*6.4. Cardiovascular Function in Preeclampsia*

At the clinical onset of preeclampsia, significant hemodynamic impairment, such as lower cardiac output, abnormal ventricular geometry, and diastolic dysfunction have been demonstrated by several maternal echocardiography studies [49,56–58]. Severe preterm disease is associated with a worse cardiovascular profile, which is in turn associated with higher rates of serious peripartum complications, such as pulmonary edema [59–61]. In keeping with these findings, a number of cardiovascular biomarkers, such as ANP-related proteins and Corin, have been shown to be altered in pregnancy in women with preeclampsia [61–63].

#### *6.5. Abnormal Cardiovascular Function Persists after Preeclampsia*

Birth is considered to be a "cure" for preeclampsia. While it is not in doubt that the signs, symptoms, and risks of preeclampsia regress in the vast majority of women within days after birth, the paradigm that delivery normalizes maternal health after preeclampsia is not supported by postpartum studies. The risk for developing chronic hypertension postnatally is much higher after preeclampsia than after normotensive pregnancy, with rates of up to 30% for chronic hypertension being reported at one year postpartum [64]. A large register-based study of over a million women confirmed a 20-fold increase in the rate of antihypertensive medication in pregnancies complicated by hypertensive disorders used within the first year after birth [65]. Even in women who are normotensive postpartum, asymptomatic moderate-severe cardiac dysfunction was significantly higher in preterm preeclampsia (56%) compared with term preeclampsia (14%) versus matched controls [66]. The issue of whether the latter findings were caused by preeclampsia or pre-existing was evaluated in a large Norwegian epidemiological study, which suggested that the increased postpartum cardiovascular risk after preeclampsia may most probably be due to pre-existing risk factors, rather than a detrimental e ffect of preeclampsia on the maternal cardiovascular system [67].

#### **7. Analogy between Preeclampsia and Diabetes in Pregnancy**

There are multiple clinical similarities between hypertension and diabetes in pregnancy, despite the fact that one is considered purely of placental origin and the other related to maternal pancreatic dysfunction [68–70]. Both disorders are diagnosed because of new-onset hypertension or hyperglycemia in pregnancy, predisposing risk factors are similar to adult-onset disease, the definitive treatment is birth, and both disorders leave a post-partum legacy of disease (Figure 4). The most convincing alignment between these two disorders is apparent when one considers the phenotypes of the disease. Pre-gestational diabetes and preterm pre-eclampsia both reflect primary organ dysfunction, and as such, are predisposed to pre-pregnancy disease and have a more severe, early-onset phenotype [71,72]. Gestational diabetes and term preeclampsia reflect normal organ function, being overcome by increased vascular/glycemia load late in pregnancy, and as such, are di fficult to screen for and present themselves later in pregnancy with a milder phenotype [73].

**Figure 4.** Interaction between maternal cardiovascular function and placental function, maternal health, and fetal well-being. Placental oxidative stress or hypoxia is related to the relative balance of cardiovascular functional reserve and the cardiovascular volume/resistance load of pregnancy. The final common pathway that results in the signs and symptoms of preeclampsia involves the release of placental vasoactive substances. Adapted with permission from Thilaganathan and Kalafat. Hypertension. 2019;73:522–531 [68].

#### **8. Apparent Inconsistencies with Cardiovascular Origin Hypothesis**

There are many iconic hypotheses applied to the placental origins of preeclampsia that stem out of clinical or epidemiological associations, such as those involving parity, change in partner, assisted reproductive technology, oocyte donation, and the "protective" e ffect of smoking. These hypotheses have assumed trophoblast origins of preeclampsia in their development, and a re-examination of their biological plausibility is justified.
