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Abstract

Venous thromboembolism (VTE) is a leading cause of maternal mortality. Obesity and cesarean delivery are established risk factors for pregnancy-related VTE. We identified additional risk factors among patients with obesity who underwent a cesarean delivery to identify those who need VTE prophylaxis. We conducted a secondary analysis of data from the Maternal-Fetal Medicine Units Network (MFMU) Cesarean Registry Database using a case-control design. Cases were identified as women with obesity having a pre-pregnancy body mass index of >30 kg/m², who underwent cesarean delivery and subsequently developed deep venous thrombosis (DVT) or pulmonary embolism (PE). These women were compared to a control group of women with obesity who underwent cesarean delivery but did not develop DVT or PE. Analysis of risk factors associated with VTE was performed using Chi-Square test and Fisher's exact test. We identified 43 VTE cases and 172 controls in the MFMU database. Increased risk of VTE was noted in women with endometritis (OR of 4.58 [95% CI: 1.86-11.2, P = .0004]), receiving a blood transfusion (OR 17.07 [95% CI: 4.46-65.3, P = .0001]), having a coagulopathy (OR 27.73 [95% CI: 3.24-237.25, P = .0003]), and urinary tract infection (OR 2.39 [95% CI: 1.08-5.28, P = .03]). Important risk factors for VTE in women with obesity who undergo cesarean delivery include endometritis, intra- or post-operative transfusion, coagulopathy, and urinary tract infection. The presence of one or more of these factors may help guide provider decision-making regarding whether to administer thromboprophylaxis.

Keywords

cesarean delivery venous thromboembolism obesity anticoagulation prophylaxis

Introduction

Venous thromboembolism (VTE) is a leading cause of maternal mortality in the developed world, responsible for 9.3% of maternal deaths in the United States (US).^1,2 Obesity and cesarean delivery (CD) are established risk factors for pregnancy-related VTE.^3,4 With the increasing burden of obesity in the US, as well as rising rates of CD in proportion to vaginal delivery, the identification of candidates for VTE prophylaxis is becoming increasingly important.^5–7

Wide use of mechanical VTE prophylaxis has been shown to decrease mortality related to death from VTE in the general population.⁸ Furthermore, data from non-obstetric populations show that a combination of mechanical and pharmacologic prophylaxis decreases the incidence of VTE compared to mechanical prophylaxis alone.⁸ This suggests a role for combining both modalities of prophylaxis to further decrease the burden of this disease.

Major organizations including the American College of Obstetricians and Gynecologists (ACOG), the American College of Chest Physicians (CHEST), and the Royal College of Obstetricians and Gynaecologists (RCOG) have put forth guidelines to help obstetric providers in their selection of appropriate candidates for prophylaxis for VTE prevention; however, these recommendations are widely divergent and not routinely applied.^9,10

Although the above organizations are consistent in their recommendation that all women should be assessed for VTE risk during pregnancy, their specificity and method of assessment is varied. ACOG recommends prophylactic or therapeutic anticoagulation be given for women “at significant risk of VTE during pregnancy or postpartum period such as those with high risk acquired or inherited thrombophilias.”¹¹ The CHEST guidelines are more specific, emphasizing prophylaxis for very high risk individuals, particularly those who demonstrate reduced mobility, history of VTE, or known thrombophilia.¹² RCOG guidelines are the most specific, with recommendations based on a risk scoring system. This 4-point system scores patient's overall VTE risk by accounting for a variety of established risk factors.¹³ Although these guidelines differ in their scope, they all highlight the importance of identifying risk factors for VTE.

Additionally, a 2013 review of practice in over 600 acute care hospitals in the US show low rates of post-cesarean mechanical or pharmacologic prophylaxis, with about 41.6% use of either mechanical or chemical prophylaxis and 1.3% used pharmacologic prophylaxis alone.¹⁴ Use of anticoagulation therapy could potentially reduce the recurrence of postpartum VTE, specifically in a population of women with obesity undergoing CD, as these are known risk factors for postpartum VTE.

Our study objective was to examine women with obesity who were diagnosed with VTE and delivered via CD to identify any additional risk factors that put them at increased risk for VTE in order to help obstetricians provide routine targeted post-cesarean VTE prophylaxis.

Methods

Setting and Design

We performed a case control study of women with obesity who delivered via CD in the Maternal-Fetal Medicine Unit (MFMU) Cesarean Registry. This registry includes information collected in a prospective fashion at 19 medical centers belonging to the National Institute of Child Health and Human Development (NICHD)-MFMU Network between 1999 and 2002. The registry was designed to collect sufficient information to allow for examination of uncommon and rare pregnancy complications.

The study population included women with pre-pregnancy body mass index (BMI) > 30 kg/m² who delivered by CD and were between ages 16 and 45 years old. Women with concurrent cancer diagnoses during pregnancy were excluded. This yielded a total of 13 784 women. A case-control study design was used to analyze the risk factors associated with the occurrence of peripartum VTE.

Data Collection

Women who developed deep venous thrombosis (DVT) or pulmonary embolism (PE) or both were identified as cases. Controls were matched to each of the identified cases based on age, year of delivery, race, and obesity class in order to maximize the power of the analysis with a ratio of 4:1. By matching cases and controls for the respective variables, the goal was to increase power and reduce overall sample size but these may have also been predictors in the model as risk factors for VTE. Our case-control study design allowed for 99% power in detecting a significant difference of effect size of 0.75.

Study Outcomes

The primary outcome was identification of risk factors that increase the risk for VTE in women with obesity who were diagnosed with VTE and delivered via CD. The risk factors analyzed (see Table 1) included emergent CD, plurality, preeclampsia/gestational HTN, diabetes, chorioamnionitis, endometritis, placenta previa, placenta abruption, history of heart disease, smoking, transfusion, stillbirth, coagulopathy (defined as a history of bleeding), drug use in pregnancy, UTI in pregnancy (pyelonephritis), and preterm delivery. These particular factors were analyzed in part because of their already established relationship with pregnancy and CD.

Table 1.

Risk Factors for VTE.

N (%) or mean ± SD	Cases (n = 43)	Controls (n = 172)	Odds ratio (95% CI)	P-value
Emergent CD	5 (11.6%)	12 (7.0%)	1.75 (0.58-5.28)	.31
Plurality (singleton)	41 (95.4%)	164 (95.4%)	1.00 (0.20-4.89)	1.0
Preeclampsia/Gestational HTN	11 (25.6%)	34 (19.8%)	1.39 (0.64-3.05)	.40
Diabetes	9 (20.9%)	33 (19.2%)	1.12 (0.49-2.55)	.80
Chorioamnionitis	1 (2.3%)	8 (4.7%)	0.49 (0.06-4.01)	.50 (FE 0.69)
Endometritis	11 (25.6%)	12 (7.0%)	4.58 (1.86-11.29)	.0004*
Placenta Previa	1 (2.3%)	2 (1.2%)	2.02 (0.18-22.85)	.56 (FE 0.49)
Placenta abruption	1 (2.3%)	1 (0.6%)	4.07 (0.25-66.44)	.29 (FE 0.36)
History of heart disease	0 (0%)	2 (1.2%)	NE	.48 (FE 1.0)
Smoking	6 (14.0%)	23 (13.4%)	1.05 (0.40-2.77)	.92 (FE 1.0)
Transfusion	10 (23.3%)	3 (1.7%)	17.07 (4.46-65.39)	<.0001 (FE <.0001)*
Stillbirth	2 (4.7%)	4 (2.3%)	2.05 (0.36-11.57)	.41 (FE 0.34)
Coagulopathy	6 (14.0%)	1 (0.6%)	27.73 (3.24-237.25)	<.0001 (FE 0.0003)*
Drug use in pregnancy	2 (4.7%)	8 (4.7%)	1.00 (0.20-4.89)	1.0 (FE 1.0)
UTI during pregnancy	12 (27.9%)	24 (14.0%)	2.39 (1.08-5.28)	.0284*
Pyelonephritis	0 (0%)	1 (0.6%)	NE	.80
Preterm delivery	5 (11.6%)	8 (4.7%)	2.70 (0.84-8.71)	.09

Data are in mean ± standard deviation or n (%). Transfusion—patients were included with intraoperative and postoperative transfusion.

Abbreviations: VTE, venous thromboembolism; CD, cesarean delivery; HTN, hypertension; UTI, urinary tract infection; FE, Fisher's exact.

*P < .05 was considered statistically significant (calculated via Chi-square or Fisher's exact test where appropriate).

Statistical Analysis

Analyses of risk factors associated with VTE were performed using odds ratios and Chi-square and Fisher's exact testing for statistical significance. Analysis was performed using SAS version 9.4 (Cary, North Carolina.) This secondary analysis of the MFMU cesarean registry was approved by George Washington University Hospital Institutional Review Board.

Results

There was a total of 43 (0.31%) peripartum VTE cases identified from the study population of 13,784 women with obesity who delivered via cesarean section. A total of 172 controls were matched to these cases. The population characteristics are described in Table 2.

Table 2.

Patient Characteristics.

Variable	VTE (n = 48)	No VTE (N = 13 736)	P-value
N(%) or mean ± SD
Maternal age (years)	28.9 ± 6.5	28.9 ± 5.8	.99
Race/ethnicity			.02*
African American	27 (56.3%)	4481 (32.6%)
Caucasian	15 (31.3%)	6116 (44.5%)
Hispanic	6 (12.5%)	2648 (19.3%)
Pre-pregnancy BMI			.0002*
Obesity Class I	17 (35.4%)	7389 (53.8%)
Obesity Class II	10 (20.8%)	3585 (26.1%)
Obesity Class III	21 (43.8%)	2762 (20.1%)
Gestational age (days)	263 ± 25.3	266.3 ± 22.4	.31
Education (years)	12.6 ± 2.0	12.3 ± 2.6	.58

Data are in mean ± standard deviation or n (%).

Abbreviation: VTE, venous thromboembolism.

*P < .05 was considered statistically significant.

Women with class 3 obesity (BMI of 40 or greater) had significantly higher rates of VTE compared to women with class 1 (BMI 30.0-34.9) and class 2 (BMI 35.0-39.9) obesity. Of women with class I obesity, 0.23% developed VTE. The rate of VTE slightly increased in women with class II obesity to 0.28%, however, this difference was not statistically significant (P-value > .05). Women with class III obesity had a VTE rate of 0.75%; this difference was statistically significant when compared to both women with class I and class II obesity (P < .01).

In addition to obesity, 4 other risk factors were elucidated from our analysis. Increased risk of VTE was noted in women with endometritis (OR of 4.58 [95% CI: 1.86-11.2, P = .0004]), receiving a blood transfusion (OR 17.07 [95% CI: 4.46-65.3, P = .0001]), having a coagulopathy (OR 27.73 [95% CI: 3.24-237.25, P = .0003]), and having an active urinary tract infection (UTI) (OR 2.39 [95% CI: 1.08-5.28, P = .0284]). We have summarized the risk factors for VTE in Table 1.

Discussion

The prevalence and morbidity of VTE in the peripartum period necessitate further research given it is a significant contributor to maternal death. Ultimately, the goal of our study was to better identify women who would need additional prophylactic interventions for VTE risk reduction throughout the peripartum period.^1,5,6

In this large multi-center database study, we demonstrate additional risk factors for VTE in patients with obesity who undergo cesarean deliveries. This builds toward the larger need for the development of a consistent standard protocol for VTE prophylaxis based on the risk factors elucidated in our study and the many other studies that have pointed to the same risk factors.^1,5,15–18 As discussed above, the varied specificity and clinical application of recommendations made by ACOG, CHEST, and RCOG further emphasize the need for consistent guidelines. Knowing these risk factors and developing a standard evidence-based protocol would aid in the prevention of the largest cause of maternal morbidity in developed countries.^3,6,19–22

These findings were in accordance with the study results published in 2020 by Alsheef et al.²³ This particular study demonstrated that a history of coagulopathy, systemic infection, and PPH or blood transfusion were associated with an increased risk of thrombosis in the form of either DVT, PE, or DVT that was complicated by PE. Furthermore, this necessitated administration of anti-coagulant medications, either low molecular weight heparin or oral forms to nearly all the subjects that developed these postpartum venous thromboembolic complications.

Another study, conducted by Waldman et al,²⁴ showed that women who received a blood transfusion during or after CD developed both early and late DVT (OR = 2.0, 95% CI = 1.15-3.5 and OR = 11.0, CI = 2.25-55.5; respectively). Interestingly, the risk of VTE in obese women was also documented in non-obstetric surgical fields. In a large multi-institutional center study published in 2014, Jamal et al concluded that VTE events were identified in 57 patients (1.3%) among 4293 patients who underwent primary or revisional bariatric surgery from 2005 to 2013 although, some of these patients had negative duplex studies of the lower extremities before surgery.²⁵

Study Limitations

One area of potential limitation in this study is the older data set. The study population was derived from a national database with data collected by the NICHD MFMU Network between 1999 and 2002. However, the robust nature of this database allowed us to study the incidence of VTE, a relatively rare outcome; thus lending strength to this study. Given the well-documented and researched increase in CD and obesity as independently increasing factors, the premise of this study being additional risk factors would still lend favor to the development of a VTE risk factor calculator that includes the risk factors of endometritis, transfusion, coagulopathy, and UTI.^1,5,6,15,16

Additionally, there was no information on inherited thrombophilia included in this data set. It is well known that inherited thrombophilia is a risk factor for the development of VTE and as such, this population would have been excluded from the study population. Ideally, we would have adjusted for this confounder if it was available in the data set. As a result of this missing information, it is possible that our data might underestimate the effects of certain risk factors.

We acknowledge that the study could benefit from a multi-variable model but believe the main findings would not change significantly given that other studies have shown similar variables (ie, transfusion) are linked to thromboembolism.^26,27 This will not detract from the fact that the identified risk factors are significant; in fact, this may mean the true relationship may be stronger than that was identified in this study.

Conclusion

Important risk factors for VTE in women with obesity who undergo CD include endometritis, intra- or post-operative transfusion, coagulopathy, and UTI. Addition of prophylactic anticoagulation to standard mechanical VTE prophylaxis to patients who possess one or more of these risk factors may significantly decrease their risk of VTE and the downstream associated morbidity and mortality.

Footnotes

Author Contributions

All authors contributed to the study conception,design,material preparation,data collection,analysis,and/or manuscript.

Author's Note

Homa K. Ahmadzia is also affiliated with Department of Obstetrics and Gynecology,Inova Health System,Falls Church,VA,USA.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research,authorship,and/or publication of this article.

Funding

The authors received no financial support for the research,authorship,and/or publication of this article.

ORCID iD

Homa K. Ahmadzia

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