Preeclampsia negatively affects future maternal metabolic and endocrine outcomes

先兆子痫对未来母体代谢和内分泌的影响

妊娠是母体所有器官和系统的一个强有力的功能和代谢应激源, 可能对母亲和后代之后的生活产生影响。先兆子痫、子痫和其他高血压疾病是母亲和胎儿的严重并发症, 有时只能通过终止妊娠来控制病情。这些疾病与早产、胎儿生长受限、围产期/产妇死亡率、新生儿重症监护室入院、婴儿呼吸系统并发症和窒息以及脑出血有关[1]。除其他因素外, 先兆子痫还与较高的胆固醇水平、体重指数增加(BMI)和晚年患慢性高血压的较高风险有关。妊娠 24-32 周时母亲心血管健康状况越好, 几种不良妊娠结局的风险就越低[2]。患有早发型子痫前期合并小于胎龄儿(SGA)的孕妇在产后更容易出现代谢综合征；因此, 这表明早发型先兆子痫会增加发展为代谢综合征的风险[3]。

先兆子痫的病理生理学很复杂, 并且与内皮功能障碍导致的内皮产生的血管扩张素（即一氧化氮和前列环素）减少和血管收缩素（即内皮素-1 和血栓素 A2）增加有关, 从而导致全身性内皮功能障碍、高血压、以及基质金属蛋白酶和细胞外基质的变化 [4,5]。妊娠期胰岛素抵抗和代谢综合征也与内皮功能障碍、氧化应激和炎症反应减少有关[6]。Hooijschuur 等人[7] 报道说, 与代谢综合征相关的心脏代谢危险因素的存在与母体因素有关, 而不是胎盘综合征。同时患有先兆子痫和SGA代谢综合征发病率最高；并且, 妊娠与早发型子痫前期和SGA相关。这表明初筛时患有早发型先兆子痫和SGA病史可能是产后代谢综合征病情发展的良好预测因素[3]。

先兆子痫不仅对母体和胎儿结局有重要的临床意义, 而且对未来母体心血管疾病和内分泌/代谢有重要的临床意义, 甚至在妊娠数年后也是如此[8–10]。在过去的几十年里, 队列研究和荟萃分析表明, 与无妊娠并发症的女性相比, 有先兆子痫病史的妇女患心脏、脑血管和外周动脉疾病的风险明显更高[9, 11, 12]。尽管有这方面的证据, 但早发型先兆子痫仍然是一个未被充分认识的未来女性肥胖、心血管、代谢和肾脏疾病的风险因素。

与血压正常妊娠的女性相比, 孕期患有先兆子痫的超重和肥胖女性在产后第一年出现持续性高血压和生物标志物异常的高血压风险更高[13]。

我们的荟萃分析[10]提示, 妊娠期患有先兆子痫在多年后体重、BMI、腰围和腰臀比显著增加；与健康妊娠女性相比, 除了总胆固醇、LDL-C、甘油三酯、葡萄糖、胰岛素、HOMA-IR、C反应蛋白水平较高之外, 患高血压和代谢综合征的风险也较高。这些结果表明, 有先兆子痫病史的女性将来内分泌和代谢状况更差, 患心血管疾病的风险更高。与没有先兆子痫病史的女性相比, 患有早发型和晚发型先兆子痫的女性发生心脑血管疾病、心源性猝死、高血压、代谢综合征和需服用抗高血压药物的风险几乎高2-4倍[14]。虽然两种类型的先兆子痫(早发型和晚发型)与较高的心血管疾病风险相关, 但早发型先兆子痫的发病率和死亡率最高。

先兆子痫与母体未来患糖尿病的风险增加独立相关, 即使在BMI指数调整后或出现妊娠期糖尿病后也是如此[15]。通过将血压正常的妊娠女性和先兆子痫的妊娠女性两者先前的胰岛素抵抗水平进行比较后, 假设胰岛素抵抗与先兆子痫的病理生理学[16]。然而, 在排除患有妊娠糖尿病的女性后, 发现曾患先兆子痫的女性患糖尿病的风险相对增加[17]。这两种疾病之间是否有共同的病理生理学机制？他们是彼此的病因吗？它们是临床表现的一部分吗？这些问题需要在不久的将来得到验证。

考虑到上述临床意义, 由于心血管、内分泌和代谢风险增加, 应根据人体测量、代谢和肾功能对孕妇进行监测。对有先兆子痫病史的女性进行密切的临床随访, 并在先兆子痫妊娠多年后采取严格的干预措施来预防肥胖、高血压和其他代谢改变, 这可能会对临床带来益处；尽管在妊娠几十年后是否还有影响仍有待确定。未来有待寻找一组可进行评估血浆代谢组学生物标志物, 这些生物标志物不仅有助于筛查妊娠早期的先兆子痫和非先兆子痫女性、预测分娩时的先兆子痫, 还可以预测未来妊娠后数年内分泌和代谢变化以及相关风险。患有先兆子痫或妊娠期高血压疾病的女性需要长期随访, 因为后续内分泌和代谢风险可能会对未来女性的健康产生负面影响。

综上所述的一个严重的困惑:先兆子痫真的可以通过分娩治愈吗？我们的回答是:不会。因此, 考虑到之后内分泌和代谢风险可能会对她们未来的健康产生负面影响, 这些患先兆子痫的女性应该长期随访。

文章来自

GYNECOLOGICAL ENDOCRINOLOGY https://doi.org/10.1080/09513590.2021.1948996

Pregnancy is a strong functional and metabolic stressor for all maternal organs and systems that may impose consequences for the later life of the mother and offsprings. Preeclampsia, eclampsia, and other hypertensive disorders are severe complications for both the mother and the fetus that sometimes can only be controlled by the termination of pregnancy. These conditions are associated with preterm birth, fetal growth restriction, perinatal/maternal mortality, neonatal intensive care unit admissions, infant respiratory complications and asphyxia, and brain hemorrhage [1]. Preeclampsia has also been associated with higher cholesterol levels, increased body mass index (BMI), and a higher risk of developing chronic hypertension later in life, among other issues. A more favorable maternal cardiovascular health at 24–32 weeks of gestation was associated with lower risks for several adverse pregnancy outcomes [2]. Women who had early-onset preeclampsia combined with small-for-gestational-age (SGA) fetuses present the metabolic syndrome more frequently in the postpartum period; hence, suggesting that preeclampsia of early-onset increases the risk of developing this syndrome [3].

The pathophysiology of preeclampsia is complex and has been linked to endothelial dysfunction with a decrease of endothelium-produced vasodilators (i.e. nitric oxide and prostacyclin) and an increase of vasoconstrictors (i.e. endothelin-1 and thromboxane A2), producing generalized endothelial dysfunction, hypertension, and changes in matrix metalloproteinases and extracellular matrix [4,5]. Insulin resistance and the metabolic syndrome during pregnancy are also associated with endothelial dysfunction, oxidative stress, and reduced inflammatory response [6]. Hooijschuur et al. [7] reported that the presence of cardiometabolic risk factors related to the metabolic syndrome was associated to the maternal factor rather than the placental syndrome. The incidence of the metabolic syndrome was highest in the presence of both preeclampsia and SGA fetuses; moreover, in gravids with early-onset preeclampsia and SGA fetuses. This suggests that a history of early-onset preeclampsia and SGA at the time of screening could be a good predictor of the development of the metabolic syndrome in the postpartum period [3].

Preeclampsia has not only important clinical implications on maternal and fetal outcomes but also on future maternal cardiovascular disease and endocrine/metabolic outcomes even years after a given pregnancy [8–10]. Over the past decades, cohort studies and meta-analyses have elucidated a significantly higher risk of cardiac, cerebrovascular, and peripheral arterial disease in women with a history of preeclampsia compared to those with uncomplicated pregnancies [9,11,12]. Despite the evidence in this matter, early-onset preeclampsia remains an under-recognized risk factor for future female obesity and cardiovascular, metabolic, and kidney disease.

Overweight and obese women who had preeclampsia during their pregnancy present at the first postpartum year a higher risk of displaying sustained hypertension and hypertension with abnormal biomarkers as compared to women with normotensive pregnancies [13]. Our meta-analysis [10] showed that pregnancies complicated with preeclampsia displayed, many years later, significantly increased weight, BMI, waist circumference, and waist-to-hip ratio; in addition to higher levels of total cholesterol, LDL-C, triglycerides, glucose, insulin, HOMA-IR, C reactive protein, and a higher risk of developing hypertension and the metabolic syndrome in comparison to healthy pregnancies. These results show that women with a history of preeclampsia have a worse endocrine and metabolic profile in the future, and a higher chance of developing cardiovascular disease. In women who had early- and late-onset preeclampsia the risk of cardiocardiovascular and cerebrovascular disease, cardiac death, hypertension, the metabolic syndrome, and the need for anti-hypertensive drugs was almost 2–4 times higher as compared to women with no history of preeclampsia [14]. Although the two types of preeclampsia (early and late) are associated with a higher risk of cardiovascular disease, it was the early form that supposed the highest morbidity and mortality.

Preeclampsia is independently associated with an increased maternal future risk of diabetes mellitus, even after adjusting for BMI or the presence of gestational diabetes [15]. Insulin resistance has been hypothesized to contribute to the pathophysiology of preeclampsia after comparing normotensive pregnancies and preeclamptic ones with prior insulin resistance [16]. However, after excluding women with gestational diabetes, the risk of developing diabetes has been seen to be moderately increased in women who had preeclampsia [17]. Are there pathophysiological mechanisms shared between both entities? Are they the cause of each other? Are they part of a clinical spectrum? These questions need to be clarified in the near future.

Taking into account the above-mentioned clinical implications, pregnant women should be monitored in terms of anthropometrics, and metabolic and renal functions due to the increased cardiovascular, endocrine, and metabolic risks. A close clinical follow-up of women with a history of preeclampsia and rigorous interventions to prevent obesity, hypertension, and other metabolic alterations years after a preeclampsia complicated pregnancy might provide clinical benefits; although it remains to be determined decades after reproductive events. Future challenges should evaluate a panel of plasma metabolomic biomarkers that may aid at not only discriminating preeclamptic from non-preeclamptic women during the initial part of pregnancy and predict preeclampsia at delivery yet also predict future endocrine and metabolic changes and associated risks years after pregnancy. Women who have had preeclampsia or gestational hypertensive disorders require a long-term follow-up due to the later endocrine and metabolic risks that may negatively affect future woman’s health.

All the aforementioned implications create a strong dilemma: Is preeclampsia really cured by giving birth? Our response is: no. Therefore, these women deserve a long-term follow-up given that late endocrine and metabolic risks may negatively affect their future health.