**3. From preeclampsia to normal pregnancy: the hidden adaptation!**

There are a very large number of both prospective and retrospective studies investigating the preeclampsia recurrence rate, with different sample sizes, target populations, study designs, and main outcome measures, resulting in contrasting conclusions. Yet, maternal and perinatal outcomes in the subsequent pregnancy are generally better than in the first; most women will not have recurrent preeclampsia, and those who do usually will give birth at a greater gestational age compared with their index birth. Even though, women who have experienced a pregnancy complicated by preeclampsia, including their caregivers, undoubtedly have a fear of recurrence and should be counseled about their reproductive future. Many of these mothers and babies are at increased risk of severe adverse outcomes that include acute renal or hepatic failure, antepartum and postpartum hemorrhage, stroke, maternal death, intrauterine growth restriction, and perinatal death. Long-term, the burden of preterm birth is immense, particularly in terms of neurodevelopmental impairment, impaired learning, cerebral palsy, and need for special care resources [11].

Another evidence for the hidden adaptation is the ability of the placenta to survive the oxidative stress. Uterine artery Doppler studies are proposed to be abnormal in the second trimester of pregnancy because of increased vascular resistance indicating failed remodeling of the vessels of the intervillous space. About half of women with abnormal uterine artery Doppler findings go on to have preeclampsia, preterm birth, or pregnancies complicated by IUGR, while, the other half go on to normal outcomes. Besides to the Doppler scans, biochemical markers, like reduced circulating ascorbate, increased concentrations of nitric oxide synthase, and AT1 angiotensin receptor inhibitors, show evidence of oxidative stress both in women with or without abnormal uterine artery velocimetry. These markers are present regardless of whether the pregnancy proceeds to IUGR, preeclampsia, or a normal outcome.

These findings support the concept that poor placentation (Stage 1 of the model) alone is not sufficient to cause preeclampsia, and that there are other factors that adjust the physiological wheel of oxidative stress toward adaptation and normal pregnancy or toward preeclampsia (stage 2 of the model) [12]. In other words, it appears that the placenta starts as preeclamptic, and then somehow overcomes the oxidative stress and continues the placentation normally. This raises many questions on what are the hidden mechanisms that enable the placenta to survive the oxidative stress and overcome the disease? What could happen in a subsequent pregnancy that renders them to be protected? Why the placenta from normal pregnancies survives the oxidative stress?
