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The Human Placenta in Health and Disease

      The placenta is arguably the most important organ for continued survival of Homo sapiens. The human placenta is the director of pregnancy, performing many diverse functions that control maternal metabolism and fetal growth and development that mediate survival of the offspring. Despite the biological importance of this organ, we have only begun to scratch the surface of understanding both normal placental function and, to an even lesser extent, the placental dysfunction that accompanies many disorders of pregnancy. This knowledge deficit was the rationale underpinning The Human Placenta Project, which is sponsored by the National Institute of Child Health and Human Development as a collaborative research effort to understand the role of the placenta in health and disease. This endeavor aims to develop new tools to study the organ in real time, to dissect placental development from the earliest stages of implantation onward, and to elucidate mechanisms that maintain optimal function throughout pregnancy. Contributions from a broad range of scientists and clinicians synergize to pursue the secrets of this unique organ.
      The following articles target key disorders associated with placental pathology and dysregulated pathophysiology. We give an overview of the topics below, bolding the subjects covered. We introduce the series with a hot topic in the literature, the Developmental Origins of Health and Disease, commonly dubbed DOHaD.
      Our knowledge of DOHaD has flourished over the 2 decades since the Barker Hypothesis described a thrifty phenotype in babies who were born growth restricted. The small size of such fetuses reflected placental dysfunction that was associated first with subsequent hypertension in adult men, and later, with a constellation of adult diseases irrespective of sex, including hypertension, cardiovascular disease, and strokes. Extensive research into the in utero mechanisms that predispose to these maladies in later life led to the concept of in utero programming of some fetuses, independent of their genetic constitution. Mechanisms underlying the epigenetic programming of offspring exposed to in utero stress via placental dysfunction have been identified in a variety of organs, notably the kidneys, heart, and pancreas, among others.
      • McMillen I.C.
      • Robinson J.S.
      Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.
      Such dysfunction commonly results from implantation disorders that yield a placenta that exhibits inadequate nutrient transport, hypoxia, or enhanced oxidative stress, but also the effect of other conditions that may be encountered during a pregnancy, including obesity, diabetes, and environmental pollutants. Collectively, the DOHaD studies indicate that fetuses are susceptible to developmental programming during gestation, which predisposes to clinically apparent maladies in childhood or adult ages.
      If babies are affected by their placentas, how about mothers? In the last 2 decades, follow-up studies of women with pregnancy complications associated with placental maldevelopment, dysfunction, or both have shown a number of common disorders that occur with advancing age in the parturient and which link in part to a history of a pregnancy disorder. These observations have evolved into an area of research targeting Cardiovascular Health After Maternal Placental Syndromes, commonly dubbed CHAMPS. Preeclampsia, intrauterine growth restriction (IUGR), and preterm birth, among other placenta-related issues, associate with a 2- to 10-fold increased future risk for a woman to develop diabetes mellitus, chronic hypertension, cardiovascular disease, cerebrovascular disease, or metabolic syndrome, compared with women with uncomplicated pregnancy outcomes.
      • Staff A.C.
      • Redman C.W.
      • Williams D.
      • et al.
      Pregnancy and long-term maternal cardiovascular health: progress through harmonization of research cohorts and biobanks.
      This burgeoning association suggests that pregnancy complications secondary to placental dysfunction provide a window into the future health of the affected individual.
      DOHaD and CHAMPS underscore the importance of recognition that placental function contributes to the future health of some individuals from womb to tomb. It is now apparent that the sex of the fetus and its associated placenta affect adverse outcomes from fetal programming and also later life events in the mother and therefore need to be considered in all basic science and clinical scenarios. Together, this knowledge sets the stage to consider 2 important topics related to placental development and evolution over gestation. Placental pathology is all too often an afterthought following a high-risk delivery, yet histopathologic diagnoses offer retrospective explanations for some suboptimal outcomes while also offering data for counseling couples about their risk for future pregnancies. Immunology is pivotal in determining the success or failure of every pregnancy, as the fetoplacental unit is nature’s transplant. Immune dysfunction or mismatch may underlie a whole spectrum of pregnancy outcomes, including failure of implantation, early and late pregnancy loss, preeclampsia, and preterm birth. Clinicians with basic knowledge in these 2 areas will serve patients better in both preconception counseling and pregnancy management.
      Multiple disease phenotypes emanate from the normal function or suboptimal performance of the human placenta. Gestational diabetes is the direct result of diabetogenic placental hormones stressing insulin reserves in a pregnant woman. The growing obesity epidemic contributes to the increasing incidence of gestational diabetes and is itself associated with placental dysfunction and adverse pregnancy outcomes, including large- and small-for-gestational-age babies. IUGR derives from several sources, which includes placental chromosomal mosaicism, inadequacy of placental development of uteroplacental perfusion, and inadequate placental transport of nutrients.
      Patients and families are commonly ecstatic when told that there is not 1, but 2, fetuses present in the uterus when scanned by ultrasound. Two for the price of one! This said, twins can certainly be “double trouble,” whether there are 2 separate placentas or 1 placenta supplying both babies. Indeed, the advent of high-resolution ultrasound and fetal surgery has revolutionized the management of both dichorionic and monochorionic placentas. Knowing the specialized anatomy present in the placenta(s) of multifetal gestations, from early gestation through the third trimester, helps clinicians to optimize outcomes of this especially high-risk group.
      Implantation disorders of the placenta are gaining expanded recognition among practitioners, especially those without tertiary care facilities readily available, as antenatal transfer for potentially life-threatening events has become increasingly important to optimize both maternal and fetal care. The diagnosis of placenta previa in the third trimester and the marked rise in incidence of placenta accreta secondary to previous cesarean-section scars are implantation disorders with high morbidity, especially due to hemorrhage. Preterm birth requiring acute response teams, massive transfusion protocols, and complicated abdominopelvic surgery with cesarean-hysterectomy are commonly the result of abnormal placental location or invasion into the uterus.
      The chorioamnionic fetal membranes play vital, if underappreciated, roles in regulation of amniotic fluid volume and in signaling cascades that are associated with both term and preterm birth. Preterm premature rupture of membranes is an ominous condition. Infections of the chorionic villi or within the chorioamnion may lay dormant for days or weeks before clinical signs or diagnostic tests can determine the nature of a patient’s problem among a panoply of findings, such as suboptimal fetal growth, diffuse nonspecific clinical signs, or fetal abnormalities. Placental infections are a major source for poor pregnancy outcomes, and understanding the routes by which infectious agents gain access to the fetoplacental unit helps clinicians to predict what tests to run and what agents are involved.
      Imaging of the human placenta has been revolutionized by high-resolution ultrasound, including 3-dimensional imaging and Doppler flow studies. Management of all pregnancies have benefited from this revolution, as dating is rarely a question and high-risk pregnancies are monitored for growth and to provide reassurance of fetal well-being. Newer technologies are now being implemented to assess functional and structural parameters not available from ultrasound assessments. Importantly, MRI is increasingly applied to study of the placenta, as this offers new insights into blood flow and transport of some nutrients. The article on imaging offers insights into the future tools that will be available to clinicians to enhance assessment of pregnancy progression.
      Artificial reproductive technologies (ART) are now standard of care throughout the westernized world. ART has been a boon for women with a number of fertility disorders, yet pregnancies that result from some of the manipulations employed are predisposed to an increased risk for placental developmental abnormalities and poor outcomes, including preeclampsia. ART pregnancies show significantly increased placental thickness and a higher incidence of hematomas, with both linked to an increased perinatal risk.
      • Joy J.
      • Gannon C.
      • McClure N.
      • et al.
      Is assisted reproduction associated with abnormal placentation?.
      A recent metaanalysis identified that pregnancies of ART patients, compared with those conceived without ART, exhibited a higher incidence of placenta previa, placental abruption, and morbidly adherent placenta. The mechanisms by which ART adds risk to placental development are generally unknown, but disturbed trophoblast-decidual interactions in early pregnancy after ART conception may predispose to later complications in the pregnancies.
      Few events are more devastating than experiencing a stillbirth. Many questions arise. Why has this happened? What did I do to cause this? Did my provider miss something? Is this punishment for my previous actions? Guilt and remorse characterize the patient and family of a pregnancy ending with a stillbirth. The article on stillbirth addresses the issues related to stillbirth and outlines key components for clinicians to consider in managing all pregnancies, high risk or not. Placental dysfunction, particularly associated with obesity and gestational diabetes, is high on the list. Importantly, the future pregnancies of such individuals carry substantial risks for placental dysfunction, whether this be stillbirth or placental dysfunction associated with preterm birth, IUGR, or preeclampsia.
      We hope you enjoy reading the articles in this issue. The placenta is clearly important from womb to tomb. Stay tuned for new developments as The Human Placenta Project in particular, and placental research in general, elucidates new discoveries about this important organ.

      References

        • McMillen I.C.
        • Robinson J.S.
        Developmental origins of the metabolic syndrome: prediction, plasticity, and programming.
        Physiol Rev. 2005; 85: 571-633
        • Staff A.C.
        • Redman C.W.
        • Williams D.
        • et al.
        Pregnancy and long-term maternal cardiovascular health: progress through harmonization of research cohorts and biobanks.
        Hypertension. 2016; 67: 251-260
        • Joy J.
        • Gannon C.
        • McClure N.
        • et al.
        Is assisted reproduction associated with abnormal placentation?.
        Pediatr Dev Pathol. 2012; 15: 306-314