Original Article
283
Impact of Antepartum Anemia on the Development of Chorioamnionitis at Term Vrishali Lopes, MS2
Brenna Anderson, MD, MSc3
1 Division of Maternal Fetal Medicine, Department of Obstetrics,
Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 2 Division of Research, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island 3 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island
Address for correspondence Karen Archabald, MD, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, P. O. Box 208063, New Haven, CT 06520 (e-mail: [email protected]).
Am J Perinatol 2015;32:283–288.
Abstract
Keywords
► ► ► ►
anemia chorioamnionitis term infection
Objective The aim of this study is to assess the association of antepartum anemia with chorioamnionitis at term. Study Design This is a case control study of women with and without chorioamnionitis who delivered following spontaneous or induced labor at 37 weeks’ gestation. Cases had both intrapartum fever 38°C and histologic chorioamnionitis. Controls were afebrile and matched by physician practice group. Anemia was defined by CDC guidelines as hemoglobin < 10.5 g/dL (second trimester) or < 11.0 g/dL (third trimester). Results A total of 101 cases and 197 controls were identified. The prevalence of anemia at the second and third trimester complete blood count (CBC) was significantly higher in the chorioamnionitis group (p ¼ 0.02). This association persisted after multiple logistic regression controlling for known clinical risk factors (adjusted odds ratios, 2.47; range, 1.24–4.94). Conclusion Anemia at the time of the second and third trimester CBC was more prevalent among women who developed chorioamnionitis at term. Antepartum anemia may be a modifiable risk factor in the prevention of chorioamnionitis at term.
Chorioamnionitis affects approximately 3 to 6% of term pregnancies1–3 and is a recognized risk factor for subsequent development of cerebral palsy in this population.4–6 Chorioamnionitis at term is also associated with increased fetal and maternal morbidity, including dysfunctional labor, uterine atony, neonatal sepsis, and low 5-minute Apgar scores.1,7,8 Intrapartum risk factors for the development of chorioamnionitis at term are well established and include length of labor, duration of ruptured membranes, meconiumstained amniotic fluid, internal fetal or uterine monitoring, and number of digital exams.9–11 Demographic risk factors
have also been identified, including primiparity and race.12,13 Identifying modifiable risk factors in the antepartum period remains an area open to investigation. Anemia, a marker for overall nutritional status, is prevalent in pregnancy. The CDC estimates anemia impacts 7.3% of women in the first trimester, progressing to 11.6% during the second trimester and 33.8% in the third trimester.14 Anemia has been associated with adverse obstetric outcomes including increased risk of low-birth-weight infants, preterm delivery, and perinatal mortality.15–17 A retrospective cohort study of preterm births found that women with anemia at
received September 15, 2013 accepted after revision June 1, 2014 published online July 31, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1384638. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Karen Archabald, MD1
Anemia and Chorioamnionitis at Term
Archabald et al.
the time of admission, defined as hemoglobin (Hgb) < 11.0 g/dL, were twice as likely to develop chorioamnionitis as their counterparts (odds ratio [OR], 2.17).18 The biological mechanism for the impact of anemia on pregnancy outcomes is unclear; however, in vitro, iron deficiency anemia has been shown to depress immune function, therefore increasing susceptibility to bacterial infection and therefore possibly chorioamnionitis.19,20 To our knowledge, no studies to date have assessed the impact of anemia on chorioamnionitis among term births. Given the prevalence of anemia during pregnancy and the serious consequences of chorioamnionitis at term, the objective of this study was to investigate whether exposure to anemia during pregnancy is associated with an increased risk of chorioamnionitis at term. Because of increasing iron requirements, the majority of women with inadequate iron stores exhibit anemia by 20 weeks.21,22 In the United States, it is part of routine clinical care to collect a complete blood count (CBC) in the late second or early third trimester. We therefore chose anemia at the time of the routine second/third trimester CBC as our primary exposure because anemia from inadequate iron stores would be apparent. We hypothesized that women who develop chorioamnionitis at term are more likely to have been exposed to anemia at the time of the routine second/third trimester CBC than women who do not develop chorioamnionitis at term.
Patients and Methods This was a case control study of women admitted to Women and Infants Hospital in Providence, RI, in spontaneous or induced labor at greater than or equal to 37 weeks between December 1, 2007, and June 1, 2009. Detailed individual chart abstractions of all cases and controls were conducted by the principal investigator (K.A.). Women and Infants Hospital has a unique mix of both hospital-employed and communitybased private practice providers at a single tertiary care academic institution. The hospital delivers approximately 8,000 infants annually, representing 70% of the deliveries in the state of Rhode Island. Cases were identified via International Classification of Diseases, 9th Revision, Clinical Modification codes and confirmed via individual chart abstraction. Sequential cases were reviewed for eligibility beginning on June 1, 2009, and continued retrospectively until 100 cases were identified. Women were excluded if they had prelabor cesarean section or a known hemoglobinopathy. Chorioamnionitis was rigorously defined with objective measures including a documented fever greater than or equal to 38°C, as well as placental pathology consistent with histologic chorioamnionitis. Histologic chorioamnionitis was defined as acute chorioamnionitis on clinical pathology. While women with clinical chorioamnionitis have evidence of histologic chorioamnionitis only approximately 60% of the time,23 correlation between documented histological chorioamnionitis, and clinical infection is high.24 We therefore chose a combination of these two indicators to decrease the likelihood that other causes of intrapartum fever, including epidural fever, were misclassified as chorioamnionitis. American Journal of Perinatology
Vol. 32
No. 3/2015
Controls were chosen via a random number generator in a 2:1 ratio from women delivering during the same time period. Women were excluded if they had an intrapartum fever greater than or equal to 38°C. Placental pathology was available for 15 (7.6%) of controls. Controls were matched by location of prenatal care, including private or public clinic as well as by private practice group. Matching was done to account for both differences in patient population, as well as for differences in habits among physicians who send placentas to pathology for evaluation. Our primary exposure was anemia at the time of the routine second/early third trimester CBC. We defined anemia using CDC guidelines as a second trimester Hgb < 10.5 g/dL, or a third trimester Hgb < 11.0 g/dL.25 Data on Hgb were collected at three points during pregnancy; presentation for prenatal care, second/third trimester CBC, and at admission for delivery. We collected demographic information including age, race, insurance status (private vs. Medicaid), education, gravidity, parity, and type of obstetrical provider. We collected data on known intrapartum risk factors for chorioamnionitis including antenatal infection, induction of labor, duration of labor, duration of rupture of membranes, duration of labor, number of cervical exams, use of internal monitoring, and Group B streptococcus (GBS) status. Sample size calculation was completed assuming a 33% prevalence of anemia in the third trimester and a case/control ratio of 1:2. We therefore needed 100 cases and 200 controls to detect an OR of 2.0 with 80% power, α of 0.05. An OR of 2.0 was chosen as it was felt to represent a clinically significant increase in prevalence of anemia among women with chorioamnionitis. Categorical variables were compared by Chi square or Fisher exact tests. Continuous variables were compared using t-test or Wilcoxon rank sum test. Multiple logistic regression was used to calculate adjusted odds ratios for the association of antepartum anemia exposure with chorioamnionitis at term, controlling for potential confounding variables.
Results We identified 101 cases of chorioamnionitis and 197 cases of controls. The demographic characteristics of the study population by outcome are described in ►Table 1. Women who developed chorioamnionitis were significantly less likely to be multiparous than their counterparts (p 0.0001). Race, education, and insurance status were not significantly different between the two groups. In univariate analysis, anemia at the time of the second/ third trimester CBC as defined by CDC standards was more prevalent in women who developed chorioamnionitis at term (p ¼ 0.02). Mean Hgb in the women who developed chorioamnionitis was not significantly different from women who did not develop chorioamnionitis (11.05 vs. 11.17 mg/dL, p ¼ 0.23) nor was mean corpuscular volume (89.0 vs. 90.08 fL, p ¼ 0.30) First trimester anemia was more prevalent in women who developed chorioamnionitis (p ¼ 0.001) and funisitis
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
284
Anemia and Chorioamnionitis at Term
Archabald et al.
285
Table 1 Maternal characteristics Maternal characteristic
Chorioamnionitis n ¼ 101
No chorioamnionitis n ¼ 197
p Value
Age (mean)
26
27
0.17a
Multiparous, n (%)
25 (25)
112 (43)
< 0.0001b
Hispanic
41 (41)
70 (36)
0.10b
White
33 (33)
92 (47)
African American
9 (9)
13 (7)
Other
18 (18)
22 (12)
Private insurance, n (%)
36 (36)
73 (37)
0.83b
12 y education, n (%)
47 (61)
94 (61)
1.0b
Prenatal care–private, n (%)
41 (41)
81 (41)
0.93b
a
t-test. Chi square test.
b
(p ¼ 0.001) as was anemia that persisted from the first trimester through the second/third trimester CBC until delivery (chorioamnionitis [p ¼ 0.02] and funisitis [p ¼ 0.01]). Prevalence of anemia was not different at the time of presentation for delivery (p ¼ 0.11). (►Table 2) Univariate analysis revealed duration of labor > 12 hours (p 0.0001), duration of ruptured membranes > 12 hours (p ¼ 0.0001), cervical dilation 4 at the time of admission (p ¼ 0.0002), cervical exams 8 (p < 0.0001), presence of meconium (p ¼ 0.0003), and the use of an intrauterine pressure catheter (p < 0.0001) to be associated with increased risk of chorioamnionitis as expected (►Table 2). GBS carrier status and type of labor (induced vs. spontaneous) were not significant. Multiple logistic regression was performed to determine the OR of chorioamnionitis in women who were exposed to antenatal anemia. The regression controlled for practice group,
parity, number of cervical exams, duration of ruptured membranes, and the use of intrauterine pressure catheter as these variables were clinically important and significant in univariate analysis. Anemia at the time of the second/third trimester CBC, duration of ruptured membranes, number of cervical exams, parity, and use of intrauterine pressure catheter were associated with a significantly increased OR of developing chorioamnionitis. Duration of ruptured membranes and number of cervical exams had the strongest association with development of chorioamnionitis (►Table 3).
Discussion We found a higher prevalence of anemia at the time of the second/third trimester CBC in women who developed chorioamnionitis at term. Anemia in the first trimester and persistent anemia throughout pregnancy were also more
Table 2 Association of anemia and other clinical risk factors for chorioamnionitis with development of chorioamnionitis at term Risk factor
Chorioamnionitis, n ¼ 101
No chorioamnionitis, n ¼ 197
p value
2nd/3rd trimester anemia n/total n (%)
36 (36)
46 (23)
0.02a
1st trimester anemia, n/total n (%)
10/78 (13)
3/148 (2)
0.001a
Anemia at delivery, n/total n (%)
22/101 (22)
28/194 (14)
0.11a
Persistent anemia, n/total n (%)
8/100 (8)
3/184 (2)
0.02b
Induction of labor
23 (23)
57 (29)
0.29ª
Duration of labor > 12 h
85 (85)
54 (28)
< 0.0001ª
Duration of rupture > 12 h
59 (59)
23 (12)
< 0.0001ª
Number of cervical exams 8
43 (43)
12 (6)
< 0.0001ª
IUPC
53 (52)
33 (17)
< 0.0001ª
Group B streptococcus positive
20 (20)
51 (26)
0.23ª
Abbreviation: IUPC, intrauterine pressure catheter. Note: Anemia defined as Hgb < 10.5 g/dL in 2nd trimester, Hgb < 11.0 g/dL in first and third trimester. a Chi square test. b Fisher exact test. American Journal of Perinatology
Vol. 32
No. 3/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Race/ethnicity, n (%)
Anemia and Chorioamnionitis at Term
Archabald et al.
Table 3 Adjusted and unadjusted odds ratio of the development of chorioamnionitis at term by anemia and other clinical risk factors Risk factor
Univariate OR (95% CI)
Adjusted OR (95% CI)
2nd/3rd trimester anemia
1.82 (1.07–3.07)
2.47 (1.24–4.94)
1st trimester anemia
7.11 (1.89–26.6)
11.5 (2.35–56.5)
Persistent anemia
5.24 (1.36–20.2)
8.92 (1.95–40.7)
Duration of rupture > 12 h
10.6 (5.90–19.1)
6.05 (3.12–11.7)
Cervical exams 8
11.4 (5.65–23.1)
5.73 (2.55–12.9)
Multiparity
0.25 (0.15–0.42)
0.45 (0.23–0.86)
IUPC
5.48 (3.19–9.42)
2.35 (1.21–4.57)
Prenatal care–private
0.98 (0.60–1.59)
0.82 (0.43–1.56)
Abbreviations: CI, confidence interval; IUPC, intrauterine pressure catheter; OR, odds ratio.
prevalent in women who developed chorioamnionitis. We also identified more first trimester and persistent anemia in women who developed funisitis, a marker of severe inflammation and infection that has been linked to the fetal inflammatory response as well as cerebral palsy.26 In vitro, iron deficiency anemia has been shown to depress neutrophil, natural killer, and T-cell function. Impaired immune function theoretically increases susceptibility to bacterial infection and therefore chorioamnionitis.19,20 We therefore expect to see more chorioamnionitis when the diagnosis of anemia reflects a true iron deficiency and not simply physiologic changes of pregnancy. Unlike the study published by Aly et al that showed an association between anemia at the time of presentation and chorioamnionitis in preterm delivery,18 our study found antepartum anemia in the first and late second/early third trimesters but not at the time of presentation for term delivery to be associated with chorioamnionitis. Similar results have been found in studies assessing the impact of anemia on other pregnancy outcomes. A large retrospective cohort analysis of 173,031 women attending public health clinics in 10 states found low first and second but not third trimester Hgb to be associated with increased risk of preterm delivery.27 Two large prospective Chinese studies have found low first trimester Hgb to be associated with preterm birth and small for gestational infants28 as well as an increased risk of preterm premature rupture of membranes (PROM).29 A meta-analysis confirmed the increased risk of preterm delivery in women with low first and second trimester Hgb, as well as a possible increase in small for gestational age infants.30 Because the majority of plasma expansion occurs during the second trimester, the higher impact of early anemia on pregnancy outcomes both in the literature and in our study American Journal of Perinatology
Vol. 32
No. 3/2015
may represent the more accurate diagnosis of iron deficiency in the first trimester compared with the late second and third trimesters. Later in pregnancy, iron deficiency anemia can be more difficult to distinguish from the dilutional anemia of pregnancy in nutritionally replete women particularly when iron indices are not included in evaluation. Because of the retrospective nature of this study, we defined anemia by Hgb and CDC guidelines as more detailed iron study parameters were not available. Therefore, anemia diagnosed in the first and early second/third trimesters is more likely to be secondary to iron deficiency than anemia diagnosed at the time of presentation for delivery. This corresponds with the statistically stronger association between first trimester anemia and chorioamnionitis compared with second/third trimester and anemia at the time of presentation for delivery. Treatment for presumed iron deficiency anemia in patients without evidence of another etiology of anemia is common in pregnancy and is recommended by the American Congress of Obstetricians and Gynecologists.31 Documentation of iron supplementation and compliance in our study was overall inconsistent and likely underreported, and precluded our ability to complete an analysis on the impact of supplementation on chorioamnionitis at term. The data on the impact of iron supplementation in anemic pregnant women are inconsistent, with evidence of improved hematologic indices, but without convincing evidence of improved pregnancy outcomes.32 However, on the basis of the impact of iron deficiency on functioning of the immune system, we would expect to see less chorioamnionitis in women who were supplemented with iron. Our study has several strengths. Our data were obtained with precision through detailed, individualized chart abstraction by a single investigator. Administrative level data were not used. Rather, our definition of chorioamnionitis was strict, including both clinical and histologic criteria, increasing the reliability of the diagnosis. Finally, our sample size was robust and well powered to detect a difference in the prevalence of anemia among women with chorioamnionitis compared with those without chorioamnionitis. Because of the retrospective nature of our study, we are unable to determine causality. In addition, because of the lack of iron indices, we were unable to objectively differentiate between iron deficiency anemia and dilutional anemia. However, this study lays the groundwork for future studies. Evaluation of the impact of iron deficiency anemia, defined with iron indices, would help further clarify the identified link of anemia with chorioamnionitis. Prospective interventional studies comparing standard care with aggressive iron supplementation are needed to determine the role of supplementation in possible prevention of chorioamnionitis at term. We found antepartum anemia in the first as well as late second/early third trimester to be associated with the development of chorioamnionitis at term. The association with anemia from the first to the early third trimester, the similarity in temporal distribution of anemia on pregnancy outcomes similar to findings of other pregnancy outcomes, as well as the association with funisitis is compelling for a true
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
286
association. Anemia may be a modifiable risk factor for a disease with serious fetal and maternal morbidity. 16
Acknowledgment The authors thank Christina Raker, ScD, for her expert statistical input regarding the design and analysis of this study.
17
18
19
References 1 Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the
prognosis for term infants. Obstet Gynecol 1999;94(2):274–278
20
2 Bailit JL, Gregory KD, Reddy UM, et al. Maternal and neonatal
3 4
5 6 7 8
9 10
11
12 13 14
15
outcomes by labor onset type and gestational age. Am J Obstet Gynecol 2010;202(3):e1, e12 Newton E. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol 1993;36(4):795–808 Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290(20):2677–2684 Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA 2000;284(11):1417–1424 Grether JK, Cummins SK, Nelson KB. The california cerebral palsy project. Paediatr Perinat Epidemiol 1992;6(3):339–351 Mark S, Groughan-Minihane M, Kilpatrick S. Chorioamnionitis and uterine function. Obstet Gynecol 2000;95(6):909–912 Rouse DJ, Landon M, Leveno KJ, et al; National Institute of Child Health And Human Development, Maternal-Fetal Medicine Units Network. The Maternal-Fetal Medicine Units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes. Am J Obstet Gynecol 2004;191(1):211–216 Newton ER. Preterm labor, preterm premature rupture of membranes, and chorioamnionitis. Clin Perinatol 2005;32(3):571–600 Tran SH, Cheng YW, Kaimal AJ, Caughey AB. Length of rupture of membranes in the setting of premature rupture of membranes at term and infectious maternal morbidity. Am J Obstet Gynecol 2008;198(6):e1–e5 Seaward PG, Hannah ME, Myhr TL, et al. International Multicentre Term Prelabor Rupture of Membranes Study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term. Am J Obstet Gynecol 1997;177(5):1024–1029 Stürchler D, Menegoz F, Daling J. Reproductive history and intrapartum fever. Gynecol Obstet Invest 1986;21(4):182–186 Fiscella K. Race, perinatal outcome, and amniotic infection. Obstet Gynecol Surv 1996;51(1):60–66 Centers for Disease Control. Pregnancy and pediatric surveillance system. 2011. Table 2-D. Available at: http://www.cdc.gov/pednss/ pnss_tables/pdf/national_table2.pdf Accessed October 9, 2013 Rasmussen K. Is there a causal relationship between iron deficiency or iron-deficiency anemia and weight at birth, length of
21 22
23
24
25
26
27
28
29
30
31
32
Archabald et al.
gestation and perinatal mortality? J Nutr 2001;131 (2S-2) 590S–601S, discussion 601S–603S Scholl TO, Hediger ML. Anemia and iron-deficiency anemia: compilation of data on pregnancy outcome. Am J Clin Nutr 1994;59 (2, Suppl):492S–500S, discussion 500S–501S Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr 1992;55(5):985–988 Aly H, Alhabashi G, Hammad TA, Owusu-Ansah S, Bathgate S, Mohamed M. ABO phenotype and other risk factors associated with chorioamnionitis. J Pediatr 2008;153(1):16–18 Allen LH. Biological mechanisms that might underlie iron’s effects on fetal growth and preterm birth. J Nutr 2001;131 (2S-2) 581S–589S Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr 2001;131 (2S-2)616S–633S, discussion 633S–635S Bothwell TH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr 2000;72 1, Suppl):257S–264S Casanueva E, Pfeffer F, Drijanski A, Fernández-Gaxiola AC, Gutiérrez-Valenzuela V, Rothenberg SJ. Iron and folate status before pregnancy and anemia during pregnancy. Ann Nutr Metab 2003;47(2):60–63 Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Ananth CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol 1999;94(6):1000–1005 Heller DS, Rimpel LH, Skurnick JH. Does histologic chorioamnionitis correspond to clinical chorioamnionitis? J Reprod Med 2008; 53(1):25–28 Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep 1998;47 (RR-3) 1–29 Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 2005;192(2): 452–457 Scanlon KS, Yip R, Schieve LA, Cogswell ME. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol 2000;96(5 Pt 1):741–748 Ren A, Wang J, Ye RW, Li S, Liu JM, Li Z. Low first-trimester hemoglobin and low birth weight, preterm birth and small for gestational age newborns. Int J Gynaecol Obstet 2007;98(2): 124–128 Zhang Q, Ananth CV, Li Z, Smulian JC. Maternal anaemia and preterm birth: a prospective cohort study. Int J Epidemiol 2009; 38(5):1380–1389 Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy and birth outcome: a meta-analysis. Am J Perinatol 2000;17(3):137–146 American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 95: Anemia in pregnancy. Obstet Gynecol 2008; 112(1):201–207 Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for irondeficiency anaemia in pregnancy. Cochrane Database Syst Rev 2011;(10):CD003094–CD003094
American Journal of Perinatology
Vol. 32
No. 3/2015
287
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Anemia and Chorioamnionitis at Term
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
283
Impact of Antepartum Anemia on the Development of Chorioamnionitis at Term Vrishali Lopes, MS2
Brenna Anderson, MD, MSc3
1 Division of Maternal Fetal Medicine, Department of Obstetrics,
Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 2 Division of Research, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island 3 Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, Women and Infants Hospital, Providence, Rhode Island
Address for correspondence Karen Archabald, MD, Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, 333 Cedar Street, P. O. Box 208063, New Haven, CT 06520 (e-mail: [email protected]).
Am J Perinatol 2015;32:283–288.
Abstract
Keywords
► ► ► ►
anemia chorioamnionitis term infection
Objective The aim of this study is to assess the association of antepartum anemia with chorioamnionitis at term. Study Design This is a case control study of women with and without chorioamnionitis who delivered following spontaneous or induced labor at 37 weeks’ gestation. Cases had both intrapartum fever 38°C and histologic chorioamnionitis. Controls were afebrile and matched by physician practice group. Anemia was defined by CDC guidelines as hemoglobin < 10.5 g/dL (second trimester) or < 11.0 g/dL (third trimester). Results A total of 101 cases and 197 controls were identified. The prevalence of anemia at the second and third trimester complete blood count (CBC) was significantly higher in the chorioamnionitis group (p ¼ 0.02). This association persisted after multiple logistic regression controlling for known clinical risk factors (adjusted odds ratios, 2.47; range, 1.24–4.94). Conclusion Anemia at the time of the second and third trimester CBC was more prevalent among women who developed chorioamnionitis at term. Antepartum anemia may be a modifiable risk factor in the prevention of chorioamnionitis at term.
Chorioamnionitis affects approximately 3 to 6% of term pregnancies1–3 and is a recognized risk factor for subsequent development of cerebral palsy in this population.4–6 Chorioamnionitis at term is also associated with increased fetal and maternal morbidity, including dysfunctional labor, uterine atony, neonatal sepsis, and low 5-minute Apgar scores.1,7,8 Intrapartum risk factors for the development of chorioamnionitis at term are well established and include length of labor, duration of ruptured membranes, meconiumstained amniotic fluid, internal fetal or uterine monitoring, and number of digital exams.9–11 Demographic risk factors
have also been identified, including primiparity and race.12,13 Identifying modifiable risk factors in the antepartum period remains an area open to investigation. Anemia, a marker for overall nutritional status, is prevalent in pregnancy. The CDC estimates anemia impacts 7.3% of women in the first trimester, progressing to 11.6% during the second trimester and 33.8% in the third trimester.14 Anemia has been associated with adverse obstetric outcomes including increased risk of low-birth-weight infants, preterm delivery, and perinatal mortality.15–17 A retrospective cohort study of preterm births found that women with anemia at
received September 15, 2013 accepted after revision June 1, 2014 published online July 31, 2014
Copyright © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI http://dx.doi.org/ 10.1055/s-0034-1384638. ISSN 0735-1631.
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Karen Archabald, MD1
Anemia and Chorioamnionitis at Term
Archabald et al.
the time of admission, defined as hemoglobin (Hgb) < 11.0 g/dL, were twice as likely to develop chorioamnionitis as their counterparts (odds ratio [OR], 2.17).18 The biological mechanism for the impact of anemia on pregnancy outcomes is unclear; however, in vitro, iron deficiency anemia has been shown to depress immune function, therefore increasing susceptibility to bacterial infection and therefore possibly chorioamnionitis.19,20 To our knowledge, no studies to date have assessed the impact of anemia on chorioamnionitis among term births. Given the prevalence of anemia during pregnancy and the serious consequences of chorioamnionitis at term, the objective of this study was to investigate whether exposure to anemia during pregnancy is associated with an increased risk of chorioamnionitis at term. Because of increasing iron requirements, the majority of women with inadequate iron stores exhibit anemia by 20 weeks.21,22 In the United States, it is part of routine clinical care to collect a complete blood count (CBC) in the late second or early third trimester. We therefore chose anemia at the time of the routine second/third trimester CBC as our primary exposure because anemia from inadequate iron stores would be apparent. We hypothesized that women who develop chorioamnionitis at term are more likely to have been exposed to anemia at the time of the routine second/third trimester CBC than women who do not develop chorioamnionitis at term.
Patients and Methods This was a case control study of women admitted to Women and Infants Hospital in Providence, RI, in spontaneous or induced labor at greater than or equal to 37 weeks between December 1, 2007, and June 1, 2009. Detailed individual chart abstractions of all cases and controls were conducted by the principal investigator (K.A.). Women and Infants Hospital has a unique mix of both hospital-employed and communitybased private practice providers at a single tertiary care academic institution. The hospital delivers approximately 8,000 infants annually, representing 70% of the deliveries in the state of Rhode Island. Cases were identified via International Classification of Diseases, 9th Revision, Clinical Modification codes and confirmed via individual chart abstraction. Sequential cases were reviewed for eligibility beginning on June 1, 2009, and continued retrospectively until 100 cases were identified. Women were excluded if they had prelabor cesarean section or a known hemoglobinopathy. Chorioamnionitis was rigorously defined with objective measures including a documented fever greater than or equal to 38°C, as well as placental pathology consistent with histologic chorioamnionitis. Histologic chorioamnionitis was defined as acute chorioamnionitis on clinical pathology. While women with clinical chorioamnionitis have evidence of histologic chorioamnionitis only approximately 60% of the time,23 correlation between documented histological chorioamnionitis, and clinical infection is high.24 We therefore chose a combination of these two indicators to decrease the likelihood that other causes of intrapartum fever, including epidural fever, were misclassified as chorioamnionitis. American Journal of Perinatology
Vol. 32
No. 3/2015
Controls were chosen via a random number generator in a 2:1 ratio from women delivering during the same time period. Women were excluded if they had an intrapartum fever greater than or equal to 38°C. Placental pathology was available for 15 (7.6%) of controls. Controls were matched by location of prenatal care, including private or public clinic as well as by private practice group. Matching was done to account for both differences in patient population, as well as for differences in habits among physicians who send placentas to pathology for evaluation. Our primary exposure was anemia at the time of the routine second/early third trimester CBC. We defined anemia using CDC guidelines as a second trimester Hgb < 10.5 g/dL, or a third trimester Hgb < 11.0 g/dL.25 Data on Hgb were collected at three points during pregnancy; presentation for prenatal care, second/third trimester CBC, and at admission for delivery. We collected demographic information including age, race, insurance status (private vs. Medicaid), education, gravidity, parity, and type of obstetrical provider. We collected data on known intrapartum risk factors for chorioamnionitis including antenatal infection, induction of labor, duration of labor, duration of rupture of membranes, duration of labor, number of cervical exams, use of internal monitoring, and Group B streptococcus (GBS) status. Sample size calculation was completed assuming a 33% prevalence of anemia in the third trimester and a case/control ratio of 1:2. We therefore needed 100 cases and 200 controls to detect an OR of 2.0 with 80% power, α of 0.05. An OR of 2.0 was chosen as it was felt to represent a clinically significant increase in prevalence of anemia among women with chorioamnionitis. Categorical variables were compared by Chi square or Fisher exact tests. Continuous variables were compared using t-test or Wilcoxon rank sum test. Multiple logistic regression was used to calculate adjusted odds ratios for the association of antepartum anemia exposure with chorioamnionitis at term, controlling for potential confounding variables.
Results We identified 101 cases of chorioamnionitis and 197 cases of controls. The demographic characteristics of the study population by outcome are described in ►Table 1. Women who developed chorioamnionitis were significantly less likely to be multiparous than their counterparts (p 0.0001). Race, education, and insurance status were not significantly different between the two groups. In univariate analysis, anemia at the time of the second/ third trimester CBC as defined by CDC standards was more prevalent in women who developed chorioamnionitis at term (p ¼ 0.02). Mean Hgb in the women who developed chorioamnionitis was not significantly different from women who did not develop chorioamnionitis (11.05 vs. 11.17 mg/dL, p ¼ 0.23) nor was mean corpuscular volume (89.0 vs. 90.08 fL, p ¼ 0.30) First trimester anemia was more prevalent in women who developed chorioamnionitis (p ¼ 0.001) and funisitis
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
284
Anemia and Chorioamnionitis at Term
Archabald et al.
285
Table 1 Maternal characteristics Maternal characteristic
Chorioamnionitis n ¼ 101
No chorioamnionitis n ¼ 197
p Value
Age (mean)
26
27
0.17a
Multiparous, n (%)
25 (25)
112 (43)
< 0.0001b
Hispanic
41 (41)
70 (36)
0.10b
White
33 (33)
92 (47)
African American
9 (9)
13 (7)
Other
18 (18)
22 (12)
Private insurance, n (%)
36 (36)
73 (37)
0.83b
12 y education, n (%)
47 (61)
94 (61)
1.0b
Prenatal care–private, n (%)
41 (41)
81 (41)
0.93b
a
t-test. Chi square test.
b
(p ¼ 0.001) as was anemia that persisted from the first trimester through the second/third trimester CBC until delivery (chorioamnionitis [p ¼ 0.02] and funisitis [p ¼ 0.01]). Prevalence of anemia was not different at the time of presentation for delivery (p ¼ 0.11). (►Table 2) Univariate analysis revealed duration of labor > 12 hours (p 0.0001), duration of ruptured membranes > 12 hours (p ¼ 0.0001), cervical dilation 4 at the time of admission (p ¼ 0.0002), cervical exams 8 (p < 0.0001), presence of meconium (p ¼ 0.0003), and the use of an intrauterine pressure catheter (p < 0.0001) to be associated with increased risk of chorioamnionitis as expected (►Table 2). GBS carrier status and type of labor (induced vs. spontaneous) were not significant. Multiple logistic regression was performed to determine the OR of chorioamnionitis in women who were exposed to antenatal anemia. The regression controlled for practice group,
parity, number of cervical exams, duration of ruptured membranes, and the use of intrauterine pressure catheter as these variables were clinically important and significant in univariate analysis. Anemia at the time of the second/third trimester CBC, duration of ruptured membranes, number of cervical exams, parity, and use of intrauterine pressure catheter were associated with a significantly increased OR of developing chorioamnionitis. Duration of ruptured membranes and number of cervical exams had the strongest association with development of chorioamnionitis (►Table 3).
Discussion We found a higher prevalence of anemia at the time of the second/third trimester CBC in women who developed chorioamnionitis at term. Anemia in the first trimester and persistent anemia throughout pregnancy were also more
Table 2 Association of anemia and other clinical risk factors for chorioamnionitis with development of chorioamnionitis at term Risk factor
Chorioamnionitis, n ¼ 101
No chorioamnionitis, n ¼ 197
p value
2nd/3rd trimester anemia n/total n (%)
36 (36)
46 (23)
0.02a
1st trimester anemia, n/total n (%)
10/78 (13)
3/148 (2)
0.001a
Anemia at delivery, n/total n (%)
22/101 (22)
28/194 (14)
0.11a
Persistent anemia, n/total n (%)
8/100 (8)
3/184 (2)
0.02b
Induction of labor
23 (23)
57 (29)
0.29ª
Duration of labor > 12 h
85 (85)
54 (28)
< 0.0001ª
Duration of rupture > 12 h
59 (59)
23 (12)
< 0.0001ª
Number of cervical exams 8
43 (43)
12 (6)
< 0.0001ª
IUPC
53 (52)
33 (17)
< 0.0001ª
Group B streptococcus positive
20 (20)
51 (26)
0.23ª
Abbreviation: IUPC, intrauterine pressure catheter. Note: Anemia defined as Hgb < 10.5 g/dL in 2nd trimester, Hgb < 11.0 g/dL in first and third trimester. a Chi square test. b Fisher exact test. American Journal of Perinatology
Vol. 32
No. 3/2015
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Race/ethnicity, n (%)
Anemia and Chorioamnionitis at Term
Archabald et al.
Table 3 Adjusted and unadjusted odds ratio of the development of chorioamnionitis at term by anemia and other clinical risk factors Risk factor
Univariate OR (95% CI)
Adjusted OR (95% CI)
2nd/3rd trimester anemia
1.82 (1.07–3.07)
2.47 (1.24–4.94)
1st trimester anemia
7.11 (1.89–26.6)
11.5 (2.35–56.5)
Persistent anemia
5.24 (1.36–20.2)
8.92 (1.95–40.7)
Duration of rupture > 12 h
10.6 (5.90–19.1)
6.05 (3.12–11.7)
Cervical exams 8
11.4 (5.65–23.1)
5.73 (2.55–12.9)
Multiparity
0.25 (0.15–0.42)
0.45 (0.23–0.86)
IUPC
5.48 (3.19–9.42)
2.35 (1.21–4.57)
Prenatal care–private
0.98 (0.60–1.59)
0.82 (0.43–1.56)
Abbreviations: CI, confidence interval; IUPC, intrauterine pressure catheter; OR, odds ratio.
prevalent in women who developed chorioamnionitis. We also identified more first trimester and persistent anemia in women who developed funisitis, a marker of severe inflammation and infection that has been linked to the fetal inflammatory response as well as cerebral palsy.26 In vitro, iron deficiency anemia has been shown to depress neutrophil, natural killer, and T-cell function. Impaired immune function theoretically increases susceptibility to bacterial infection and therefore chorioamnionitis.19,20 We therefore expect to see more chorioamnionitis when the diagnosis of anemia reflects a true iron deficiency and not simply physiologic changes of pregnancy. Unlike the study published by Aly et al that showed an association between anemia at the time of presentation and chorioamnionitis in preterm delivery,18 our study found antepartum anemia in the first and late second/early third trimesters but not at the time of presentation for term delivery to be associated with chorioamnionitis. Similar results have been found in studies assessing the impact of anemia on other pregnancy outcomes. A large retrospective cohort analysis of 173,031 women attending public health clinics in 10 states found low first and second but not third trimester Hgb to be associated with increased risk of preterm delivery.27 Two large prospective Chinese studies have found low first trimester Hgb to be associated with preterm birth and small for gestational infants28 as well as an increased risk of preterm premature rupture of membranes (PROM).29 A meta-analysis confirmed the increased risk of preterm delivery in women with low first and second trimester Hgb, as well as a possible increase in small for gestational age infants.30 Because the majority of plasma expansion occurs during the second trimester, the higher impact of early anemia on pregnancy outcomes both in the literature and in our study American Journal of Perinatology
Vol. 32
No. 3/2015
may represent the more accurate diagnosis of iron deficiency in the first trimester compared with the late second and third trimesters. Later in pregnancy, iron deficiency anemia can be more difficult to distinguish from the dilutional anemia of pregnancy in nutritionally replete women particularly when iron indices are not included in evaluation. Because of the retrospective nature of this study, we defined anemia by Hgb and CDC guidelines as more detailed iron study parameters were not available. Therefore, anemia diagnosed in the first and early second/third trimesters is more likely to be secondary to iron deficiency than anemia diagnosed at the time of presentation for delivery. This corresponds with the statistically stronger association between first trimester anemia and chorioamnionitis compared with second/third trimester and anemia at the time of presentation for delivery. Treatment for presumed iron deficiency anemia in patients without evidence of another etiology of anemia is common in pregnancy and is recommended by the American Congress of Obstetricians and Gynecologists.31 Documentation of iron supplementation and compliance in our study was overall inconsistent and likely underreported, and precluded our ability to complete an analysis on the impact of supplementation on chorioamnionitis at term. The data on the impact of iron supplementation in anemic pregnant women are inconsistent, with evidence of improved hematologic indices, but without convincing evidence of improved pregnancy outcomes.32 However, on the basis of the impact of iron deficiency on functioning of the immune system, we would expect to see less chorioamnionitis in women who were supplemented with iron. Our study has several strengths. Our data were obtained with precision through detailed, individualized chart abstraction by a single investigator. Administrative level data were not used. Rather, our definition of chorioamnionitis was strict, including both clinical and histologic criteria, increasing the reliability of the diagnosis. Finally, our sample size was robust and well powered to detect a difference in the prevalence of anemia among women with chorioamnionitis compared with those without chorioamnionitis. Because of the retrospective nature of our study, we are unable to determine causality. In addition, because of the lack of iron indices, we were unable to objectively differentiate between iron deficiency anemia and dilutional anemia. However, this study lays the groundwork for future studies. Evaluation of the impact of iron deficiency anemia, defined with iron indices, would help further clarify the identified link of anemia with chorioamnionitis. Prospective interventional studies comparing standard care with aggressive iron supplementation are needed to determine the role of supplementation in possible prevention of chorioamnionitis at term. We found antepartum anemia in the first as well as late second/early third trimester to be associated with the development of chorioamnionitis at term. The association with anemia from the first to the early third trimester, the similarity in temporal distribution of anemia on pregnancy outcomes similar to findings of other pregnancy outcomes, as well as the association with funisitis is compelling for a true
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
286
association. Anemia may be a modifiable risk factor for a disease with serious fetal and maternal morbidity. 16
Acknowledgment The authors thank Christina Raker, ScD, for her expert statistical input regarding the design and analysis of this study.
17
18
19
References 1 Alexander JM, McIntire DM, Leveno KJ. Chorioamnionitis and the
prognosis for term infants. Obstet Gynecol 1999;94(2):274–278
20
2 Bailit JL, Gregory KD, Reddy UM, et al. Maternal and neonatal
3 4
5 6 7 8
9 10
11
12 13 14
15
outcomes by labor onset type and gestational age. Am J Obstet Gynecol 2010;202(3):e1, e12 Newton E. Chorioamnionitis and intraamniotic infection. Clin Obstet Gynecol 1993;36(4):795–808 Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290(20):2677–2684 Wu YW, Colford JM Jr. Chorioamnionitis as a risk factor for cerebral palsy: A meta-analysis. JAMA 2000;284(11):1417–1424 Grether JK, Cummins SK, Nelson KB. The california cerebral palsy project. Paediatr Perinat Epidemiol 1992;6(3):339–351 Mark S, Groughan-Minihane M, Kilpatrick S. Chorioamnionitis and uterine function. Obstet Gynecol 2000;95(6):909–912 Rouse DJ, Landon M, Leveno KJ, et al; National Institute of Child Health And Human Development, Maternal-Fetal Medicine Units Network. The Maternal-Fetal Medicine Units cesarean registry: chorioamnionitis at term and its duration-relationship to outcomes. Am J Obstet Gynecol 2004;191(1):211–216 Newton ER. Preterm labor, preterm premature rupture of membranes, and chorioamnionitis. Clin Perinatol 2005;32(3):571–600 Tran SH, Cheng YW, Kaimal AJ, Caughey AB. Length of rupture of membranes in the setting of premature rupture of membranes at term and infectious maternal morbidity. Am J Obstet Gynecol 2008;198(6):e1–e5 Seaward PG, Hannah ME, Myhr TL, et al. International Multicentre Term Prelabor Rupture of Membranes Study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term. Am J Obstet Gynecol 1997;177(5):1024–1029 Stürchler D, Menegoz F, Daling J. Reproductive history and intrapartum fever. Gynecol Obstet Invest 1986;21(4):182–186 Fiscella K. Race, perinatal outcome, and amniotic infection. Obstet Gynecol Surv 1996;51(1):60–66 Centers for Disease Control. Pregnancy and pediatric surveillance system. 2011. Table 2-D. Available at: http://www.cdc.gov/pednss/ pnss_tables/pdf/national_table2.pdf Accessed October 9, 2013 Rasmussen K. Is there a causal relationship between iron deficiency or iron-deficiency anemia and weight at birth, length of
21 22
23
24
25
26
27
28
29
30
31
32
Archabald et al.
gestation and perinatal mortality? J Nutr 2001;131 (2S-2) 590S–601S, discussion 601S–603S Scholl TO, Hediger ML. Anemia and iron-deficiency anemia: compilation of data on pregnancy outcome. Am J Clin Nutr 1994;59 (2, Suppl):492S–500S, discussion 500S–501S Scholl TO, Hediger ML, Fischer RL, Shearer JW. Anemia vs iron deficiency: increased risk of preterm delivery in a prospective study. Am J Clin Nutr 1992;55(5):985–988 Aly H, Alhabashi G, Hammad TA, Owusu-Ansah S, Bathgate S, Mohamed M. ABO phenotype and other risk factors associated with chorioamnionitis. J Pediatr 2008;153(1):16–18 Allen LH. Biological mechanisms that might underlie iron’s effects on fetal growth and preterm birth. J Nutr 2001;131 (2S-2) 581S–589S Oppenheimer SJ. Iron and its relation to immunity and infectious disease. J Nutr 2001;131 (2S-2)616S–633S, discussion 633S–635S Bothwell TH. Iron requirements in pregnancy and strategies to meet them. Am J Clin Nutr 2000;72 1, Suppl):257S–264S Casanueva E, Pfeffer F, Drijanski A, Fernández-Gaxiola AC, Gutiérrez-Valenzuela V, Rothenberg SJ. Iron and folate status before pregnancy and anemia during pregnancy. Ann Nutr Metab 2003;47(2):60–63 Smulian JC, Shen-Schwarz S, Vintzileos AM, Lake MF, Ananth CV. Clinical chorioamnionitis and histologic placental inflammation. Obstet Gynecol 1999;94(6):1000–1005 Heller DS, Rimpel LH, Skurnick JH. Does histologic chorioamnionitis correspond to clinical chorioamnionitis? J Reprod Med 2008; 53(1):25–28 Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep 1998;47 (RR-3) 1–29 Redline RW. Severe fetal placental vascular lesions in term infants with neurologic impairment. Am J Obstet Gynecol 2005;192(2): 452–457 Scanlon KS, Yip R, Schieve LA, Cogswell ME. High and low hemoglobin levels during pregnancy: differential risks for preterm birth and small for gestational age. Obstet Gynecol 2000;96(5 Pt 1):741–748 Ren A, Wang J, Ye RW, Li S, Liu JM, Li Z. Low first-trimester hemoglobin and low birth weight, preterm birth and small for gestational age newborns. Int J Gynaecol Obstet 2007;98(2): 124–128 Zhang Q, Ananth CV, Li Z, Smulian JC. Maternal anaemia and preterm birth: a prospective cohort study. Int J Epidemiol 2009; 38(5):1380–1389 Xiong X, Buekens P, Alexander S, Demianczuk N, Wollast E. Anemia during pregnancy and birth outcome: a meta-analysis. Am J Perinatol 2000;17(3):137–146 American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 95: Anemia in pregnancy. Obstet Gynecol 2008; 112(1):201–207 Reveiz L, Gyte GM, Cuervo LG, Casasbuenas A. Treatments for irondeficiency anaemia in pregnancy. Cochrane Database Syst Rev 2011;(10):CD003094–CD003094
American Journal of Perinatology
Vol. 32
No. 3/2015
287
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Anemia and Chorioamnionitis at Term
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of American Journal of Perinatology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
