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Obstentrics_Williams. Picard D, Sellier S, Houivet E, et al: Incidence and risk factors for striae gravidarum. ] Am Acad DermatoIr273:699, 2015 Pitkin M, Reynolds WA, Williams GA, et al: Calcium metabolism in normal pregnancy: a longitudinal study. Amr] Obstet GynecoIr133:781, 1979 Polec A, Fedorcsik P, Eskild A, et al: The interplay of human chorionic gonadotropin (hCG) with basic fibroblast growth factor and adipokines on angiogenesis in vitro. Placenta 35:249,r2014 Pritchard ]A: Changes in the blood volume during pregnancy and delivery. Anesthesiology 26:393, 1965 Pritchard ]A, Adams RH: Erythrocyte production and destruction during pregnancy. Amr] Obstet Gynecol 79:750, 1960 Pritchard ]A, lason A: Iron stores of normal adults and their replenishment with oral iron therapy.]AMA 190:897, 1964 Pritchard ]A, Scott DE: Iron demands during pregnancy. In Iron DeficiencyPathogeneSis: Clinical Aspects and herapy. London, Academic Press, 1970, p 173


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Obstentrics_Williams. Pritchard ]A, Scott DE: Iron demands during pregnancy. In Iron DeficiencyPathogeneSis: Clinical Aspects and herapy. London, Academic Press, 1970, p 173 Rabotti C, Mischi M: Propagation of electrical activity in uterine muscle during pregnancy: a review. Acta PhysioIr213:406, 2015 Racicot K, Kwon ]Y, ldo P, et al: Understanding the complexity of the immune system during pregnancy. Am] Reprod Immunol 72: 107,r2014 Redman CW, Sargent IL, Taylor N: Immunology of normal pregnancy and preeclampsia. In Taylor RN, Roberts ]M, Cunningham FG (eds): Chesley's Hypertensive Disorders in Pregnancy, 4th ed. Amsterdam, Academic Press, 2014 Resnik ]L, Hong e, Resnik R, et al: Evaluation of B-type natriuretic peptide (BNP) levels in normal and preeclamptic women. Amr] Obstet Gynecol 193:450,r2005 Rezai S, Nakagawa ]T, Tedesco ], et al: Gestational gigantomastia complicating pregnancy: a case report and review of the literature. Case Rep Obstet GynecoIr2015:892369,r2015


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Obstentrics_Williams. Rezai S, Nakagawa ]T, Tedesco ], et al: Gestational gigantomastia complicating pregnancy: a case report and review of the literature. Case Rep Obstet GynecoIr2015:892369,r2015 Richani K, Soto E, Romero R, et al: Normal pregnancy is characterized by systemic activation of the complement system. J Matern Fetal Neonat Med 17:239, 2005 Robb AO, Din ]N, Mills NL, et al: The influence of the menstrual cycle, normal pregnancy and pre-eclampsia on platelet activation. Thromb Haemost 103:372,r2010 Rosair], Young RH: Javier Arias-Stella and his famous reaction. Int J Gynecol Pathol 34:314, 2015 Rosenfeld CR, DeSpain K, Word A, et al: Diferential sensitivity to angiotensin II and norepinephrine in human uterine arteries. ] Clin Endocrinol Metab 97(1):138, 2012 Rosenfeld CR, Gant NF ] r: The chronically instrumented ewe: a model for studying vascular reactivity to angiotensin II in pregnancy. ] Clin Invest 67:486, 1981


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Obstentrics_Williams. Rosenfeld CR, Gant NF ] r: The chronically instrumented ewe: a model for studying vascular reactivity to angiotensin II in pregnancy. ] Clin Invest 67:486, 1981 Rubi A, Sala NL: Ureteral function in pregnant women. 3. Efect of diferent positions and of fetal delivety upon ureteral tonus. Amr] Obstet Gynecol 101:230, 1968 Ruiz-Extremera A, Lopez-Garrido A, Barranco E, et al: Activity of hepatic enzymes from week sixteen of pregnancy. Am J Obstet Gyneco1r193:20 1 0, 2005 Rylander R: Magnesium in pregnancy blood pressure and pre-eclampsia-a review. Pregnancy Hypertens 4:146, 2014 Saarelainen H, Laitinen T, Raitakari OT, et al: Pregnancy-related hyperlipidemia and endothelial function in healthy women. Circr] 70:768, 2006 Saleh L, Verdonk K, Visser W, et al: he emerging role of endothelin-l in the pathogenesis of pre-eclampsia. her Adv Cardiovasc Dis 10(5):282, 2016


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Obstentrics_Williams. Sangsawang B: Risk factors for the development of stress urinary incontinence during pregnancy in primigravidae: a review of the literature. Eur J Obstet Gynecol Reprod Bioi 178:27, 2014 Santa LM, Teshima LY, Forero lV, et al: AngiomiRs: potential biomarkers of pregnancy's vascular pathologies. J Pregnancy 2015:320386,2015 Sanz-Salvador L, Garda-Perez A, Tarin ]J, et al: Bone metabolic changes during pregnancy: a period of vulnerability to osteoporosis and fracture. Eur J EndocrinoIr172:R53, 2015 Sarmento Gon:alves I, Malafaia S, Belchior H, et al: Hyperreactio luteinalis encountered during caesarean delivety of an uncomplicated spontaneous singleton pregnancy. BM] Case Rep doi: 10.1136/bcr-2015-211349: 1,r2015 Scheithauer BW, Sano T, Kovacs KT, et al: The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65:461, 1990


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Obstentrics_Williams. Scheithauer BW, Sano T, Kovacs KT, et al: The pituitary gland in pregnancy: a clinicopathologic and immunohistochemical study of 69 cases. Mayo Clin Proc 65:461, 1990 Schiessl B, Strasburger q, Bidlingmeier M, et al: Role of placental growth hormone in the alteration of maternal arterial resistance in pregnancy. J Reprod Med 52:313, 2007 Schulman A, Herlinger H: Urinary tract dilatation in pregnancy. Br J Radiol 48:638, 1975 Semins M], Matlaga BR: Kidney stones during pregnancy. Nat Rev Urol 11:163,r2014 Shah DA, Khalil A: Bioactive factors in uteroplacental and systemic circulation link placental ischemia to generalized vascular dysfunction in hypertensive pregnancy and preeclampsia. Biochem Pharmacol 95 :211, 2015 Sharief LT, Lawrie AS, Mackie I], et al: Changes in factor XIII level during pregnancy. Hemophilia 20:e 144, 2014


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Obstentrics_Williams. Sharief LT, Lawrie AS, Mackie I], et al: Changes in factor XIII level during pregnancy. Hemophilia 20:e 144, 2014 Shibata K, Fukuwatari T, Sasaki S, et al: Urinaty excretion levels of watersoluble vitamins in pregnant and lactating women in Japan.r] Nutr Sci Vitaminol 59:178, 2013 Shin GH, Toto EL, Schey R: Pregnancy and postpartum bowel changes: constipation and fecal incontinence. Am J Gastroenterol 110:521, 2015 Shinagawa S, Suzuki S, Chihara H, et al: Maternal basal metabolic rate in twin pregnancy. Gynecol Obstet Invest 60: 145, 2005 Shnaekel L, Magann EF, Ahmadi S: Pubic symphysis rupture and separation during pregnancy. Obstet Gynecol Surv 70:713,r2015 Siddiqui AH, Tauheed N, hmad A, et al: Pulmonary function in advanced uncomplicated singleton and twin pregnancy. J Bras PneumoI40:244, 2014 Simeone S, Marchi L, Canarutto R, et al: Doppler velocimetry and adverse outcome in labor induction for late IUGR. J Matern Fetal Neonatal Med 30(3):323,r2017


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Obstentrics_Williams. Simeone S, Marchi L, Canarutto R, et al: Doppler velocimetry and adverse outcome in labor induction for late IUGR. J Matern Fetal Neonatal Med 30(3):323,r2017 Simpson KR, James DC: Eicacy of intrauterine resuscitation techniques in improving fetal oxygen status during labor. Obstet Gynecolrl05:1362, 2005 Sisti G, Kanninen TT, Witkin SS: Maternal immunity and pregnancy outcome: focus on preconception and autophagy. Genes Immun 17:1,r2016 Song CS, Kappas A: he influence of estrogens, progestins and pregnancy on the liver. Vitam Horm 26:147, 1968 Stephens V, Payne M, Ball RO, et al: Protein requirements of healthy pregnant women during early and late gestation are higher than current recommendations. J Nutr 145:73,r2015 Stewart D, Nelson DB, Matulevicius SA, et al: Cardiac magnetic resonance imaging to assess the impact of maternal habitus on cardiac remodeling during pregnancy. Am] Obstet GynecoI214:640.e1, 2016


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Obstentrics_Williams. Stewart D, Nelson DB, Matulevicius SA, et al: Cardiac magnetic resonance imaging to assess the impact of maternal habitus on cardiac remodeling during pregnancy. Am] Obstet GynecoI214:640.e1, 2016 Straach KJ, Shelton ]M, Richardson ]A, et al: Regulation of hyaluronan expression during cervical ripening. Glycobiology 15:55, 2005 Sunitha M, Chandrasekharappa S, Brid SV: Electrocradiographic QRS axis, Q wave and T-wave changes in 2nd and 3rd trimester of normal pregnancy. J Clin Diagn Res 8:BC17, 2014 Syed S: Iodine and the "near" eradication of cretinism. Pediatrics 135:594,2015 Tamas p, Szilagyi A, Jeges S, et al: Efects of maternl central hemodynamics on fetal heart rate patterns. Acta Obstet Gynecol Scand 86:71r1, 2007


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Obstentrics_Williams. Taylor BD, Ness RB, Olsenr], et al: Serum leptin measured in early pregnancy is higher in women with preeclampsia compared with normotensive pregnant women. Hypertension 65:594, 2015 homsen ]K, Fogh-Andersen N, Jaszczak P, et al: Atrial natriuretic peptide, blood volume, aldosterone, and sodium excretion during twin pregnancy. Acta Obstet Gynecol Scand 73(1):14,r1994 Thornburg LL, Queenan R, Brandt-Griith B, et al: Procalcitonin for prediction of chorioamnionitis in preterm premature rupture of membranes. ] Matern Fetal Neonatal Med 29:2056, 2016 horpe-Beeston ]G, Nicolaides KH, Snijders R]M, et al: Fetal thyroid-stimulating hormone response to maternal administration of thyrotropin-releasing hormone. Am] Obstet GynecoIr164:1244, 1991 Tsai CH, de Leeuw NK: Changes in 2,3-diphosphoglycerate during pregnancy and puerperium in normal women and in 3-thalassemia heterozygous women. Am] Obstet Gynecol 142:520, 1982


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Obstentrics_Williams. Tsai CH, de Leeuw NK: Changes in 2,3-diphosphoglycerate during pregnancy and puerperium in normal women and in 3-thalassemia heterozygous women. Am] Obstet Gynecol 142:520, 1982 Tsai PJ, Davisr], Bryant-Greenwood G: Systemic and placentalrleptin and its receptors in pregnancies associated with obesity. Reprod Sci 22:189, 2015 Uchikova EH, Ledjev 11: Changes in haemostasis during normal pregnancy. Eur J Obstet Gynecol Reprod Bioi 119: 185, 2005 Ulmsten U, Sundstrom G: Esophageal manometty in pregnant and nonpregnant women. Am] Obstet Gynecol 132:260, 1978 Valera MC, Parant 0, Vayssiere C, et al: Physiological and pathologic changes of platelets in pregnancy. Platelets 21(8):587, 2010 Van den Akker CH, Schierbeek H, et al: Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res 70:566, 2011


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Obstentrics_Williams. Van den Akker CH, Schierbeek H, et al: Amino acid metabolism in the human fetus at term: leucine, valine, and methionine kinetics. Pediatr Res 70:566, 2011 Van den Akker CH, Van Goudoever ]B: Recent advances in our understanding of protein and amino acid metabolism in the human fetus. Curr Opin Clin Nutr Metab Care 13:75,r2010 van Veelen GA, Schweitzer KJ, van Hoogenhuijze NE, et al: Association between levator hiatal dimensions on ultrasound during irst pregnancy and mode of delivery. Ultrasound Obstet GynecoI45:333, 2015 Van Wagenen G, Jenkins RH: An experimental examination of factors causing ureteral dilatation of pregnancy. J UroIr42:1010, 1939 Vargas-Rojas MI, Solleiro-Villavicencio H, Soto-Vega E: h1, h2, Th17 and Treg levels in umbilical cord blood in preeclampsia. J Matern Fetal Neonatal Med 29:1642,r2016


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Obstentrics_Williams. Vargas-Rojas MI, Solleiro-Villavicencio H, Soto-Vega E: h1, h2, Th17 and Treg levels in umbilical cord blood in preeclampsia. J Matern Fetal Neonatal Med 29:1642,r2016 Vazquez M], Ruiz-Romero A, Tena-Sempere M: Roles of leptin in reproduction, pregnancy and polycystic ovary syndrome: consensus knowledge and recent developments. Metabolism 64:79, 2015 Vignini A, Cecati M, Nanetti L, et al: Placental expression of endothelial and inducible nitric oxide synthase and NO metabolism in gestational hypertension: a case-control study.] Matern Fetal Neonatal Med 29:576, 2016 Vodstrcil A, Tare M, Novakr], et al: Relaxin mediates uterine artety compliance during pregnancy and increases uterine blood flow. FASEB J 26(10):4035,r2012 V0llestad NK, Torjesen PA, Robinson HS: Association between the serum levels of relaxin and responses to the active straight leg raise test in pregnancy. Man her 17:225,r2012


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Obstentrics_Williams. V0llestad NK, Torjesen PA, Robinson HS: Association between the serum levels of relaxin and responses to the active straight leg raise test in pregnancy. Man her 17:225,r2012 Vrachnis N, Grigoriadis C, Siristatidis C, et al: he Janus face of maternal serum relaxin: a facilitator of birth, might it also induce preterm birth? J Matern Fetal Neonatal Med 28:218, 2015 Walker Me, Garner PR, Keely EJ, et al: Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 177: 162, 1997 Wang L, Liu G, Xu Z, et al: Hepcidin levels in hyperprolactinemic women monitored by nanopore thin film based assay: correlation with pregnancyassociated hormone prolactin. N anomedicine. 11: 871, 2015 Wang L, Yang T, Ding Y, et al: Chemerin plays a protective role by regulating human umbilical vein endothelial cell-induced nitric oxide signaling in preeclampsia. Endocrine 48:299, 2015


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Obstentrics_Williams. Wang L, Yang T, Ding Y, et al: Chemerin plays a protective role by regulating human umbilical vein endothelial cell-induced nitric oxide signaling in preeclampsia. Endocrine 48:299, 2015 Wang Y, Kannan A, Nunn L,et al: IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections. lucosal Immunol 7: 1036, 2014 Watanabe M, Meeker CI, Gray MJ, et al: Secretion rate of aldosterone in normal pregnancy. J Clin Invest 42:1619, 1963 Watts DH, rohn A, Wener MH, et al: C-reactive protein in normal pregnancy. Obstet Gynecol 77:176,r1991 Waugh J, Bell SC, Kilby MO, et al: Urinary microalbumin/creatinine ratios: reference range in uncomplicated pregnancy. Clin Sci 104:103,r2003 Williams JW: Williams Obstetrics, New York, O. Appleton and Co., 1903 Wilson M, Morganti A, Zervoudakis I, et al: Blood pressure, the renin-aldo sterone system and sex steroids throughout normal pregnancy. Am J Med 68:97, 1980


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Obstentrics_Williams. Wilson MJ, Lopez M, Vargas M, et al: Greater uterine artery blood low during pregnancy in multigenerational (Andean) than shorter-term (European) highaltitude residents. AmJ Physiol Regul Integr Comp Physio1r293:R1313, 200 Wong CA, Lofredi M, Ganchif IN, et al: Gastric emptying of water in term pregnancy. Anesthesiology 96: 1395, 2002 Wong CA, McCarthy RJ, Fitzgerald PC, et al: Gastric emptying of water in obese pregnant women at term. Anesth Analg 105:751,r2007 World Health Organization: Human energy requirements. Food and nutrition technical report series 1. Rome, Food and Agriculture Organization of the United Nations, 2004, p 53 Wright HP, Osborn SB, Edmonds DG: Changes in rate of low of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg Gynecol Obstet 90:481, 1950


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Obstentrics_Williams. Wright HP, Osborn SB, Edmonds DG: Changes in rate of low of venous blood in the leg during pregnancy, measured with radioactive sodium. Surg Gynecol Obstet 90:481, 1950 Yurteri-Kaplan L, Saber S, Zamudio S: Brain natriuretic peptide in term pregnancy. Reprod Sci 19(5):520,r2012 Zeeman GG, Cunningham FG, Pritchard JA: The magnitude of hemoconcentration with eclampsia. Hypertens Pregnancy 28(2): 127, 2009 Zeeman GG, Hatab M, Twickler OM: Maternal cerebral blood low changes in pregnancies. Am J Obstet Gynecol 189:968,2003 Zimmermann MB: The efects of iodine deiciency in pregnancy and infancy. Paediatr Perinat Epidemiolr26(Supp 1):108,r2012 OMETRIAL CYCLE. . .... 80 DECIDUA. . .... 85 FORMATION.. ............ . . .... 87 PLACENTA AND CHORION . .90 AMNION . . .... 95 UMBILICAL CORD ................... . . .... ..... 97 PLACENTAL HORMONES. .98 INTERACTIONS. . . . . .... . . . . . . ...... . . . . . .. . ... 104


Obstentrics_Williams

Obstentrics_Williams. PLACENTA AND CHORION . .90 AMNION . . .... 95 UMBILICAL CORD ................... . . .... ..... 97 PLACENTAL HORMONES. .98 INTERACTIONS. . . . . .... . . . . . . ...... . . . . . .. . ... 104 Almost immediately ater the impamltio1 of the ovum, its trophoblast begins to prolerate and lJ1d, the s.rrounding decidual tissue. As it does so, it breaks through the walls of the moumal capilaries, from which the blood escapes and orms cavities, which are bounded party by trophobast and party by decidua. ?he maternal blood spaces established in this manner represent the earliest stages of the intervillous blood spaces of the inure placenta. -). Whitridge Williams (1903)


Obstentrics_Williams

Obstentrics_Williams. -). Whitridge Williams (1903) In 1903, the histopathological and embryological descrip tions of ovum implanrarion and placental development had been extensively studied and described. However, the origins and functions of pregnancy hormones were largely unknown. Indeed, it was another 25 to 30 years before estrogen and progesterone were discovered. In the past 50 years, remarkable strides have followed to uncover the steps of implantation and placental structure and function.


Obstentrics_Williams

Obstentrics_Williams. All obstetricians should understand the basic biological steps required for women to successully achieve pregnancy. Several abnormalities can fect each of these and lead to infertili' or pregnancy loss. In most women, spontaneous, cyclical ovulation continues during almost 40 years between menarche and menopause. Without contraception, there are approximately 400 opportunities for pregnancy, namely, the day of ovulation and its few preceding days. his narrow window for fertilization is controlled by tightly regulated production of ovarian steroids. Moreover, these hormones promote optimal endometrial regeneration after menstruation in preparation for the next implantation window.


Obstentrics_Williams

Obstentrics_Williams. If fertilization occurs, events thac begin ater blastocyst implantation persist until parturition. hese derive from a unique interaction between fetal trophoblasts and the maternal endometrium. which has been transformed into the decidua. The ability of a mother and her fetus to coexist as two distinct immunological systems results from endocrine. paracrine. and immunological modiication of fetal and maternal tissues in a manner not seen elsewhere. In addition. the placenta mediates a unique fetal-maternal communication system. which creates a hormonal environment that initially maintains pregnancy and eventually initiates events leading to parturition.


Obstentrics_Williams

Obstentrics_Williams. Predictable. regular. cyclical. and spontaneous ovulatory menstrual cycles are regulated by complex interactions of the hypothalamic-pituitay-ovarian axis. Concurrently, cyclical changes in endometrial histology are faithfully reproduced ;-1). Essentials players in this process include follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are pituitary-derived gonadotropins, and the ovarian sex steroid hormones estrogen and progesterone.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-1 Gonadotropin control of the ovarian and endometrial cycles. The ovarian-endometrial cycle has been structured as a 28-day cycle. The follicular phase (days 1 to 14) is characterized by rising estrogen levels, endometrial thickening, and selection of the dominant "ovulatory" follicle. During the luteal phase (days 14 to 21 I, the corpus luteum (ell produces estrogen and progesterone, which prepare the endometrium for implantation. If implantation occurs, the developing blastocyst begins to produce human chorionic gonadotropin (hCG) and rescues the corpus luteum, thus maintaining progesterone production. FSH = follicle-stimulating hormone; LH = luteinizing hormone. The average cycle duration approximates 28 days but ranges from 25 to 32 days, even for a given woman. The follicular or proliferative phase shows considerable phase-length variation. This contrasts with the luteal or secretory POStovulatory phase of the cycle, which is remarkably constant at 12 to 14 days.


Obstentrics_Williams

Obstentrics_Williams. The human ovary contains 2 million oocytes at birth, and approximately 400,000 follicles are present at puberty onset (Baker, 1963). These are depleted at a rate of approximately 1000 follicles per month until age 35, when this rate accelerates (Faddy, 1992). Only 400 follicles are normally released during female reproductive life. Therefore, more than 99.9 percent of these undergo atresia through a process of cell death termed apoptosis (Gougeon, 1996; Kaipia, 1997).


Obstentrics_Williams

Obstentrics_Williams. Follicular development consists of several stages. Primordial follicles undergo gonadotropin-independent recruitment from the resting pool and then progress from primary and secondary follicles to the antral stage. This appears to be controlled by locally produced growth factors. Two members of the transforming growth factor-3 family include growth diferentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP-15), which regulate granulosa cell proliferation and diferentiation as primary follicles grow (Trombly, 2009; Yan, 2001). hey also stabilize and expand the cumulus oocyte complex in the oviduct (Hreinsson, 2002). These factors are produced by oocytes, suggesting that the early steps in follicular development are, in part, oocyte controlled. As antral follicles develop, surrounding stromal cells are recruited, by a yet-to-be-deined mechanism, to become thecal cells.


Obstentrics_Williams

Obstentrics_Williams. Although not required for early follicular maturation, FSH is required for further development of large antral follicles (Hillier, 2001). During each ovarian FOLLICULAR PHASE LUTEAL PHASE/PREGNANCY cycle. a group of antral follicles, known as a cohon, begins a phase of semisynchro ________ •! CAMP--------.! phase of rhe previous cycle. This FSH increase leading to further follicular developmenr is called the seection winow of C',,""'.o me ovarian cycle (Macklon, 2001). Only follicles progressing to this stage develop Basement membrane the capacity [Q produce estrogen. During rhe follicular phase, estro gen levels rise in proportion to growth � of a dominant follicle and {Q rhe , increase in its number of granulosa cells , , l.


Obstentrics_Williams

Obstentrics_Williams. During rhe follicular phase, estro gen levels rise in proportion to growth � of a dominant follicle and {Q rhe , increase in its number of granulosa cells , , l. (see Fig. 5-1). These cells are rhe exclucAMP sive site of FSH receptor expression. Cholesterol lle elevation of Circulating FSH levels during the late luteal phase of the previous cycle stimulates an increase in FSH FSH receptors and subsequently, the ability


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-2 The two-cell, two-gonadotropin principle of ovarian steroid hormone produc tion. During the follicular phase (left panen, luteinizing hormone (LH) controls theca cell granulosa cells to conven androstenedi production of androstenedione, which diffuses into the adjacent granulosa cells and acts as one into estradiol. The requirement for precursor for estradiol biosynthesis. The granulosa cell capacity to convert androstenedione thecal cells, which respond ro LH, and to estradiol is controlled by follicle-stimulating hormone (FSH), After ovulation (right panen, granulosa cells, which respond to FSH, the corpus luteum forms and both theca-lutein and granulosa-lutein cells respond to LH. represents the two-gonadotropin, twoThe theca-lutein cells continue to produce androstenedione, whereas granulosa-lutein cells ceH hypothesis for estrogen biosynthesis greatly increase their capacity to produce progesterone and to convert androstenedione to estradiol. LH and hCG bind to the


Obstentrics_Williams

Obstentrics_Williams. whereas granulosa-lutein cells ceH hypothesis for estrogen biosynthesis greatly increase their capacity to produce progesterone and to convert androstenedione to estradiol. LH and hCG bind to the same LH-hCG receptor. If pregnancy occurs (right pane�, (Short, 1962). As shown in 5-2, human chorionic gonadotropin (hCG) rescues the corpus luteum through their shared LH hCG receptor. Low-density lipoproteins (LOL) are an important source of cholesterol for sion of the antrum of growing follicles.


Obstentrics_Williams

Obstentrics_Williams. steroidogenesis, cAMP =cyclic adenosine monophosphate. The follicle within the cohorr that is most responsive to FSH is likely to be the irst to produce estradiol and initiate expression of LH precise predictor of ovulation. It occurs 34 to 36 hours before receptors. ovum release from the follicle (see Fig. 5-1). LH secretion peaks


Obstentrics_Williams

Obstentrics_Williams. Mrer the appearance of LH receptors, the preovulatory 10 to 12 hours before ovulation and stimulatcs resumption of granulosa cells begin to secrete small quantities of progesterone. meiosis in the ovum and release of the irst polar body. Studies The preovulatory progesterone secrecion, although somewhat suggest that in response to LH, greater progesterone and proslimited, is believed to exert positive feedback on the estrogentaglandin production by the cumulus cells, as well as GDF9 primed pituitary to either calise or augment LH release. In addiand BMP-15 by the oocyte, activates expression of genes critition, during the late follicular phase, LH stimulates thecal cell cal to formarion of a hyaluronan-rich extracellular matrix by production of androgens, particularly androstenedione, which the cumulus complex (Richards, 2007). As seen in are then transferred to the adjacent follicles where they are aroduring synthesis of this matrix, cumulus cells lose contact with matized to


Obstentrics_Williams

Obstentrics_Williams. which the cumulus complex (Richards, 2007). As seen in are then transferred to the adjacent follicles where they are aroduring synthesis of this matrix, cumulus cells lose contact with matized to esnadiol (see Fig. 5-2). During the early follicular one another and move outward from the oocyte along the hyalphase, granulosa cells also produce in hi bin 3, which can feed uronan polymer-this process is called expansion. This results back on the pituitary to inhibit FSH release (Groome, 1996). in a 20-fold augmentation of the cumulus complex volume and As the dominant foHicle begins to grow, estradiol and inhibin coincides with an LH-induced remodeling of the ovarian extraproduction rises and results in a decline of follicular-phase cellular matrix. hese allow release of the mature oocyte and FSH. This drop in FSH levels is responsible for the failure of its surrounding cumulus cells through the surface epirhelium. other follicles to reach preovulatory status-the Graaian folActivation of


Obstentrics_Williams

Obstentrics_Williams. FSH. This drop in FSH levels is responsible for the failure of its surrounding cumulus cells through the surface epirhelium. other follicles to reach preovulatory status-the Graaian folActivation of proteases likely plays a pivotal role in weakening licle stage-during any one cycle. Thus, 95 percent of plasma the follicular basement membrane and ovulation (Curry, 2006; estradiol produced at this time is secreted by the dominant Ny, 2002). follicle-thc one destined to ovulate. Concurrently, the con tralateral ovary is relatively inactive.


Obstentrics_Williams

Obstentrics_Williams. Following ovulation, rhe corpus luteum develops from the remains of the Graaian follicle in a process referred to as The onset of rhe gonadotropin surge resulting from increasluteiniation. The basement membrane separating the granuing estrogen secretion by preovulatory follicles is a relatively losa-lutein and theca-lutein cells breaks down, and by day 2 FIGURE 5-3 An ovulated cumulus-oocyte complex. An oocyte is at the center of the complex. Cumulus cells are widely separated from each other by the hyaluronan-rich extracellular matrix. (Used with permission from Dr. Kevin J. Doody.) postovulation, blood vessels and capillaries invade the granulosa cell layer. The rapid neo�ascularization of the once-avascular granulosa may be due to angiogenic factors that include vas by theca-lutein and granulosa-lutein cells in response to LH (Albrecht, 2003; Fraser, 2001). During luteinization, these cells undergo hypertrophy and increase their capacity to synthesize hormones.


Obstentrics_Williams

Obstentrics_Williams. LH is the primary luteotropic factor responsible for corpus luteum maintenance (Vande Wiele, 1970). Indeed, LH injec tions can extend the corpus luteum life span in normal women by 2 weeks (Segalof, 1951). The hormone secretion pattern of the corpus luteum difers from that of the follicle (see Fig. 5-1). As depicted in Figure 5-2, the greater capacity of granulosa-lutein cells to produce progesterone results from enhanced access to considerably more steroidogenic precursors through blood-borne, low-densiry lipoprotein (LDL)-derived cholesterol (Carr, 1981a). Ovarian progesterone production peaks at 25 to 50 mg/d during the midluteal phase. With pregnancy, the corpus luteum continues progesterone production in response to placental human chorionic gonadotropin (hCG), which binds to the same receptor as LH. Estrogen levels follow a more complex pattern of secretion.


Obstentrics_Williams

Obstentrics_Williams. Estrogen levels follow a more complex pattern of secretion. Specifically, just after ovulation, estrogen levels decline, but then exhibit a secondary rise that reaches a peak production of 0.25 mg/d of 173-estradiol in the midluteal phase. Toward the end of the luteal phase, estradiol production again drops. The human corpus luteum is a transient endocrine organ that, in the absence of pregnancy, will rapidly regress 9 to 11 days after ovulation via apoptosis (Vaskivuo, 2002). The mechanisms that control luteolysis, that is, the regression of the corpus luteum, remain unclear. However, it results in part from dropping levels of circulating LH in the late luteal phase and rising LH insensitivity by luteal cells (Duncan, 1996; Filicori, 1986). he role of other factors is less established. The dramatic drop in circulating estradiol and progesterone levels initiate molecular events that lead to menstruation.


Obstentrics_Williams

Obstentrics_Williams. Estrogen is the essential hormonal signal on which most events in the normal menstrual cycle depend. They function in many cell types to regulate follicular development, uterine receptivity, and blood flow. The most biologically potent naturally occur ring estrogen is 173-estradiol, which is secreted by granulosa cells of the dominant follicle and luteinized granulosa cells of the corpus luteum. Estradiol action is complex and appears estrogen receptor a (ERa) and 3 (ER3) (Katzen ellenbogen, 2001). These isoforms are the products of separate genes and can exhibit distinct tissue expression. Both estradiol-receptor complexes act as transcriptional factors that become associ ated with the estrogen-response element of speciic genes. They share a robust activation by estradiol. However, diferences in their binding ainities to other estrogens and their cell-speciic may have both distinct and overlapping function (Saunders, 2005).


Obstentrics_Williams

Obstentrics_Williams. Most progesterone actions on the female reproductive tract are mediated through the nuclear hormone receptors, progesterone-receptor type A (PR-A) and B (PR-B). Progesterone enters cells by difusion, and in responsive tissues it becomes associated with its receptors (Conneely, 2002). Progesteronereceptor isoforms arise from a single gene and regulate transcription of target genes. hese receptors have unique actions. When PR-A and PR-B receptors are coexpressed, it appears that PR-A can inhibit PR-B gene regulation. The endometrial glands and stroma appear to have diferent expression patterns for progesterone receptors that vary during the menstrual cycle (Mote, 1999). Progesterone can also evoke rapid responses, such as changes in intracellular free calcium levels, which cannot be explained by genomic mechanisms. G-protein-coupled membrane receptors for progesterone have been identiied, but their role in the ovarian-endometrial cycle remains to be elucidated (Peluso, 2007).


Obstentrics_Williams

Obstentrics_Williams. In the endometrium, epithelial cells line the endometrial glands and are supported by stromal cells. These cells and supplying blood vessels replicate rapidly and cyclically in reproductiveaged women and are regenerated each ovarian-endometrial cycle. The superficial endometrium, termed the functionalis layer, is shed and reconstructed from the deeper basalis layer (Fig. 5-4). There is no other example in humans of such cyclical shedding and regrowth of an entire tissue. Fluctuations in estrogen and progesterone levels produce striking efects on the endometrium. Follicular-phase estradiol production is the most important factor in endometrial recovery following menstruation, and both ERa and ER3 receptors are expressed here. Although up to rwo thirds of the functionalis endometrium is fragmented and shed with menses, reepithelialization begins even before menstrual bleeding has ceased. By the fifth day of the endometrial cycle-ifth day of menses-the


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-4 The endometrium consists of two layers, the functionalis layer and basalis layer. These are supplied by the spiral and basal arteries, respectively. Numerous glands also span these layers. As the menstrual cycle progresses, greater coiling of the spiral arteries and increased gland folding can be seen. Near the end of the menstrual cycle (day 27), the coiled arteries constrict, deprive blood supply to the functionalis layer, and lead to necrosis and sloughing of this layer.


Obstentrics_Williams

Obstentrics_Williams. epithelial surface of the endometrium has been restored, and revascularization has begun. he preovulatory endometrium is characterized by proliferation of glandular, stromal, and vascular endothelial cells. During the early part of the proliferative phase, the endometrium is usually less than 2 mm thick. he glands are narrow, tubular structures that pursue almost a straight and parallel course from the basalis layer toward the endometrial cavity. Mitotic igures, especially in the glandular epithelium, are identiied by the fifth cycle day. Mitotic activity in both epithelium and stroma persists until day 16 to 17, that is, 2 to 3 days after ovulation. Blood vessels are numerous and prominent.


Obstentrics_Williams

Obstentrics_Williams. Clearly, reepithelialization and angiogenesis are important to cessation of endometrial bleeding (Chennazhi, 2009; Rogers, 2009). hese are dependent on tissue regrowth, which is estrogen regulated. Epithelial cell growth also is regulated in part by epidermal growth factor and transforming growth factor a (TGPa). Stromal cells proliferate through paracrine and autocrine actions of estrogen and greater local levels of fibroblast growth factor-9 (Tsai, 2002). Estrogens also raise local production ofVEGF, which causes angiogenesis through vessel elongation in the basalis (Gargett, 2001; Sugino, 2002). By the late proliferative phase, the endometrium thickens from both glandular hyperplasia and augmented stromal ground substance, which is edema and proteinaceous material. he loose stroma is especially prominent, and the glands in the functionalis layer are widely separated. his is compared with those of the basalis layer, in which the glands are more crowded and the stroma is denser.


Obstentrics_Williams

Obstentrics_Williams. At midcycle, as ovulation nears, glandular epithelium becomes taller and pseudostratiied. he surface epithelial cells acquire numerous microvilli, which increase epithelial surface area, and develop cilia, which move endometrial secretions during the secretory phase (Perenczy, 1976).


Obstentrics_Williams

Obstentrics_Williams. After ovulation, the estrogen-primed endometrium responds to rising progesterone levels in a highly predictable manner. By day 17, glycogen accumulates in the basal portion of glandular epithelium, creating subnuclear vacuoles and pseudostratification. hese changes likely result from direct progesterone action through receptors expressed in glandular cells (Mote, 2000). On day 18, vacuoles move to the apical portion of the secretory non ciliated cells. By day 19, these cells begin to secrete glycoprotein and mucopolysaccharide contents into the gland lumen (Hafez, 1975). Glandular cell mitosis ceases with secretory activity due to rising progesterone levels, which antagonize the mitotic efects of estrogen. Estradiol action also diminishes because of glandular expression of the type 2 isoform of 173-hydroxysteroid dehydrogenase. his converts estradiol to the less active estrone (Casey, 1996). On cycle days 21 to 24, the stroma becomes edematous. Next, on days 22 to 25, stromal cells


Obstentrics_Williams

Obstentrics_Williams. of 173-hydroxysteroid dehydrogenase. his converts estradiol to the less active estrone (Casey, 1996). On cycle days 21 to 24, the stroma becomes edematous. Next, on days 22 to 25, stromal cells surrounding the spiral arterioles begin to enlarge, and stromal mitosis becomes apparent. Days 23 to 28 are characterized by pre decidual cells, which surround spiral arterioles.


Obstentrics_Williams

Obstentrics_Williams. Between days 22 and 25, the secretory-phase endometrium undergoes striking changes associated with predecidual transformation of the upper two thirds of the functionalis layer. The glands exhibit extensive coiling, and luminal secretions become visible. Changes within the endometrium also can mark the so-called window of implantation seen on days 20 to 24. Epithelial surface cells show fewer microvilli and cilia, but luminal protrusions appear on the apical cell surface (Nikas, 2003). hese pinopodes help prepare for blastocyst implantation. hey also coincide with changes in the surface glycocalyx that allow acceptance of a blastocyst (Aplin, 2003). Another highlight of the secretory phase is the continuing growth and development of the spiral arteries. hese vessels arise from the radial arteries, which are myometrial branches of the arcuate and, ultimately, uterine vessels (see Fig. 5-4).


Obstentrics_Williams

Obstentrics_Williams. he morphological and functional properties of the spiral arter ies are unique and essential to blood flow changes seen during menstruation or implantation. During endometrial growth, spiral arteries lengthen at a rate appreciably greater than the rate of endometrial tissue thickening. his growth discordance obliges even greater coiling. Spiral artery development relects a marked induction of angiogenesis, with widespread vessel sprouting and extension. Such rapid angiogenesis is regulated, in part, through estrogen-and progesterone-regulated synthesis ofVEGF (Ancelin, 2002; Chennazhi, 2009). The midluteal-secretory phase of the endometrial cycle is a tiation. With corpus luteum rescue and continued progesterone secretion, the endometrium is transformed into the decidua. With luteolysis and declining luteal progesterone production, events leading to menstruation are initiated (Critchley, 2006; Thiruchelvam, 2013).


Obstentrics_Williams

Obstentrics_Williams. With luteolysis and declining luteal progesterone production, events leading to menstruation are initiated (Critchley, 2006; Thiruchelvam, 2013). In the late premenstrual-phase endometrium, the stroma is invaded by neutrophils to create a pseudo inflammatory appearance. These cells iniltrate primarily on the day or two immediately preceding menses onset. he endometrial stromal and epithelial cells produce interleukin-8 (IL-8), a chemotactic-activating factor for neutrophils (Arici, 1993). Similarly, monocyte chemotactic protein-1 (MCP-1) is synthesized by endometrium and promotes monocyte recruitment (Arici, 1995).


Obstentrics_Williams

Obstentrics_Williams. Leukocyte iniltration is considered key to both endometrial extracellular matrix breakdown and repair of the functionalis layer. The term "inflammatory tightrope" refers to the ability of macrophages to assume phenotypes that vary from proinflammatory and phagocytic to immunosuppressive and reparative. These are likely relevant to menstruation, in which tissue breakdown and restoration occur simultaneously (Evans, 2012; Maybin, 2015). Invading leukocytes secrete enzymes that are members of the matrix metalloprotease (MMP) family. These add to the proteases already produced by endometrial stromal cells and efectively initiate matrix degradation. During menses as tissue shedding is completed, microenvironment-regulated changes in macrophage phenotype then promote repair and resolution (Evans, 2012; Thiruchelvam, 2013).


Obstentrics_Williams

Obstentrics_Williams. The classic study by Markee (1940) described tissue and vascular alterations in endometrium before menstruation. With endometrial regression, spiral artery coiling becomes suiciently severe that resistance to blood flow rises to cause endometrial hypoxia. Resultant stasis is the primary cause of endometrial ischemia and tissue degeneration. Intense spiral artery vasoconstriction precedes menstruation and also serves to limit menstrual blood loss. Prostaglandins playia key role in the events leading to menstruation that include vasoconstriction, myometrial contractions, and upregulation of proinflammatory responses (Abel, 2002).


Obstentrics_Williams

Obstentrics_Williams. Prostaglandins playia key role in the events leading to menstruation that include vasoconstriction, myometrial contractions, and upregulation of proinflammatory responses (Abel, 2002). Large amounts of prostaglandins are present in menstrual blood. Painful menstruation is common and likely caused by myometrial contractions and uterine ischemia. This response is believed to be mediated by prostaglandin F2a (PGF2a)-induced spiral artery vasoconstriction, which render the uppermost endometrial zones hypoxic. The hypoxic environment is a potent inducer of angiogenesis and vascular permeability factors such as VEGF.


Obstentrics_Williams

Obstentrics_Williams. Progesterone withdrawal increases expression of cyclooxygenase 2 (COX-2), also called prostaglandin synthase 2, to synthesize prostaglandins. Withdrawal also lowers expression of 15-hydroxyprostaglandin dehydrogenase (PGDH), which degrades prostaglandins (Casey, 1980, 1989). The net result is higher prostaglandin production by endometrial stromal cells and greater prostaglandin-receptor density on blood vessels and surrounding cells. Actual menstrual bleeding follows rupture of spiral arterioles and consequent hematoma formation. With a hematoma, the superficial endometrium is distended and ruptures. Subsequently, fissures develop in the adjacent functionalis layer, and blood and tissue fragments are sloughed. Hemorrhage stops with arteriolar constriction. Changes that accompany partial tissue necrosis also serve to seal vessel tips.


Obstentrics_Williams

Obstentrics_Williams. he endometrial surface is restored by growth of langes, or collars, that form the everted free ends of the endometrial glands (Markee, 1940). These flanges rapidly grow in diameter, and epithelial continuity is reestablished by fusion of the edges of these sheets of migrating cells.


Obstentrics_Williams

Obstentrics_Williams. his is a specialized, highly modiied endometrium of pregnancy. It is essential for hemochorial placentation, that is, one in which maternal blood contacts trophoblasts. This relationship requires trophoblast invasion, and considerable research has focused on the interaction between decidual cells and invading trophoblasts. Decidualization, that is, transformation oO proliferating endometrial stromal cells into specialized secretory cells, is dependent on estrogen, progesterone, androgens, and factors secreted by the implanting blastocyst (Gibson, 2016). The decidua produces factors that regulate endometrial receptivity and modulate immune and vascular cell functions within the maternal-fetal microenvironment. The special relationship existing between the decidua and the invading trophoblasts ensures success of the pregnancy semiallograft yet seemingly deies the laws of transplantation immunology.


Obstentrics_Williams

Obstentrics_Williams. The decidua is classiied into three parts based on anatomical location. Decidua directly beneath blastocyst implantation is modiied by trophoblast invasion and becomes the decidua basalis. The decidua capsularis overlies the enlarging blastocyst and initially separates the conceptus from the rest of the uterine cavity (Fig. 5-5). This portion is most prominent during the second month of pregnancy and consists of stromal decidual cells covered by a single layer of lattened epithelial cells. Internally, it contacts the avascular, extraembryonic fetal membrane-the chorion laeve. he remainder of the uterus is lined by decidua parietalis. During early pregnancy, there is a space between the decidua capsularis and parietalis because the gestational sac does not fill the entire uterine cavity. The gestation sac is the extraembryonic coelom and also called the chorionic cavity. By 14 to 16 weeks' gestation, the expanding sac has enlarged to completely ill the uterine cavity. The resulting


Obstentrics_Williams

Obstentrics_Williams. The gestation sac is the extraembryonic coelom and also called the chorionic cavity. By 14 to 16 weeks' gestation, the expanding sac has enlarged to completely ill the uterine cavity. The resulting apposition of the decidua capsularis and parietalis creates the decidua vera, and the uterine cavity is functionally obliterated.


Obstentrics_Williams

Obstentrics_Williams. Decidua basalis Cervical canal parietal is Chorionic villi cavity FIGURE 5-5 Three portions of the decidua-the basalis, capsularis, and parietalis-are illustrated. In early pregnancy, the decidua begins to thicken, eventually attaining a depth of 5 to 10 mm. With magnification, furrows and numerous small openings, representing the mouths of uterine glands, can be detected. Later in pregnancy, the decidua becomes thinner, presumably because of pressure exerted by the expanding uterine contents. he decidua parietalis and basalis are composed of three layers. here is a surface or compact zone-zona compacta; a middle portion or spongy zone-zona spongiosa-with remnants of glands and numerous small blood vessels; and a basal zone-zona basalis. The zona compacta and spongiosa together form the zona functionalis. The basal zone remains after delivery and gives rise to new endometrium.


Obstentrics_Williams

Obstentrics_Williams. In human pregnancy, the decidual reaction is completed only with blastocyst implantation. Predecidual changes, however, commence irst during the midluteal phase in endometrial stromal cells adjacent to the spiral arteries and arterioles. hereafter, they spread in waves throughout the uterine endometrium and then from the implantation site. The endometrial stromal cells enlarge to form polygonal or round decidual cells. he nuclei become vesicular, and the cytoplasm becomes clear, slightly basophilic, and surrounded by a translucent membrane. As a consequence of implantation, the blood supply to the decidua capsularis is lost as the embryo-fetus grows. Blood supply to the decidua parietalis through spiral arteries persists. These arteries retain a smooth-muscle wall and endothelium and thereby remain responsive to vasoactive agents.


Obstentrics_Williams

Obstentrics_Williams. In contrast, the spiral arterial system that supplies the decidua basalis and ultimately the placental intervillous space is altered remarkably. These spiral arterioles and arteries are invaded by trophoblasts, and during this process, the vessel walls in the basalis are destroyed. Only a shell without smooth muscle or endothelial cells remains. Importantly, as a result, these vascular conduits of maternal blood-which become the utero placental vessels-are unresponsive to vasoactive agents. Conversely, the fetal chorionic vessels, which transport blood between the placenta and the fetus, contain smooth muscle and thus do respond to vasoactive agents.


Obstentrics_Williams

Obstentrics_Williams. Early in pregnancy, the zona spongiosa of the decidua consists of large distended glands, often exhibiting marked hyperplasia and separated by minimal stroma. At first, the glands are lined by typical cylindrical uterine epithelium with abundant secretory activity that contributes to blastocyst nourishment. With advanced pregnancy, the glandular elements largely disappear. he decidua basalis contributes to formation of the placental basal plate (Fig. 5-6). he spongy zone of the decidua basalis consists mainly of arteries and widely dilated veins, and by term, glands have virtually disappeared. Also, the decidua basalis is invaded by many interstitial trophoblasts and trophoblastic giant cells. Although most abundant in the decidua, the giant cells commonly penetrate the upper myometrium. Their number and invasiveness can be so extensive as to resemble choriocarcinoma.


Obstentrics_Williams

Obstentrics_Williams. The Nitabuch layer is a zone of fibrinoid degeneration in which invading trophoblasts meet the decidua basalis. If the decidua is defective, as in placenta accreta, the Nitabuch layer is usually absent (Chap. 41, p. 778). here is also a more supericial, but inconsistent, deposition of ibrin-Rohr stria-at the bottom of the intervillous space and surrounding the anchoring FIGURE 5-6 Section through a junction of chorion, villi, and decidua basalis in early first-trimester pregnancy. (Used with permission from Dr. Kurt Benirschke.) villi. Decidual necrosis is a normal phenomenon in the irst and probably second trimesters (McCombs, 1964). hus, necrotic decidua obtained through curettage after spontaneous abortion in the irst trimester should not necessarily be interpreted as either a cause or an efect of the pregnancy loss.


Obstentrics_Williams

Obstentrics_Williams. Both decidua types contain numerous cell groups whose composition varies with gestational stage (Loke, 1995). he primary cellular components are the true decidual cells, which diferentiated from the endometrial stromal cells, and numerous maternal bone marrow-derived cells. Accumulation of lymphocytes with unique properties at the maternal-fetal interface is essential to evoke tolerance mechanisms that prevent maternal immune rejection of the fetus. These include regulatolY T cells, decidual macrophages, and decidual natural killer cells. Collectively, these cells not only provide immunotolerance but also play an important role in trophoblast invasion and vasculogenesis (PrabhuDas, 2015).


Obstentrics_Williams

Obstentrics_Williams. In addition to placental development, the decidua potentially provides other functions. The decidua is the source of prolactin, which is present in enormous amounts in amnionic luid (Colander, 1978; Riddick, 1979). Decidual prolactin is a product of the same gene that encodes for anterior pituitary prolactin, but the exact physiological role of decidual prolactin is unknown. Notably, decidual prolactin is not to be confused with placental lactogen (hPL), which is produced only by syncytiotrophoblast. Prolactin preferentially enters amnionic luid, and little enters maternal blood. Consequently, prolactin levels in amnionic luid are extraordinarily high and may reach 10,000 ng/mL at 20 to 24 weeks' gestation (Tyson, 1972). This compares with fetal serum levels of 350 ng/mL and maternal serum levels of 150 to 200 ngl mL. As a result, decidual prolactin is a classic example of paracrine function between maternal and fetal tissues.


Obstentrics_Williams

Obstentrics_Williams. The ferus is dependent on the placenta for pulmonary, hepatic, and renal functions. These are accomplished through the anatomical relationship of the placenta and its uterine interface. In overview, maternal blood spurts from uteroplacental vessels into the placental intervillous space and bathes the outer syncytiotrophoblast. his allows exchange of gases, nutrients, and other substances with fetal capillary blood within the core of each villus. hus, fetal and maternal blood does not normally mix in this hemochorial placenta. A paracrine system also links mother and ferus through the anatomical and biochemical juxtaposition of the maternal decidua parietalis and the extraembryonic chorion laeve, which is fetal. This is an extraordinarily important arrangement for communication between fetus and mother and for maternal immunological acceptance of the conceptus (Cuzeloglu-Kayisli, 2009).


Obstentrics_Williams

Obstentrics_Williams. With ovulation, the secondary oocyte and adhered cells of the cumulus-oocyte complex are freed from the ovary. Although technically this mass of cells is released into the peritoneal cavity, the oocyte is quickly engulfed by the fallopian tube infundibulum. Further transport through the tube is accomplished by directional movement of cilia and tubal peristalsis. Fertilization, which normally occurs in the oviduct, must take place within a few hours, and no more than a day after ovulation. Because of this narrow window, spermatozoa must be present in the fallopian tube at the time of oocyte arrival. Almost all pregnancies result when intercourse occurs during the 2 days preceding or on the day of ovulation.


Obstentrics_Williams

Obstentrics_Williams. Fertilization is highly complex. Molecular mechanisms allow spermatozoa to pass between follicular cells; through the zona pellucida, which is a thick glycoprotein layer surrounding the oocyte cell membrane; and into the oocyte cytoplasm. Fusion of the two nuclei and intermingling of maternal and paternal chromosomes creates the zygote. Early human development is described by days or weeks postfertilization, that is, postconceptional. By contrast, in most chapters of this book, clinical pregnancy dating is calculated from the irst day of the last menstrual period (LMP). hus, 1 week postfertilization corresponds to approximately 3 weeks from the LMP in women with regular 28-day cycles. As an example, 8 weeks' gestation refers to 8 completed weeks following the LMP. After fertilization, the zygote-a diploid cell with 46 chromosomes-undergoes cleavage, and zygote cells produced by this division are called blastomeres (Fig. 5-7). In the two-cell


Obstentrics_Williams

Obstentrics_Williams. After fertilization, the zygote-a diploid cell with 46 chromosomes-undergoes cleavage, and zygote cells produced by this division are called blastomeres (Fig. 5-7). In the two-cell FIGURE 5-7 Zygote cleavage and blastocyst formation. The morula period begins at the 12-to 16-cell stage and ends when the blastocyst forms, which occurs when there are 50 to 60 blastomeres present. The polar bodies, shown in the 2-cell stage, are small nonfunctional cells that soon degenerate. zygote, the blastomeres and polar body continue to be surrounded by the zona pellucida. he zygote undergoes slow cleavage for 3 days while still remaining in the fallopian tube. As the blastomeres continue to divide, a solid mulberry-like ball of cells-the morula-is produced. The morula enters the uterine cavity approximately 3 days after fertilization. Gradual accumulation of luid beween the morula cells leads to formation of the early blastocyst.


Obstentrics_Williams

Obstentrics_Williams. As early as 4 to 5 days after fertilization, the 58-cell blastula diferentiates into ive embryo-producing cells-the inner cel mass (see Fig. 5-7). he remaining 53 outer cells, called the trophectoderm, are destined to form trophoblasts (Hertig, 1962). Interestingly, the 107 -cell blastocyst is found to be no larger than the earlier cleavage stages, despite the accumulated fluid within the blastocyst cavity. At this stage, the eight formative, embryo-producing cells are surrounded by 99 trophoblastic cells. And, the blastocyst is released from the zona pellucida secondary to secretion of specific proteases from the secretoryphase endometrial glands (O'Sullivan, 2002).


Obstentrics_Williams

Obstentrics_Williams. Release from the zona pellucida allows blastocyst-produced cytokines and hormones to directly influence endometrial receptivity (Lindhard, 2002). IL-la and IL-lj are secreted by the blastocyst, and these cytokines likely directly influence the endometrium. Embryos also have been shown to secrete hCG, which may influence endometrial receptivity (Licht, 2001; Lobo, 2001). The receptive endometrium is thought to respond by producing leukemia inhibitoY factor (LIF), follistatin, and colony-stimulating factor-l (CSF-l). LIF and follistatin activate signaling pathways that collectively inhibit proliferation and promote diferentiation of the endometrial epithelia and stroma to enable uterine receptivity (Rosario, 20 16b). At the maternal-fetal interface, CSF-1 has proposed immunomodulatory actions and pro angiogenic actions that are required for implantation (Rahmati, 2015).


Obstentrics_Williams

Obstentrics_Williams. Six or 7 days after fertilization, the blastocyst implants into the uterine wall. This process can be divided into three phases: (1) apposition-initial contact of the blastocyst to the uterine wall; (2) adhesion-increased physical contact between the blastocyst and decidua; and (3) invasion-penetration and invasion of syncytiotrophoblast and cytotrophoblasts into the decidua, inner third of the myometrium, and uterine vasculature. Successful implantation requires a receptive endometrium appropriately primed with estrogen and progesterone by the corpus luteum. Such uterine receptivity is limited to days 20 to 24 of the cycle. Adherence is mediated by cell-surface receptors at the implantation site that interact with blastocyst receptors (Carson, 2002; Lessey, 2002; Lindhard, 2002). If the blastocyst approaches the endometrium after cycle day 24, the potential for adhesion is diminished because antiadhesive glycoprotein synthesis prevents receptor interactions (N avot, 1991).


Obstentrics_Williams

Obstentrics_Williams. At the time of its interaction with the endometrium, the blastocyst is composed of 100 to 250 cells. The blastocyst loosely adheres to the decidua by apposition. This most commonly occurs on the upper posterior uterine wall. Attachment of the blastocyst trophectoderm to the decidual surface by apposition and adherence appears to be closely regulated by paracrine interactions between these two tissues. Successful endometrial blastocyst adhesion involves modiication in expression of cellular adhesion molecules (CMs). The integrins-one of four families of CAMs-are cell-surface receptors that mediate cell adhesion to extracellular matrix proteins (Lessey, 2002). Endometrial integrins are hormonally regulated, and a specific set of integrins is expressed at implantation (Lessey, 1995). Recognition-site blockade of integrins needed for binding will prevent blastocyst attachment (Kaneko, 2013).


Obstentrics_Williams

Obstentrics_Williams. Human placental formation begins with the trophectoderm, which gives rise to a trophoblast cell layer encircling the blastocyst. From then until term, trophoblasts playia critical part at the fetal-maternal interface. Trophoblasts exhibit the most variable structure, function, and developmental pattern of all placental components. Their invasiveness promotes implantation, their nutritional role for the conceptus is relected in their name, and their endocrine organ function is essential to maternal physiological adaptations and to pregnancy maintenance.


Obstentrics_Williams

Obstentrics_Williams. By the eighth day postfertilization, after initial implantation, trophoblasts have diferentiated into an outer multinucleated syncytium-primitive syncytiotrophoblast, and an inner layer of primitive mononuclear cells-cytotrophoblasts. The latter are germinal cells for the syncytium. As cytotrophoblasts proliferate, their cell walls disappear, and the cells fuse to add to the expanding outer layer of syncytiotrophoblast. Each cytotrophoblast has a well-demarcated cell border, a single nucleus, and ability to undergo DNA synthesis and mitosis (Arnholdt, 1991). These are lacking in the syncytiotrophoblast, which provides transport functions of the placenta. It is so named because instead of individual cells, it has an amorphous cytoplasm without cell borders, nuclei that are multiple and diverse in size and shape, and a continuous syncytial lining. This coniguration aids transport.


Obstentrics_Williams

Obstentrics_Williams. After implantation is complete, trophoblasts further differentiate along two main pathways, giving rise to villous and extravillous trophoblasts. As shown in Figure 5-8, both have distinct functions (Loke, 1995). Villous trophoblasts generate chorionic villi, which primarily transport oxygen, nutrients, and other compounds between the fetus and mother. Extravillous trophoblasts migrate into the decidua and myometrium and also penetrate maternal vasculature, thus coming into contact with various maternal cell types (Pijnenborg, 1994). Extravillous trophoblasts are further classiied as interstitial trophoblasts and endovascular trophoblasts. he interstitial trophoblasts invade the decidua and eventually penetrate the myometrium to form placental-bed giant cells. These trophoblasts also surround spiral arteries. The endovascular trophoblasts penetrate the spiral artery lumens (Pijnenborg, 1983). hese are both discussed in greater detail in subsequent sections.


Obstentrics_Williams

Obstentrics_Williams. Early End of 1st pregnancy trimester FIGURE 5-8 Extravillous trophoblasts are found outside the villus and can be subdivided into endovascular and interstitial categories. Endovascular trophoblasts invade and transform spiral arteries during pregnancy to create low-resistance blood flow that is characteristic of the placenta. Interstitial trophoblasts invade the decidua and surround spiral arteries.


Obstentrics_Williams

Obstentrics_Williams. After gentle erosion between epithelial cells of the surface endometrium, invading trophoblasts burrow deeper. At 9 days of development, the blastocyst wall facing the uterine lumen is a single layer of lattened cells. By the 10th day, the blastocyst becomes totally encased within the endometrium (Fig. 5-9). he blastocyst wall opposite the uterine lumen is thicker and comprises two zones-the trophoblasts and the embryo-forming inner cell mass. As early as 7Y2 days postfertilization, the inner cell mass or embryonic disc diferentiates into a thick plate of primitive ectoderm and an underlying layer of endoderm. Some small cells appear between the embryonic disc and the trophoblasts and enclose a space that will become the amnionic cavity.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-9 Drawing of sections through implanted blastocysts. A. At 10 days. B. At 12 days ater fertilization. This stage is characterized by the intercommunication of the lacunae filled with maternal blood. Note in (B) that large cavities have appeared in the extraembryonic mesoderm, forming the beginning of the extraembryonic coelom. Also note that extraembryonic endodermal cells have begun to form on the inside of the primitive yolk sac. (Redrawn from Moore KL, Persaud, W, Torchia, MG (eds): The Developing Human. Clinically Oriented Embryology, 9th edition, Philadelphia, Saunders, 201o3.)


Obstentrics_Williams

Obstentrics_Williams. Extraembryonic mesenchyme first appears as groups of isolated cells within the blastocyst cavity, and later this mesoderm completely lines the cavity. Spaces form and then fuse within the extraembryonic mesoderm to form the chorionic cavity (extraembryonic coelom). The chorion is composed of trophoblasts and mesenchyme. Some mesenchymal cells eventually will condense to form the body stalk. his stalk joins the embryo to the nutrient chorion and later develops into the umbilical cord. The body stalk can be recognized at an early stage at the caudal end of the embryonic disc (Fig. 7-3, p. 126). As the embryo enlarges, more maternal decidua basalis is invaded by syncytiotrophoblast. Beginning approximately 12 days after conception, the syncytiotrophoblast is permeated


Obstentrics_Williams

Obstentrics_Williams. As the embryo enlarges, more maternal decidua basalis is invaded by syncytiotrophoblast. Beginning approximately 12 days after conception, the syncytiotrophoblast is permeated FIGURE 5-10 Electron micrograph of term human placenta villus. A villus capillary filled with fetal red blood cells (asterisks) is seen in close proximity to the microvilli border. (Reproduced with permission from Boyd JD, Hamilton WJ: The Human Placenta. Cambridge, Heffer, 1970.) 90 Placentation, Embryogenesis, and Fetal Development by a system of intercommunicating channels called trophoblastic lacunae. After invasion of supericial decidual capillary walls, lacunae become filled with maternal blood. At the same time, the decidual reaction intensifies in the surrounding stroma. This is characterized by decidual stromal cell enlargement and glycogen storage.


Obstentrics_Williams

Obstentrics_Williams. With deeper blastocyst invasion into the decidua, solid primary villi arise from buds of cytotrophoblasts that protrude into the primitive syncytium before 12 days postfertilization. Primary villi are composed of a cytotrophoblast core covered by syncytiotrophoblast. s the lacunae join, a complicated labyrinth is formed that is partitioned by these solid cytotrophoblastic columns. The trophoblast-lined channels form the intervillous space, and the solid cellular columns form theprimay villous stalks.


Obstentrics_Williams

Obstentrics_Williams. Beginning on approximately the 12th day after fertilization, mesenchymal cords derived from extraembryonic mesoderm invade the solid trophoblast columns. These form seconday villi. Once angiogenesis begins in the mesenchymal cords, tertiay villi are formed. Although maternal venous sinuses are tapped early in implantation, maternal arterial blood does not enter the intervillous space until around day 15. By approximately the 17th day, however, fetal blood vessels are functional, and a placental circulation is established. The fetal-placental circulation is completed when the blood vessels of the embryo are connected with chorionic vessels. In some villi, angiogenesis fails from lack of circulation. They can be seen normally, but the most striking exaggeration of this process is seen with hydatidiform mole (Fig. 20-1, p. 389).


Obstentrics_Williams

Obstentrics_Williams. Villi are covered by an outer layer of syncytiotrophoblast and an inner layer of cytotrophoblasts, which are also known as Langhans cels. Cytotrophoblast proliferation at the villous tips produces the trophoblastic cell columns that form anchoring villi. hey are not invaded by fetal mesenchyme, and they are anchored to the decidua at the basal plate. Thus, the base of the intervillous space faces the maternal side and consists of cytotrophoblasts from cell columns, the covering shell of syncytiotrophoblast, and maternal decidua of the basal plate. The base of the chorionic plate forms the roof of the intervillous space. It consists of two layers of trophoblasts externally and fibrous mesoderm internally. The "deinitive" chorionic plate is formed by 8 to 10 weeks as the amnionic and primary chorionic plate mesenchyme fuse together. This formation is accomplished by expansion of the amnionic sac, which also surrounds the connective stalk and the allantois and joins these structures to


Obstentrics_Williams

Obstentrics_Williams. chorionic plate mesenchyme fuse together. This formation is accomplished by expansion of the amnionic sac, which also surrounds the connective stalk and the allantois and joins these structures to form the umbilical cord (Kaufmann, 1992).


Obstentrics_Williams

Obstentrics_Williams. Interpretation of the ine structure of the placenta came from electron microscopic studies of Wislocki and Dempsey (1955). There are prominent microvilli on the syncytial surface that correspond to the so-called brush border described by light microscopy. Associated pinocytotic vacuoles and vesicles are related to absorptive and secretory placental functions. Microvilli act to increase surface area in direct contact with maternal blood. This contact between the trophoblast and maternal blood is the deining characteristic of a hemochorial placenta (Fig. 5-10).


Obstentrics_Williams

Obstentrics_Williams. In early pregnancy, the villi are distributed over the entire periphery of the chorionic membrane (Fig. 5-11). As the blastocyst with its surrounding trophoblasts grows and expands into the decidua, one pole faces the endometrial cavity. he opposite pole will form the placenta. Here, chorionic villi in contact with the decidua basalis proliferate to form the chorion rondosumor leay chorion. As growth of embryonic and extraembryonic tissues continues, the blood supply to the chorion facing the endometrial cavity is restricted. Because of this, villi in contact with the decidua capsularis cease to grow and then degenerate. his portion of the chorion becomes the avascular fetal membrane that abuts the decidua parietalis and is called the chorion laeve-or smooth chorion. This smooth chorion is composed of cytotrophoblasts and fetal mesodermal mesenchyme.


Obstentrics_Williams

Obstentrics_Williams. Until near the end of the third month, the chorion laeve is separated from the amnion by the exocoelomic cavity. hereater, they are in intimate contact to form an avascular amniochorion. These two structures are important sites of molecular transfer and metabolic activity. Moreover, they constitute an important paracrine arm of the fetal-maternal communication system. • Regulators of Trophoblast Invasion


Obstentrics_Williams

Obstentrics_Williams. Implantation and endometrial decidualization activate a unique population of maternal immune cells that iniltrate the uterus and play critical functions in trophoblast invasion, angiogenesis, spiral artery remodeling, and maternal tolerance to fetal alloantigens. Decidual natural killer cells (dNK) make up 70 percent of decidual leukocytes in the first trimester and are found in direct contact with trophoblasts. In contrast to natural killer cells in peripheral blood, these cells lack cytotoxic functions. They produce specific cytokines and angiogenic factors to regulate invasion of fetal trophoblasts and spiral artery remodeling (Hanna, 2006). hese and other unique properties distinguish dNK cells from circulating natural killer cells and from natural killer cells in the endometrium before pregnancy (Fu, 2013; Winger, 2013). dNK cells express both IL-8 and interferoninducible protein-1 0, which bind to receptors on invasive trophoblastic cells to promote their decidual invasion


Obstentrics_Williams

Obstentrics_Williams. before pregnancy (Fu, 2013; Winger, 2013). dNK cells express both IL-8 and interferoninducible protein-1 0, which bind to receptors on invasive trophoblastic cells to promote their decidual invasion toward the spiral arteries. dNK cells also produce proangiogenic factors, including VEGF and placental growth factor (PIGF), which both promote vascular growth in the decidua.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-1 1 Complete abortion specimens. A. Initially, the entire chorionic sac is covered with villi, and the embryo within is not visible B. With further growth, stretch and pressure prompt partial regression of the villi. Remaining villi form the future placenta, whereas the smooth portion is the chorion.


Obstentrics_Williams

Obstentrics_Williams. Trophoblasts also secrete speciic chemokines that attract the dNK cells to the maternl-fetal interface. hus, both cell types simultaneously attract each other. Decidual macro phages account for approximately 20 percent of leukocytes in the first trimester and elicit an M2-immunomodulatory phenotype (Williams, 2009). Remember, M1 macrophages are pro inflammatory, and M2 macrophages counter proinflammatory responses and promote tissue repair. In addition to a role in angiogenesis and spiral artery remodeling, dNK cells promote phagocytosis of cell debris (Faas, 2017). Concurrent with the critical role of maternal dNK cells and macro phages, T cell subsets aid tolerance toward the allogenic fetus. Regulatory T cells (Tregs) are essential for promoting immune tolerance. Other T cell subsets are present, such s Th 1, Th2 and Th 17, although their unctions are tightly regulated (Ruocco, 2014) .


Obstentrics_Williams

Obstentrics_Williams. Extravillous trophoblasts of the first-trimester placenta are highly invasive. his process occurs under low-oxygen conditions, and regulatory factors that are induced under hypoxic conditions are contributory (Soares, 2012). Invasive trophoblasts secrete numer vate proteinases already present in the decidua. Trophoblasts produce urokinase-type plasminogen activator, which converts plasminogen into the broadly acting serine protease, plasmin. This in turn both degrades matrix proteins and activates M.1Ps. One member of the MMP family, MMP-9, appears to be criti cal. The timing and extent of trophoblast invasion is regulated by a balanced interplay between pro-and anti invasive factors.


Obstentrics_Williams

Obstentrics_Williams. One member of the MMP family, MMP-9, appears to be criti cal. The timing and extent of trophoblast invasion is regulated by a balanced interplay between pro-and anti invasive factors. he relative ability to invade maternal tissue in early preg nancy compared with limited invasiveness in late pregnancy is ual factors. Trophoblasts secrete insulin-like growth factor II that promotes invasion into the decidua. Decidual cells secrete insulin-like growth factor binding-protein type 4, which blocks this autocrine loop.


Obstentrics_Williams

Obstentrics_Williams. Low estradiol levels in the irst trimester are critical for trophoblast invasion and remodeling of the spiral arteries. nimal studies suggest that the rise in second-trimester estradiol levels suppresses and limits vessel remodeling by reducing trophoblast expression of VEGF and speciic integrin receptors (Bonagura, 2012). Namely, extravillous trophoblasts express integrin receptors that recognize the extracellular matrix proteins collagen IV, laminin, and ibronectin. Binding of these matrix proteins and integrin receptors initiates signls to promote trophoblast cell migration and differentiation. However, as pregnancy advances, rising estradiol levels downregulate VEGF and integrin receptor expression. This represses and controls the extent of uterine vessel transformation.


Obstentrics_Williams

Obstentrics_Williams. One of the most remarkable features of human placental development is the extensive modification of maternal vasculature by trophoblasts, which are by definition of fetal origin. These events occur in the first half of pregnancy and are considered in detail because of their importance to uteroplacental blood flow. They are also integral to some pathological conditions such as preeclampsia, fetal-growth restriction, and preterm birth. Spiral artery modiications are carried out by two populations of extravillous trophoblasts-endovascular trophoblasts, which penetrate the spiral-artery lumen, and interstitial trophoblasts, which surround the arteries (see Fig. 5-8). Interstitial trophoblasts constitute a major portion of the placental bed. They penetrate the decidua and adjacent myometrium and aggregate around spiral arteries. Although less defined, their functions may include vessel preparation for endovascular trophoblast invasion.


Obstentrics_Williams

Obstentrics_Williams. Endovascular trophoblasts irst enter the spiral artery lumens and initially form cellular plugs. They then destroy vascular endothelium via an apoptosis mechanism and invade and modiy the vascular media. hus, fibrinoid material replaces smooth muscle and connective tissue of the vessel media. Spiral arteries later regenerate endothelium. Invading endovascular trophoblasts can extend several centimeters along the vessel lumen, and they must migrate against arterial flow. Of note, invasion by trophoblasts involves only the decidual spiral arteries and not decidual veins.


Obstentrics_Williams

Obstentrics_Williams. Uteroplacental vessel development proceeds in two waves or stages (Ramsey, 1980). The irst occurs before 12 weeks' postfertilization, and spiral arteries are invaded and modiied up to the border between the decidua and myometrium. he second wave, between 12 and 16 weeks, involves some invasion of the intramyometrial segments of spiral arteries. Remodeling converts narrow-lumen, muscular spiral arteries into dilated, low-resistance uteroplacental vessels. Molecular mechanisms of these crucial events, their regulation by cytokines, signaling pathways, and their significance in the pathogenesis of preeclampsia and fetal-growth restriction has been reviewed by several authors (Pereira de Sousa, 2017; ie, 2016; Zhang, 2016). Approximately 1 month after conception, maternal blood enters the intervillous space in fountain-like bursts from the spiral arteries. Blood is propelled outside of the maternal vessels and sweeps over and directly bathes the syncytiotrophoblast.


Obstentrics_Williams

Obstentrics_Williams. Although certain villi of the chorion frondosum extend from the chorionic plate to the decidua to serve as anchoring villi, most villi arborize and end freely within the intervillous space. s gestation proceeds, the short, thick, early stem villi branch to form progressively iner subdivisions and greater numbers of increasingly smaller villi (Fig. 5-12). Each of the truncal or main stem villi and their ramiications constitutes a placental lobule, or cotyledon. Each lobule is supplied with a single chorionic artery. And each lobule has a single vein, so that lobules constitute the functional units of placental architecture.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-12 Electron micrographs (A, C) and photomicrographs (B, D) of early and late human placentas. A and B. Limited branching of villi is seen in this early placenta. C and D. With placental maturation, increasing villous arborization is seen, and villous capillaries lie closer to the surface of each villus. (Photomicrographs used with permission from Dr. Kurt Benirschke. Electron micrographs reproduced with permission from King BF, Menton DN: Scanning electron microscopy of human placental villi from early and late in gestation. Am J Obstet Gynecol 122:824, 1975.) In the irst trimester, placental growth is more rapid than that of the fetus. But by approximately 17 weeks' gestation, placen tal and fetal weights are approximately equal. By term, placen tal weight is approximately one sixth of fetal weight.


Obstentrics_Williams

Obstentrics_Williams. he mature placenta and its variant forms are discussed in detail in Chapter 6 (p. 112). Briely, viewed from the mater nal surface, the number of slightly elevated convex areas, called lobes, varies from 10 to 38. Lobes are incompletely separated by grooves of variable depth that overlie placental septa, which arise as upward projections of decidua. he total number of placental lobes remains the same throughout gestation, and individual lobes continue to grow-although less actively in the inal weeks (Crawford, 1959). Although grossly visible lobes are commonly referred to as cotyledons, this is not accurate. Correctly used, lobules or cotyledons are the functional units supplied by each main stem villus.


Obstentrics_Williams

Obstentrics_Williams. Correctly used, lobules or cotyledons are the functional units supplied by each main stem villus. As villi continue to branch and the terminal ramiications become more numerous and smaller, the volume and promi nence of cytotrophoblasts decrease. As the syncytium thins, the fetal vessels become more prominent and lie closer to the sur face (see Fig. 5-10). he villous stroma also exhibits changes as gestation progresses. In early pregnancy, the branching connec tive-tissue cells are separated by an abundant loose intercellular matrix. Later, the villous stroma becomes denser, and the cells are more spindly and closely packed.


Obstentrics_Williams

Obstentrics_Williams. Another change in the stroma involves the iniltration of Hobauer cels, which are fetal macrophages. hese are nearly round with vesicular, often eccentric nuclei and very granular or vacuolated cytoplasm. hey grow in number and maturational state throughout pregnancy and appear to be important mediators of protection at the maternal-fetal interface Qohnson, 2012). These macrophages are phagocytic, have an immunosuppressive phenotype, can produce various cytokines, and are capable of paracrine regulation of trophoblastic functions (Cervar, 1999; Reyes, 2017). As discussed further in Chapter 64 (p. 1219), recent studies suggest that Zika virus can infect Hofbauer cells to allow fetal transmission (Simoni, 2017).


Obstentrics_Williams

Obstentrics_Williams. Some of the histological changes that accompany placental growth and maturation improve transport and exchange to meet advancing fetal metabolic requirements. Among these changes are a thinner syncytiotrophoblst, signiicantly reduced cytotrophoblast number, decreased stroma, and increased number of capillaries with close approximation to the syncytial surface. By 16 weeks' gestation, the apparent continuity of the cytotrophoblasts is lost. At term, villi may be focally reduced to a thin layer of syncytium covering minimal villous connective tissue in which thinwalled fetal capillaries abut the trophoblast and dominate the villi. There are some changes in placental architecture that can cause decreased placental exchange eiciency if they are substantive. These include thickening of the basal lamina of trophoblast or capillaries, obliteration of certain fetal vessels, greater villous stroma, and ibrin deposition on the villous surface.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-1 3 Uterus showing a normal placenta and its membranes in situ. Because the placenta is functionally an intimate approximation of the fetal capillary bed to maternal blood, its gross anatomy primarily concerns vascular relations. he fetal surface is covered by the transparent amnion, beneath which chorionic vessels course. A section through the placenta includes amnion, chorion, chorionic villi and intervillous space, decidual (basal) plate, and myometrium (Figs. 5-13 and 5-14). FIGURE 5-14 Photomicrograph of early implanted blastocyst. Trophoblasts are seen invading the decidua basalis. eNS central nervous system. (Used with permission from Dr. Kurt Benirschke.)


Obstentrics_Williams

Obstentrics_Williams. FIGURE 5-14 Photomicrograph of early implanted blastocyst. Trophoblasts are seen invading the decidua basalis. eNS central nervous system. (Used with permission from Dr. Kurt Benirschke.) Deoxygenated venous-like fetal blood flows to the placenta through the two umbilical arteries. As the cord joins the placenta, these umbilical vessels branch repeatedly beneath the amnion as they run across the chorionic plate. Branching continues within the villi to ultimately form capillary networks in the terminal villous branches. Blood with signiicantly higher oxygen content returns from the placenta via a single umbilical vein to the fetus.


Obstentrics_Williams

Obstentrics_Williams. The branches of the umbilical vessels that traverse along the fetal surface of the placenta in the chorionic plate are referred to as the placental surface or chorionic vessels. These vessels are responsive to vasoactive substances, but anatomically, morphologically, histologically, and functionally, they are unique. Chorionic arteries always cross over chorionic veins. Vessels are most readily recognized by this interesting relationship, but they are diicult to distinguish by histological criteria. Truncal arteries are perforating branches of the surface arteries that pass through the chorionic plate. Each truncal artery supplies one main stem villus and thus one cotyledon. As the artery penetrates the chorionic plate, its wall loses smooth muscle, and its caliber increases. The loss of muscle continues as the truncal arteries and veins branch into their smaller rami.


Obstentrics_Williams

Obstentrics_Williams. Before 10 weeks' gestation, there is no end-diastolic low pattern within the umbilical artery at the end of the fetal cardiac cycle (Fisk, 1988; Loquet, 1988). After 10 weeks, however, end-diastolic low appears and is maintained throughout normal pregnancy. Clinically, these flow patterns are studied with Doppler sonography to assess fetal well-being (Chap. 10, p. 213).


Obstentrics_Williams

Obstentrics_Williams. Mechanisms of placental blood low must allow blood to leave syncytiotrophoblast, rather than remaining in contact with villi long enough for adequate exchange. For this, maternal blood enters through the basal plate and is driven high up toward the chorionic plate by arterial pressure before laterally dispersing (Fig. 5-15). After bathing the external microvillous surface of chorionic villi, maternal blood drains back through venous oriices in the basal plate and enters uterine veins. Thus, maternal blood traverses the placenta randomly without preformed channels. The previously described trophoblast invasion of the spiral arteries creates low-resistance vessels that can accommodate massive increase in uterine perfusion during gestation. Generally, spiral arteries are perpendicular to, but veins are parallel to, the uterine wall. his arrangement aids closure of veins during a uterine contraction and prevents the exit of maternal blood from the intervillous space. The number of


Obstentrics_Williams

Obstentrics_Williams. to, but veins are parallel to, the uterine wall. his arrangement aids closure of veins during a uterine contraction and prevents the exit of maternal blood from the intervillous space. The number of arterial openings into the intervillous space is gradually reduced by cytotrophoblastic invasion. here are about 120 spiral arterial entries into the intervillous space at term (Brosens, 1963). hese discharge blood in spurts that bathes the adjacent villi (Borell, 1958). After the 30th week, a prominent venous plexus lies between the decidua basalis and myometrium and helps develop the cleavage plane needed for placental separation after delivery.


Obstentrics_Williams

Obstentrics_Williams. Both inlow and outlow are curtailed during uterine contractions. BIeker and associates (1975) used serial sonography during normal labor and found that placental length, thickness, and surface area grew during contractions. They attributed this to distention of the intervillous space by impairment of venous outlow compared with arterial inlow. During contractions, therefore, a somewhat larger volume of blood is available for exchange even though the rate of low is decreased. Similarly, Doppler velocimetry has shown that diastolic low veloci ty in spiral arteries is diminished during uterine contractions. Thus, principal factors regulating intervillous space blood low are arterial blood pressure, intrauterine pressure, uterine contraction pattern, and factors that act specifically on arterial walls. • Breas in the Placental"Barrier" he placenta does not maintain absolute integrity of the fetal and maternal circulations. here are numerous examples of


Obstentrics_Williams

Obstentrics_Williams. • Breas in the Placental"Barrier" he placenta does not maintain absolute integrity of the fetal and maternal circulations. here are numerous examples of FIGURE 5-15 Schematic drawing of a section through a full-term placenta. Maternal blood flows into the intervillous spaces in funnel-shaped spurts. Exchanges occur with fetal blood as maternal blood flows around the villi. Infiowing arterial blood pushes venous blood into the endometrial veins, which are scattered over the entire surface of the decidua basalis. Note also that the umbilical arteries carry deoxygenated fetal blood to the placenta and that the umbilical vein carries oxygenated blood to the fetus. Placental lobes are separated from each other by placental (decidual) septa. traicking cells between mother and fetus in both directions. This situation is best exempliied clinically by erythrocyte


Obstentrics_Williams

Obstentrics_Williams. traicking cells between mother and fetus in both directions. This situation is best exempliied clinically by erythrocyte D-antigen alloimmunization (Chap. 15, p. 301). Fetal cell admixtures likely are small in most cases, although rarely the fetus exsanguinates into the maternal circulation. Fetal cells can also engraft in the mother during pregnancy and can be identiied decades later. Fetal lymphocytes, CD34+ mesenchymal stem cells, and endothelial colony-forming cells all reside in maternal blood, bone marrow, or uterine vascula ture (Nguyen, 2006; Piper, 2007; Sipos, 2013). Termed micro chimerism, such residual stem cells have been implicated in the disparate female:male ratio of autoimmune disorders (Greer, 2011; Stevens, 2006). As discussed in Chapter 59 (p. 1139), they are associated with the pathogenesis of lymphocytic thy roiditis, scleroderma, and systemic lupus erythematosus.


Obstentrics_Williams

Obstentrics_Williams. Survival of the semi allogenic fetal graft requires complex interactions between fetal trophoblasts and maternal decidual immune cells. The fetal-maternal interface is not immunologically inert. Rather, it is an active hub of interactions that allows implantation and appropriate placental development and ensures immuno tolerance of the fetus. Despite this, a functional immune system must be maintained to protect the mother. Immunogenicity of the Trophoblasts Trophoblastic cells are the only fetus-derived cells in direct contact with maternal tissues and blood. Fetal syncytiotrophoblast synthesizes and secretes numerous factors that regulate the immune responses of maternal cells both at the implantation site and systemically.


Obstentrics_Williams

Obstentrics_Williams. Human leukocyte antigens (HLAs) are the human analogue of the major histocompatibility complex (MHC) (Hunt, 1992). There are 17 HLA class I genes, including three classic genes, HLA-A, -B, and -C, that encode the major class I (class Ia) transplantation antigens. Three other class I genes, designated HLA-E, -F, and -G, encode class Ib HLA antigens. MHC class I and II antigens are absent from villous trophoblasts, which appear to be immunologically inert at all gestational stages (Weetman, 1999). Invasive extravillous cytotrophoblasts do express MHC class I molecules. Thus, the ability of these cells to bypass transplantation rejection is the focus of considerable study.


Obstentrics_Williams

Obstentrics_Williams. Mofett-King (2002) reasoned that normal implantation depends on controlled trophoblastic invasion of maternal decidua and spiral arteries. Such invasion must proceed far enough to provide for normal fetal growth and development, but a mechanism must regulate invasion depth. She suggests that dNK cells combined with unique expression of three speciic HLA class I genes in extravillous cytotrophoblasts act in concert to permit and subsequently limit trophoblast invasion.


Obstentrics_Williams

Obstentrics_Williams. Class I antigens in extravillous cytotrophoblasts are accounted for by the expression of classic HLA-C and nonclassic class Ib molecules of HLA-E and HLA-G. HLA-G antigen is expressed only in humans, with expression restricted to extravillous cytotrophoblasts contiguous with maternal tissues. Embryos used for in vitro fertilization do not implant if they do not express a soluble HLA-G isoform (Fuzzi, 2002). hus, HLA-G may be immunologically permissive of the maternalfetal antigen mismatch (LeBouteiller, 1999). HLA-G has a proposed role in protecting extravillous trophoblasts from immune rejection via modulation of dNK functions (Apps, 2011; Rajagopalan, 2012). Last, Goldman-Wohl and associates (2000) have provided evidence for abnormal HA-G expression in extravillous trophoblasts from women with preeclampsia.


Obstentrics_Williams

Obstentrics_Williams. Natural killer cells are the predominant population of leukocytes present in midluteal phase endometrium and in decidua throughout the first trimester Oohnson, 1999). By term, however, relatively few dNK cells are present in decidua. In first-trimester decidua, dNK cells lie close to extravillous trophoblasts, and there they purportedly serve to regulate invasion. These dNKs have a distinct phenotype characterized by a high surface density of CD56 or neural cell adhesion molecules (Manaster, 2008; Mofett-King, 2002). Their infiltration is increased by progesterone and by stromal cell production of IL-15 and decidual prolactin (Dunn, 2002; Gubbay, 2002). Although dNK cells have the capacity for cytotoxicity, they are not cytotoxic toward fetal trophoblasts. Their cytotoxic potential is prevented by molecular cues from decidual macrophages. In addition, the expression of specific HLA molecules protects against dNK killing. Also, dNK cells function to restrict trophoblast invasiveness to


Obstentrics_Williams

Obstentrics_Williams. by molecular cues from decidual macrophages. In addition, the expression of specific HLA molecules protects against dNK killing. Also, dNK cells function to restrict trophoblast invasiveness to protect the mother.


Obstentrics_Williams

Obstentrics_Williams. Of other cell types, decidual macro phages are distinct from proinflammatory M 1 or antiinlammatory M2 macro phages. Decidual macro phages express the complement receptor COlIc at high or low levels: CD11cHI and CD11cLO. These cells function to regulate adaptive T cell responses; control dNK diferentiation, activation, and cytotoxicity; and produce antiinlammatory cytokines such as IL-10 to ensure fetal tolerance and inhibition of harmful immune responses. Dendritic cells are cells that present antigens to T cells. hey play an important role in the development of a receptive endometrium for implantation.


Obstentrics_Williams

Obstentrics_Williams. Dendritic cells are cells that present antigens to T cells. hey play an important role in the development of a receptive endometrium for implantation. Maternal T cels, as part of the adaptive immune response, increase in number and function after encounter with a speciic antigen. These cells subsequently retain the ability to respond rapidly in a subsequent encounter with the same antigen. Specific populations of Treg cells persist and can protect against aberrant immune responses. During pregnancy, there is a systemic expansion of maternal Treg cell populations. These cells are FOXP3+ cells with defined fetal speciicity. They are immunosuppressive and playia role in fetal tolerance.


Obstentrics_Williams

Obstentrics_Williams. At term, the amnion is a tough and tenacious but pliable membrane. his innermost avascular fetal membrane is contiguous with amnionic fluid and plays a role of incredible importance in human pregnancy. he amnion provides almost all tensile strength of the fetal membranes. Thus, its resilience to rupture is vitally important to successful pregnancy outcome. Indeed, preterm rupture of fetal membranes is a major cause of preterm delivery (Chap. 42, p. 819). FIGURE 5-16 Photomicrograph of fetal membranes. From left to right: AE = amnion epithelium; AM = amnion mesenchyme; S zona spongiosa; eM = chorionic mesenchyme; TR = trophoblast; 0= decidua. (Used with permission from Dr. Judith R. Head.)


Obstentrics_Williams

Obstentrics_Williams. Bourne (1962) described five separate amnion layers. he inner surface, which is bathed by amnionic luid, is an uninterrupted, single layer of cuboidal epithelium (Fig. 5-16). his epithelium is attached irmly to a distinct basement membrane that is connected to an acellular compact layer composed primarily of interstitial collagens. On the outer side of the compact layer, there is a row of ibroblast-like mesenchymal cells, which are widely dispersed at term. here also are a few fetal macrophages in the amnion. he outermost amnion layer is the relatively acellular zona spongiosa, which is contiguous with the second fetal membrane, the chorion laeve. he human amnion lacks smooth muscle cells, nerves, lymphatics, and importantly, blood vessels.


Obstentrics_Williams

Obstentrics_Williams. Early during implantation, a space develops between the embryonic cell mass and adjacent trophoblastic cells (see Fig. 5-9). Small cells that line this inner surface of trophoblasts have been called amniogenic cells-precursors of amnionic epithelium. The amnion is irst identiiable on the 7th or 8th day of embryo development. It is initially a minute vesicle, which then develops into a small sac that covers the dorsal embryo surface. As the amnion enlarges, it gradually engulfs the growing embryo, which prolapses into its cavity (Benirschke, 2012).


Obstentrics_Williams

Obstentrics_Williams. Distention of the amnionic sac eventually brings it into contact with the interior surface of the chorion laeve. Apposition of the chorion laeve and amnion near the end of the irst trimester then causes an obliteration of the extraembryonic coelom. he amnion and chorion laeve, although slightly adhered, are never intimately connected and can be separated easily. Placental amnion covers the placental surface and thereby is in contact with the adventitial surface of chorionic vessels. Umbilical amnion covers the umbilical cord. With diamnionic-monochorionic placentas, there is no intervening tissue between the fused amnions. In the conjoined portion of membranes of diamnionic-dichorionic twin placentas, amnions are separated by fused chorion laeve.


Obstentrics_Williams

Obstentrics_Williams. Amnionic luid ills this amnionic sac. Until about 34 weeks' gestation, the normally clear fluid increases in volume as pregnancy progresses. Mter this, the volume declines. At term, amnionic luid averages 1000 mL, although this may vay widely in normal and especially abnormal conditions. The origin, composition, circulation, and function of amnionic luid are discussed further in Chapter 11 (p. 225). Epithelial cells of the amnion derive from fetal ectoderm of the embryonic disc. hey do not arise by delamination from trophoblasts. his is an important consideration from both embryological and functional perspectives. For example, HLA class I gene expression in amnion is more akin to that in embyonic cells than to that in trophoblasts.


Obstentrics_Williams

Obstentrics_Williams. he ibroblast-like mesenchymal cell layer of the amnion is likely derived from embryonic mesoderm. Early in human embryogenesis, the amnionic mesenchymal cells lie immediately adjacent to the basal surface of the amnion epithelium. At this time, the amnion surface is a two-cell layer with approximately equal numbers of epithelial and mesenchymal cells. Simultaneously with growth and development, interstitial collagens are deposited between these two cell layers. his marks formation of the amnion compact layer, which separates the two layers of amnion cells.