Challenges in diagnosing and managing massive pulmonary thromboembolism during pregnancy following in vitro fertilization: A case report

doi:10.21203/rs.3.rs-4916527/v1

Download PDF

Case Report

Challenges in diagnosing and managing massive pulmonary thromboembolism during pregnancy following in vitro fertilization: A case report

https://doi.org/10.21203/rs.3.rs-4916527/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Background : In vitro fertilization (IVF) significantly increases the risk of venous thromboembolism (VTE), particularly pulmonary thromboembolism (PTE), due to elevated estrogen levels during ovarian stimulation. Diagnosing PTE in pregnancy is challenging, making early detection and management essential to prevent severe maternal complications.

Case presentation : This case report describes a 32-year-old woman, 9 weeks pregnant with twins, who presented with sudden dizziness and syncope. She had a history of four IVF procedures. Initial vital signs included tachycardia and normal blood pressure; however, she later developed severe hypotension and shock. Chest computed tomography confirmed the PTE, which was suggested on electrocardiogram and echocardiography. The performance of urgent thrombolysis with tissue plasminogen activator stabilized her condition but resulted in the loss of the twin gestational sacs. The patient was administered rivaroxaban and LMWH after being diagnosed with estrogen-associated PTE and mild anti-phospholipid antibody syndrome and successfully achieved a healthy pregnancy and delivery after further IVF attempts and prophylactic LMWH treatment.

Conclusions : This case highlights the importance of rapid diagnosis and intervention for PTE during pregnancy and the need for tailored anticoagulation strategies to ensure maternal and fetal safety. Despite the tragic loss of the twin gestational sacs, appropriate anticoagulation therapy enabled the patient to achieve a successful pregnancy and healthy delivery in subsequent IVF attempts.

In vitro fertilization

pulmonary thromboembolism

anticoagulation

Despite decreased fecundity for more than four decades, in vitro fertilization (IVF) has fulfilled the desire of many women to conceive. Generally, IVF involves controlled ovarian stimulation with exogenous hormones to induce ovulation. Ovarian stimulation leads to the growth of multiple follicles and typically increases 10–100 times supraphysiological estrogen levels and signs of hypercoagulability [1]. Furthermore, ovarian hyperstimulation syndrome risk is associated with an increased incidence of venous thromboembolism (VTE). Recently, a sevenfold increase was found in the incidence of pulmonary thromboembolism (PTE) during the first trimester of IVF pregnancy compared to spontaneous pregnancy [2]. Estrogen surge during ovarian stimulation has been hypothesized to be the initiating pathophysiological event [3]. This increased thromboembolic risk coincides with a persistent increase in estrogen levels. VTE, such as PTE, is a rare event; however, it has potentially severe consequences and is one of the leading causes of maternal mortality in the Western World [4]. PTE is often challenging to diagnose, particularly during pregnancy, because of the difficulty in performing computed tomography (CT), either resulting from a failure to recognize that women’s symptoms may be due to VTE or concerns about the fetal effects of radiation used in imaging studies preventing the conduct of appropriate investigations. In addition, pregnancy is a high risk for women who have VTE; therefore, family planning is especially imperative.

This case underscores the critical need for the timely diagnosis and management of PTE in pregnant patients and highlights the delicate balance between maternal and fetal safety during treatment. Finally, we report the process that enabled a woman of childbearing age to achieve a safe pregnancy successfully.

A 32-year-old woman presented to our hospital emergency room with sudden dizziness, syncope, and loss of consciousness and was 9 weeks pregnant with twins conceived after undergoing four in-vitro fertilization (IVF) procedures. Initial vital signs were normal blood pressure (127/97 mmHg), tachycardia (heart rate, 117 beats/min), and no evidence of tachypnea (respiratory rate, 19 beats/min). About 5–6 hours after arriving at the emergency room, she suddenly developed shock accompanied by severe hypotension. At that time, vital signs included hypotension (42/35 mmHg) and tachypnea (respiratory rate 40 beats/min), accompanied by a sudden loss of consciousness.

Electrocardiogram revealed a sinus tachycardia with an S1Q3T3 pattern (large S wave in lead I, prominent Q wave, and inverted T wave in lead III) (Fig. 1). Emergency performance of transthoracic echocardiography revealed dilated right ventricle and D-shaped left ventricle with severe pulmonary hypertension (measured right ventricular systolic pressure 70 mmHg) (Fig. 2). This is a typical finding suggestive of a PTE in a hemodynamically unstable state.

The patient’s dangerous condition due to the serious collapse of the left ventricular cavity with circulatory shock prompted a necessary resolution. Although PTE was strongly suspected, the guardian hesitated to consent to further evaluation using chest CT because of concerns about the fetal effects of the radiation used in the imaging studies. However, considering that it would be difficult to protect the 9-week fetus in any situation, chest CT was performed to confirm the massive PTE (Fig. 3).

We decided to perform thrombolysis using a tissue plasminogen activator (tPA). The US Food and Drug Administration (FDA)-approved dosing regimen for IV tPA is 100 mg administered over two hours. We administered tPA as a bolus, as an infusion over 15 min, or as a 20 mg IV bolus followed by an infusion of 80 mg over the next two hours owing to the urgency of her condition (impending cardiac arrest) [5]. The patient’s condition stabilized; however, the vaginal bleeding worsened with the discharge of two gestational sacs.

PTE in this patient could have been associated with elevated estrogen levels (pregnancy); nevertheless, additional laboratory examinations were performed to rule out hereditary thrombophilia because the patient was young. Protein C activity, protein S activity, and antithrombin III levels were unremarkable. Anti-cardiolipin antibody IgG was weakly positive at 13.6. Finally, the patient was diagnosed with estrogen-associated PTE accompanied by a mild state of anti-phospholipid antibody syndrome and was administered rivaroxaban 20 mg once daily for 6 months.

After treatment, the patient continued to attempt IVF fertilization for pregnancy. Compared with non-pregnant women, pregnant women are associated with an approximately five-fold increased risk of VTE and an approximately 20-fold increased risk of VTE at the puerperium [6]. Previous VTE is a major risk factor for recurrent VTE during pregnancy, with a higher adjusted odds ratio [7]. In addition, this patient may have a higher risk of recurrence because of repeated estrogen administration during IVF. Therefore, during the preparatory and gestational periods, the patient was treated with low-molecular-weight heparin (LMWH) at standard prophylactic doses instead of therapeutic doses. LMWH does not pass through the placenta and is safe for the fetus without the risk of teratogenic adverse events. Two years later, the patient succeeded in maintaining a normal pregnancy after three additional IVF attempts. Eventually, the patient gave birth to a healthy baby via normal vaginal delivery.

The risk of VTE, including PTE, involving blockage of the main artery of the lung or one of its branches by an embolus, increases in pregnant women [7]. Registry-based studies in Sweden and Denmark showed an increased incidence of VTEs and PTEs during the first trimester of IVF pregnancies [8, 9].

Hypotheses concerning the cause of thromboembolism have been raised and are generally believed to be initiated by an estrogen surge during the ovarian stimulation phase. This surge precedes the first trimester of fresh embryo transfer. Ovarian stimulation, with an estrogen surge, may be a prerequisite for triggering an increase in VTEs and PTE [3]. In addition, estrogen increase during the ovarian stimulation phase coupled with an increase in procoagulant factors, a decrease in anticoagulant factors such as antithrombin III, Protein S and Protein C, and acquired activated protein C resistance; furthermore, fibrinolysis decreases [2, 10].

The dilemma faced in this case was the decision to perform a chest CT to confirm the diagnosis of massive PTE despite concerns about fetal radiation exposure. This decision was critical, as the patient’s condition rapidly deteriorated. Chest CT confirmed the presence of a massive PTE, justifying the use of thrombolytic therapy with tPA. There is consensus regarding the use of thrombolysis in non-pregnant patients with massive PTE associated with hypotension and circulatory collapse at presentation or with life-threatening ischemic complications from massive iliofemoral vein thrombosis. Thrombolysis should be considered in patients with life-threatening complications such as acute VTE.

The tragic loss of the twin gestational sacs while stabilizing the mother using tPA administration underscores the complexity of managing PTE in pregnancy. Maintaining a balance between saving the mother’s life and protecting the fetus is exceptionally challenging, particularly in emergency settings. Despite this loss, the patient’s recovery was uneventful, and she was subsequently managed with rivaroxaban and LMWH to prevent recurrent thromboembolic events. Following this event, the patient’s successful pregnancy after further IVF attempts and prophylactic LMWH treatment illustrates the feasibility of achieving favorable maternal and fetal outcomes with appropriate anticoagulation therapy. LMWH, which does not cross the placenta, was selected for its safety profile, which minimizes the risk of teratogenic adverse effects.

This case also underscores the potential etiological role of elevated estrogen levels in PTE development, particularly in IVF. Although laboratory tests ruled out significant hereditary thrombophilia, mild anti-phospholipid antibody syndrome was noted, possibly contributing to the thrombotic event. This finding highlights the need for vigilant thromboembolic risk assessment and prophylaxis in women undergoing IVF.

In conclusion, this case emphasizes the importance of rapid diagnosis and intervention for PTE during pregnancy, the complexities of managing such cases, and the need for tailored anticoagulant strategies to prevent recurrence while ensuring the safety of both the mother and fetus. Experiences from this case can guide clinical decision-making and improve outcomes in similar scenarios.

Acknowledgements

None.

Author contributions

First author wrote main manuscript, provided patient care, and participated in decision-making.

Funding

Not applicable

Data availability

All data generated or analyzed in the case report are included in this published article.

Ethics approval and consent to participate

Not applicable

Consent for publication

Due informed consent was taken from the patient and no individual information which reveals the patient's identity was given in the article.

Competing interests

No competing interests.

Olausson N, Discacciati A, Nyman AI, Lundberg F, Hovatta O, Westerlund E, Wallén HN, Mobarrez F, Bottai M, Ekbom A et al: Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilization with fresh respectively frozen-thawed embryo transfer: Nationwide cohort study. J Thromb Haemost 2020, 18(8):1965-1973.
Balandina AN, Koltsova EM, Teterina TA, Yakovenko AG, Simonenko EU, Poletaev AV, Zorina IV, Shibeko AM, Vuimo TA, Yakovenko SA et al: An enhanced clot growth rate before in vitro fertilization decreases the probability of pregnancy. PLoS One 2019, 14(5):e0216724.
Henriksson P: Cardiovascular problems associated with IVF therapy. J Intern Med 2021, 289(1):2-11.
Creanga AA, Berg CJ, Syverson C, Seed K, Bruce FC, Callaghan WM: Pregnancy-related mortality in the United States, 2006-2010. Obstet Gynecol 2015, 125(1):5-12.
Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F et al: Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012, 141(2 Suppl):e419S-e496S.
Jacobsen AF, Skjeldestad FE, Sandset PM: Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium--a register-based case-control study. Am J Obstet Gynecol 2008, 198(2):233.e231-237.
Sultan AA, West J, Tata LJ, Fleming KM, Nelson-Piercy C, Grainge MJ: Risk of first venous thromboembolism in and around pregnancy: a population-based cohort study. Br J Haematol 2012, 156(3):366-373.
Henriksson P, Westerlund E, Wallén H, Brandt L, Hovatta O, Ekbom A: Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study. Bmj 2013, 346:e8632.
Hansen AT, Kesmodel US, Juul S, Hvas AM: Increased venous thrombosis incidence in pregnancies after in vitro fertilization. Hum Reprod 2014, 29(3):611-617.
Westerlund E, Henriksson P, Wallén H, Hovatta O, Wallberg KR, Antovic A: Detection of a procoagulable state during controlled ovarian hyperstimulation for in vitro fertilization with global assays of haemostasis. Thromb Res 2012, 130(4):649-653.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Challenges in diagnosing and managing massive pulmonary thromboembolism during pregnancy following in vitro fertilization: A case report

Status:

Version 1

Abstract

Figures

Background

Case report

Discussion

Conclusion

Declarations

References

Additional Declarations

Status:

Version 1