*4.1. Abdominal Pregnancy*

A recent case report described an advanced abdominal pregnancy where the placenta was implanted outside the uterus in the right-lateral pelvic side wall [24]. The authors took the initiative to describe the uterine artery Doppler findings, which demonstrated a low-resistance waveform consistent with a normal pregnancy placentation. The question this observation raises is how complete spiral artery transformation occurred in order to create the observed low-resistance uterine artery waveform consistent with a normal pregnancy when the placenta was implanted in an extra-uterine site. Case reports are often disregarded by scientists and clinical academics; however, in certain unique situations, the exception observed in a single clinical case may prove (or disprove) the rule. However, the latter finding has previously been consistently reported in extra-uterine pregnancy [25], and suggests that changes observed universally in the maternal uterine and spiral arteries that are reflected by uterine Doppler indices do not occur as a direct consequence of trophoblast invasion.

#### *4.2. Late Pregnancy Uterine Artery Resistance Changes*

Binder et al. studied 5887 pregnancies with longitudinal uterine Doppler assessment into the third trimester. They found that one-third of patients demonstrated a de-novo increase in uterine artery resistance in the late third trimester, having previously exhibited normal indices—and that this group had a 30% higher prevalence of preeclampsia [26]. If the conventional paradigm that normal trophoblast invasion causes spiral artery transformation and a decrease in uterine artery resistance is true, then the

demonstration of an increase in third-trimester uterine artery resistance would require hypothetical "de-transformation" of the spiral arteries—an implausible biological phenomenon. An alternative explanation for the uterine artery Doppler findings in abdominal or late pregnancy is that observed variations are not caused by localized trophoblast invasion, but may, in fact, reflect maternal systemic vascular resistance changes [27,28].

#### *4.3. Ophthalmic and Radial Artery Doppler Assessment*

If, indeed, uterine artery waveform changes reflect maternal systemic hemodynamic perturbations rather than trophoblast invasion, then the Doppler assessment of non-uterine arterial vessels should mirror the findings in the uterine artery. Recent systematic reviews of Doppler assessment of the radial and ophthalmic arteries in pregnancy have demonstrated that these vessels also reduce their resistance with advancing gestation and demonstrate persistent high resistance in the first trimester in pregnancies at increased risk of preeclampsia [29,30]. These vessels seem to have the same ability to predict preeclampsia as the use of the uterine artery Doppler in isolation.

### *4.4. Pre-Pregnancy Maternal Systemic Vascular Resistance*

Above all, the findings sugges<sup>t</sup> that maternal systemic and uterine vascular resistance in pregnancy changes independently of the direct physical consequences of placental invasion and trophoblast cell behavior. If this were the case, it would imply that the biological associations described previously are inversely causal—that is to say, that increased uterine resistance and poor placental perfusion may result in impaired trophoblast invasion and function, rather than the other way around. The hypothesis that maternal systemic and uterine vascular impairment predates placental maldevelopment is supported by a recent prospective study assessing pre-pregnancy cardiovascular function in 530 women [31]. Women who subsequently developed preeclampsia had lower cardiac output and higher systemic vascular resistance in the pre-pregnancy state prior to the development of the trophoblast. The authors concluded that an altered pre-pregnancy hemodynamic phenotype was associated with the subsequent development of preeclampsia and/or fetal growth restriction.

#### **5. Reviewing Evidence Supporting Placental Origins of Preeclampsia**

Etiology and pathophysiology are two specific terms referring to distinct processes. The former refers to the origin of the disease, whilst pathophysiology refers to the biological mechanism by which the disease manifests clinical signs and symptoms. Whilst the role of the placenta in the pathophysiology of preeclampsia is indisputable, the observations supporting the hypothesis that abnormal placentation is the etiology of preeclampsia are restricted to spiral artery transformation (discussed above), abnormal placental histology, and fetal size.
