Von Willebrand disease (VWD) and pregnancy: a comprehensive overview

Abstract

Von Willebrand disease (VWD) is a hereditary bleeding disorder characterized by a quantitative or qualitative deficiency of von Willebrand factor (VWF). Pregnancy significantly impacts hemostasis, leading to a hypercoagulable state. However, women with VWD experience unique challenges due to the interplay between pregnancy-related hormonal changes and VWF deficiencies. This review delves into the intricate relationship between VWD and pregnancy. We explored the physiological changes that occur during pregnancy, including hormonal fluctuations, hemodilution, and alterations in platelet–VWF interactions. We discuss how these changes can exacerbate bleeding tendencies in women with VWD, particularly during childbirth and the postpartum period. This review highlights the increased risk of postpartum hemorrhage (PPH) in women with VWD and the potential for severe maternal morbidity and mortality. We examine the various types of VWD and their specific implications for pregnancy outcomes. Additionally, we discuss the challenges associated with diagnosing and managing VWD during pregnancy, as well as the importance of prenatal counseling and careful monitoring. The management of VWD during pregnancy involves a multidisciplinary approach, including the use of prophylactic treatments, such as desmopressin and tranexamic acid, as well as factor replacement therapy when necessary. Careful planning of delivery, including the choice of delivery mode and the timing of interventions, is essential to minimize bleeding complications. By understanding the complexities of VWD during pregnancy and implementing appropriate management strategies, healthcare providers can significantly improve the outcomes for women with VWD and their offspring.

Introduction

Von Willebrand disease (VWD), a genetic hemorrhagic disease resulting from a quantitative or qualitative deficiency in von Willebrand factor (VWF), was first identified by Dr. Erik von Willebrand [1, 2]. VWF, a multimeric glycoprotein synthesized by megakaryocytes and endothelial cells, is essential for both primary and secondary hemostasis [3]. As part of primary hemostasis, VWF encourages platelet adhesion and aggregation [4]. In secondary hemostasis, it regulates blood levels of factor VIII (FVIII) by cycling in complex with it and protects it from inactivation [4]. Therefore, impaired platelet adhesion or lower FVIII concentrations can cause bleeding if problems with VWF exist. Since not all patients with VWD experience bleeding symptoms, the prevalence of the disease differs across investigations and is defined differently. It is estimated that between 0.01% and 1.3% of individuals are affected by VWD [2, 5–7].

Three primary forms of the disease have been identified: type 1, type 2, and type 3 VWD. The predominant patient population is type 1, characterized by a partial quantitative deficit of VWF, which usually presents with mild to severe bleeding symptoms [8]. Type 2 VWF can be further categorized as 2 A, 2B, 2 M, or 2 N on the basis of distinct functional and structural abnormalities; it impacts up to one-third of individuals [9]. Compared with type 1 VWD, more severe and frequent bleeding is a symptom of type 2 VWD [9]. The most severe form is type 3, which results from an almost complete shortage of VWF [10]. Some symptoms that patients with VWD may encounter include easy bruising, bleeding from the mouth or gums, severe menstrual bleeding, and bleeding following dental work, surgery, or giving birth [11]. In cases of a more severe shortage, joint bleeding is also possible [12]. According to autosomal inheritance, the patterns of VWD distribution in men and women are the same [9, 13]. However, there is a greater probability of women being affected, and this is primarily due to the specific hemostasis issues that women are experiencing, such as pregnancy, menstruation, and childbirth [2, 14].

Pregnancy results in many alterations in hemostasis that ultimately lead to hypercoagulable conditions [15]. Numerous hemostatic factors, such as factors VII and X, fibrinogen, and plasminogen activator inhibitor type 1, are present in relatively high concentrations. A reduction in anticoagulant components, such as protein S, is observed in the opposite direction. Additionally, the levels of FVIII and VWF are altered in pregnant women with and without VWD [2, 16]. In Fig. 1, we graphically describe the alterations in hemostasis throughout pregnancy.

Fig. 1.

During pregnancy, hemostasis parameters change. An increase in blood clotting occurs during pregnancy. This occurs because anticoagulant factors decrease and procoagulant factors increase

Pregnant women with types 1 and 2 VWD often reach normal levels of VWF and FVIII; pregnant women with type 3 VWD do not experience any changes in these levels (Table 1) [10]. After giving birth, women with VWD quickly decline in FVIII and VWF levels; after one week, they show signs of returning to baseline, and after three weeks, they reach baseline again [2, 17, 18]. As a result, postpartum hemorrhage and related complications, such as multiorgan injury from tissue hypoperfusion and transfusion support, are more likely in pregnant patients with VWD, increasing the risk of difficulties during birth and the postpartum period [19]. The purpose of this narrative review is to investigate the challenges related to VWD during pregnancy, as well as the management techniques and potential impacts on newborns and mothers.

Table 1.

Classification of von Willebrand disease

Type	Description
1	Partial quantitative deficiency of VWF
2	Qualitative deficiency of VWF
2 A	Qualitative variants with decreased platelet-dependent function associated with the absence of high and intermediate-molecular-weight VWF multimers
2B	Qualitative variants with increased affinity for platelet GPIb
2 M	Qualitative variants with decreased platelet-dependent function not caused by the absence of high-molecular-weight VWF multimers
2 N	Qualitative variants with markedly decreased affinity for factor VIII
3	Virtually complete deficiency of VWF

VWF dynamics in pregnancy

Hormonal changes

Hemostasis involves various molecules and pathways, and their intricate interaction leads to a delicate balance between thrombus production and breakdown [20, 21]. In females, blood coagulation is significantly affected by natural hormonal variations related to the menstrual cycle, pregnancy, and external factors such as hormonal therapies, including contraceptives or hormone replacement therapy [16, 21]. The hormonal levels change, particularly in the final trimester, resulting in peak levels of estrogen and progesterone, creating a hypercoagulable state to prevent postpartum hemorrhage [22]. The development of a prothrombotic state during pregnancy may be linked to changes in estrogen and progestogen levels, which are known to fluctuate during pregnancy [23]. Estrogen contributes to increased vWF levels by stimulating endothelial cells and encouraging their replication, which affects blood clotting [24]. Rabbani et al. found that postmenopausal women had higher vWF levels after four weeks of oral equine estrogen treatment [25]. Additional studies show no change in vWF levels in postmenopausal women at the 12-month and 36-month follow-ups [26, 27]. Estradiol levels rise significantly from the initial measurement at approximately four weeks into pregnancy, which coincides with the alterations observed in coagulation factors [23, 28]. Compared with prepregnancy conditions, beginning at 24 days of gestation, estradiol levels are increased by 67%, indicating a large spike that might influence coagulation factor gene expression thereafter [23]. Research conducted by Powazniak et al. suggested that E2 can potentially increase the expression of the VWF gene [29]. Changes in coagulation protein levels, such as VWF, are connected to hormone level shifts, especially the sex hormone that varies during pregnancy. More research is needed to understand how these hormones affect the coagulation system.

Hemodilution

Pregnant women experience hemodilution due to increased plasma volume [30]. VWF levels rise during pregnancy despite an increase in plasma volume [31]. As previously stated, the procoagulant state that occurs during pregnancy is believed to be an evolutionary response to the high danger of bleeding during and immediately after childbirth [16, 21, 32]. Researchers have shown that in healthy pregnant women, FVIII and VWF rise steadily throughout pregnancy, with a dramatic spike in the third trimester [32, 33]. Studies show that healthy pregnant women have higher plasma levels of VWF: antigen (VWF: Ag), and there is a significant link between blood type and this increase in VWF [33–35]. Drury-Stewart et al. studied coagulation parameters like VWF: Ag, VWF propeptide (VWFpp), FVIII, and ADAMTS13 activity in healthy pregnant women. They found that VWF and FVIII activity increased during pregnancy, while ADAMTS13 activity stayed the same [36]. In addition, they reported that the multimeric structure of VWF changed during pregnancy compared with nonpregnancy [36]. They speculated that the higher levels of VWF: Ag and FVIII in healthy pregnant women might be because VWF has a longer half-life in its modified multimer form.

Pregnant women with VWD usually have higher VWF levels, but the increase varies by the type of VWD. VWF: Ag, von Willebrand ristocetin cofactor (VWF: RCo), and factor VIII activity (FVIII: C) were shown to be significantly increased in patients with VWD type 1 [35, 37]. The plasma concentrations of the coagulation markers that were assessed at the end of the third trimester were normal in almost all of the individuals with VWD type 1 [35]. Women who have type 2 VWD may have elevated levels of VWF: Ag and factor VIII. This is due to more abnormal VWF protein, but it doesn’t mean VWF: RCo activity is higher [38, 39]. Type 2B VWD worsens in pregnancy, causing low platelet counts from high levels of abnormal VWF [38, 39]. Research conducted by Castaman et al. indicated that a significant correction of FVIII and VWF: Ag is prevalent in women with type 2 M VWD, whereas VWF: RCo does not reach levels of 50 U/dL [40]. Although the levels of both VWF and FVIII increase during pregnancy in women with type 2 N VWD, the FVIII levels tend to remain low because the remaining defective VWF hinders the binding of this factor. The impact of pregnancy on alterations in FVIII levels and the bleeding phenotype may be predicted by the type of mutation in the VWF gene and the severity of the consequent binding deficiency [40, 41]. Given that type 3 VWD is a completely quantitative deficiency with almost undetectable amounts of VWF, pregnant women with this disorder usually do not exhibit any increase in FVIII or VWF [10, 40]. Therefore, during pregnancy, it may be necessary to use VWF/FVIII concentrates to manage intermittent vaginal bleeding, as well as during delivery or a cesarean Sect. [10].

Platelet–VWF interaction

Platelets are megakaryocyte-derived cells that participate in hemostasis by adhering to the injured endothelium [42]. Their interaction depends on the local shear rate of the blood [43, 44]. Platelets interact with extracellular matrix molecules like collagen, fibronectin, and laminin at moderate flow rates (100–1000 s-1) [43, 45]. Under arterial flow (high shear rates, 1000–4000 s-1), platelet GPIbα binds to collagen (subendothelial matrix) via VWF [43, 45]. Exposed endothelium collagen derived from injury binds to VWF [46]. As a result of this action, VWF unfolds to reveal the A1 domain to bind platelets via the GPIb-IX-V complex [47]. VWF and platelets connect briefly, causing platelets to roll at the blood/surface interface as GPIbα-VWF bonds form and break [46]. Thus, fast-moving platelets slow down and stick to the vessel wall, allowing more platelet receptors to bind to matrix proteins and ensuring platelet adherence.

The red blood cell volume percentage, often known as hematocrit (HCT), is a critical variable that controls proper plug formation and, by extension, the clotting process. Multiple studies have shown that HCT is essential for binding platelets to VWF [48–50]. A high level of red blood cells changes blood viscosity, which helps platelets stick to the vessel wall [48]. In small veins with low shear stress, erythrocyte accumulation promotes platelet deposition and plug formation [49]. Therefore, alterations in HCT or red blood cell count impact the binding of platelets to VWF. During pregnancy, changes in plasma level and an increase in blood volume decrease the PLT and Hb concentration [51]. Cowmen et al. reported that a healthy pregnancy leads to a reduction in platelet interactions with VWF [52]. The diminished interaction between platelets and VWF is likely attributable to reduced platelet counts and HCT levels resulting from hemodilution during pregnancy [52]. A technique that assesses platelet activity under physiological circumstances was developed by Cowmen et al., which allows us to precisely quantify platelet translocational behavior on a VWF surface. Another important finding from this study is that platelet translocation speeds decrease during pregnancy, regardless of hemodilution [52]. These findings suggest that there is a fundamental alteration in the function of platelets that occurs only during pregnancy. The stable adherence of platelets to damaged endothelium results from the deceleration of platelet translocation in the blood, facilitated by the interaction between GPIbα on platelets and exposed VWF. Therefore, GPIbα may play a significant role in the speed of translocation. Wu et al. employed flow cytometry analysis to investigate the expression of GPIbα (CD42b) on platelets in severe preeclampsia, mild preeclampsia, and normotensive pregnant and nonpregnant individuals [53]. Researchers discovered that the severe preeclampsia group had significantly lower levels of GPIbα than the other groups did, whereas no variations in expression were noted among the other groups [53]. Platelet GPIIb-IIIa can bind to VWF at the RGD site in the C4 domain when fibrinogen levels are low or nonexistent [54]. Therefore, a possible explanation for the decrease in platelet translocation might be an increase in GPIIb-IIIa expression. Holthe et al. evaluated CD61 (Integrin beta 3) expression in preeclamptic, normotensive, and nonpregnant women [55]. Researchers have reported no difference in the expression levels of GPIb and GPIIb/IIIa between pregnant and nonpregnant women [55]. This finding is in line with the results of Wu et al. and Safiullina et al., who likewise reported no change in GPIIb/IIIa expression patterns before or during pregnancy [53, 56]. Additional research is needed to fully understand the changes that take place in platelets during pregnancy; however, these changes may be unrelated to the GPIb-IX-V complex and GPIIb/IIIa.

Fetal and maternal risks associated with VWD and bleeding complications

Postpartum hemorrhage (PPH) is defined as blood loss of a minimum of 500 ml following a vaginal delivery or exceeding 1000 ml after Cesarean Sect. [57]. When this occurs within the first 24 h postdelivery, it is classified as primary PPH; if bleeding takes place between 24 h and 12 weeks postpartum, it is referred to as secondary PPH [58]. This phenomenon manifests in both hereditary and nonhereditary variants [59]. Women who experience severe PPH exhibit a greater incidence of unfavorable maternal outcomes, including hysterectomy, total volume of blood loss ≥ 2.5 L, and fatality [60]. PPH is a leading cause of maternal mortality, accounting for an estimated 140,000 deaths annually, and its prevalence is notably higher in economically underdeveloped countries [58, 61]. Consequently, prompt recognition and intervention for these patients is paramount [62].

According to multiple studies, PPH is notably common in VWD patients, likely due to the functional deficiency of VWF or the inadequate elevation of its levels, together with FVIII levels, particularly in types 2 and 3 [14, 63, 64]. In type 3 patients, anemia and CNS hemorrhage are observed, bleeding before pregnancy is prevalent, the median blood loss is significant, and overall, severe PPH is more common than other subtypes are [10, 14]. The occurrence of primary PPH and severe primary PPH is high among individuals with type 2 VWD [63]. Like type 3, type 2B also involves an extended duration of hemorrhage; furthermore, thrombocytopenia is observed in the majority of patients [65]. Additionally, complications, including placenta-mediated disorders and, in fewer cases, preeclampsia, placenta previa, retained placenta, chorioamnionitis, and placental abruption, have been reported [38]. The prevalence of PPH among individuals diagnosed with VWD type 1, particularly in cases of primary PPH, is relatively minimal. Nevertheless, the likelihood of secondary PPH is greater than that of the primary variant [66]. Women who are diagnosed with mild type 1 VWD infrequently require therapeutic intervention. The comparative elevation of VWF in the final stages of gestation shows a mild manifestation of the disease, where therapeutic interventions such as replacement therapies or prophylactic measures are infrequently required [2, 67].

Management of VWD during pregnancy

Prenatal care

The management of pregnant women with VWD is a significant problem for the healthcare system especially during childbirth and planning for it, which is assessed in this section. VWD is a heterogeneous condition marked by various clinical symptoms and requires multiple therapeutic strategies [68, 69]. The elevation of VWF and factor VIII levels, typically observed in healthy pregnancies, is significantly diminished in pregnant women with VWD. The incidence of PPH in these patients ranges from 5 to 40%, whereas in the general population, it is between 2% and 10% [70]. Given the suboptimal physiological response and multiple studies indicating a heightened incidence of PPH when VWF and factor VIII levels are maintained at a minimum of 50%, it is recommended that factor replacement therapy be administered to individuals with levels below 50%. The objective should be to achieve levels of 100–150% at the time of delivery and maintain trough levels of 50% for 7–10 days postdelivery [69, 70]. The risk of PPH in women with VWD is elevated if untreated; thus, a preventative strategy should be implemented prior to delivery [61]. For example, invasive delivery methods, such as ventous or rotational forceps, should be avoided because of the potential for bleeding and the risk created for a possibly carrier neonate [61, 71]. The results from a test-infusion with desmopressin should ideally be obtained prior to pregnancy for all women with VWD and baseline levels of factor VIII and VWF below 30 U/dL. Choosing the treatment at parturition on the basis solely of basal levels, without considering the mutational background and/or the changes in factor VIII and VWF during pregnancy, may pose risks owing to the potential for various heterogeneous patterns. Patients with VWD should undergo monitoring of vWF: RCo and factor VIII coagulant activity (FVIII: C) at least once during the third trimester of pregnancy [72, 73]. The risk of bleeding is minimal when FVIII: C and vWF: RCo levels exceed 50 U/dL during pregnancy and at the childbirth time without treatment. The risk of bleeding is greatest among individuals who do not self-correct, regardless of treatment [61].

In VWD type 1, pregnant women exhibiting FVIII: C and/or VWF levels below 30 U/dL at the time of delivery necessitate the administration of desmopressin following umbilical clamping and for an additional 3‒4 days, particularly in cases where a midline episiotomy is performed. The intravenous route produces a similar increase as the subcutaneous route does; however, the time to peak is typically shorter. Monitoring FVIII and VWF levels is recommended, particularly during the administration of repeated doses [61, 74]. Several common VWF DNA variants, such as c.3614G > A (p.Arg1205His) and c.3388T > C (p.Cys1130Phe), exhibit high penetrance and expressivity, which are linked to enhanced clearance of VWF. This is evidenced by an elevated VWF propeptide/VWF: Ag ratio, which blocks the attainment of normal VWF levels by the end of pregnancy [61, 74]. Studies, both retrospective and prospective, have demonstrated that women with these DNA variants can be safely treated with desmopressin in this context. Monitoring the flow of urine and subsequent fluid restriction are essential for minimizing the risk of hyponatremia. A similar approach, with reduced infusions, can be utilized for individuals with VWF levels between 30 and 50 U/dL. Recent findings indicate the feasibility of initiating treatment prior to delivery, with no apparent adverse effects on the mother or newborn. Alternative approaches utilizing VWF/FVIII concentrates are employed in certain countries, particularly when close patient surveillance is not readily accessible. In this scenario, 40-60 IU/kg VWF is administered during the late stage of labor and is repeated daily for a minimum of three days, followed by one week of oral tranexamic acid [69, 75]. Compared with untreated patients, VWD patients treated with VWF/FVIII concentrate exhibit improved clot formation, indicating the effectiveness of treatment [76].

Prophylactic treatment

Table 2 illustrates the methods used for the peri-partum management of VWD, whereas Table 3 presents the different products available for VWF replacement during the peri-partum period [77]. Humate P, a plasma-derived factor VIII concentrate containing VWF, was utilized for the first time. Conversely, greater efficacy may be considered, in which case Vonvendi, which has a prolonged half-life of 3–6 h, may be beneficial. The crucial aspect of utilizing this medication is the requirement for lowered dosages; however, simultaneously, the absence of factor VIII diminishes the potential risk of thrombosis postdelivery [78, 79].

Table 2.

Management of VWD before delivery

Prophylaxis		If 3rd trimester VWF level < 50%, replace to > 100–200% peripartum then minimum ≈ 5 day if vaginal delivery; ≈7 days postpartum if C/S if prior robust responder to DDAVP, could consider DDAVP In lieu of replacement
		Consider peripartum IV TxA and post discharge oral TxA especially if high bleeding score or h/o PPH
Treatment		1. Fundal massage 2. Crystalloid resuscitation and red cells as indicated 3. Double uterotonics- e.g. oxytocin and misoprostol 4. Continue VWF/FVIII replacement and IV TxA q8h 5. Continued obstetrical assessment and possible intervention 6. Fibrinogen replacement for superimposed DIC if falling fibrinogen

Abbreviation: DDAVP, Desmopressin; DIC, Disseminated Intravascular Coagulopathy; C/S, C Section; FVIII, Factor VIII; PPH, Post Partum Hemorrhage; IV TxA, Intravenous Tranexamic Acid; VWF, von Willebrand Factor; h/o, history of; q8h, Every 8 h

Table 3.

VWF products

		FDA approval	VWF: RCO/VWF: Ag	VWF: RCO/FVIII: C ratio	Ultralarge multimers
Recombinant VWF	Vonvendi	✔	1.16	No FVIII	✔
Plasma derived VWF-containing FVIII concentrates	Humate	✔	0.91	2.88	×
	Alphanate	✔	0.43	0.82	×
	Wilate	✔	0.9-1.0	1.0	×
	Wilfactin	×	0.95	50	×

Antifibrinolytics play a role in prophylactic therapy, as outlined in the 2021 guidelines from the American Society of Hematology, the International Society of Hemostasis and Thrombosis, the National Hemophilia Foundation, and the World Federation of Hemophilia (ASH/ISTH/NHF/WFH), which conditionally recommend the use of postpartum tranexamic acid [80]. According to the recommendation, the dosage should be between 1000 and 1300 mg three times/ day, and it should be continued for 10–14 days. This quantity needs to be increased in the event that bleeding persists. It is also considered safe during breastfeeding. Currently, there is significant variability in the application of tranexamic acid in postpartum treatment for patients with VWD [69, 81]. In collaboration with a gynecologist, the use of this strategy should be restricted to women who have had a positive challenge test before pregnancy and who are considered to have a low peripatum risk for maternal hyponatremia during childbirth. There is a recommendation in the 2018 UK guidelines that neuraxial anesthesia should be used only if the VWF activity is greater than 50%. Neuronal anesthesia is not recommended for pregnant individuals with type 2 disease, and this procedure is contraindicated for patients with type 3 disease [69]. Instead of 150 IU/mL, the ASH/ISTH/NHF/WFH 2021 guidelines strongly recommend that factor activity levels in women with VWD who are suitable candidates for neuraxial anesthesia should be between 0.50 and 1.50 IU/mL [80].

The primary emphasis is on preventing PPH and bleeding during delivery; however, bleeding complications in newborns are particularly relevant for certain type 2 and type 3 patients. Newborns of women with type 1 disease, even if affected, typically exhibit only mild decreases in VWF levels. This is due to the physiological elevation of VWF levels observed in healthy newborns [82]. Management of these women with careful monitoring of factor levels during pregnancy and postpartum, especially when they receive factor replacement therapy, is essential to prevent bleeding and thrombosis [61]. In these patients, the risk of thrombosis in the postpartum period is high because of the increase in the level of factor VIII. This condition has a low incidence and is typically mild to moderate in severity. However, VWD patients undergoing surgical procedures or those receiving extended infusions through central venous access devices (CVADs) are at relatively increased risk compared with other patient groups [76]. It seems that cesarean sections may provide an elevated thrombosis risk compared to vaginal births in individuals administered FVIII/VWF concentrates. Systemic thromboprophylaxis using low-molecular-weight heparin is infrequently warranted, except in cases where postpartum factor replacement results in excessively elevated levels exceeding 250% [69].

Patients with VWD type 2B, characterized by a gain-of-function mutation in the A1 domain that enhances the affinity of VWF for platelets and results in increased clearance, necessitate careful monitoring of their platelet levels. Transfusion is required if the platelet count falls below 50 × 10⁹/L [69].

Delivery planning

During the prenatal period, especially during the third trimester, it is essential to monitor factors VIII and VWF to effectively plan for delivery. This consideration is crucial owing to the pathophysiological changes linked to elevated procoagulant factors, which generally remain within the normal range, with values reaching 100 IU/dL [83, 84]. For safe vaginal delivery, the VWF and factor VIII levels should exceed 50 IU/dL. In cesarean section, the VWF level should be greater than 50 IU/dL, and the factor VIII level should exceed 80 IU/dL (especially in type 1 disease) [85]; however, in VWD types 2 and 3, this value should be greater than 100 IU/dL [85].

The indicated treatments for the intrapartum phase of the disease include intravenous desmopressin at a dose of 0.3 µg/kg (maximum dose: 25–30 µg) or 300 µg nasally; its peak is 30–90 min after administration, and it should be repeated every 12–24 h [85, 86].

To improve this condition, the use of antifibrinolytics, such as tranexamic acid (1000 mg three times a day [87] or epsilon aminocaproic acid) 100–150 mg/kg), followed by an epsilon aminocaproic acid infusion of 10–15 mg/kg/hour [88], is recommended. These drugs are indicated for postpartum bleeding caused by uterine atony. Avoiding instrumentation during labor is very important because of the increased risk of maternal and infant bleeding associated with the genetic inheritance of this disease [61, 89]. Genetic counseling is recommended in this situation.

The routine administration of oxytocin during active labor may align with standard childbirth protocols for females without VWD. However, caution is warranted when it is used concurrently with desmopressin owing to the heightened risk of hyponatremia [85].

Postpartum care

Postdelivery, the plasma levels of VWF and FVIII decrease, reaching baseline levels by three weeks postpartum [72]. ISTH conducted an international survey of healthcare providers to assess current clinical practices in managing pregnancy for women with VWD. Variations were observed in antenatal monitoring, peripartum management, and postpartum protocols [81, 90]. This survey revealed that for laboratory monitoring after delivery, mainly a VWF activity test along with an examination of the antigen level of this factor and a factor VIII assay were used.

Antenatal anemia is linked to PPH, with hemoglobin levels less than 9 g/dL resulting resulting in an increased risk (> 2) of severe PPH necessitating transfusion. Furthermore, severe antenatal anemia, defined as hemoglobin levels less than 7 g/dL, increases the risk of PPH tenfold [91]. While research has suggested that severe anemia could negatively affect myometrial contractility due to diminished oxygenation, thereby increasing the likelihood of uterine atony, the exact mechanisms by which anemia elevates the risk of postpartum hemorrhage remain ambiguous. Screening for anemia in the first trimester and again at 24–28 weeks of pregnancy is recommended by the recent American College of Obstetricians and Gynecologists (ACOG) guidelines, and for all pregnant women, low-dose iron supplementation is recommended [92].

The 2021 VWD guidelines introduce definitions for primary (blood loss exceeding 1000 mL within 24 h of birth or any blood loss capable of causing hemodynamic instability) and secondary PPH (blood loss greater than typical lochia loss between 24 h and 6 weeks postpartum that requires medical evaluation or intervention or persists beyond 6 weeks postchildbirth) in women with VWD, marking a significant advancement in clinical practice and research [93]. A unified approach to diagnosing PPH aims to enhance both the identification and management of pregnant women with VWD [93, 94]. Owing to the risk of delayed postpartum bleeding in females, it is essential to conduct close in-hospital monitoring for 5–7 days. Pharmacological management should involve either desmopressin or combined VWF/FVIII medications, as VWF depletion is more pronounced during this period, increasing the risk of obstetric bleeding within the first 48 h postdelivery. These females necessitate careful monitoring in intensive or step-down care units because of the potential for hemodynamic instability [85].

Impact of VWD on the newborn

Von Willebrand disease (VWD) in the neonatal period, especially in infants born to mothers with VWD, presents various challenges [15]. Bleeding in this neonatal period is considered a rare event, although recent studies have shown hemorrhagic manifestations during the first weeks of life [95]. Factors such as age, physical activity, family history, the VWF level at birth and delivery method can affect the risk of bleeding in newborns [96]. In addition, the probability of bleeding in newborns is significantly dependent on the type and severity of maternal VWD. Mothers with Type 3 VWD, recognized as one of the rarest and most severe forms of VWD, have a greater risk of neonatal bleeding [96, 97]. The genetic inheritance pattern of VWD varies by type, primarily affecting transmission risk to newborns [98]. Type 3 and type 2 N VWD are inherited in an autosomal recessive manner, but most types of VWD, including type 1 VWD, and some types of type 2 VWD, such as type 2 A, 2B and 2 M, typically follow an autosomal dominant inheritance pattern. When one parent has a dominant form of VWD, each sibling has a 50% chance of inheriting the condition, whereas in an autosomal recessive manner, both parents should carry a copy of the altered gene for their child to be affected [9, 99–101]. Early identification of VWD in newborns is essential for preventing bleeding complications, although universal screening presents several challenges [96]. The screening of high-risk infants, especially infants with a family history of VWD, is the current approach [102]. History and examination information will determine the need for further laboratory tests. There is no single test for VWD screening, but a series of laboratory tests, including complete blood and platelet counts, prothrombin times, partial thromboplastin times and probability fibrinogen levels and thrombin times, are needed. By examining the quantity and quality parameters of VWF via laboratory tests, their deviation from the normal range can be determined [103]. In addition, genetic analysis can provide appropriate management of the disease through more specific diagnoses [104].

Future directions

The personalized medical management of VWD during pregnancy is an evolving topic of research, with a focus on tailoring medication on the basis of genetic analyses and particular risk factors. Women with VWD may benefit from genetic counseling before pregnancy to comprehend inheritance patterns and potential hazards to offspring. The management of this disease remains largely consistent regardless of prenatal sex because of its predominantly dominant autosomal inheritance. Generally, there is a 50% probability that the fetus will inherit the mutation and, consequently, the disorder [69]. Genetic counseling is crucial for families with additional children diagnosed with type 3 VWD. Prenatal diagnostic procedures can aid in identifying the type and severity of VWD, enhancing planning and management during gestation and delivery. Treatment modalities for VWD, which are dependent on the exact type and individual hemorrhagic risk, may include desmopressin, vWF concentrates, or antifibrinolytic agents. The letter to editor by Zizhen Xu, et al. demonstrated that adherence to their practice guidelines (by evaluating the patient`s files fro 1997–2016) for managing VWD during pregnancy resulted in favorable obstetrical outcomes. Bleeding complications were notably reduced when the guidelines were meticulously followed. The selection of delivery method, whether vaginal or cesarean, was determined by the patient’s VWD status and was effectively managed through appropriate interventions. The application of desmopressin and other hemostatic agents, played a crucial role in mitigating bleeding risks during delivery. The study highlighted the significance of specialized care and customized management plans for pregnant women with VWD to achieve improved outcomes. This valuable study presents an approach for addressing issues faced by patients during pregnancy, childbirth, and the postpartum period [105, 106]. It seems that large-scale studies such as this one are needed.

Conclusion

Pregnancy significantly impacts hemostasis, and women with von Willebrand disease (VWD) face unique challenges due to the interplay between pregnancy-related hormonal changes and VWF deficiencies. This narrative review has delved into the complexities of VWD during pregnancy, highlighting the increased risk of postpartum hemorrhage and other bleeding complications. Understanding the underlying pathophysiology, including hormonal influences, hemodilution, and platelet–VWF interactions, is crucial for effective management. A multidisciplinary approach is essential to optimize patient care, involving careful prenatal planning, prophylactic treatment, and timely interventions during and after delivery. While significant progress has been made in the management of VWD during pregnancy, further research is needed to refine treatment strategies, improve patient outcomes, and minimize the risks associated with this condition. By addressing the specific needs of women with VWD, healthcare providers can significantly increase their quality of life and ensure safe and successful pregnancies.

Author contributions

HSS, MNK, AR, MLE, AS, MA were involved in the conception of the study, data analysis, manuscript preparation, and monitoring. Moreover, MA, AS and HSS contributed to the search for relevant manuscripts and the preparation of the manuscript. MA, MNK, AR, HS and AS contributed to the development of the search strategy, article search, and manuscript preparation. Finally, all the authors reviewed and approved the manuscript.

Funding

This research did not receive any financial support from public, commercial, or nonprofit organizations.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.