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Risk Factors for Severe Postpartum Hemorrhage After Cesarean Delivery

Case-Control Studies

Butwick, Alexander J., MBBS, FRCA, MS*; Ramachandran, Bharathi, BS*; Hegde, Priya, BA*; Riley, Edward T., MD*; El-Sayed, Yasser Y., MD; Nelson, Lorene M., MS, PhD

doi: 10.1213/ANE.0000000000001962
Obstetric Anesthesiology: Original Clinical Research Report
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BACKGROUND: Women who undergo intrapartum caesarean delivery (CD) are at increased risk of postpartum hemorrhage (PPH) compared with those undergoing prelabor CD. To determine whether the presence and strength of the associations between individual risk factors and severe PPH vary among women undergoing prelabor CD or intrapartum CD, stratified analyses are needed according to CD subtype.

METHODS: To identify risk factors for severe PPH within 2 distinct CD populations, prelabor CD and intrapartum CD, we performed 2 case-control studies. Women in each study cohort delivered at a tertiary obstetric center in the United States between 2002 and 2012. For each study, cases were women who had a blood loss ≥1500 mL or who received an intraoperative or postoperative transfusion up to 48 hours after delivery. Risk factors for severe PPH among women undergoing prelabor CD or intrapartum CD were examined in separate logistic regression models.

RESULTS: For prelabor CD, we identified 269 cases and 550 controls. Clinical factors with the highest adjusted odds for severe PPH during prelabor CD were general anesthesia (adjusted odds ratio [aOR] = 22.3; 95% confidence interval [CI], 4.9–99.9; reference group = spinal anesthesia), multiple pregnancies (aOR = 8.0; 95% CI, 4.2–15.0; reference group = singleton pregnancy), and placenta previa (aOR = 6.3; 95% CI, 3.4–11.8). For intrapartum CD, we identified 278 cases and 572 controls. Clinical factors with the highest adjusted odds for severe PPH during intrapartum CD were general anesthesia (aOR = 5.4; 95% CI, 1.7–17.1), multiple pregnancies (aOR = 3.2; 95% CI, 1.7–6.3), and a predelivery hemoglobin ≤ 9.9 g/dL (aOR = 3.0; 95% CI, 1.3–6.9; reference group = predelivery hemoglobin ≥ 11 g/dL).

CONCLUSIONS: Women who undergo prelabor CD and intrapartum CD have several shared risk factors for severe PPH (general anesthesia and multiple pregnancies). However, the risk factor profiles for severe PPH differed between these CD cohorts. Recognizing these differences may be important when planning resources and interventions for high-risk patients undergoing either prelabor or intrapartum CD.

Published ahead of print March 8, 2017.

From the Departments of *Anesthesiology, Perioperative, and Pain Medicine; Obstetrics and Gynecology; and Health Research and Policy (Division of Epidemiology), Stanford University School of Medicine, Stanford, California.

Published ahead of print March 8, 2017.

Accepted for publication January 12, 2017.

Funding: This study was supported and funded by the Eunice Kennedy Shriver National Institute of Child Health and Development, National Institute of Health. The study was also supported by the Department of Anesthesiology, Perioperative, and Pain Medicine; and Department of Obstetrics and Gynecology, Stanford University School of Medicine. A.J.B. was supported by an award from the Eunice Kennedy Shriver National Institute of Child Health and Development (K23HD070972).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Alexander J. Butwick, MBBS, FRCA, MS, Department of Anesthesiology, Perioperative and Pain Medicine (MC: 5640), Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305. Address e-mail to ajbut@stanford.edu.

Severe postpartum hemorrhage (PPH) is an important cause of maternal death and severe maternal morbidity.1–3 Compared with vaginal delivery, women undergoing cesarean delivery (CD) incur the highest risk of PPH and hemorrhage-related morbidity.4,5 Furthermore, evidence suggests that PPH during CD is occurring more frequently. In the United States, between 1994 and 2006, the rate of atonic PPH increased 160% among women undergoing CD after induction and 130% among women undergoing noninduced CD.6

The International PPH Collaborative group, which comprises an international panel of clinical epidemiologists, has called for more studies using clinically rich data to better understand relevant, and potentially preventable, risk factors associated with PPH.7 Once risk factors for PPH are identified, clinical predictive rules could be developed. Implementation of predictive rules into clinical practice could optimize patient outcomes8,9 by improving the planning and timely mobilization of staffing and resources before bleeding onset. For example, when an “at-risk” pregnant patient is identified before delivery, providers would have the opportunity to order and prepare blood products, obtain additional venous access, and prepare additional equipment for PPH management. High-risk pregnant patients could also receive enhanced postpartum surveillance for excessive blood loss. Finally, for high-risk patients awaiting prelabor CD, arrangements could be made for delivery in an obstetric center with the necessary staff and resources for providing effective PPH management.

Identifying risk factors for PPH during CD has been challenging because key differences exist in patient, obstetric, and intrapartum characteristics for women who undergo prelabor CD versus CD after onset of labor or induction of labor (hereafter referred to as intrapartum CD). Based on data from 2 population-wide studies in Norway, the risk of PPH is reported to be higher for women undergoing intrapartum CD compared with prelabor CD (3.1% vs 2%, respectively).4,10 Although intrapartum factors, such as chorioamnionitis and oxytocin exposure,11–13 may explain why the risk of atonic PPH is higher after labor induction, to the best of our knowledge, only 3 studies have investigated risk factors for PPH for women who underwent elective CD and nonelective or emergency CD.14–16 Only 1 study differentiated women by the presence or absence of labor before CD.16 To determine whether the presence and strength of the associations between individual risk factors and severe PPH vary among women undergoing prelabor CD or intrapartum CD, stratified analyses are needed according to CD subtype.

The primary objectives of this observational study were to perform 2 case-control studies to identify independent predictors for severe PPH within each of the following CD subpopulations: prelabor CD and intrapartum CD.

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METHODS

This study was approved by the Stanford University IRB (Protocol ID = 25236). We performed 2 case-control studies to identify clinical risk factors for severe PPH after prelabor CD and intrapartum CD. Our study cohorts were identified from a population who delivered by CD at Lucile Packard Children’s Hospital (LPCH), a tertiary care obstetric center, between January 2002 and December 2012.

To identify women who underwent CD between January 2002 and December 2006, we used the Stanford Translational Research Integrated Database Environment (STRIDE) through a combined search of International Classification of Diseases (ICD-9) procedure codes (74.x) and Current Procedural Terminology codes (01961, 01963, 01968, 59510, 59515, 59618, 59620, 59622, 1008991, 1014218, and 1014220). Based on a standards-based informatics platform, STRIDE is a clinical data warehouse that contains linked demographic, administrative, and clinical data (from electronic or scanned medical records) from LPCH and Stanford University Medical Center. The clinical data warehouse can be searched using search queries input by programmers based in the Stanford Center for Clinical Informatics, Stanford University. We identified women with severe PPH through a combined search for ICD-9 codes for postpartum hemorrhage (666.x). Because an electronic medical record system was implemented at LPCH in 2007, we searched a computerized clinical database (LPCH Information and Knowledge System) to identify CDs between January 2007 and December 2012 through a search of Medicare Severity Diagnosis Related Group codes 765 and 766. Estimated blood loss (EBL) and transfusion data for CDs between 2007 and 2012 were available in the clinical database. Between 2002 to 2006 and 2007 to 2012, there were a total of 6997 CDs and 8192 CDs, respectively.

Trained research assistants (P.H. and B.R.) reviewed medical charts to determine whether patients met inclusion criteria for prelabor CD or intrapartum CD. Inclusion criteria for prelabor CD were scheduled CD without labor; CD following unsuccessful external cephalic version; and CD for obstetric or fetal indications, such as preeclampsia, non-reassuring fetal trace without labor or induction. Inclusion criteria for intrapartum CD were women with documented evidence of painful regular contractions or induction of labor before CD. We excluded women with known hematologic or coagulation disorders (apart from those with HELLP [hemolysis, elevated liver enzymes, low platelet count] syndrome) or who were anticoagulated before CD. Based on literature review,4,5,10,17–19 the criteria for severe PPH were an EBL ≥ 1500 mL after CD or red blood cell (RBC) transfusion during or within 48 hours after CD. We selected severe PPH as our primary outcome for several reasons. First, average EBL values during CD can approach EBL thresholds for defining PPH. Second, an EBL of 1500 mL may reflect the point where physiological compensation starts to fail resulting in greater obstetric morbidity.20 Third, EBL may often be underestimated. Therefore, to account for subjects in whom EBL may have been underestimated, we incorporated RBC transfusion within 48 hours of CD as a classifier for severe PPH. In each CD cohort, 2 controls were randomly selected with same year of delivery as each case using incidence density sampling. Each control had an EBL < 1500 mL and no transfusion. EBL and transfusion data were reviewed in the medical records to confirm correct classification of each case and control.

Based on literature review5,10,14–16,21–23 and clinical plausibility, potential risk factors for severe PPH in each CD cohort were considered. For both CD cohorts, we abstracted data from the medical records for the following candidate variables: maternal age, self-reported race/ethnicity, weight, parity, gestational age at delivery, number of previous CDs, chronic hypertension, gestational diabetes, singleton/multiple pregnancies, gestational hypertension, preeclampsia, HELLP syndrome, hemoglobin (Hb) most proximate to delivery, time of CD (classified as weekday daytime [between 7:00 AM and 4:59 PM], weekday night time [between 5:00 PM and 6:59 AM], and weekend) and mode of anesthesia (spinal, epidural, combined spinal-epidural [CSE], or general anesthesia). We designated the final mode of anesthesia before surgical incision as the mode of anesthesia in our analysis (data on final anesthesia mode are presented in Supplemental Digital Content, Figures 1 and 2, http://links.lww.com/AA/B691). For example, if, before surgery, a patient received a spinal as the primary anesthetic that “failed,” and then received a second block—a CSE—which provided adequate surgical anesthesia, the designated anesthesia mode was CSE. To account for temporality of the potential relationship between the preincision mode of anesthesia with severe PPH, we did not include information for patients who required intraoperative conversion from neuraxial to general anesthesia in our analyses. For prelabor CD, we abstracted additional data for the following characteristics: earlier history of dilation and curettage (D&C) or dilation and evacuation (D&E), and previous myomectomy. For CD after labor, we abstracted additional data for the following characteristics: spontaneous versus induced labor, labor augmentation with oxytocin, chorioamnionitis, and cervical dilation before CD. In light of American College of Obstetricians and Gynecologists guidelines to avoid nonmedically indicated deliveries before 39 weeks of gestation,24 we presumed that some women with a history of earlier CD were admitted with spontaneous labor and underwent intrapartum CD before 39 weeks. Therefore, we accounted for number of earlier CDs in our regression model for intrapartum CD. Because curettage of the uterus during a D&E or D&C may significantly damage the endometrium and uterine cavity to influence placental adherence, we only considered this variable in the prelabor CD cohort. Primary indications for prelabor and intrapartum CD were also examined (data presented in Supplemental Digital Content, Tables 1 and 3, http://links.lww.com/AA/B691) and were stratified by mode of anesthesia. The most common indications for prelabor CD were prior CD (56%) and macrosomia (23%). The most common indications for intrapartum CD were non-reassuring fetal trace (76%) and labor arrest (32%). (Frequencies total more than 100% as some patients had more than 1 indication for intrapartum CD.)

Among intrapartum CDs, we performed subanalyses to assess rates of severe PPH among women with cervical dilation <10 cm who did and did not experience arrest of the first stage, and women with a cervical dilation of 10 cm who did and did not experience a prolonged second stage of labor. Women were classified with arrest of the first stage of labor and prolonged second stage by using criteria described by the American College of Obstetricians and Gynecologists25 (see Appendix for full descriptions). These guidelines were in place during the study period.

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STATISTICAL ANALYSIS

We performed 2 analyses to assess characteristics and risk factors for (1) women undergoing prelabor CD and (2) women undergoing intrapartum CD. Within each CD population, patient and obstetric characteristics for women with and without severe PPH were compared using analysis of variance, Mann-Whitney U tests for continuous variables and χ2 test and Fisher exact test for categorical variables. For each analysis, the primary outcome was severe PPH. For each continuous variable associated with PPH, we used restricted cubic spline functions to test whether the associations met the assumptions of a linear relationship. Continuous variables were categorized if they were not linearly related to the outcome using cubic spline function plots (maternal age and gestational age at delivery) or clinically relevant cut points (predelivery Hb). Multivariable analysis was performed using multivariable logistic regression, which included all variables with P < .10 in the univariable analyses. We used variance inflation factor testing to assess collinearity between candidate variables. Collinearity was determined to be insignificant as variance inflation factor (VIF) scores for the prelabor CD ranged from 1.03 to 1.27 (mean VIF score = 1.14) and for CD after labor ranged from 1.01 to 1.6 (mean VIF score = 1.21). To account for the increased probability of making a type I error when making multiple comparisons, we adjusted the confidence intervals and P values for each comparison in our multivariable models using a Bonferroni correction.26 Goodness of fit was evaluated using the Hosmer-Lemeshow statistic. We calculated the area under the receiver-operating characteristic curve (AUROC) using standard methods.27 We recalculated the c-index for each model using 500 iterations of the Efron enhanced bootstrap method.28 With approximately 270 cases in each CD cohort, a 1:2 ratio of case:control, a 10% prevalence for characteristics among controls, and an α of .05, we calculated that the smallest odds greater than 1 that could be detected with 80% power is an odds ratio of 1.85.

All analyses were conducted using STATA version 12 (StataCorp, College Station, TX). Data are presented as mean (SD), median (interquartile range), or n (%).

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RESULTS

Prelabor Cesarean Delivery

In this cohort, we identified 269 women with severe PPH and 550 matched controls. Women with severe PPH had a significantly higher median EBL compared with controls (1600 [1500–2000] mL vs 800 [600–900] mL; P < .001). Among severe PPH cases, 223 (82.9%) women had at least 1500 mL EBL, and 148 (55%) women received RBC intraoperatively or within 48 hours after CD. Among all women who received RBC, 91 women received RBC intraoperatively and 90 women received RBC within 48 hours after CD, of whom 33 (36.7%) had an EBL < 1500 mL and did not receive intraoperative RBC. Twenty-four women (19 cases; 5 controls) experienced primary anesthetic block failure before surgery (Supplemental Digital Content, Figure 1, http://links.lww.com/AA/B691).

Table 1

Table 1

Table 2

Table 2

Maternal, obstetric, intrapartum, and perioperative characteristics of women with and without severe PPH are presented in Table 1. Unadjusted and adjusted odds ratios for clinical factors selected for multivariable analysis are presented in Table 2. In the multivariable model, factors independently associated with severe PPH were general anesthesia (adjusted odds ratio [aOR] = 22.3; 95% confidence interval [CI], 4.9–99.9; reference group = spinal anesthesia), multiple pregnancies (aOR = 8.0; 95% CI, 4.2–15.0; reference group = singleton pregnancy), placenta previa (aOR = 6.3; 95% CI, 3.4–11.8), predelivery Hb ≤ 9.9 g/dL (aOR = 2.8; 95% CI, 1.0–7.5 [reference group = predelivery Hb ≥ 11 g/dL]), Hispanic race (aOR = 2.4; 95% CI, 1.0–5.8 [reference group = non-Hispanic white]), and a history of previous D&C or D&E (aOR = 1.9; 95% CI, 1.2–3.0). Model calibration (Hosmer–Lemeshow test, P = .3) and model discrimination (AUROC = 0.86; 95% CI, 0.83–0.89) were good. After 500 cycles of bootstrapping, the c-index remained unchanged.

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Intrapartum Cesarean Delivery

Table 3

Table 3

Table 4

Table 4

In this cohort, we identified 278 women with severe PPH and 572 matched controls. The mean EBL values were significantly higher among cases compared with controls (1685 [665] mL vs 781 [202] mL; P < .001). Among severe PPH cases, 209 (75.4%) women had at least 1500 mL EBL, and 157 (56.5%) women received RBC intraoperatively or within 48 hours after CD. Among all women who received RBC, 51 women received RBC intraoperatively and 122 women received RBC within 48 hours after CD, of whom 59 (48.4%) had an EBL < 1500 mL and did not receive intraoperative RBC. Maternal, obstetric, intrapartum, and perioperative characteristics are presented in Table 3. Because earlier clinical studies have observed an association between labor augmentation with PPH,11,23,29,30 we forced labor augmentation with oxytocin into the final multivariable model. Sixteen patients (10 cases; 6 controls) experienced primary neuraxial block failure before surgery (Supplemental Digital Content, Figure 2, http://links.lww.com/AA/B691). Severe PPH was more common among women who underwent CSE anesthesia and general anesthesia. Clinical factors independently associated with severe PPH are presented in Table 4. In the multivariable model, factors independently associated with severe PPH were general anesthesia (aOR = 5.4; 95% CI, 1.7–17.1), multiple pregnancies (aOR = 3.2; 95% CI, 1.7–6.3), predelivery Hb ≤ 9.9 g/dL (aOR = 3.0; 95% CI, 1.3–6.9), predelivery Hb = 10–10.9 g/dL (aOR = 2.6; 95% CI, 1.4–4.9 [reference group = predelivery Hb ≥ 11 g/dL]), multiple pregnancies (aOR = 1.8; 95% CI, 1.1–2.9), and government-assisted insurance (aOR = 1.6; 95% CI, 1.0–2.4). Compared with women who underwent primary CD, women with one previous CD had a reduced odds of severe PPH (aOR = 0.4; 95% CI, 0.2–0.9). Women aged ≥30 years had a reduced odds of PPH compared with women aged <30 years (aOR = 0.7; 95% CI, 0.5–1.0). The model had good calibration (Hosmer–Lemeshow test, P = .47) and modest discrimination (AUROC = 0.75; 95% CI, 0.71–0.78). After bootstrapping, the c-index was unaltered. In separate models, the interactions between magnesium with preeclampsia and gestational age at delivery were not statistically significant (data not presented).

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Sensitivity and Subgroup Analyses

To determine whether point estimates for modes of anesthesia were influenced by women who experienced primary neuraxial block failure before surgery, we performed sensitivity analyses examining women in each CD cohort whose primary mode of anesthesia was successful. For each CD cohort, point estimates for mode of anesthesia did not appreciably change from those in the original multivariable models (data not presented).

Because general anesthesia may be considered more often for women with placental disorders, for the prelabor CD cohort, we performed an additional sensitivity analysis to assess point estimates for anesthetic techniques excluding women with abnormal placentation (n = 51) or placenta previa (n = 121). On the basis of chart review, we identified women with abnormal placentation based on information in the obstetrician’s operative note or from a placental pathology report (if available). Among those without these placental disorders, we observed comparable point estimates for anesthetic techniques to those in our original multivariable model (CSE: aOR = 3.87; 95% CI, 1.93–7.73; epidural: aOR = 1.7; 95% CI, 0.3–9.5; general anesthesia: aOR = 47.6; 95% CI, 7.26–311.9).

For women undergoing intrapartum CD, we compared PPH frequencies among those with versus without labor arrest before full cervical dilation. Severe PPH was more common among women with versus without labor arrest (132/203 (65%) vs 214/382 (56%), respectively; P = .04). Similarly, we compared PPH rates between those with versus without a prolonged second stage of labor; rates were similar in both groups (36/61 [59%] vs 99/151 [66%], respectively; P = .37).

In both CD cohorts, we assessed the frequency of women who experienced an EBL ≥ 1500 mL, intraoperative and postoperative RBC transfusion stratified by predelivery Hb categories (Supplemental Digital Content, Tables 2 and 4, http://links.lww.com/AA/B691). Among cases identified in each CD cohort, rates of intraoperative and postoperative transfusion were highest among women with a predelivery Hb level <10 g/dL. Finally, to determine whether predelivery Hb influences the magnitude of blood loss, we performed sensitivity analyses with the outcome based solely on the criteria of an EBL ≥ 1500 mL. On multivariable analyses, we observed that predelivery Hb category was not independently associated with an EBL ≥ 1500 mL in each CD cohort (data not presented).

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DISCUSSION

Using detailed clinical data abstracted from 1669 medical records, we performed 2 case-control studies to identify risk factors for severe PPH during prelabor CD and intrapartum CD. Risk factors common to each CD cohort included general anesthesia, predelivery anemia, and multiple pregnancies. Other risk factors identified in our analyses were also well recognized: placenta previa (prelabor CD) and chorioamnionitis (intrapartum CD). We identified several risk factors that were less established, such as CSE anesthesia, nontransverse uterine incision, earlier D&C, and Hispanic race (prelabor CD); and gestational diabetes (GDM), young maternal age, government-assisted insurance, and primary CD (intrapartum CD). Future studies are needed to determine whether confounding by indication explains the associations between CSE and general anesthesia with severe PPH.

Although a number of studies have sought to identify risk factors for PPH during CD,15,16,21,31 the majority have not accounted for key differences in the maternal characteristics and delivery indications between prelabor and intrapartum CDs.32 Only 2 studies examined risk factors across distinct CD populations; elective/nonelective CD16 and planned/emergency CD.15 Consistent with our findings, these studies identified placenta previa and general anesthesia as key risk factors across all CD cohorts. However, neither study stratified cohorts according to the presence versus the absence of labor or induction before CD.

We believe that our approach to construct separate logistic models according to CD subtype is clinically justified for several reasons. It is not clinically intuitive to consider labor or other intrapartum characteristics as potential predictors in a single multivariable model for severe PPH during prelabor CD. Similarly, women with placenta previa are unlikely to be considered for induction or trial of labor; therefore, it would be intuitive to consider placenta previa as a candidate variable only for women who undergo prelabor CD. However, from an epidemiological standpoint, we acknowledge that future cohort studies using nuanced clinical data are needed to investigate whether interactions truly exist between relevant predictors and the presence versus the absence of labor or induction before CD. Large study populations would also be needed to construct adequately sized derivation and validation study cohorts.

In both CD cohorts, general anesthesia had the highest adjusted odds of severe PPH compared with spinal anesthesia. Because some anesthesiologists may prefer to use general anesthesia for patients with placenta previa or abnormal placentation,33 we excluded these conditions in our sensitivity analyses for the prelabor cohort and observed that the association between general anesthesia and severe PPH persisted, albeit with wider confidence intervals. This association has been reported in other observational and randomized studies, with varying degrees of magnitude.15,16,21,31,34–36 General anesthesia may itself directly influence the likelihood of severe blood loss. Volatile agents have a concentration-dependent inhibitory effect in vitro on uterine smooth muscle contractility,37,38 thereby increasing the likelihood of uterine atony. Volatile agents (halothane, sevoflurane) and induction agents (propofol) can also inhibit platelet function in a dose-dependent manner.39 However, we cannot exclude the possibility of confounding by indication because patients with anticipated risk factors for PPH may be more likely to receive general anesthesia. For example, in the prelabor CD cohort, general anesthesia was used for 21% of women with placenta previa, 46% of women with abnormal placentation, and 22% of women with antenatal vaginal bleeding (Supplemental Digital Content, Table 1, http://links.lww.com/AA/B691). In the prelabor CD cohort, women who underwent CSE anesthesia had a 3-fold increased odds of severe PPH compared with those receiving a single-shot spinal. The reason for this finding is unclear. Because equivalent doses of intrathecal local anesthetic drugs are commonly used for spinal and CSE anesthesia, it is doubtful that a drug effect explains this finding. Therefore, confounding by indication is also likely, because patients with anticipated risk factors for PPH may require longer durations of surgery and receive a CSE technique. To assess the potential for bias from confounding by indication for CSE and general anesthesia, context-specific studies are needed to examine the relations between these modes of anesthesia with severe PPH.

Predelivery anemia was associated with our primary outcome, which included a composite of major blood loss or postpartum transfusion; this association was not confirmed in our sensitivity analysis that focused on major blood loss only. These findings are consistent with those by Butwick et al40 who reported that predelivery anemia is an independent risk factor for severe postpartum anemia after CD, classified by a postpartum Hb ≤ 8 g/dL. Furthermore, several obstetric societies, including The Royal College of Obstetricians and Gynecologists (UK) and the French College of Gynecologists and Obstetricians, have published PPH guidelines recommending that a Hb level above 8 g/dL is a therapeutic goal.41 These observations, coupled with our findings, have important clinical relevance for several reasons. First, antenatal anemia is a modifiable risk factor for transfusion. Second, in the nonobstetric literature, limiting anemia before surgery is a key component of patient blood management.42 With antenatal anemia affecting up to 25% pregnant women,43 similar initiatives may be necessary to promote anemia correction before delivery. Future studies are needed to examine whether optimization of maternal Hb levels before delivery limits the likelihood of postpartum RBC transfusion. Third, RBC transfusion may be used during acute episodes of blood loss as well as for treating symptomatic postpartum anemia in a nonbleeding patient. Studies are also needed to determine best approaches for anemia management during and after an episode of severe PPH.

We identified a number of other well-established risk factors, including multiple gestations (both cohorts), placenta previa (prelabor CD), and chorioamnionitis (intrapartum CD).5,15,31,44 Other risk factors are less recognized. Hispanic women had a 2-fold increased odds of severe PPH compared with whites, after prelabor CD, but not intrapartum CD. Disparities in PPH have been described by others.45 These may due to differences in the provision of medical care as well as underlying social, biological, and genetic factors. Only 1 study has investigated whether the type of uterine incision influences PPH risk. Combs et al21 reported that a classical uterine incision was an independent risk factor. Compared with a low transverse incision, a greater degree of blood loss may occur with nontransverse incisions because thicker and more vascular myometrial tissue may be surgically incised. The risk of PPH among women with earlier D&E or D&C may be related to altered placentation.46 Future studies are needed to determine whether this association is observed among women undergoing intrapartum CD. The relationship between GDM and severe PPH may be explained by fetal macrosomia, a recognized risk factor for PPH.47 In the intrapartum CD cohort, women with a history of 1 previous CD had a lower adjusted odds of severe PPH compared with women with no previous CDs. Because of concern of uterine rupture, it is possible that obstetric providers are less likely to consider long periods of labor or augmentation for women undergoing trial of labor after previous CD. This may partly explain why these women were at lower risk of severe PPH compared with those without a history of previous CD.

Our study had a number of limitations. Although we considered a large number of candidate variables, unmeasured factors may have influenced PPH risk, such as obstetric or anesthesia provider experience. In a systematic review, Bauer et al48 previously reported that the risk of failed conversion of labor epidural analgesia to CD anesthesia is higher if care is provided by a nonobstetric anesthesiologist compared with care given by an obstetric anesthesiologist. Studies are needed to evaluate whether specific anesthetic practices that may influence the magnitude of blood loss, such as the use of high concentrations of volatile anesthetic and blood product use, vary according to anesthesia provider experience. Because of the low frequency of several factors, such as fibroids and prolonged second-stage labor, we could not accurately examine associations between these variables with severe PPH. We did not collect data for the frequency, timing, or indications for patients who underwent intraoperative conversion from neuraxial to general anesthesia. Given that combined rates of preoperative and intraoperative conversion from neuraxial to general anesthesia are low (1.7%–5.8%),49–51 any influence of intraoperative conversion on the point estimates for severe PPH among those undergoing neuraxial anesthesia is likely to be small.

We did not assess risk factors among women who underwent elective or nonelective CD because we chose to differentiate our cohorts by the presence versus the absence of spontaneous labor or induction of labor. We chose this approach because patient characteristics and CD indications are known to markedly differ across these cohorts.32 Furthermore, determining the “electiveness” of CD may have been more challenging, resulting in misclassification bias.

We identified women with abnormal placentation based on information in the medical record documented after the time of delivery. We elected not to include abnormal placentation as an a priori risk factor because we could not ascertain, from chart review, whether all cases of abnormal placentation were suspected during the antenatal period. We acknowledge this as an important limitation because abnormal placentation is strongly associated with major postpartum hemorrhage and massive transfusion.52 However, placenta previa and number of earlier CDs are well-known risk factors for abnormal placentation,53 and both variables were considered as candidate variables in our regression model for the prelabor cesarean cohort.

The findings from our analyses cannot be used to determine individual patient prediction of severe PPH. Such analyses would require large population-wide cohort studies using nuanced clinical data. However, our data could be used to guide investigators in the selection of relevant candidate variables in studies investigating prediction models of PPH during CD. Relevant prediction models require external validation in independent cohorts.

In conclusion, our findings suggest that the risk factor profile for severe PPH differs according to whether CD is performed before or after the onset of labor or induction. To confirm these findings, population-wide studies are needed to determine whether data should be partitioned according to CD subtype.

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APPENDIX

Criteria for Arrest of First Stage of Labor and Prolonged Second Stage of Labor

We defined arrest of active phase of the first stage of labor if latent phase was completed and no documented evidence of cervical change for >2 hours. These criteria were also used to define prolonged second stage for nulliparous women (second stage exceeding 2 hours and 3 hours with and without regional anesthesia, respectively) and for multiparous women (second stage exceeding 1 hour and 2 hours with and without regional anesthesia, respectively).

These definitions were based on guidelines published by the American College of Obstetricians and Gynecologists in 2003.25

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ACKNOWLEDGMENTS

The authors are grateful for the assistance of Dr G. Hilton and L. Tian who assisted with some of the data collection for this project. They also wish to acknowledge the support of researchers based in the Stanford Center for Clinical Informatics (Stanford School of Medicine) for identifying patients study from STRIDE and electronic hospital databases. STRIDE is a research and development project at Stanford University to create a standards-based informatics platform supporting clinical and translational research. The STRIDE project is supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health, through grant UL1 RR025744.

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DISCLOSURES

Name: Alexander J. Butwick, MBBS, FRCA, MS.

Contribution: This author helped conceive the work, acquire, analyze and interpret the data, and draft and revise the manuscript.

Name: Bharathi Ramachandran, BS.

Contribution: This author helped acquire the data.

Name: Priya Hegde, BA.

Contribution: This author helped acquire the data.

Name: Edward T. Riley, MD.

Contribution: This author helped conceive the work, interpret the data, and revise the manuscript.

Name: Yasser Y. El-Sayed, MD.

Contribution: This author helped conceive the work, interpret the data, and revise the manuscript.

Name: Lorene M. Nelson, MS, PhD.

Contribution: This author helped conceive the work, analyze and interpret the data, and revise the manuscript.

This manuscript was handled by: Jill M. Mhyre, MD.

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