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Journal of Midwifery & Women’s Health www.jmwh.org Original Review

The Fascinating and Complex Role of the in and Fetal Well-being CEU Gwen Latendresse, CNM, PhD, Sandra Founds, CNM, PhD, FNP-BC

Existing evidence implicates the placenta as the origin of some common pregnancy complications. Moreover, some maternal conditions, such as inadequate nutrition, diabetes, and obesity, are known to adversely affect placental function, with subsequent negative impact on the and newborn. The placenta may also contribute to fetal programming with health consequences into adulthood, such as cardiovascular, metabolic, and mental health disorders. There is evidence that altered placental development, specifically impaired trophoblast invasion and spiral artery remodeling in the first trimester, is the origin of preeclampsia. Prenatal care providers who understand the relationships between placental health and maternal-newborn health can better inform and guide women to optimize health early in pregnancy and prior to conception. This article reviews the current understanding of placental function; placental contributions to normal fetal brain development and timing of birth; and impact of maternal nutrition, obesity, and diabetes on the placenta. J Midwifery Womens Health 2015;60:360–370 c 2015 by the American College of Nurse-Midwives.

Keywords: fetal origins of adult disease, placenta, pregnancy

INTRODUCTION pregnancy complications, such as preeclampsia and preterm The placenta is an amazing organ. Not only does it play birth. Implications for clinical practice are also addressed. avitalroleinthedeliveryofnutrientsandoxygentothe growing fetus, but also it contributes significantly to the hor- monal milieu of both mother and fetus during pregnancy. The PLACENTAL DEVELOPMENT word placenta originates from the Greek word plakoenta, meaning flat, slab-like object. The placenta is variously re- A brief review and overview of placental development dur- garded and dispatched based on cultural, societal, personal, ing pregnancy may assist the reader to better understand or institutional foundations; that is, some are planted un- how the placenta contributes to perinatal outcomes, such as der a tree, some are eaten, some are incinerated, and some preeclampsia and preterm birth (PTB), and how maternal receive ceremonial treatment and burial.1 Readers are re- conditions, such as diabetes and obesity, can negatively im- ferred to the companion article in this issue of the Journal pact placental function. of Midwifery & Women’s Health to learn more about the The fertilized ovum develops into the blastocyst by the contemporary Western trend in the practice of consuming fifth day postconception. The multistructured blastocyst con- one’splacenta(seeTable1).2,3 However, how much do we re- sists of the embryonic inner cell mass; a fluid-filled cavity; ally know about what the placenta does? and the surrounding trophectoderm, which becomes the pla- Prenatal and intrapartum care providers obtain essential centa. The trophectoderm bilayer is comprised of 2 types of knowledge and skills pertinent to the identification and ap- trophoblasts: the cytotrophoblast stem cells, some of which propriate management of placental abnormalities, such as pla- develop into the outermost layer of syncytiotrophoblasts. The centa previa and abruption. Midwives and other intrapartum blastocyst implants within the maternal decidua, and at 10 to care providers also inspect the placenta after the birth to 12 days postconception is encased in a mantle of syncytiotro- 4 ensure that it is intact and appears normal. However, in recent phoblasts (Figure 1). Lacunaearefluid-filledpocketsamong years the depth of knowledge regarding placental function has the syncytiotrophoblasts. These grow and eventually merge to expanded profoundly. Maternity care providers can benefit form the intervillous spaces that later fill with maternal blood. by increasing their awareness of new insights into placental The syncytiotrophoblast layer remains in direct contact with function and contributions to maternal and fetal outcomes. maternal blood throughout pregnancy. Syncytiotrophoblasts 4 This article 1) reviews current understanding of placental produce as well as deliver nutrients to the fetus. development and function, including placental contributions At 12 days postconception, the cytotrophoblasts pro- to normal fetal brain development and stress response system; liferate and penetrate into the lacunar spaces (Figure 1). 2) describes the impact of nutrition, maternal obesity, and Approximately 2 days later, these cells grow laterally to form diabetes on placental function; and 3) explores existing ev- the cytotrophoblastic shell. These first developmental events Ͻ idence regarding the relationships between the placenta and occur in relatively hypoxic conditions ( 15 mm Hg pO2)that favor cell proliferation (multiplication of cells).5 Appropriate oxygen tension is critical to normal processes to establish a Address correspondence to Gwen Latendresse, CNM, PhD, University of healthy placenta and pregnancy. Cytotrophoblasts leaving Utah College of Nursing, 10 South 2000 East, Salt Lake City, UT 84112. the shell differentiate into extravillous trophoblasts (EVTs). E-mail: [email protected] Proliferative EVTs in cell columns anchor the placenta to

360 1526-9523/09/$36.00 doi:10.1111/jmwh.12344 c 2015 by the American College of Nurse-Midwives ✦ The placenta is a major source of steroid and hormones, such as corticotropin-releasing , which orches- trate the timing of birth, and serotonin, which is essential for fetal neurodevelopment. ✦ The origins of preeclampsia can be traced to inadequate trophoblast invasion and spiral artery remodeling in the placenta during the first trimester of pregnancy. ✦ The placenta may contribute to fetal programming for adult cardiovascular, metabolic, and mental health disorders by failing to protect the fetus from glucocorticoid overexposure. the maternal decidua. Endovascular EVTs form plugs in the to the hormonal environment for both mother and the de- maternal spiral arteries, maintaining the relatively hypoxic en- veloping fetus throughout pregnancy.5 This hormonal envi- vironment early in pregnancy. Deeper layers of decidua and ronment contributes to fetal brain development, continuance maternal blood vessels increase the oxygen tension, which of the pregnancy, labor initiation, and maturation of the fetal stimulates invasiveness of the EVTs migrating into maternal stress response via the hypothalamic-pituitary-adrenal (HPA) tissue.6 Interstitial EVTs invade the decidua and inner one- axis.5,15,18–20 third of the maternal myometrium to remodel 100 to 150 spi- ral arteries. The EVT plugs dissipate at 10 to 12 weeks’ ges- Role of Placental Hormones in Fetal Development tation, establishing early uteroplacental circulation and in- and Fetal Programming creased oxygenation. Remodeling continues in the myome- trial portion of maternal vessels until 20 to 22 weeks’ gestation Recent evidence indicates that placental production of to create low-resistance, high-flow funnels providing mater- some substances, such as serotonin, directly or indirectly nal blood to the intervillous spaces (Figure 2).4,7 contributes to fetal neurodevelopment or neuroprotection. The placenta is a vascular organ (Figure 3),8 which is ap- For example, the placenta synthesizes serotonin from its parent to clinicians upon delivery and inspection. The pla- precursor, tryptophan, which is obtained from maternal 21 cental vasculature begins to develop at 5 weeks’ gestation. dietary sources. Normal fetal brain development requires Bloodvesselsformfromvillousmesenchymalcellsunderthe serotonin, a neurotransmitter crucial for fetal forebrain 22 influence of growth factors, such as fibroblast growth fac- neurogenesis and interconnection between neurons. This tor and vascular endothelial growth factor (see Table 2).5,7,9 process begins early in gestation, with increasing concentra- Angiogenesis, the branching outgrowths of vessels, contin- tions of serotonin and serotonin receptors within the fetal ues throughout pregnancy, later forming capillary sprouts and brain. The fetal brain also selectively accumulates placentally loops that become the mature terminal placental villi.10,11 At derived serotonin over time. Data implicate sensitivity of the maternal–fetal interface, trophoblasts remodel maternal the fetal brain to placental serotonin. Disruptions in the spiral arteries. Meanwhile, vasculogenesis and angiogenesis fetal serotonin system are observed in association with an occur within the fetoplacental tissues. increased risk of serotonin-associated mental illness and behavioral abnormalities in offspring. The consequences of PLACENTAL FUNCTION disruption may extend into adulthood.21–23 The placenta plays several essential roles during pregnancy, Another example is the placental production of enzymes such as delivering nutrients to the growing fetus, exchang- that are often precursors to fetal neuroactive steroids syn- 24 ing oxygen and carbon dioxide, and serving as gatekeeper be- thesized in the placenta and the fetal brain. For example, tween the mother and fetus.12 The placenta is both a passive allopregnanolone is a neuroactive steroid known to provide filter and an active participant in these exchanges.13 neuroprotection to the fetus, but it requires placentally pro- Thegatekeeperroleincludesprotectionofthefetus duced 5-alpha reductase for production in both the placenta 18 against potentially harmful over- or underexposure to sub- and the fetal brain. Additionally, produced in stances of maternal origin, such as the mother’s immune theplacentaisasteroidhormonethatcontributestoadequate and hormonal systems.14 For example, the placenta plays a quantities of neuroactive steroids in the fetal brain. In the central role in maintenance of the pregnancy by producing case of 5-alpha reductase and progesterone, the placenta both progesterone and and preventing the mother’s is contributing indirectly to neuroprotection of the fetus— immune system from identifying the fetus as foreign matter, particularly during the third trimester, labor, and birth—and thus avoiding attack and rejection.5,15 The placenta also often in response to acute stressors, such as a hypoxic or 24 offers protection, with varying degrees of success, against ischemic insult to the fetus. environmental substances with harmful or mutagenic prop- The placenta is also a major source of corticotropin- erties via transporter and inactivating enzymes.16,17 releasing hormone (CRH) and adrenocorticotropic hormone, Table 2 displays a lengthy but still incomplete list of bioac- whichareknowntocontributetonormaldevelopmentand 25 tive substances produced by the placenta, along with the asso- maturation of the fetal stress response system. In addi- ciated functions and features of each, if known. Via produc- tion, the placental enzyme 11␤-hydroxysteroid dehydroge- tion of these substances, the placenta contributes significantly nase type 2 (11␤-HSD2) converts active glucocorticoids such

Journal of Midwifery & Women’s Health r www.jmwh.org 361 Table 1. Placentophagy a,2,3 of the stress response system affects glucocorticoid-sensitive tissues. Adverse maternal–fetal environments associated with It is a common myth that humans across cultures have elevated levels, such as undernutrition, obesity, severe historically consumed their . depression, and smoking, can be implicated in fetal origins of Humans appear to be the rare mammal not to eat their adult disorders. Several factors can affect the development, size, efficiency, placentas. and gene expression of the placenta, including over- and un- Placentophagy is a rapidly increasing Western trend. dernutrition (eg, calories, ), hypoxia (eg, smoking), re- There are no well-conducted studies to document benefit or stricted uterine blood flow, administration of glucocorticoids, harm of placentophagy harm. and hyperglycemia (eg, diabetes).27 One classic example, ma- It is difficult to advise women whether they should or should ternal smoking, directly and indirectly alters the expression of more than 200 different genes in the placenta34; and increased not consume the placenta without good evidence on which to maternal cortisol levels are associated with increased produc- base a recommendation. tion of placental CRH, a major contributor to timing of labor and development of the fetal HPA axis.35 In the following aeating one’s placenta. sections, we discuss 3 maternal contributors to alterations of placental function: nutrition, maternal obesity, and diabetes. as cortisol into inactive metabolites, thereby protecting the fetus from overexposure to cortisol levels that are naturally 26 10 times higher in the mother. Anumberofenvironmental THE IMPACT OF NUTRITION, DIABETES, factors, including infection and hypoxia, result in decreased HYPERGLYCEMIA, AND OBESITY ON PLACENTAL ␤ placental 11 -HSD2 and thus contribute to increased fetal FUNCTION and placental exposure to glucocorticoids.27 Excess glucocor- ticoids are directly associated with decreased growth of the The Impact of Nutrition on Placental Function placenta and the fetus but are also implicated in program- The nutritional status and birth weight of the fetus are not ming of the HPA axis.27 Another environmental exposure is only dependent on the mother’s nutrition but also on the pla- the treatment of severe asthma with steroids; readers are re- centa’s ability to deliver that nutrition. The exchange of nu- ferred to the significant work of Clifton et al, which addresses trients from mother to fetus via the placenta depends on a the effects of glucocorticoids and asthma on the placenta.28,29 variety of factors, including the surface area of the placenta, concentration gradients, blood flow across the placenta, and Fetal Programming availability of placental transporters—proteins that actively Often referred to as the Barker Hypothesis,fetalprogram- move nutrient molecules across the placental epithelial mem- ming is the process that occurs when environmental factors brane from maternal to fetal circulation. Alterations in any influence gene expression during early fetal development, of these factors are linked with intrauterine growth restric- resulting in programming for adverse health outcomes tion (IUGR).4 For example, changes in the activity of several later in life.30 Thehypothesisisrootedinepidemiologic placental protein transporters are observed in af- observations originally made by Dr. David Barker in the fected with IUGR. One specific transporter, placental system 1970s after examination of European birth registries and A,isdownregulatedinIUGRandinplacentasofobesewomen health outcomes among those born to mothers exposed to but upregulated in women who are diabetic. This may par- adversity and famine. For example, data from the Helsinki tially explain the increased rate of low-birth-weight neonates Birth Cohort Study (men and women born 1924-1944 in born to women who are obese (but not diabetic) and higher- Helsinki, Finland) and the Dutch famine (a 6-month period birth-weight neonates born to women who have diabetes.4 of severe food restriction in Holland 1944-1945) provided The placenta has an amazing ability to adapt to adverse evidence that men and women born during periods of adver- conditions, such as undernutrition. For example, the placenta sityhadahigherriskforcardiovasculardiseaselaterinlife.31 can alter its size, shape, weight, and thickness, as well as its Since the earliest reports by Barker, the list of adverse health gene expression, in response to environmental influences.31 outcomes has increased to include adulthood metabolic, An undernourished placenta can enlarge its surface area, neoplastic, and neurological disorders in association with in therebyincreasingitsabilitytoextractmorenutrientsfrom utero exposures to adversity.30 The phenomenon is frequently the maternal circulation. Table 3 lists some of the observed referred to as fetal origins of adult disease (FOAD). One changes in the placenta in response to nutritional challenges, major mechanism that explains these adverse outcomes is the such as famine during pregnancy. These adaptations opti- effect of excess glucocorticoids on the fetus and placenta.32 mize survival for the offspring but often at the expense of The developing fetal brain, as well as other fetal tissues, is long-term health, a classic premise of the Barker Hypothe- extremely sensitive to glucocorticoids. This mechanism un- sis and subsequent theory of FOAD.36 For example, placental derpins many of the theoretical explanations for how an ad- enzymes that ordinarily protect the fetus from overexposure verse intrauterine environment and glucocorticoids (corti- to cortisol are decreased among women with low protein in- sol) can contribute to fetal origins of adult disorders, such take. Subsequently, increasing cortisol levels provide the fetus as diabetes, obesity, affective disorders, and cardiovascular with the ability to survive low protein intake (eg, famine) in disease.33 An increased cortisol level is a normal physiologic the short term but negatively impact cardiovascular health of response to stress. However, chronic or excessive activation the adult.

362 Volume 60, No. 4, July/August 2015 Figure 1. Schematic Representation of Early Placental Development between Days 9 and 16.

Reprinted with permission from Gabbe et al.4 The Barker Hypothesis predicts that in utero undernutri- trauterine programming and health outcomes later in life, as tion will program for cardiovascular and metabolic diseases well as the directional and interactive relationships involved.27 laterinlife.30 In the wake of the original Barker Hypothesis, a substantial amount of evidence has supported FOAD, link- ing placental function with adulthood disease.31 For example, The Impact of Diabetes and Hyperglycemia on Placental Function low birth weight has been identified as a better predictor of coronary disease later in life than are known behavioral The effects of diabetes and hyperglycemia on biologic pro- factors, and birth weight has a direct relationship with placen- cesses in the human body are well known. These include the tal weight. Morphology of the placenta has also come under damaging effects of advanced glycosylation end products and scrutiny as a contributor to adult disorders.31,37 inappropriate kinase C activation, which alter cell structure Of course, nutrition is not the sole contributing factor to and function as well as produce alterations in protein, lipid, placental function or intrauterine programming. Other en- and carbohydrate metabolism.38 The consequences for the vironmental insults and interactions between various expo- placenta can be viewed as parallel to those seen in individuals sures can contribute to FOAD, but it is beyond the scope of who are not pregnant, primarily in vascular effects. Microvas- this article to discuss these in detail. Briefly, examples of other cular and macrovascular changes develop, such as basement environmental insults and interactions that appear to be in- membrane thickening and reduction of blood flow through volved in intrauterine programming include placental expo- constricted, damaged blood vessels.39,40 Figure 5 depicts the sure to chemicals; hypoxemia; oxidative stress among preg- sequence of events that eventually leads to fetal hypoxia as a nant women who smoke34; and placental exposure to exces- consequence of hyperglycemia. sive glucocorticoids during chronic activation of the physi- Hyperglycemia also appears to have a direct effect on ologic stress response (HPA axis), as reviewed earlier in this some placental cells, such as fetal macrophages called Hof- article.32 Figure 4 depicts the theoretical links between the en- bauer cells.41 The consequence is a switch of Hofbauer cells vironment, mother, placenta, and fetus that contribute to in- from an anti-inflammatory role to a proinflammatory role.

Journal of Midwifery & Women’s Health r www.jmwh.org 363 Figure 2. Physiologic Conversion of the Maternal Spiral Arteries.

Reprinted with permission from Gabbe et al.4

ondary to hyperglycemia is placental insufficiency and asso- ciated increases in adverse perinatal outcomes, including the increased incidence of fetal demise, IUGR, and stillbirth seen among women with .39

The Impact of Maternal Obesity on Placental Function Maternal obesity is associated with an increased risk for adverse perinatal outcomes, including maternal hypertensive morbidity and mortality, newborn admissions to the neona- tal intensive care unit, fetal-newborn mortality, and even programming for health outcomes later in life.42,43 Until very recently, it was not understood how maternal obesity might be linked with poor maternal–newborn outcomes or how maternal obesity contributes to adverse health conditions later in life. There is now evidence that maternal obesity Figure 3. Placental Circulation. affects placentation starting early in gestation. Inflammation Open Use Permission from Human Physiology Wikispace.8 appears to be the significant link between obesity and adverse placental effects. The metabolic and oxidative stress in obese individuals leads to cellular injury and subsequent systemic Inflammation goes hand in hand with the activation of chem- and placental inflammation.44,45 Oxidative stress refers to ical signaling that creates vascular permeability, cell prolifer- tissue damage resulting from harmful ions that are inade- ation, additional tissue damage, and further vascular insult.38 quately neutralized by antioxidants.7 Inflammation activates One likely conclusion to the vascular insults that occur sec- a cascade of physiologic events in the body, including in the

364 Volume 60, No. 4, July/August 2015 Table 2. Placental Products: Hormones, Neurotransmitters, Growth Factors, and Peptides3,16 Product Primary Function Features Activin A Local tissue growth Increases sensitivity Decreases throughout pregnancy ACTH Stimulates maternal and fetal cortisol synthesis Elevated in PE and IUGR CRH Stimulates ACTH release, affects uterine blood flow Increases throughout pregnancy. and myometrial contractility Elevated levels associated with preterm birth, PE, and IUGR Key role in placental implantation, growth, and Increases in early pregnancy and differentiation decreases in later pregnancy Estriol, estrone, Stimulates uterine blood flow and progesterone Increases throughout pregnancy release, contributes to maternal weight gain Fibroblast growth factor Angiogenesis and placental growth Increased in gestational diabetes Follistatin Uncertain releasing hormone Stimulates hCG release hCG Supports corpus luteum Maternal serum marker for chromosomal disorders Regulates food intake Decreases throughout pregnancy releasing hormone Regulates fetal and placental growth Human placental growth Mobilizes transfer to fetus and contributes to hormone maternal Human Stimulates insulin production, promotes maternal Increases throughout pregnancy weight gain Inhibin A Unknown Maternal serum marker for chromosomal disorders Insulin-like growth factor Fetal and placental growth Regulates food intake Decreases throughout pregnancy NeuropeptideY Vasoconstriction Myometrial contractions Increases throughout pregnancy -related protein Transfer of calcium across placenta Placental growth factor Angiogenic and recruits macrophages Increases in early pregnancy and decreases in later pregnancy Progesterone Myometrial quiescence, growth of decidua Increases throughout pregnancy; withdrawal associated with pregnancy loss and labor Promotes maternal weight gain Promotes uterine blood flow Regulates maternal blood pressure and uterine blood flow Increases insulin resistance Increases throughout pregnancy Serotonin Fetal neurogenesis Thyrotropin Releases -stimulating hormone from fetal pituitary Transforming growth factor-beta Anticellular proliferation and differentiation, apoptosis SimilartoCRH Vascular endothelial growth factor Regulates vasculogenesis and angiogenesis Visfatin Affects insulin metabolism

Abbreviations: ACTH, adrenocorticotropic hormone; CRH, corticotropin releasing hormone; hCG, human chorionic gonadotropin; IUGR, intrauterine growth restriction; PE, pulmonary edema.

Journal of Midwifery & Women’s Health r www.jmwh.org 365 Table 3. TheImpactofNutritiononthePlacenta Nutritional Alteration Placental Effects Clinical Implications Low protein intake Decreased placental enzyme Higher cortisol exposure to placenta and fetus results in 11␤-hydroxysteroid dehydrogenase decreased weight of placenta and newborn type 2 results in decreased metabolism of cortisol Dutch famine studies: decreased placental area; Increased birth weight of newborn and increased risk of undernutrition increased placental thickness HTN and CVD later in life

Short periods of caloric restriction decreased placenta weight; No change in birth weight of newborn (eg, Ramadan) increased efficiency of the placenta

Short mothers (reflects early life decreased placental area; Increased risk of HTN and CVD later in life undernutrition) same placental weight

Helsinki famine studies: decreased placental area and weight Increased risk of HTN and CVD later in life lower socioeconomic status

Excessive caloric intake and obesity Metabolic and oxidative stress, Increased risk of obesity and CVD later in life hypothalamic-pituitary-adrenal activation, inflammation, endothelial damage, vascular compromise Decreased placental growth and function

Abbreviations: CVD, cardiovascular disease; HTN, hypertension. placenta, and alters the vascular, plasma protein, clotting, (see Figure 2).49–51 For example, in a study using surplus and immune systems. Pathological lesions and disruption of chorionic villus sampling tissues, genomic differences in placental morphology have been found in association with the placenta were found between pregnancies affected by maternal obesity.46,47 preeclampsia and those of uncomplicated pregnancies. Fur- Obesity contributes to endothelial damage in both ma- thermore, one-third of the genomic differences identified in ternal and placental blood vessels, leading to a compromised the preeclampsia samples were dysregulated immune system vascular bed with impaired growth and function of the pla- genes.52 centa as well as the fetus.45 At the molecular level, differential Unremodeled or partially remodeled spiral arteries retain expression of nearly 290 placental genes has been identified vasoreactivity, which sets up pathophysiologic responses in between obese and lean women. Furthermore, there is a the placenta. Vasoconstriction reduces blood flow, producing known lipotoxicity within the placentas of obese women.48 placental hypoperfusion–reperfusion injury. Systemic prob- These alterations in placental function and pathological lems result due to inflammation, endothelial dysfunction, ox- processes are beginning to explain how obesity is linked to idative stress, and activation of the coagulation cascade.53,54 poor maternal and newborn outcomes. The vasoconstriction in preeclampsia contributes to IUGR through poor oxygen and nutrient delivery, as well as im- paired clearance of metabolic waste. Life-threatening conse- THE PLACENTA AND PREGNANCY quences may result from these adverse processes: placental COMPLICATIONS abruption, disseminated coagulopathy, pulmonary edema, re- Placental Origins of Preeclampsia nal failure, ruptured capsule, and eclampsia.55 Giving Preeclampsia complicates up to 10% of all pregnancies, birth is the only curative treatment for preeclampsia. Indi- cated birth for preeclampsia, however, accounts for 8% of all and recent evidence supports the premise that the origins 49 of preeclampsia begin in early gestation and the earliest PTB. Additionally, one-third of the in pregnancies af- stages of placentation.49 Fetal trophoblast cells in the first to fected by preeclampsia are growth-restricted, a problem with second trimester normally invade the maternal decidua for both acute health implications for the child, such as impaired growthandneurodevelopment,andfortheadultlaterinlife, implantation and remodel the elastic uterine spiral arteries 56 into flaccid vessels to ensure adequate fetoplacental blood such as cardiovascular disease. flow. Current consensus is that genetic, immunologic, and behavioral/environmental interactions predispose to im- The Placenta and Preterm Birth paired trophoblast invasion, resulting in shallow placentation and incomplete physiologic conversion of the myome- It is well established that the placenta produces increas- trial spiral arteries and setting the stage for preeclampsia ing amounts of CRH during pregnancy, resulting in up to

366 Volume 60, No. 4, July/August 2015 Figure 4. The Interaction between Mother, Placenta, and Fetus and Programming Effects of Environmental Challenges

Reprinted with permission from Fowden et al.27

Basement Membrane Decreased Thickening Uteroplacental Blood Flow Fetal Hyperglycemia & Vasoconstriction Hypoxia Decreased Oxygen Decreased Supply Oxygen Diffusion

Figure 5. Maternal Hyperglycemia Results in Fetal Hypoxia

10,000 times the amount found in nonpregnant women.19 It CLINICAL IMPLICATIONS is also known that CRH has a significant role in maintain- Given what is currently known about placental function and ing pregnancy, but more so in preparation and initiation of dysfunction, women’s health care and prenatal care providers 57 labor. Indeed, CRH has been described as a placental clock will be concerned about how to optimize placental function, because it appears to determine the length of gestation and how to avoid dysfunction and potential sequelae, and how 57 the timing of labor and birth. A well-characterized trajec- best to advise pregnant women and any woman of reproduc- tory of placental CRH has been delineated with a thresh- tive age. Clearly, preconceptional wellness and risk assessment old level that precedes labor initiation by approximately 6 would be an optimal approach and should be conducted at weeks, a threshold level that also precedes preterm labor by all nonemergent health care visits for females of childbear- 6weeks.Ofnote,innonpregnantindividualsCRHplaysan ing age.61 These visits should include evaluation of nutrition, importantroleintheHPAaxisandthehumanstressre- physical activity, body mass index (BMI), and health and sponse. In contrast to the HPA axis negative feedback sys- risk factor assessments. Corresponding recommendations for tem, where rising cortisol levels reduce the production of achieving and maintaining ideal weight and nutrition, as CRH in the brain, there is a positive feedback system func- well as improving risk status, would follow. Clinical and self- tioning in the placenta; rising cortisol levels stimulate the management will ensure optimal conditions in the mater- placenta to increase production of CRH. Elevated cortisol nal endometrium to prepare for implantation if pregnancy levels occur in response to undernutrition, infection, and should occur. Among the evidence-based recommendations psychosocial stress, and infection, and adverse psychosocial are diet and exercise for optimal BMI; adequate folate intake; conditions, may be one mechanism that produces the pre- avoidanceofpotentiallyharmfulsubstancessuchassmoking, mature elevated CRH observed to occur prior to prema- alcohol, illicit drugs, and medications; and management of 58,59 ture initiation of labor. Of course, there are several fac- environmental exposures in home, neighborhood, and work. tors that contribute to PTB other than precocious and/or Furthermore, attention to the provision of adequate informa- elevated placental CRH production, including genetics, in- tion and guidance regarding maternal conditions known to flammation and infection, and placental/uterine structural impact the health of the placenta, such as hyperglycemia and 60 issues. smoking, need to be undertaken.

Journal of Midwifery & Women’s Health r www.jmwh.org 367 During pregnancy, the health care approach will be turely).Itwouldbeunwisetoadvisewomennottotakemedi- similar to preconception, with special attention to nutrition cations known to improve maternal-newborn outcomes, but it and avoidance of exposures known or suspected of altering is important to be on the alert for any future recommendations placental function. For example, beginning as early in preg- for reducing or avoiding the impact of antenatal medications. nancy as possible, prenatal visits should include assessment of adequate protein intake to avoid reduction in placental pro- CONCLUSION duction of 11␤-HSD2 and overexposure to maternal cortisol. Womenshouldbeadvisedtoconsumetherecommended The overarching goal of this article was to increase the knowl- daily protein intake during pregnancy, which is 71 grams.62 edge of prenatal care providers and to encourage them to Another example is to provide sufficient counseling to better appreciate the fascinating and complex contributions pregnant women to optimize and maintain stable metabolic of the placenta. To that end, we have presented evidence of states, such as normalizing blood glucose levels and achieving the important role of placental physiology and function in recommended caloric/nutrient intake and weight gain during maternal-fetal-newborn well-being, as well as perspectives on pregnancy. Prenatal care providers could also team up with the impact of maternal conditions on the placenta and the researchers to evaluate whether specific interventions might contributions that the placenta makes toward perinatal out- improve maternal-newborn outcomes associated with obesity comes, even affecting infants into adulthood. or other nutrition challenges. For example, is it possible that supplementation of the maternal diet with antioxidants, such AUTHORS as vitamin C and beta-carotene, can ameliorate or prevent the Gwen Latendresse, CNM, PhD, FACNM, is Associate Profes- adverse effects of obesity-related oxidative stress? sor at the University of Utah College of Nursing in Salt Lake In addition to advising women not to smoke, those who City,Utah.Sheresearchestheimpactoftheenvironmenton do smoke should be offered sufficient support to be success- pregnancy outcomes and is in clinical midwifery practice with ful in their efforts to quit. Most states offer free smoking ces- the Birthcare Healthcare faculty practice. sation resources; we refer readers to effective psychosocial approaches to smoking cessation.63 However, little is known Sandra Founds, CNM, PhD, FNP-BC, is Associate Professor about the placental impact of pharmacologic smoking cessa- in the University of Pittsburgh School of Nursing and a mem- tion methods such as nicotine patches and e-cigarettes; thus, ber of the Magee-Womens Research Institute in Pittsburgh, caution is recommended. Pennsylvania. She researches genomics of preeclampsia and Given the current lack of sufficient knowledge about how practices in the obstetrics/gynecology clinic. many environmental exposures may affect placental func- tion, there is an understandable concern about the impact CONFLICT OF INTEREST of medications and environmental exposures. One exemplar The authors have no conflicts of interest to disclose. is that it is not yet known whether use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy affects sero- tonin metabolism in the placenta, subsequent fetal brain REFERENCES neurogenesis, or even developmental programming for adult- hood mental health. However, the work of Bonnin et al in 1.YoungSM,BenyshekDC.Insearchofhumanplacentophagy:Across- cultural survey of human placenta consumption, disposal practices, animal models supports the premise that an altered serotonin and cultural beliefs. Ecol Food Nutr. 2010;49(6):467-484. signaling system, which may occur with early fetal exposure 2.Cremers GE, Low KG. Attitudes toward placentophagy: A brief report. to SSRIs, has long-term neurobehavioral consequences for Health Care Women Int. 2014;35(2):113-119. the offspring, likely via epigenetic mechanisms that may 3.Selander J, Cantor A, Young SM, Benyshek DC. 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Journal of Midwifery & Women’s Health r www.jmwh.org 369 55.SibaiB,DekkerG,KupfermincM.Pre-eclampsia.Lancet. 62.Dietary Reference Intakes for Energy, Cholesterol, Protein, and 2005;365(9461):785-799. Amino Acids. Washington, DC: National Academies Press; 2005. 56.Ilekis JV, Reddy UM, Roberts JM. Preeclampsia-a pressing prob- 63.Chamberlain C, O’Mara-Eves A, Oliver S, et al. Psychosocial interven- lem: An executive summary of a National Institute of Child Health tions for supporting women to stop smoking in pregnancy. Cochrane and Human Development workshop. Reprod Sci. 2007;14(6):508- Database SystRev. 2013;10:CD001055. 523. 64.Bonnin A, Torii M, Wang L, Rakic P, Levitt P. Serotonin modulates the 57.McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R. A pla- response of embryonic thalamocortical axons to netrin-1. Nat Neu- cental clock controlling the length of human pregnancy. Nat Med. rosci. 2007;10(5):588-597. 1995;1(5):460-463. 65.Bonnin A, Zhang L, Blakely RD, Levitt P. The SSRI citalopram affects 58.Latendresse G, Ruiz RJ. Maternal corticotropin-releasing hormone fetal thalamic axon responsiveness to netrin-1 in vitro independently and the use of selective serotonin reuptake inhibitors independently of SERT antagonism. Neuropsychopharmacology. 2012;37(8):1879- predict the occurrence of preterm birth. JMidwiferyWomensHealth. 1884. 2011;56(2):118-126. 59.Latendresse G. The interaction between chronic stress and pregnancy: Preterm birth from a biobehavioral perspective. JMidwiferyWomens Continuing education units (CEUs) for this article are of- Health. 2009;54(1):8-17. fered as part of a CEU collection in this issue. To obtain 60.Behrman RE, Stith Butler A. Preterm Birth: Causes, Consequences, CEUs online, please visit www.jmwhce.org. A CEU form and Prevention. Washington, DC: National Academies Press; 2007. that can be mailed or faxed is available in the print edition 61.Founds S. Innovations in prenatal genetic testing beyond the fetal kary- of this issue. otype. Nurs Outlook. 2014;62(3):212-218.

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