Biological therapies in the prevention of maternal mortality

Aleksandar Ljubić; Tatjana Bozanovic; Vesna Piperski; Emilija Đurić; Aleksa Begovic; Marina Sikiraš; Andjela Perovic; Jovana Vukovic; Džihan Abazović

doi:10.1515/jpm-2022-0403

Article Publicly Available

Biological therapies in the prevention of maternal mortality

Aleksandar Ljubić , Tatjana Bozanovic , Vesna Piperski , Emilija Đurić , Aleksa Begovic , Marina Sikiraš , Andjela Perovic , Jovana Vukovic and Džihan Abazović

Published/Copyright: November 28, 2022

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From the journal Journal of Perinatal Medicine Volume 51 Issue 2

Abstract

Although the maternal mortality rate has decreased and significant improvements have been made in maternal care, maternal death remains one of the substantial problems of our society. The leading causes of maternal death are postpartum hemorrhage, the most important cause of death in developing countries, and preeclampsia and venous thromboembolism, which are more prevalent in developed countries. To treat these conditions, a variety of therapeutic approaches, including pharmacologic agents and surgical techniques, have been adopted. However, a certain number of pregnant women do not respond to any of these options. That is the main reason for developing new therapeutic approaches. Biological medications are isolated from natural sources or produced by biotechnology methods. Heparin is already successfully used in the therapy of deep venous thrombosis and pulmonary embolism. Blood derivatives, used in an autologous or allogenic manner, have proven to be efficacious in achieving hemostasis in postpartum hemorrhage. Mesenchymal stem cells, alpha-1-microglobulin, and antithrombin exhibit promising results in the treatment of preeclampsia in experimental models. However, it is essential to evaluate these novel approaches’ efficacy and safety profile throughout clinical trials before they can become a standard part of patient care.

Keywords: biological therapy; maternal mortality; postpartum hemorrhage; preeclampsia; venous thromboembolism

Introduction

Maternal death, as defined by the World Health Organization (WHO), is the death of a woman while pregnant or within 42 days of termination of pregnancy, irrespective of the duration and site of the pregnancy, from any cause related to or aggravated by the pregnancy or its management but not from unintentional or incidental causes [1]. Although significant improvement in maternal care and survival has been made and maternal mortality rates have dramatically decreased, an estimated 295.000 maternal deaths occurred worldwide in 2017 [2]. However, when analyzing maternal mortality rates across different parts of the world, a considerable discrepancy between developed and developing countries may still be observed [3, 4]. For example, the estimated maternal mortality rate in Sub-Saharan Africa for 2017 was 542 per 100,000 live births compared to 9.2 per 100,000 in the United Kingdom in 2015–17 [2].

The leading causes of maternal death may be classified into direct and indirect causes. Direct causes are related to the pregnancy and include postpartum hemorrhage, preeclampsia, deep venous thrombosis with consequent pulmonary embolism, and amniotic fluid embolism [5, 6]. Indirect causes are pre-existing health conditions like heart disease, obesity, diabetes mellitus, and hyperlipidemia, which may pose a significant risk to pregnancy outcomes [5, 6].

Considering the seriousness of this problem, many therapeutic approaches concerning the specific cause of maternal death have been adopted. These include applying pharmacological agents, such as uterotonics, for achieving hemostasis in postpartum hemorrhage, antihypertensive medications in the treatment of preeclampsia, and different surgical procedures. However, many pregnant women and women in the postpartum period do not respond to these therapies, which is a rationale for developing new treatment options, such as biological therapeutics.

As defined by the United States Food and Drug Administration (FDA), biological therapeutics include various products such as vaccines, blood and blood components, allergens, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. They can be composed of carbohydrates, proteins, nucleic acids or combinations, or living entities such as cells and tissues. Biological therapeutics are isolated from various natural sources – human, animal, or microorganism – and may be produced by biotechnology methods and other innovative technologies [7].

In this short review, we give a concise summary of biological therapeutics that can be used to treat or prevent conditions causing maternal mortality. After briefly outlining the leading direct causes of maternal death, we describe biological medications that are already in use or in the development process to be applied in the treatment of this serious global problem.

Postpartum hemorrhage

Postpartum hemorrhage (PPH) is defined as a cumulative blood loss greater than or equal to 1,000 mL or blood loss accompanied by signs or symptoms of hypovolemia within 24 h after the birth [8]. The Royal College of Obstetricians and Gynaecologists categorizes PPH as minor (500–1,000 mL) or major (more than 1,000 mL) [9].

PPH is caused by obstetric complications, including uterine atony, placenta previa, genital tract trauma, or placental abruption. More typically, PPH is encountered in women who have had an instrumental delivery, induction of labor, or cesarean section. An increased risk for PPH is found in women with pre-existing bleeding disorders and taking anticoagulant therapy [9].

Postpartum hemorrhage remains one of the most common causes of maternal mortality worldwide. In the United States, PPH has generally ranked among the top three etiologies of maternal death, along with embolism and preeclampsia [10].

Despite the improvements in surgical techniques and the development of diverse pharmaceuticals, the effective management of hemostasis is still one of the main concerns in obstetrics [11]. Managing hemostasis is an ongoing fight, and it demands the use of both traditional and bioregenerative approaches. Combining these two therapy modalities will be beneficial for maternal and fetal well-being.

Since the most common cause of postpartum hemorrhage is uterine atony, uterotonics remain the first-line therapy, particularly oxytocin, which has been used for more than 50 years. Blood loss of more than 1000 mL requires the administration of blood products. Surgical and mechanical measures also have their place in managing this life-threatening condition. All these therapeutic approaches are shown in Table 1.

Table 1:

Different treatment options for postpartum hemorrhage.

Pharmacological

Biological

Surgical

Mechanical

Uterotonics

Oxytocin
Ergot alkaloids
Prostaglandins

Antifibrinolytics

Tranexamic acid
Aprotinin

Blood products

Packed red blood cells
Platelets
Fresh frozen plasma
Cryoprecipitate
Fibrinogen concentrates
Prothrombin complex concentrate

Additional options

Recombinant human factor VIIa
Cell salvage

Topical hemostatic agents

Bio-regenerative fibrin

Uterine compression suture
Uterine artery ligation
Selective arterial embolization
Aortic/iliac artery compression
Hysterectomy, supracervical
Hysterectomy, total

Bimanual uterine compression
Aortic compression
Non-pneumatic antishock garment
Intrauterine balloon tamponade

Biological therapeutics for PPH treatment

Blood derivatives are used in PPH to replace different blood components lost during bleeding. Packed red blood cells, platelets, and fresh frozen plasma are employed for volume replacement, while cryoprecipitate, fibrinogen concentrate, prothrombin complex concentrate, and recombinant human factor VIIa compensate for lost coagulation factors necessary for hemostasis. Topical hemostatic agents comprise another group of biologicals (Table 1).

Cryoprecipitate

Cryoprecipitate is a frozen derivative of blood prepared from blood plasma that contains high fibrinogen and coagulation factors VIII and IX. It is generally used to replenish fibrinogen concentrations in patients with acquired coagulopathy undergoing heart surgery, liver transplantation, trauma, or postpartum hemorrhage. Cryoprecipitate has the advantage of high fibrinogen levels in a low-volume product but carries a risk of infectious disease transmission and needs to be thawed, which are drawbacks of this pooled blood product [12].

Fibrinogen concentrates

Fibrinogen plays a crucial role in achieving and sustaining hemostasis, particularly in patients with acquired fibrinogen deficiency during major bleeding, where early treatment with fibrinogen concentrate seems essential. Pooled human plasma is used to make heat-treated and lyophilized fibrinogen (Factor I) powder [13]. In most cases, it is administered alone, but it can be given together with a cryoprecipitate. Since thawing is unnecessary, it can be administered earlier than cryoprecipitate, and studies show improved outcomes.

A combination of intraoperative thromboelastography (TEG) or rotational thromboelastometry (ROTEM) for monitoring clotting disorders and administration of fibrinogen concentrate could be the best strategy when fast evaluation and treatment are needed. Using ROTEM-guided fibrinogen concentrate administration minimizes the need for blood component therapy in massive obstetric hemorrhage [14].

Prothrombin complex concentrate

Prothrombin complex concentrate (PCC) is a human-derived virus-inactivated pooled plasma product. It combines blood clotting factors II, VII, IX, and X with Protein C and Protein S and has been used as an alternative to fresh frozen plasma. The advantages of PCC are decreased risk of volume overload, no need for thawing and determining blood group type, and reduced possibility of transfusion-associated acute lung injury and hypersensitivity reactions. High prices and a greater risk of thrombosis are disadvantages of this therapeutic. PCC can be used to rapidly reverse the effects of warfarin treatment or vitamin K deficit in patients with severe bleeding signs or needing urgent surgical procedures [15].

Recombinant factor VIIa

Recombinant human activated factor VII (rFVIIa), made by recombinant technology, was developed to promote hemostasis in hemophilic patients. Later, its use expanded to patients with intractable postpartum hemorrhage caused by atony, placenta accreta, or uterus rupture [16].

The results of retrospective clinical studies in women with massive postpartum hemorrhage demonstrated that administration of rFVIIa effectively stopped or decreased bleeding and reduced the need for arterial embolization, ligation of arteries, or hysterectomy in some patients [17]. However, it may increase the risk of thrombotic events, and the medicine is costly, which is also one of its drawbacks [17].

Cell salvage

Cell salvage is an autotransfusion technique used for minimizing allogeneic transfusion in major blood loss surgeries. Historically, cell salvage has been considered contraindicated in maternal hemorrhage due to the risk of contaminating the collected blood with amniotic fluid. Recently acquired data show that this risk is unfounded, and many medical societies now recommend autotransfusion during maternal hemorrhage [18].

Topical hemostatic agents

Topical hemostatic agents (HA) are synthetic or biological adhesives or sealants with hemostatic properties. Studies in various surgical specialties have demonstrated that hemostasis can be achieved effectively with topical HA, with decreased blood loss, reduced operative times, and minimized perioperative transfusion. HA could be used in surgery as an alternative to diathermy to avoid thermal damage, devascularization, and necrosis of the tissue caused by diathermy [19]. There is some concern about the blood-borne disease while using biological sealants because they are made from pooled human donor plasma. On the other hand, synthetic products can cause significant foreign body reactions. In addition, these products necessitate the use of high-dose exogenous thrombin derived from bovine or human sources [19].

Bio-regenerative fibrin (BRF)

Our research group developed an autologous fibrin sealant, bio-regenerative fibrin (BRF), by multiple filtrations of patients’ blood. This procedure separates plasma and concentrates all proteins, particularly fibrinogen. BRF is an autologous product, so it does not induce immunologic rejection, can be safely and quickly made in the operating theater, and helps reduce the need for allogeneic blood transfusions in cardiac surgery. These properties also make it a candidate for future use in PPH [20].

Preeclampsia (PE)

Preeclampsia is a disorder defined by elevated blood pressure and proteinuria, which occurs in pregnant women without a history of hypertension and can cause maternal and fetal death. One in ten women has high blood pressure during the gestational period, and 2–8% of pregnancies are complicated by preeclampsia [21]. PE is considered severe when the diastolic blood pressure is higher than 110 mmHg. The main complication of preeclampsia is HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome occurring in 10–20% of preeclamptic women [22]. PE and eclampsia are responsible for 10–15% of all direct maternal fatalities [23, 24].

The exact etiology of PE has not yet been identified. PE is a two-stage illness, according to the most widely accepted concept [25]. The impairment of the spiral arteries during placental formation is the first step in reducing uteroplacental perfusion, which leads to placental damage. Circulating toxic substances released from the placenta, such as syncytiotrophoblast microvesicles, free fetal DNA, cytokines, and antiangiogenic factors, pass the blood-placenta barrier and enter the maternal circulation, triggering an inflammatory reaction and endothelial injury [26]. As a result, general organ damage occurs, leading to PE after the 20th week of gestation.

Previous studies have shown that one of the prominent contributors to the etiology and pathogenesis of PE is extracellular fetal hemoglobin (HbF), which causes oxidative stress by producing reactive oxygen species (ROS). They damage the blood-placenta barrier and allow extracellular HbF to leak into the maternal bloodstream [27]. As a result, extracellular HbF concentrations in maternal plasma increase in the first three months of pregnancy in women who eventually develop PE. Elevated concentrations of HbF in plasma in the later stages of the third trimester correlated with maternal blood pressure [28].

PE pathogenesis cannot be entirely reversed or stopped, and it is more challenging to treat than to prevent. The current preeclampsia treatment options focus on diagnosing the disease, assessing its severity, initiating antihypertensive therapy, and eventually deciding on delivery time [29]. Labor induction is the only proven treatment for PE and HELLP syndrome, resulting in preterm birth and low birth weight [24].

Potential biological therapeutics for PE

Due to the inability of standard therapy to cope with severe preeclampsia and HELLP syndrome, biotherapeutics have emerged as a potential treatment approach. Biological drugs investigated for this indication are anticoagulant antithrombin (AT), free radical scavenger alpha-1-microglobulin (A1M), and mesenchymal stem cells (MSCs) because of their regenerative potential [30, 31].

Antithrombin

The primary enzyme in thrombosis and hemostasis is thrombin. Thrombin formation on the injured endothelium’s surface induces coagulation and the secretion of vasoactive agents, which cause vasoconstriction. In individuals with preeclampsia/eclampsia, vasoconstriction may be accompanied by a hypercoagulable condition triggered by thrombin production.

Antithrombin (AT) is a principal inhibitor of coagulation that forms irreversible complexes with numerous clotting factors. A reduction of the AT level indicates increased thrombin binding due to increased thrombin production, contributing to the development of PE. AT concentrations appear to be linked to maternal and fetal morbidity in PE [32].

Antithrombin effects have been studied in women with PE and animal models of PE [33], [34], [35]. A clinical study evaluating AT treatment of severely preeclamptic women in the 3rd trimester of pregnancy found significant improvement of the gestosis index (hypertension, proteinuria, edema) and estimated fetal weight gain in AT group, as well as prolongation of gestation and a significant decrease in the number of infants with low birth weight. AT treatment was effective and safe and improved perinatal outcomes [33]. In addition, a clinical study comparing AT administration with heparin in preeclamptic women with intrauterine growth retardation revealed that the AT group had considerably lower systolic blood pressure and higher fetal weight gain than the heparin group [34]. In a rodent model of PE, high-dose AT induced a substantial reduction in blood pressure and proteinuria compared to the control or low-dose groups [35]. All these results suggest that AT could be valuable biomedicine for treating PE.

Alpha-1-microglobulin (A1M)

Alpha-1-microglobulin (A1M) is a small globular circulating protein involved in neutralizing the detrimental effects of extracellular hemoglobin (Hb) and ROS, acting as a part of the heme scavenger system [36]. Elevated oxidative stress and Hb/heme upregulate cellular A1M expression. Earlier studies have found increased plasma concentration of A1M in pregnant preeclamptic women, which agrees with elevated concentrations of oxidant agents, Hb, and heme in this condition [37].

The effects of A1M administration were studied in experiments using mice, rabbits, and sheep. To induce preeclamptic-like symptoms, researchers used various techniques, including transgene animals, HbF infusions, and fasting. In a transgenic mice model of PE, human recombinant A1M significantly reduced hypertension and proteinuria during gestation and diminished cellular damage in both placenta and kidneys [38]. Positive effects of A1M have also been demonstrated in the preeclamptic rabbit model, where proteinuria was significantly lowered in animals treated with A1M [39]. Also, in an ex vivo study, treatment with A1M inhibited the Hb leakage, morphological damage, and gene up-regulation caused by Hb-perfusion [40]. These results suggest that A1M could have beneficial effects in treating PE.

Mesenchymal stem cells (MSCs)

MSCs are adult stem cells that can self-renew and differentiate into many cell lineages. In animal models of cardiac disorder, lung injury, and hypertension, human MSCs isolated from bone marrow, placenta, and umbilical cord have exhibited anti-inflammatory, immunoregulatory, and healing properties.

The beneficial effects of human umbilical cord-derived MSCs were documented in an endotoxin-induced rat model of PE. The blood pressure, levels of urine proteins, the number of leukocytes, and the proinflammatory cytokines TNF-α and IL-1β were significantly lower in the treated group [41]. In another study in the Th1-induced PE mice model, MSCs isolated from decidua significantly decreased both clinical and histopathological manifestations of PE’s severity and protected the fetoplacental development via the suppression of TNF-α expression [42]. In one ex vivo study, the administration of placenta-derived MSC conditioned medium decreased pro-inflammatory cytokines and anti-angiogenic agents, specific to preeclamptic placentae, such as macrophage-migration inhibitory factor, tumor necrosis factor, interleukin 6, and anti-angiogenic soluble fms-like tyrosine kinase-1 mRNA in PE villous explants [43]. All these results mark MSC-based therapy as a potential treatment option for PE.

Venous thromboembolism (VTE)

Venous thromboembolism is a term that unifies two related diseases – deep venous thrombosis (DVT) and pulmonary embolism. In most cases, DVT precipitates pulmonary embolic events, although they may occur independently of DVT [44]. As stated by multiple epidemiological reports, thrombosis and thromboembolism represent the leading direct cause of maternal death across developed countries [45].

Pregnancy is a physiologically hypercoagulable state, and the risk for thromboembolic events increases up to 5 times in otherwise healthy women, with a prevalence of approximately 1 per 1,000 pregnant women [46]. Levels of fibrin and thrombin, as well as factors VII, VIII, and X, all increase during gestation, with a simultaneous decrease of fibrinolytic activity and anticoagulant proteins C and S. In addition, the gravid uterus causes the obstruction of venous blood flow and blood vessel damage is inevitable during delivery [47]. Pulmonary embolism is the most significant complication of DVT and the leading cause of mortality. The incidence of thrombosis is similar throughout all three trimesters and 4–6 weeks after delivery. The additional risk factors for VTE comprise previous thromboembolic events, antiphospholipid syndrome, hereditary or acquired thrombophilia, and delivery via cesarean section [47].

Biological therapeutics for venous thromboembolism

Unfractionated heparin (UFH)

UFH was the drug of choice in the prophylaxis and treatment of VTE for more than 50 years until the introduction of low molecular weight heparin (LMWH) in the 1980s. UFH is a heterogeneous mixture of sulfated polysaccharides with a mean molecular weight of approximately 15.000 Da, produced from porcine intestines. The primary anticoagulant mechanism of action is the inactivation of thrombin and activated factor X (FXa) by potentiating the effect of antithrombin III and restriction of fibrin formation and thrombin-dependent platelet aggregation [48]. UFH does not cross the placenta, so it is believed safe for the fetus. However, it can produce significant side effects in mothers, such as allergic reactions, heparin-induced thrombocytopenia, and osteoporosis. UFH has some unfavorable pharmacokinetic properties, such as a short half-life, and requires frequent monitoring of activated partial thromboplastin time [49].

Low molecular-weight heparin (LMWH)

LMWH has a lower molecular weight than UFH, and it is more active against FXa than against thrombin. LMWH replaced UFH during the last decades because of its more favorable pharmacokinetic profile, with a longer half-life and better bioavailability. Also, monitoring during therapy is not required. Like UFH, LMWH does not cross the placenta, so it is considered safe for the fetus and the mother as it does not induce thrombocytopenia and osteoporosis [49]. The safety profile of LMWH has been confirmed in several clinical studies [50, 51]. The most serious complication of LMWH administration is bleeding, especially during labor and peripartum. Therefore, it is necessary to stop its application at least 12 h before planned delivery [52].

Although numerous studies have confirmed the significance of LMWH in treating acute VTE in pregnancy, recognizing women at high risk for developing VTE is still tricky, and there are no straightforward answers to this question. The American College of Obstetricians and Gynecologists Guidelines define pregnant women with previous spontaneous thromboembolic events and/or thrombophilia as candidates for prophylactic LMWH therapy, although with inconsistent evidence [53]. For example, a Cochrane review comparing the results of 29 clinical trials (from 1975 to 2016) did not find any significant difference between pregnancy outcomes in women at high risk treated with heparin vs. placebo [54]. Positive effects of LMWH application, such as the lower incidence of pregnancy loss, were also observed. However, these results should be interpreted cautiously because of study heterogeneity and different designs [54].

LMWH is a part of the standard treatment of VTE during pregnancy, based on practice and experience. However, extensive randomized clinical trials including more patients, need to be conducted to obtain relevant data about LMWH efficacy and safety and develop optimal prevention strategies.

Conclusions

Research in the field of biological therapeutics attracts more and more scientists worldwide. The utilization of MSCs, A1M, or BRF in the management of conditions that cause maternal death in everyday gynecologic and obstetric practice is still a long way off due to a lack of relevant studies and ethical, regulatory, and other concerns. It is necessary to conduct more clinical trials and provide rigorous evidence of the safety and effectiveness of these innovative treatment approaches to implement them in standard measures of patient care.

Corresponding author: Aleksandar Ljubić, Biocell Hospital, Belgrade, Serbia; Special Gynecology Hospital with Maternity Ward Jevremova, Belgrade, Serbia; and Libertas International University, Dubrovnik, Croatia, E-mail: aleksljubicpriv@gmail.com

Research funding: None declared.
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: Authors state no conflict of interest.
Informed consent: Not applicable.
Ethical approval: Not applicable.

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Received: 2022-08-18

Accepted: 2022-11-13

Published Online: 2022-11-28

Published in Print: 2023-02-23

Articles in the same Issue

https://doi.org/10.1515/jpm-2022-0403

Keywords for this article

biological therapy; maternal mortality; postpartum hemorrhage; preeclampsia; venous thromboembolism