shown and may result from a constellation of environmental and intergenerational risk factors including psychosocial stress, diet, intrauterine growth and genes [16]. The rate of histologic chorioamnionitis was previously investigated by race and by gestation in a cross-sectional study involving 1,843 deliveries. The severity of chorioamnionitis was graded histologically and the conclusion was that overall rates of histologic chorioamnionitis did not contribute to racial disparities in low birthweight despite black women having twice the rate of severe histologic chorioamnionitis [17]. Only severe histologic chorioamnionitis predicted preterm delivery [17]. This study did not subdivide the women by maternal age. To our knowledge, this study is the first to explore the interaction between maternal race/ethnicity, maternal age and histologic chorioamnionitis. Our data suggest that larger population based studies are needed to further interrogate this association. Our study has a number of limitations. First, our population sample was limited to VLBW infants and with each step of our analysis the numbers of our subpopulations became smaller. Due to this fact, we did not include the Hispanic and Asian populations or stratify further the maternal age categories. Although the exclusion of Hispanic patients is a potential limitation, we also consider it a
strength because the study population is more homogenous and is influenced less by factors related to gestational age. Second, the procedure used to weigh the placentas was not standardized in the data set. Third, the degree of severity of histologic chorioamnionitis was not reported. Fourth, the possibility of interobserver variability when making the different diagnosis of the placental pathology or weighing placentas does exist. However, because all patients are from a single institution and adhering to the same standard definition and similar clinical practices, the influence of this potential variability is diminished. As this study is limited to single center’s catchment population, it will need to be reproduced in order to be more generalizable. Additionally, our study sample was limited to VLBW infants and may not apply to term infants or other populations of preterm infants.
Conclusions To our knowledge, this study is the first to evaluate the effect of maternal age and maternal race/ethnicity on placental weight, placental weight/birthweight ratio and placental pathology in a very low birthweight infant population. In our population of VLBW infants, advanced maternal age was associated with a decrease in placental weight and placental weight/birthweight ratio. From our data we cannot determine if older maternal age is causal for reduced placental weight/birthweight or representative of unmeasured confounding variables. Further research is needed to explore possible causal mechanisms, which may explain the relationship between AMA and reduced placental weight in VLBW infants. Conflict of interest The authors of this paper have nothing to disclose. No financial or non-financial interests to declare.
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