Postpartum haemorrhage in pregnant carriers of haemophilia and women with von Willebrand disease: a nationwide inpatient database study

ABSTRACT

BACKGROUND

Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide. Previous studies have presented varying conclusions regarding the PPH risk in pregnant haemophilia carriers or women with von Willebrand disease (VWD). We aimed to evaluate PPH occurrence in this demographic using a nationwide inpatient database in Japan.

METHODS

In this retrospective study, we identified women aged 15–49 years who gave birth while hospitalised between July 2010 and March 2021, using the Japanese Diagnosis Procedure Combination database. These pregnant women were categorised into three groups: the haemophilia, VWD, and control cohort groups. The assessed outcomes were PPH and interventions for bleeding. Multivariable logistic regression analyses were performed to assess the association between coagulation disorders and patient outcomes.

RESULTS

We identified 113 pregnant women in the haemophilia group, 184 in the VWD group, and 1,459,451 in the control group. The outcomes of multivariable logistic regression analyses demonstrated that PPH occurrence was not higher in the haemophilia group (odds ratio, 0.74; 95% confidence interval, 0.46–1.17) than in the control group. Conversely, the VWD group was significantly associated with PPH (odds ratio, 1.46; 95% confidence interval, 1.05–2.02) and a higher incidence of interventions for bleeding (odds ratio, 2.49; 95% confidence interval, 1.55–4.00).

CONCLUSIONS

Despite the absence of a substantial correlation between haemophilia and PPH in pregnant haemophilia carriers, a discernible association emerged between VWD and PPH in pregnant women. Healthcare providers need to be mindful of the high prevalence of undiagnosed VWD and prepare adequately for delivery.

 INTRODUCTION

Postpartum haemorrhage (PPH) is a major cause of maternal mortality worldwide¹⁾. While Western countries have seen a decline in PPH-related deaths²⁾, Japan continues to grapple with it as a leading cause³⁾. PPH can be triggered by various factors, including abnormal coagulation, with haemophilia and von Willebrand disease (VWD) emerging as the most common inherited disorders. Haemophilia A and B, rare X-linked recessive disorders, result from deficiencies in clotting factors VIII or IX, with many women being carriers⁴⁾. In contrast, VWD stems from a deficiency in the von Willebrand factor.

Several studies have noted that coagulation factor VIII and von Willebrand factor levels in pregnant women typically rise as pregnancy progresses^5–8). However, for some pregnant women, this increase in coagulation activity may be insufficient, necessitating treatments such as coagulation factors, desmopressin, and tranexamic acid to mitigate PPH risk^7),9),10). Despite these interventions, pregnant haemophilia carriers (2–11%)^9–11) and pregnant women with VWD (3–26%)^9),12),13) have been reported to experience higher incidences of PPH (blood loss >1000 mL) compared to unaffected women (2–3%)^14),15).

In Japan, previous studies have reported varying rates of PPH among pregnant haemophilia carriers and pregnant women with VWD. One study reported a severe PPH rate (blood loss >1000 mL) of 29% among haemophilia carriers¹⁶⁾, while another reported 0%¹⁷⁾. Similarly, concerning pregnant women with VWD, one study reported a 0% PPH rate¹⁸⁾; however, this study was published over two decades ago. Furthermore, investigations into pregnant haemophilia carriers and pregnant women with VWD have largely been confined to single-centre, small-scale settings.

Given the disparate findings from prior studies with limited sample sizes, there arises a need for a more comprehensive study to compare bleeding events during delivery among pregnant women with and without these diseases. Therefore, our study aimed to investigate the nationwide incidence of PPH in pregnant haemophilia carriers and pregnant women with VWD using a nationwide inpatient database in Japan.

 METHODS

 DATA SOURCE

In this retrospective observational study, we utilised the Japanese Diagnosis Procedure Combination database, a nationwide inpatient database encompassing administrative claims data and discharge abstracts from approximately 1,800 acute care hospitals, including roughly 90% of tertiary care hospitals across Japan¹⁹⁾. The database contains comprehensive information on patient age, sex, body weight and height at admission, emergency hospitalisation, intensive care unit admission, admission and discharge dates, pregnancy status (whether the patient was pregnant at the time of hospitalisation), delivery during hospitalisation, amount of blood loss during delivery, discharge status (transfer to another hospital, discharge to home, or death during hospitalisation), prescriptions, and procedures and surgeries coded according to the Japanese medical procedure system. The database also includes the following diagnoses: main diagnosis, admission-precipitating diagnosis, primary and secondary resource-consuming diagnoses, comorbidities present at admission, and complications arising after admission. These diagnoses are recorded using the International Classification of Diseases, 10th Revision (ICD-10) codes and Japanese text. A validation study demonstrated a sensitivity of 78.9% and a specificity of 93.2% for the diagnosis and procedure records²⁰⁾.

Notably, information on uncomplicated spontaneous deliveries is not included in this claims database because such deliveries are not covered by the Japanese universal health insurance system. Consequently, this database includes only pregnant women who required medical interventions such as instrumental delivery or caesarean sections, or those with conditions such as placenta praevia, multiple pregnancies, and hypertensive disorders of pregnancy, which are covered by the insurance system. This study obtained approval from the Institutional Review Board of the University of Tokyo (approval number: 3501-(5) [May 19th, 2021]) and was conducted in compliance with the Declaration of Helsinki. The requirement for informed consent was waived because the data were anonymous.

 PATIENT SELECTION AND CHARACTERISTICS

We identified women aged 15–49 years who underwent childbirth during hospitalisation between July 2010 and March 2021. These women were categorised by ICD-10 codes into three groups: haemophilia carriers (ICD-10 codes D66 or D67; haemophilia group), those with VWD (D68.0; VWD group), and those without either condition (control group). If women had both ICD-10 codes for haemophilia and VWD, they were classified as follows: women who received factor concentrates for haemophilia (factor VIII or IX concentrates) were placed in the haemophilia group, those who received factor concentrates for VWD (factor VIII/von Willebrand factor concentrates) were allocated to the VWD group, and women who did not receive any factor concentrates were excluded from the analysis.

 VARIABLES AND OUTCOMES

We gathered data on various patient characteristics, including age, body mass index at admission, admission type (emergency or intensive care unit), hospital volume, delivery methods (instrumental delivery, caesarean section, emergency caesarean section), anaesthesia type (epidural, spinal, and general anaesthesia), and risk factors for PPH. These risk factors encompassed grand multiparity (Z35.4), multiple gestation (O30, O43.0, O63.2, O66.1, O84.9, Z38.3), fibroids (D25, O34.1, O65.5), early pregnancy haemorrhage (O20), placenta praevia (O44.1), polyhydramnios (O40), large foetus (O33.5, O36.6, O66.2), hypertensive disorders (O10, O11, O12, O13, O14, O16), infection of amniotic sac and membranes (O41.1), prolonged pregnancy (O48), foetal malpresentation (O32.9, O64.0), prolonged labour (O63, O75.5), amniotic fluid embolism (O88.1), third- or fourth-degree perineal lacerations during delivery (O70.2, O70.3), and retained placenta (O72.0, O73). Additionally, we recorded the use of antibiotics, oxytocic agents (oxytocin or methylergometrine), intravenous iron infusion, factor concentrates for haemophilia, factor concentrates for VWD, desmopressin, and tranexamic acid.

Three outcomes were identified: PPH, defined as either a documented diagnosis of PPH (O72.1) or blood loss exceeding 1,000 mL during delivery²¹⁾; intervention for bleeding, including blood transfusion during hospitalisation (including red blood cells, fresh frozen plasma, fibrinogen concentrate, platelets, or autologous transfusion), uterine ballooning, bimanual uterine compression, transarterial embolisation, or hysterectomy; and death during hospitalisation.

 STATISTICAL ANALYSIS

Continuous variables are presented as medians with interquartile ranges (25th–75th percentiles), while categorical variables are expressed as numbers with percentages. There were 2.0% missing values for body mass index at admission, and a ‘missing’ category was used in the analysis. There were 1.6% missing values for the amount of blood loss during delivery, and these were treated as missing values without imputation. We performed the same analyses for the subgroup of pregnant women who underwent caesarean section. Additionally, the haemophilia group was classified into haemophilia A and haemophilia B. The use of coagulation factor products was recorded, and the incidence of PPH was compared between the two haemophilia subgroups. Multivariable logistic regression analyses were conducted to explore the association between inherited coagulation disorders (haemophilia and VWD) and outcomes (PPH and interventions for bleeding). To estimate the association between inherited coagulation disorders and outcomes, we adjusted for age, body mass index at admission, emergency admission, intensive care unit admission, hospital volume, instrumental delivery, caesarean section, and any risk factors for PPH. Statistical analyses were carried out using STATA/MP (version 17.0; StataCorp, College Station, TX). All tests were two-tailed, with a significance threshold set at P < 0.05.

 RESULTS

We identified a total of 1,459,749 women aged 15–49 years who gave birth during the study period. Among them, four women had both ICD-10 codes for haemophilia and VWD. Two of these women received factor concentrates for haemophilia and were categorised in the haemophilia group, while one received factor concentrates for VWD and was placed in the VWD group. The remaining one who did not receive factor concentrates was excluded from the study. Consequently, there were 113 women in the haemophilia group, 184 women in the VWD group, and 1,459,451 women in the control group (Fig. 1). Table 1 presents the patient characteristics across the groups for all pregnant women included in the study. In the haemophilia group, no women were admitted to the intensive care unit, while 6 women (3.3%) in the VWD group and 5,013 women (0.3%) in the control group were admitted. Instrumental deliveries occurred in 3 women (2.7%) in the haemophilia group, in 11 women (6.0%) in the VWD group, and in 122,478 women (8.4%) in the control group. Caesarean section deliveries were performed in 70 women (61.9%) in the haemophilia group, in 76 women (41.3%) in the VWD group, and in 656,080 women (45.0%) in the control group. Supplemental Table 1 presents a detailed breakdown of each disease and condition categorised as risk factors for PPH. Hypertensive disorders were the most common risk factor for PPH, affecting 109,601 women (7.5%).

Fig. 1  Flow diagram of patient selection

^a ICD-10, International Classification of Diseases, 10th Revision

^b VWD, von Willebrand disease.

Table 1 Patient characteristics with and without haemophilia or von Willebrand disease

	Control group N = 1,459,451	Haemophilia group N = 113	VWDa group N = 184
Age, mean (SDb), years	32.41 (5.4)	31.74 (4.7)	31.68 (5.3)
Body mass index at admission, kg/m2, n (%)
<18.5	34,168 (2.3)	2 (1.8)	3 (1.6)
18.5–24.9	789,747 (54.1)	70 (61.9)	110 (59.8)
25.0–29.9	464,093 (31.8)	35 (31.0)	55 (29.9)
≥30.0	142,152 (9.7)	6 (5.3)	11 (6.0)
missing	29,291 (2.0)	0 (0.0)	5 (2.7)
Emergency admission, n (%)	847,402 (58.1)	44 (38.9)	76 (41.3)
ICUc admission, n (%)	5,013 (0.3)	0 (0.0)	6 (3.3)
Hospital volume
Qd 1 (54–218 cases per year)	365,080 (25.0)	24 (21.2)	27 (14.7)
Q2 (219–353 cases per year)	366,063 (25.1)	47 (41.6)	69 (37.5)
Q3 (354–487 cases per year)	364,808 (24.9)	20 (17.7)	60 (32.6)
Q4 (≥488 cases per year)	363,500 (24.9)	43 (38.1)	28 (15.2)
Mode of delivery, n (%)
Instrumental delivery	122,478 (8.4)	3 (2.7)	11 (6.0)
Caesarean section	656,080 (45.0)	70 (61.9)	76 (41.3)
Emergency caesarean section	272,315 (18.7)	17 (15.0)	34 (18.5)
Any of risk factors for PPHe, n (%)	417,798 (28.6)	16 (14.2)	37 (20.1)
Drug, n (%)
Antibiotic	1,015,187 (69.6)	98 (86.7)	139 (75.5)
Oxytocic agent	1,033,107 (70.8)	95 (84.1)	152 (82.6)
Intravenous iron infusion	171,326 (11.7)	19 (16.8)	39 (21.2)
Factor concentrates for haemophilia	30 (0.0)	36 (31.9)	109 (59.2)
Factor concentrates for VWD	9 (0.0)	0 (0.0)	50 (27.2)
Desmopressin	4 (0.0)	1 (0.9)	5 (2.7)
Tranexamic acid	42,335 (2.9)	6 (5.3)	18 (9.8)

^a VWD, von Willebrand disease; ^b SD, standard deviation; ^c ICU, intensive care unit; ^d Q1–4, quartiles 1–4; ^e PPH, postpartum haemorrhage.

Table 2 displays the outcomes of the three groups. A total of 373,617 women (25.6%) experienced PPH. Specifically, PPH occurred in 24 women (21.2%) in the haemophilia group, in 57 women (31.0%) in the VWD group, and in 373,536 women (25.6%) in the control group. Regarding interventions for bleeding among the three groups, there were 4 women (3.5%) in the haemophilia group, 23 women (12.5%) in the VWD group, and 81,871 women (5.6%) in the control group. No deaths were reported in either the haemophilia or VWD groups.

Table 2 Outcomes of women with and without haemophilia or von Willebrand disease

	Control group N = 1,459,451	Haemophilia group N = 113	VWDa group N = 184
PPHb, n (%)	373,536 (25.6)	24 (21.2)	57 (31.0)
Interventions for bleeding, n (%)	81,871 (5.6)	4 (3.5)	23 (12.5)
Death, n (%)	116 (0.0)	0 (0.0)	0 (0.0)

^a VWD, von Willebrand disease; ^b PPH, postpartum haemorrhage.

The results of the multivariable logistic regression analysis are presented in Table 3. The haemophilia group was not significantly associated with either PPH or interventions for bleeding (odds ratio, 0.74; 95% confidence interval, 0.46–1.17; odds ratio, 0.75; 95% confidence interval, 0.28–2.07, respectively) compared to the control group. In contrast, the VWD group was significantly associated with both PPH and interventions for bleeding (odds ratio, 1.46; 95% confidence interval, 1.05–2.02; odds ratio, 2.49; 95% confidence interval, 1.55–4.00, respectively) compared to the control group.

Table 3 Multivariable logistic regression analysis

	Odds ratio	95% confidence interval	P value
PPHa
Haemophilia	0.74	0.46–1.17	0.194
VWDb	1.46	1.05–2.02	0.025
Interventions for bleeding
Haemophilia	0.75	0.28–2.07	0.583
VWD	2.49	1.55–4.00	<0.001

^a PPH, postpartum haemorrhage; ^b VWD, von Willebrand disease.

In the subgroup analysis, out of the 656,226 women who underwent caesarean section, 70 women were in the haemophilia group and 76 women were in the VWD group. Supplementary Table 2 outlines the baseline characteristics of these subgroups. In terms of emergency caesarean sections, there were 17 (24.3%) in the haemophilia group, 34 (44.7%) in the VWD group, and 272,315 (41.5%) in the control group. Eight women (11.4%) in the haemophilia group, two women (2.6%) in the VWD group, and 157,051 women (23.9%) in the control group received epidural anaesthesia. The most common anaesthetic method used in the VWD group was general anaesthesia without epidural anaesthesia (38 women, 50.0%). Supplemental Table 3 presents the outcomes of pregnant women who underwent caesarean section. Regarding the incidence of PPH, there were 7 women (24.3%) in the haemophilia group, 31 women (40.8%) in the VWD group, and 235,976 women (36.0%) in the control group.

Regarding the type of haemophilia, there were 86 haemophilia A carriers and 27 haemophilia B carriers. Of these, 21 (24.4%) haemophilia A carriers received factor VIII concentrates, while 15 (55.6%) haemophilia B carriers received factor IX concentrates. PPH outcomes were observed in 18 (20.9%) haemophilia A carriers and in 6 (22.2%) haemophilia B carriers (P = 0.890).

 DISCUSSION

To the best of our knowledge, this represents the first large-scale study to investigate the association between haemophilia or VWD and bleeding events in Japan. This study yielded two principal findings: firstly, no significant association was found between PPH levels and haemophilia carriers; secondly, pregnant women with VWD showed a significantly higher likelihood of experiencing PPH and requiring interventions for post-delivery bleeding such as blood transfusion, uterine ballooning, bimanual uterine compression, transarterial embolisation, or hysterectomy.

Our findings indicate that the occurrence of PPH and bleeding interventions among haemophilia carriers did not significantly differ from pregnant women without haemophilia. This contrasts with prior studies where haemophilia carriers displayed a higher likelihood of experiencing PPH^9–11). For instance, a large-scale database study in the Netherlands reported a severe PPH rate of 9% among haemophilia carriers compared to 6.4% in the general Dutch population in 2015¹¹⁾. Three potential explanations could account for the disparities between our results and previous findings. Firstly, the control group included pregnant women who required medical treatment and did not undergo uncomplicated spontaneous deliveries. As a result, some control patients might have harboured factors associated with PPH, and the risk of developing PPH in the control group was comparable to that in the haemophilia group. Secondly, over 60% of haemophilia carriers in our study underwent caesarean section. Previous studies, which reported a higher rate of caesarean sections among haemophilia carriers (47–55%), showed a lower incidence of PPH^10),22). This may explain the relatively low incidence of PPH in our study. Lastly, haemophilia carriers may have been diagnosed before pregnancy and received meticulous preparations for delivery by healthcare providers. Based on their family history, haemophilia carriers may have been identified before pregnancy. During pregnancy, healthcare providers and pregnant women might have exchanged information regarding haemophilia during pregnancy and carefully planned the delivery process, including the administration of factor concentrates before delivery and choice of delivery mode. Although haemophilia carriers may have been at higher risk for bleeding, careful planning might have effectively controlled the bleeding.

On the other hand, pregnant women with VWD experienced PPH and required interventions for bleeding, such as blood transfusions, more frequently than those without VWD. This finding aligns with prior research demonstrating significant correlations between VWD and postpartum bleeding events. For instance, a Slovenian database study reported that patients with VWD required more blood transfusions post-delivery (odds ratio, 16.3; 95% confidence interval, 2.2–120.3) compared to women without VWD²³⁾. Similarly, a US database study found that women with VWD were at a higher risk for transfusion (odds ratio, 4.7; 95% confidence interval, 3.2–7.0)²⁴⁾. Insufficient preparation for the delivery of pregnant women with undiagnosed VWD may contribute to the high frequency of bleeding interventions. Regarding the possibility of a postpartum diagnosis, several studies have indicated that some women with VWD were diagnosed for the first time after experiencing PPH^25),26). Similarly, in this study, undiagnosed patients may have received their first diagnosis of VWD through examination following PPH. Given the potential for undiagnosed VWD until delivery, healthcare providers should inquire about conditions suspicious for VWD, such as a history of hypermenorrhoea or a family history of PPH. Adequate preparation for delivery may also be crucial in cases where a diagnosis of VWD is confirmed before conception or during pregnancy.

This study has some limitations. Firstly, the control group did not include pregnant women with uncomplicated spontaneous deliveries. Although occurrences of PPH and interventions were not notably higher in the haemophilia group compared to the control group, the differences were relatively minor; thus, significant differences between the two groups may not have been observed. Secondly, the database lacked information on the coagulation activity levels and severity in each pregnant woman, potentially including many non-critical patients without a high risk of bleeding. Thirdly, it remains unclear whether haemophilia and VWD were diagnosed prior to delivery or after experiencing PPH. Furthermore, the database does not include information on whether the pregnant women were primiparous or multiparous. It is therefore unclear in what proportion of cases healthcare providers were aware of the bleeding risk before delivery compared to those where they were unaware. Fourthly, this database did not record the date of delivery; thus, we could not estimate the period during which healthcare providers prepared for delivery. Furthermore, we were unable to ascertain whether the factor concentrates administered during hospitalisation were prophylactic or therapeutic. Lastly, the timing of PPH (within or after 24 hours of delivery) and that of transfusions were not available.

 CONCLUSIONS

In conclusion, this nationwide inpatient database study in Japan revealed that haemophilia carriers experienced bleeding events during delivery comparably to pregnant women without haemophilia. Conversely, VWD was associated with PPH and interventions for bleeding during delivery, highlighting the need for healthcare providers to consider the possibility that pregnant women may have VWD.

 CONFLICTS OF INTEREST

HM was involved in a joint research project between Pfizer Inc. and the University of Tokyo (2021–2022). HM received a grant from JSPS KAKENHI (21H03159).

The other authors declare no conflicts of interest for this article.

 SOURCES OF FUNDING

This work was supported by grants from the Ministry of Health, Labour, and Welfare, Japan (23AA2003 and 24AA2006), and the Japan Agency for Medical Research and Development (grant number: JP23gk0210033).

 ACKNOWLEDGMENTS

This work was supported by grants from the Ministry of Health, Labour, and Welfare, Japan (23AA2003 and 24AA2006), and the Japan Agency for Medical Research and Development (grant number: JP23gk0210033).

 AUTHOR CONTRIBUTIONS

RI, HO, YS, KK, and DS designed the research. HO, HM, and HY acquired the data. RI and YS analysed the data. RI, YS, GI, KK, HY, and YO wrote the manuscript. HY and YO took primary responsibility for the final content. All authors have read and approved the final version of the manuscript.

 DISCLAIMER

Yusuke Sasabuchi and Hideo Yasunaga are the Editorial Board members of Annals of Clinical Epidemiology. They were not involved in the peer-review or decision-making process for this paper.

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