The initial stages of a clinical trial almost always exclude the participation of fertile women for fears that pregnancy-related complications may arise. 

The practice of treating fertile women with the greatest of care was in part triggered by the notorious thalidomide scandal, a drug that was marketed in the 1950s to treat morning sickness in pregnant women but caused significant birth anomalies instead. Since then, ethical boards have implemented stringent criteria for the inclusion of pregnant women in any clinical study.

In pregnancy, a woman’s physiology changes drastically. Nearly every organ system in a woman’s body is altered in one way or another due to hormonal and mechanical reconfigurations. The cardiovascular system is heavily affected, and some of the adaptive changes in pregnancy can have a negative effect on the right ventricle and pulmonary vasculature. 


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“Broadly, we can characterize the pregnancy effects on the cardiovascular system by volume expansion and decreased afterload,” Daraz and colleagues write in Heart Disease in Women. 

Read more about PAH etiology 

A Changing Body

Pregnant women often experience a phenomenon known as “physiological anemia,” which is a condition triggered by the plasma volume increase in the third trimester. This creates reduced blood viscosity, allowing for better perfusion of the fetoplacental unit.

In addition to this, cardiac output increases, driven by increasing levels of stroke volume and heart rate. Patients who have right ventricular pathology may experience worsening ischemia if their cardiac muscles are unable to keep up with additional cardiac output demands. 

In nonpregnant women, an increase in cardiac output manifests as lower blood pressure due to vasodilation. However, this reflex is often absent in pregnant women, meaning that a higher cardiac output causes pulmonary pressures to rise as vasodilation fails. This combination of factors can make a pregnant individual vulnerable to right ventricular decompensation. 

Pregnant women also experience hematological changes that lead to a hypercoagulable state. These changes include a rise in fibrinogen levels and a decrease in proteins C and S. This hypercoagulable state can cause pregnant women to become vulnerable to microvascular thrombotic lesions. 

Special Considerations in Pregnant Women With PAH

“Patients with pulmonary arterial hypertension (PAH) during pregnancy usually present with pedal edema, shortness of breath, and dyspnea, which all may be evident during a normal pregnancy,” according to Daraz et al. “Therefore, it can be challenging to differentiate the normal physiologic pregnancy response versus symptoms that may seem out of proportion and indicative of PAH.”

There are instances in which PAH is diagnosed incidentally during prenatal checkups. In these cases, Daraz and colleagues recommend that these patients be offered individualized counseling and therapeutic abortion in high-risk pregnancies. 

Daraz et al are not alone in their assessment of how a PAH diagnosis should be handled. According to Ballard III and colleagues in Cardiology Clinics, “Proactive counseling regarding maternal-fetal risks during pregnancy, teratogenic effects of PAH medications, and contraceptive strategies should be discussed with all women at the time of PAH diagnosis.” 

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Should a woman with PAH decide to continue with her pregnancy, physicians should be ready to carry out serial risk assessments in order to ensure that the patient is healthy throughout the pregnancy until the expected delivery date. Risk stratification in PAH is a well-developed discipline, and there are a number of risk stratification scoring systems from which physicians can choose. 

Nevertheless, scientists have not been able to identify a single variable that captures the precise risk in a patient with heterogeneous PAH. Therefore, scientists use a combination of variables to predict prognosis in pregnant patients with PAH. The goal in obstetric care is clear: to protect the life of the mother and her baby. 

Many pregnant patients with pre-existing PAH are on some form of medication, such as a calcium channel blocker. Studies indicate that the continuation of calcium channel blockers in pregnant women with PAH improves survival and overall outcomes; they are safe for use in pregnancy and decreases the risk of preterm labor. 

Other PAH medications, such as prostacyclins, inhaled nitric oxide, and phosphodiesterase inhibitors, also have an acceptable safety profile in pregnant women. Nevertheless, the use of these medications has not been codified in any guidelines, meaning that there is a lack of standardization regarding their use in pregnancy. 

Because patients with PAH are susceptible to right ventricular failure, inotropic support may be required. Once again, although inotropes such as dobutamine and milrinone are typically used in pregnancy, data examining their merits in pregnant women are lacking.  

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“Nonetheless, it is reasonable to use these agents in patients with moderate to severe right ventricular dysfunction,” Ballard III and colleagues wrote. 

Pregnant women are generally at a higher risk of developing venous thromboembolic events. They should therefore be started on prophylactic anticoagulation. Although warfarin is typically discontinued because it can cross the placenta and is teratogenic, low-molecular-weight heparin does not cross the placenta and is generally safe in pregnancy. 

“In patients who desire to proceed with pregnancy, PAH compounded by the physiologic changes of pregnancy can pose a significant hemodynamic burden that requires a multidisciplinary approach for care throughout pregnancy,” Ballard III et al wrote. “Although therapies have advanced, outcomes of patients with PAH and pregnancy are still poor, although they are improving.” 

References

Ballard W 3rd, Dixon B, McEvoy CA, Verma AK. Pulmonary arterial hypertension in pregnancyCardiol Clin. 2021;39(1):109-118. doi:10.1016/j.ccl.2020.09.007

Daraz Y, Murthy S, Wolfe D. Pregnancy in pulmonary arterial hypertension: a multidisciplinary approachJ Cardiovasc Dev Dis. 2022;9(6):196. doi:10.3390/jcdd9060196