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Obstentrics_Williams. Hassadia A, Kew FM, Tidy]A, et al: Ectopic gestational trophoblastic disease: a case series review.o] Reprod Med 57(7-8):297, 20o12 ]oergensen MW, Niemann I, Rasmussen A,et al: Triploid pregnancies: genetic and clinical features of 158 cases. Am] Obstet GynecoIo211(4):370.e1, 2014 ]oneborg U, Eloranta S, Johansson L, et al: Hydatidiform mole and subsequent pregnancy outcome: a population-based cohort study. Am ] Obstet GynecoIo211(6):681.e1,o2014 Kang WD, Choi HS, Kim SM: Prediction of persistent gestational trophoblastic neoplasia: the role of hCG level and ratio in 2 weeks after evacuation of complete mole. Gynecol OncoIo124(2):250, 2012 Kerkmeijer LG, Massuger LF, Ten Kate-Booij M], et al: Earlier diagnosis and serum human chorionic gonadotropin regression in complete hydatidiform moles. Obstet Gynecol 113:326,o2009 Kofinas ]0, Kruczek A, Sample ], et al: Thyroid storm-induced multi-organ failure in the setting of gestational trophoblastic disease.o] Emerg Med 48(1): 35,o2015


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Obstentrics_Williams. Kofinas ]0, Kruczek A, Sample ], et al: Thyroid storm-induced multi-organ failure in the setting of gestational trophoblastic disease.o] Emerg Med 48(1): 35,o2015 Kohorn EI: Worldwide survey of the results of treating gestational trophoblastic disease.o] Reprod Med 59(3-4):145, 2014 Lakovschek Ie, Streubel B, Ulm B: Natural outcome of trisomy 13, trisomy 18, and triploidy ater prenatal diagnosis. Am] Med Genet A 155A(11):262, 2011 Lawler SO, Fisher A, Dent J: A prospective genetic study of complete and partial hydatidiform moles. Am ] Obstet Gynecol 164: 1270, 1991 Lawrie TA, Alazzam M, Tidyo], et al: First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev 6:CD007102, 2016


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Obstentrics_Williams. Lawrie TA, Alazzam M, Tidyo], et al: First-line chemotherapy in low-risk gestational trophoblastic neoplasia. Cochrane Database Syst Rev 6:CD007102, 2016 Lee C, Smith HO, Kim S]: Epidemiology. In Hancock BW, Seck! M], Berkowitz RS, et al (eds): Gestational trophoblastic disease, 3rd ed. London, International Society for the Study of Trophoblastic Disease, 20o11o, p 57. Available at: http://www.isstd.org/index.html. Accessed April 23, 2016 Upata F, Parkash V, Talmor M, et al: Precise DNA genotyping diagnosis of hydatidiform mole. Obstet GynecoIo115(4):784, 2010 Lurain JR: Gestational trophoblastic disease I: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiform mole. Am J Obstet Gynecol 203(6):531, 20o10 Lurain JR: Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 204(1):11, 2011


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Obstentrics_Williams. Lurain JR: Gestational trophoblastic disease II: classification and management of gestational trophoblastic neoplasia. Am J Obstet Gynecol 204(1):11, 2011 Lybol C, Centen DW, homas CM, et al: Fatal cases of gestational trophoblastic neoplasia over four decades in the Netherlands: a retrospective cohort study. BJOG 119(12):1465,o2012 Mangili G, Garavaglia E, Cavoretto P, et al: Clinical presentation of hydatidiform mole in northern Italy: has it changed in the last 20 years? Am J Obstet GynecoIo198(3):302.e1,o2008 Massardier J, Golfner F, Journet D, et al: Twin pregnancy with complete hydatidiform mole and coexistent fetus obstetrical and oncological outcomes in a series of 14 cases. Eur J Obstet Gynecol Reprod BioI 143:84,2009 Matsui H, Iitsuka Y, Suzuka K, et al: Subsequent pregnancy outcome in patients with spontaneous resolution of HCG after evacuation of hydatidiform mole: comparison between complete and partial mole. Hum Reprod 16(6):1274,o2011


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Obstentrics_Williams. Merchant SH, Amin MB, Viswanatha DS, et al: p57KIP2 immunohistochemistry in early molar pregnancies: emphasis on its complementary role in the diferential diagnosis of hydropic abortuses. Hum Pathol 36: 180, 2005 Neubauer NL, Strohl E, Schink Jc, et al: Fatal gestational trophoblastic neoplasia: an analysis of treatment failures at the Brewer Trophoblastic Disease Center from 1979-2012 compared to 1962-1978. GynecoloOncol 138(2):339,o2015 Ngan HY, Seck! MJ, Berkowitz RS, et al: Update on the diagnosis and management of gestational trophoblastic disease. Int J Gynaecol Obstet 131 Suppl 2:S123,o2015 Ngu SF, Chan KK: Management of chemoresistant and quiescent gestational trophoblastic disease. Curr Obstet Gynecol Rep 3:84, 2014 Niemann I, Petersen LK, Hansen ES, et al: Diferences in current clinical features of diploid and triploid hydatidiform mole. BJOG 114:1273,2007


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Obstentrics_Williams. Niemann I, Petersen LK, Hansen ES, et al: Diferences in current clinical features of diploid and triploid hydatidiform mole. BJOG 114:1273,2007 Pezeshki M, Hancock BW, Silcocks P: he role of repeat uterine evacuation in the management of persistent gestational trophoblastic disease. Gynecol Oncol 95(3):423, 2004 Schmid P, Nagai Y, Agawal R: Prognostic markers and long-term outcome of placental-site trophoblastic tumours: a retrospective obsevational study. Lancet 374(9683):48, 2009 Schorge JO, Goldstein DP, Bernstein MR, et al: Recent advances in gestational trophoblastic disease. J Reprod Med 45:692, 2000 Scott EM, Smith L, Desouki MM, et al: Epithelioid trophoblastic tumor: a case report and review of the literature. Case Rep Obstet Gynecol 2012: 862472, 20o12 Sebire NJ, Fisher A, Foskett M, et al: Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG 110(1):22,2003


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Obstentrics_Williams. Sebire NJ, Fisher A, Foskett M, et al: Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG 110(1):22,2003 Sebire N], Foskett M, Fisher A, et al: Risk of partial and complete hydatidiform molar pregnancy in relation to maternal age. BJOG 109:99, 2002a Sebire NJ, Foskett M, Parainas FJ, et al: Outcome of twin pregnancies with complete hydatidiform mole and healthy co-twin. Lancet 359:2165, 2002b Sebire NJ, Foskett M, Short D, et al: Shortened duration of human chorionic gonadotrophin surveillance following complete or partial hydatidiform mole: evidence for revised protocol of a UK regional trophoblastic disease unit. BJOG 114(6): 60,o2007 Sebire NJ, Lindsay I, Fisher A: Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies. Int J Gynecol Pathol 24(3):260, 2005 Seck! MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease. Lancet 376(9742):717,o2010


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Obstentrics_Williams. Seck! MJ, Sebire NJ, Berkowitz RS: Gestational trophoblastic disease. Lancet 376(9742):717,o2010 Smith HO, Wiggins C, Verschraegen CF, et al: Changing trends in gestational trophoblastic disease. J Reprod Med 51 :777, 2006 Soper JT: Gestational trophoblastic disease. Obstet Gynecol 108: 176, 2006 Sun SY, Melamed A, Goldstein DP, et al: Changing presentation of complete hydatidiform mole at the New England Trophoblastic Disease Center over the past three decades: does early diagnosis alter risk for gestational trophoblastic neoplasia? Gynecol Oncol 138(1):46,o2015 Tidy JA, Gillespie M, Bright N, et al: Gestational trophoblastic disease: a study of mode of evacuation and subsequent need for treatment with chemotherapy. Gynecol Oncol 78 pp. 309,o2000 Tse Y, Chan KK, Tam F: 20-year experience of managing profuse bleeding in gestational trophoblastic disease. J Reprod Med (5):397, 200


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Obstentrics_Williams. Tse Y, Chan KK, Tam F: 20-year experience of managing profuse bleeding in gestational trophoblastic disease. J Reprod Med (5):397, 200 Tse Y, Ngan HY: Gestational trophoblastic disease. Best Pract Res Clin Obstet GynaecoIo26(3):357, 2012 Tuncer ZS, Bernstein MR, Goldstein DP, et al: Outcome of pregnancies occurring before completion of human chorionic gonadotropin follow-up in patients with persistent gestational trophoblastic tumor. Gynecol Oncol 73(3):345, 1999a Tuncer ZS, Bernstein MR, Goldstein DP, et al: Outcome of pregnancies occurring within 1 year of hydatidiform mole. Obstet Gynecol 94(4):588, 1999b van Trommel NE, Massuger LF, Verheijen H, et al: he curative efect of a second curettage in persistent trophoblastic disease: a retrospective cohort survey. Gynecol Oncol 99:6, 2005


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Obstentrics_Williams. Vargas R, Barroilhet LM, Esselen K, et al: Subsequent pregnancy outcomes after complete and partial molar pregnancy, recurrent molar pregnancy, and gestational trophoblastic neoplasia: an update from the New England Trophoblastic Disease Center. J Reprod Med 59(5-6):188, 2014 Wang Q, Fu J, Hu L, et al: Prophylactic chemotherapy for hydatidiform moleto prevent gestational trophoblastic neoplasia. Cochrane Database Syst Rev 9:CD007289, 2017 Wee L, Jauniaux E: Prenatal diagnosis and management of twin pregnancies complicated by a co-existing molar pregnancy. Prenat Diagn 25(9):772, 2005 Wei H, Zhang T, Uu B, et al: Choriocarcinoma of unknown origin with multiple organ metastasis and cerebral hemorrhage: a case report and literature review. Oncol Lett 11(6):3749,2016 Williams ], Short D, Dayal L, et al: Efect of early pregnancy following chemotherapy on disease relapse and fetal outcome in women treated for gestational trophoblastic neoplasia. J Reprod Med 59(5-6):248-54, 2014


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Obstentrics_Williams. Wolfberg AJ, Berkowitz RS, Goldstein DP: Postevacuation hCG levels and risk of gestational trophoblastic neoplasia in women with complete molar pregnancy. Obstet Gynecol 106(3):548,o2005 Woolas RP, Bower M, Newlands ES, et al: Influence of chemotherapy for gestational trophoblastic disease on subsequent pregnancy outcome. BJOG 105: 1032, 1998 World Health Organization Scientific Group: Gestational trophoblastic disease. WHO Tech Rep Ser 692:1,o1983 Zhang W, Uu B, Wu J, et al: Hemoptysis as primary manifestation in three women with choriocarcinoma with pulmonary metastasis: a case series. J Med Case Rep 11(1):110,o201 Physiology of Labor MATERNAL AND FETAL COMPARTMENTS .......... 400 SEX STEROID HORMONE ROLE . . ................ 401 PROSTAGLANDINS ROLE .......e..e......e..e. . ... 402 PHASE 1: UTERINE QUIESCENCE AND CERVICAL SOFTENING ................... .......... ... 403 PHASE 2: PREPARATION FOR LABOR ............... 408


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Obstentrics_Williams. PROSTAGLANDINS ROLE .......e..e......e..e. . ... 402 PHASE 1: UTERINE QUIESCENCE AND CERVICAL SOFTENING ................... .......... ... 403 PHASE 2: PREPARATION FOR LABOR ............... 408 PHASE 3: .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 411 UTEROTONINS IN PARTURITION PHASE 3 ........... 416 PHASE 4: THE PUERPERIUM ... .................. 417 From time immemorial inquiring minds have sought an explanation or the act that labour usualy ensues about 280 days after the appearance of the last menstrual perio, but thus ar no satiactory universal cause has been discovered. -J. Whitridge Williams (1903)


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Obstentrics_Williams. -J. Whitridge Williams (1903) The importance of labor physiology was highlighted in the irst edition of Wiliams Obstetrics, in which an entire section was devoted to the topic. Given the science at that time, those nine chapters were concerned with the mechanics of labor and delivery. However, the current understanding of labor includes a wide spectrum of preparedness even before the first regular contractions.


Obstentrics_Williams

Obstentrics_Williams. Labor is the last few hours of human pregnancy. It is characterized by forceful and painful uterine contractions that efect cervical dilation and cause the fetus to descend through the birth canal. Extensive preparations take place in both the uterus and cervix long before this. During the irst 36 to 38 weeks of normal gestation, the myometrium is in a preparatory yet unresponsive state. Concurrently, the cervix begins an early stage of remodeling yet maintains structural integrity. Following this prolonged uterine quiescence, a transitional phase follows during which myometrial unresponsiveness is suspended and the cervix undergoes ripening, efacement, and loss of structural cohesion.


Obstentrics_Williams

Obstentrics_Williams. The physiological processes that regulate parturition-the bringing forth of young-and the onset of labor continue to be deined. Three general contemporaneous theories describe labor initiation. Viewed simplistically, the irst is the functional loss of prenancy maintenance actors. he second focuses on synthesis of actors that induce parturition. The third suggests that the mature fetus is the source of the initial signal or parturition commencement. Current research supports a model that draws from all three themes. However, labor onset clearly represents the culmination of a series of biochemical changes in the uterus and cervix. hese result from endocrine and paracrine signals emanating from both mother and fetus. Their relative contributions vary between species, and it is these diferences that complicate elucidation of the exact factors that regulate human parturition. When parturition is abnormal, then preterm-labor, dystocia, or postterm pregnancy may result. Of these, preterm


Obstentrics_Williams

Obstentrics_Williams. that complicate elucidation of the exact factors that regulate human parturition. When parturition is abnormal, then preterm-labor, dystocia, or postterm pregnancy may result. Of these, preterm labor remains the major contributor to neonatal mortality and morbidity.


Obstentrics_Williams

Obstentrics_Williams. The myometrial layer of the uterus is composed of bundles of smooth muscle cells surrounded by connective tissue. In contrast to skeletal or cardiac muscle, the smooth muscle cell is not terminally diferentiated and therefore is readily adaptable to environmental changes. Varied stimuli such as mechanical stretch, inlammation, and endocrine and paracrine signals can modulate Physiology of Labor 401


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Obstentrics_Williams. Physiology of Labor 401 FIGURE 21-1 The amnion synthesizes prostaglandins, and late in pregnancy, synthesis is augmented by increased phospholipase A2 and prostaglandin H synthase, type 2 (PGHS-2) activity. During pregnancy, the transport of prostaglandins from the amnion to maternal tissues is limited by expression of the inactivating enzymes, prostaglandin dehydrogenase (PGDH), in the chorion. During labor, PGDH levels decline, and amnion-derived prostaglandins can influence membrane rupture and uterine contractility. The role of decidual activation in parturition is unclear but may involve local progesterone metabolism and higher prostaglandin receptor concentrations, thus enhancing uterine prostaglandin actions and cytokine production. (Redrawn from Smith R: Parturition. N Engl J Med. 2007 Jan 18;356(3):271-283.) the transition of the smooth muscle cell among phenotypes that provide cell growth, proliferation, secretion, and contractility.


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Obstentrics_Williams. In addition to this phenotypic plasticity, several smooth muscle qualities confer advantages for uterine contraction eiciency and fetal delivery. First, the degree of smooth muscle cell shortening with contractions may be one order of magnitude greater than that attained in striated muscle cells. Second, forces can be exerted in smooth muscle cells in multiple directions. his difers from the contraction force generated by skeletal muscle, which is always aligned with the axis of the muscle fibers. hird, smooth muscle is not organized in the same manner as skeletal muscle. In myometrium, the thick and thin ilaments are found in long, random bundles throughout the cells. his plexiform arrangement aids greater shortening and force-generating capacity. Last, greater multidirectional force generation in the uterine fundus compared with that of the lower uterine segment permits versatility in expulsive force directionality.


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Obstentrics_Williams. Lining the thick muscular uterine walls, the endometrium is transformed by pregnancy hormones and is then termed decidua. Composed of stromal cells and maternal immune cells, the decidua serves to maintain the pregnancy via unique immuno regulatory functions that suppress inlammatory signals during gestation. However, at the end of pregnancy, decidual activation ensues. With this, the decidua transitions to induce inflammatory signals and withdraw active immunosuppression, which contribute to parturition initiation. During pregnancy, the cervix has multiple functions that include: (1) maintenance of barrier function to protect the reproductive tract from infection, (2) maintenance of cervical competence despite greater gravitational forces as the fetus grows, and (3) orchestration of extracellular matrix changes that allow progressively greater tissue compliance.


Obstentrics_Williams

Obstentrics_Williams. In nonpregnant women, the cervix is closed and firm, and its consistency is similar to nasal cartilage. By the end of pregnancy, the cervix is easily distensible, and its consistency is similar to the lips of the oral cavity. Observations in threedimensional sonography and magnetic resonance imaging show increases in the cross-sectional area of the cervical canal and in the cervical stroma from early to late pregnancy (House, 2009; Lang, 2010). Concurrent with expansion of the stroma, the cervical epithelia proliferate and exert a pregnancy-specific immunoprotection.


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Obstentrics_Williams. In addition to providing the exchange of nutrients and waste between mother and fetus, the placenta is a key source of steroid hormones, growth factors, and other mediators that maintain pregnancy and potentially aid the transition to parturition. The fetal membranes-amnion and chorion and adjacent decidua-make up an important tissue shell around the fetus that serves as a physiological, immunological, and metabolic shield to protect against untimely parturition initiation.


Obstentrics_Williams

Obstentrics_Williams. he amnion provides virtually all of the fetal membranes' tensile strength to resist membrane tearing and rupture (Chap. 5, p. 95). This avascular tissue is highly resistant to penetration by leukocytes, microorganisms, and neoplastic cells (Fig. 21-1). It also constitutes a selective filter to prevent fetal particulatebound lung and skin secretions from reaching the maternal compartment. In this manner, maternal tissues are protected from amnionic fluid constituents that could prematurely accelerate decidual or myometrial activation or could promote adverse events such as amnionic luid embolism. The chorion is a primarily protective tissue layer and provides immunological acceptance. It is also enriched with enzymes that inactivate uterotonins, which are agents that stimulate contractions. Inactivating enzymes include prostaglandin dehydrogenase, oxytocinase, and enkephalinase (Cheung, 1990; Germain, 1994).


Obstentrics_Williams

Obstentrics_Williams. In many species, the role of sex steroid hormones is clear-estrogen promotes and progesterone inhibits the events leading to parturition. nd, the removal of progesterone, that is, progesterone withdrawa, directly precedes progression of parturition. In addition, providing progesterone to some species will delay parturition via a decline in myometrial activity and continued cervical competency (Challis, 1994). In humans, however, it seems most likely that both estrogen and progesterone are components of a broader molecular system that maintains uterine quiescence.


Obstentrics_Williams

Obstentrics_Williams. Plasma levels of estrogen and progesterone in normal pregnancy are enormous and in great excess of the ainity constants for their receptors. For this reason, it is diicult to comprehend how relatively subtle changes in the ratio of their concentrations could modulate physiological processes during pregnancy. The teleological evidence, however, for an increased progesteroneto-estrogen ratio in the maintenance of pregnancy and a decline in this ratio for parturition is overwhelming. In all species studied, including humans, administration of the progesteronereceptor antagonists miepristone (RU-48) or onapristone will promote some or all key features of parturition. These include cervical ripening, greater cervical distensibility, and augmented uterine sensitivity to uterotonins (Bygdeman, 1994; Chwalisz, 1994b; Wolf, 1993).


Obstentrics_Williams

Obstentrics_Williams. The exact role of estrogen in regulation of human uterine quiescence and cervical competency is less well understood. hat said, estrogen can advance progesterone responsiveness and, in doing so, promote uterine quiescence. At the end of pregnancy, estrogen aids processes that mediate uterine activation and cervical ripening. Both progesterone and estrogen bind to nuclear receptors that regulate gene transcription in a cell-and context-speciic pattern. Two nuclear receptors for estrogen are estrogen receptor a (ERa) and estrogen receptor 3 (ER3). Nuclear receptor isoforms of the progesterone receptor (PR-A and PR-B) are encoded by difering transcripts from a single gene (Patel, 2015).


Obstentrics_Williams

Obstentrics_Williams. Prostaglandins are lipid molecules with varied hormone-like actions. In parturition, they playia prominent role in myometrial contractility, relaxation, and inlammation. Prostaglandins interact with a family of eight diferent G-protein-coupled receptors (p. 406), several of which are expressed in myometrium and cervix (Konopka, 2015; Myatt, 2004).


Obstentrics_Williams

Obstentrics_Williams. The major synthetic pathways involved in prostaglandin biosynthesis are shown in Figure 21-2. Prostaglandins are produced using plasma membrane-derived arachidonic acid, which usually is released by the action of phospholipase A2 or C. Arachidonic acid can then act as substrate for both type 1 and 2 prostaglandin H synthase (PGHS-l and -2), which are also called cyclooxygenase-l and -2 (COX-l and -2). Both PGHS isoforms convert arachidonic acid to the unstable prostaglandin G2 and then to prostaglandin H2. hese enzymes are the target of many nonsteroidal antiinlammatory drugs (NSAIDs). Indeed, the tocolytic actions of speciic NSAIDs, as discussed in Chapter 42 (p. 826), were considered promising until they were shown to have adverse fetal efects (Loudon, 2003; Olson, 2003, 2007).


Obstentrics_Williams

Obstentrics_Williams. Through prostaglandin isomerases, prostaglandin H2 is converted to active prostaglandins. These include prostaglandins E2 (PGEJ, F2x (PGF2x), and 12 (PGI2). Isomerase expression is tissue-speciic and thereby controls the relative production of various prostaglandins. Another important control point for prostaglandin activity is its metabolism, which most often is


Obstentrics_Williams

Obstentrics_Williams. Phospholipase C with through the action of 15-hydroxyprostaglandin dehydrogenase (PGDH). Expression of this enzyme is up regulated during pregnancy in the uterus and cervix, which provides the important ability to rapidly inactivate prostaglandins (Giannoulias, 2002; Kishore, 2014). Thus, myometrial responses to prostaglandins stem from a balance between prostaglandin synthesis versus metabolism, from the relative expression of various prostaglandin receptors, or from a switch in receptor-signaling pathways (Kandola, 2014; Lyall, 2002; Olson, 2007; Smith, 2001). It is entirely possible that prostanoids contribute to myometrial relaxation at one stage of pregnancy and to myometrial contractions after parturition initiation (Myatt, 2004).


Obstentrics_Williams

Obstentrics_Williams. In addition to the myometrium, the amnion synthesizes several bioactive pep tides and prostaglandins that cause myometrial relaxation or contraction (see Fig. 21-1). Late in pregnancy, amnionic prostaglandin biosynthesis is increased, and phospholipase A2 and PGHS-2 show greater activity Oohnson, 2002). Accordingly, many hypothesize that prostaglandins regulate events leading to parturition. The amnion is likely the major source for amnionic fluid prostaglandins, and their role in the activation of cascades that promote membrane rupture is clear. he influence of amnion-derived prostaglandins on uterine quiescence and activation, however, is less delineated. his is because prostaglandin transport from the amnion through the chorion to access maternal tissues is limited by expression of PGDH. Physiology of Labor 403


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Obstentrics_Williams. Physiology of Labor 403 Importantly, the phases of parturition should not be confused with the clinical stages of labor, that is, the first, second, and third stages-which make up phase 3 of parturition (Fig. 2i1-4). arturitionContractile 1unresponsiveness, Uterine of labor cervical softening Phase 3 Stimulation Processes Uterine Phase4 Involution Parturient Uterine preparedness contraction, involution, for labo, cervical dilation, cervical repai, tion, a remarkably efective period of expUlsion (three myometrial quiescence is imposed. This stages of labor) Initiation of maintenance of cervical structural integ parturition Onset of labor FIGURE 21-3 The phases of parturition. PHASE 1: UTERINE QUIESCENCE AND CERVICAL SOFTENING


Obstentrics_Williams

Obstentrics_Williams. Initiation of maintenance of cervical structural integ parturition Onset of labor FIGURE 21-3 The phases of parturition. PHASE 1: UTERINE QUIESCENCE AND CERVICAL SOFTENING As shown in Figure 21-3, parturition can be arbitrarily divided into four overlapping phases that correspond to the major physiological transitions of the myometrium and cervix during pregnancy (Casey, 1993, 1997; Challis, 2000; Word, 2007). These phases of parturition include: (1) a prelude to it, (2) the preparation for it, (3) the process itself, and (4) recovery. Stages of Labor : Phase of of pregnancy and is characterized by


Obstentrics_Williams

Obstentrics_Williams. Stages of Labor : Phase of of pregnancy and is characterized by Delivery of uterine smooth muscle tranquility with rity (Fig. 21-5). All manner of molecular systems-neural, endocrine, paracrine, and autocrine-are likely called to implement and coordinate a state of relative uterine unresponsiveness. Moreover, a complementary "fail-safe" system that protects the uterus against agents that could perturb the tranquility of phase 1 also must be in place. During phase 1, the myometrial cells undergo a phenotypic modification to a noncontractile state, and uterine muscle is rendered unresponsive to natural stimuli. Concurrently, the uterus must initiate extensive changes in its size and vascularity to accommodate fetal growth and prepare for uterine :-6


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21-4 Composite of the average dilation curve for labor in nulliparous women. The curve is based on analysis of data derived from a large, nearly consecutive series of women. The first stage is divided into a relatively flat latent phase and a rapidly progressive active phase. In the active phase, there are three identifiable parts: an acceleration phase, a linear phase of maximum slope, and a deceleration phase. (Redrawm from Friedman EA: Labor: Clinical Evaluation and Management, 2nd ed. New York, Appleton-Century-Crofts, 1978.) contractions. he myometrial unre sponsiveness of phase 1 continues until near the end of pregnancy. That said, tractions are felt during the quiescent phase, but they do not normally cause cervical dilation. hese contractions are common toward the end of preg nancy, especially in multiparas, and are referred to as Braxton Hicks contractions oralse labor (Chap. 4, p. 50).


Obstentrics_Williams

Obstentrics_Williams. The quiescence of phase 1 likely stems from: (1) actions of estrogen and progesterone via intracellular receptors, myometrial-cell plasma membrane receptor-mediated increases in cyclic adenosine monophosphate (cMIP), generation of cyclic guanosine monophosphate (cGMP), and (4) other systems, including modiication of myometrial-cell ion channels. The balance between myometrial relaxation and contraction is controlled by steroid-and peptide-hormone transcriptional regulation of key genes and their protein products. Quiescence is achieved in part by: (1) diminished intracellular crosstalk and reduced intracellular Ca2+ ([Ca2+J levels; (2) ionchannel regulation of cell membrane • Myometrium is major site of action • Cervix is major site • Both are sites of action Phase 1 Phase 2 Phase 3 Uterine stretch Gap junction receptors Fetal signals (SPA, PAF, CRH) Fetal membrane Prostaglandins Cortisol? Phase 4


Obstentrics_Williams

Obstentrics_Williams. Phase 1 Phase 2 Phase 3 Uterine stretch Gap junction receptors Fetal signals (SPA, PAF, CRH) Fetal membrane Prostaglandins Cortisol? Phase 4 FIGURE 21-5 The key factors thought to regulate the phases of human parturition. CRH = corticotropin-releasing hormone; hCG i.):D o:sD) CRH? potential; (3) activation of the uterine endoplasmic reticulum stress-unfolded protein response; and (4) uterotonin degradation. In contrast, contractility results from: (1) enhanced interactions between the actin and myosin proteins; (2) heightened excitability of individual myometrial cells; and (3) promotion of intracellular crosstalk that allows synchronous contractions to develop.


Obstentrics_Williams

Obstentrics_Williams. Actin and myosin proteins are essential to muscle contraction. For this, actin must be converted from a globular to a ilamentous form. Indeed, a potential mechanism for maintenance of relaxation is the promotion ofactin into a globular form rather than into ibrils, which are required for contraction (Fig. 21-6). Moreover, actin must be attached to the cytoskeleton at focal points in the cell membrane to allow tension to develop. Actin must partner with myosin, which is composed of multiple light and heavy chains. The coupling of myosin and actin activates adenosine triphosphatase (ATPase), hydrolyzes adenosine triphosphate, and generates force. This interaction is brought about by enzymatic phosphorylation of the 20-kDa light chain of myosin (Stull, 1998). his is catalyzed by the enzyme myosin light-chain kinase, which is activated by calcium. Calcium binds to calmodulin, a calcium-binding regulatory protein, which in turn binds to and activates myosin lightchain kinase.


Obstentrics_Williams

Obstentrics_Williams. hus, logically, uterine relaxation ordinarily is promoted by conditions that lower concentrations of (Ca2+)i. In contrast, prostaglandin dehydrogenase; SPA surfactant protein A.


Obstentrics_Williams

Obstentrics_Williams. agents that prompt contraction act on myometrial cells to augment (Ca2+)i levels. Or, they allow an inlux of extracellular calcium through ligand-or voltage-regulated calcium channels (see Fig. 21-6). Voltage-gated ion channels open, additional calcium ions move into the cell, and cellular depolarization follows. For example, prostaglandin F2ex and oxytocin bind their respective receptors during labor to open ligand-activated calcium channels. Activation of these receptors also releases calcium from the sarcoplasmic reticulum to lower electronegativity within the cell. Additionally, greater localization of nonselective cation channels on the cell membrane promotes Ca2+ entry (Ying, 2015). The rise in (Ca2+)i levels is often transient. But, contractions can be prolonged by inhibition of myosin phosphatase, an enzyme which dephosphorylates myosin (Woodcock, 2004). Regulation of Membrane Potentials


Obstentrics_Williams

Obstentrics_Williams. Regulation of Membrane Potentials As just noted, myocyte excitability is regulated in part by changes in the electrochemical potential gradient across the plasma membrane. Before labor, myocytes maintain a relatively high interior electronegativity. Maintenance of a hyperpolarized membrane potential attenuates smooth muscle cell excitation and is regulated by ion channels. Consistent with the importance of myometrial quiescence, numerous potassium channels control membrane potential. One key regulator is the large-conductance voltage-and Ca2+activated K channel (BKeJ (Perez, 1993). In normal physiology, the myometrial BKca channel plays dual and opposing CRH, �2-sympathomimetics, 8 Oxytocin, thrombin, Physiology of Labor 405


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21 -6 Uterine myocyte relaxation and contraction. A. Uterine relaxation is maintained by factors that increase myocyte cyclic adenosine monophosphate (cAMP) levels. This activates protein kinase A (PKA) to promote phosphodiesterase activity with dephosphorylation of myosin light-chain kinase (MLCK). Other processes serve to maintain actin in a globular form and thus to prevent the fibril formation necessary for contractions. B. Uterine contractions result from reversal of these sequences. Actin now assumes a fibrillar form, and calcium enters the cell to combine with calmodulin to form complexes. These complexes activate MLCK to bring about phosphorylation of the myosin light chains. This generates ATPase activityto cause sliding of myosin over the actin fibrils, which is a uterine contraction. AC = + calcium; DAG = diacylglycerol; Gs and GQ = G-receptor proteins; IP3 = inositol triphosphate; LC20 = light chain 20; PIP3 = phosphatidylinositol 3,4,5-triphosphate;PLC =


Obstentrics_Williams

Obstentrics_Williams. a uterine contraction. AC = + calcium; DAG = diacylglycerol; Gs and GQ = G-receptor proteins; IP3 = inositol triphosphate; LC20 = light chain 20; PIP3 = phosphatidylinositol 3,4,5-triphosphate;PLC = phospholipase C; R-PKA inactive protein kinase. (Redrawn from Smith R: Parturition. N Engl J Med. 2007 Jan 18;356(3):271-283.) roles to maintain a balance between uterine quiescence and contractility. The Bca channel is abundantly expressed in the myometrium. For most of pregnancy, opening the BKca channel allows potassium to leave the cell to maintain interior electronegativity, thus preventing voltage-gated Ca2+ inlux and contraction. Enhancing Bca channel opening results in myometrial relaxation, whereas inhibition ofthe Bca channel augments myometrial contractility. he ability of Bca channel to regulate calcium dynamics and ultimately uterine contractility from early to late gestation may result from temporal changes in expression ofthe Bca channel and/or Bca interacting partners


Obstentrics_Williams

Obstentrics_Williams. channel to regulate calcium dynamics and ultimately uterine contractility from early to late gestation may result from temporal changes in expression ofthe Bca channel and/or Bca interacting partners (Wakle-Prabagaran, 2016).


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Obstentrics_Williams. Cellular signals that control myometrial contraction and relaxation can be efectively transferred between cells through intercellular junctional channels. Communication is established between myocytes by gap junctions, which aid the passage of electrical or ionic coupling currents as well as metabolite coupling. The transmembrane channels that make up the gap junctions consist of two protein "hemi-channels" (Saez, 2005). These connexons are each composed of six connexin subunit proteins (Fig. 21-7). Of these, connexin-43 is expressed in myometrium, and concentrations rise near labor onset. Pairs of connexons establish a conduit between coupled cells for the exchange of small molecules that can be nutrients, waste, metabolites, second messengers, or ions. Optimal numbers and types ofgap junctions are believed to be important for electrical myometrial synchrony.


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Obstentrics_Williams. Progesterone maintains uterine quiescence in part by mechanisms that lower expression of various key proteins needed for contractility. hese contraction-associated proteins (CAPs) include the oxytocin receptor, prostaglandin F receptor, and connexin-43. At the end of pregnancy, increased stretch along with greater estrogen dominance raises CAP levels. Integration ofdiverse regulatory pathways culminates in released inhibition ofconnexin-43 and oxytocin receptor levels to promote greater uterine contractility (Nadeem, 2016; Renthal, 2010; Williams, 2012b). As another potential mechanism, progesterone maintains uterine quiescence through support of myometrial caspase 3, which is an anticontractile agent Qeyasuria, 2009). his protein degrades both actin and the speciic gap junction protein, connexin-43 (Kyathanahalli, 2015).


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Obstentrics_Williams. called connexins. Six connexins form a hemichannel (connexon), nel. Connexons and gap junction channels can be formed from one or more connexin proteins. The composition of the gap junc tion channel is important for these channels' selectivity with regard to passage of molecules and communication between cells. In mice, myometrial caspase 3 activation is regulated by a pregnancy-induced endoplasmic reticulum stress response (ERSR). As background, the endoplasmic reticulum aids protein folding and transport. Functional irregularities cause misfolded proteins to accumulate and trigger the ERSR. he ERSR and its unolded-protein response (UPR) are cellular mechanisms that work to maintain homeostasis in the face of stimuli, such as stretch and inlammation. Prolonged ERSR promotes caspase 3 activation to preserve quiescence despite these stimuli.


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Obstentrics_Williams. Various cell surface receptors directly regulate myocyte contractility. Discussions thus far have described ion channel-linked receptors that regulate intracellular Ca2+ and membrane potential. In addition, numerous G-protein-coupled receptors appear to be modified during the phases of parturition. Several of these are present in myometrium and associated with Gos-mediated activation of adenylyl cyclase to yield higher cAMP levels. These receptors together with appropriate ligands may act with sex steroid hormones to maintain uterine quiescence (Price, 2000; Sanborn, 1998). Examples are the LH receptor and corticotropin-releasing hormone receptor 1 (CRHR1), both described in this section (Fig. 21-8). Other G-protein-coupled myometrial receptors, instead, are associated with G-protein-mediated activation of phospholipase C, which remember releases arachidonic acid. Ligands for the G-protein-coupled receptors include numerous neuropeptides, hormones, and autacoids. Many of these are


Obstentrics_Williams

Obstentrics_Williams. activation of phospholipase C, which remember releases arachidonic acid. Ligands for the G-protein-coupled receptors include numerous neuropeptides, hormones, and autacoids. Many of these are available to the myometrium during pregnancy in high concentration via endocrine or autocrine mechanisms.


Obstentrics_Williams

Obstentrics_Williams. 3-Adrenoreceptors are prototypical examples of cAMP signaling causing myometrium relaxation. 3-Adrenergic receptors mediate Gs-stimulated increases in adenylyl cyclase, elevated


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Obstentrics_Williams. FIGURE 21-8 G-protein-coupled receptor signal transduction pathways. A. Receptors coupled to heterotrimeric guanosine-triphosphate (GTP)-binding proteins (G proteins) are integral transmembrane proteins tl13t transduce extracellular signals to the cell interior. G-protein-coupled receptors exhibit a common structural motif consisting of seven membrane-spanning regions. B. Receptor occupation promotes interaction between the receptor and the G protein on the interior surface of the membrane. This induces an exchange of guanosine diphosphate (GOP) for GTP on the G protein Q subunit and dissociation of the Q subunit from the 31 heterodimer. Depending on its isoform, the GTP-Q subunit complex mediates intracellular signaling either indirectly by acting on effector molecules such as adenylyl cyclase (AC) or phospholipase C (PLC), or directly by regulating ion channel or kinase function. cAMP cyclic adenosine monophosphate; DAG diacylglycerol; IP3 inositol triphosphate.


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Obstentrics_Williams. levels of cAMP, and myometrial cell relaxation. The rate-lim iting factor is likely the number of receptors expressed and the level of adenylyl cyclase expression. Agents binding to these receptors have been used for tocolysis of preterm labor and include ritodrine and terbutaline (Chap. 42, p. 826). LH and hCG hormones share the same receptor, and this smooth muscle and blood vessels (Ziecik, 1992). Levels of myometrial LH-hCG receptors during pregnancy are greater before than during labor. Chorionic gonadotropin acts to acti vate adenylyl cyclase by way of a plasma membrane receptor G's-linked system. This lessens contraction frequency and force and lowers the number of tissue-speciic myometrial cell gap junctions (Ambrus, 1994; Eta, 1994). hus, high circulating levels of hCG may be one mechanism of uterine quiescence. In the mouse, variations in FSH-receptor density also regulate myometrial contractile activity (Stilley, 2016).


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Obstentrics_Williams. In the mouse, variations in FSH-receptor density also regulate myometrial contractile activity (Stilley, 2016). four G-protein-coupled receptors. Speciically, prostaglandin E receptors 1 through 4 (EP ,-EP 4) are expressed in the myo metrium during pregnancy and with labor onset (Astle, 2005; Leonhardt, 2003). EP2 and EP4 act through G's to raise cAMP levels and maintain myometrial cell quiescence but switch to a G'q/1i1 calcium-activating pathway during labor (Kandola, 2014). EP] and EP3 receptors act through G'q and G'i to aug ment intracellular Ca2+ and contractility.


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Obstentrics_Williams. he peptide hormone relaxin binds to the G-protein-coupled receptor named reaxin amiy peptide receptor 1 (FP 1). Binding activates adenylyl cyclase in uterine smooth muscle cells. Adenylyl cyclase in turn prevents increased intracellular Ca2+ and thus promotes uterine quiescence (Downing, 1993; Meera, 1995). There are two separate human relaxin genes, designated HI and H2. Of these, HI is primarily expressed in the decidua, trophoblast, and prostate, whereas H2 is primarily expressed in the corpus luteum. Relaxin in plasma of pregnant women is believed to originate exclusively from corpus luteum secretion. Plasma levels peak at approximately 1 ng/mL between 8 and 12 weeks' gestation. Thereater, they decline to lower levels that persist until term.


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Obstentrics_Williams. Corticotropin-releasing hormone (CRH) is synthesized in the placenta and hypothalamus. Discussed on page 410, CRH plasma levels rise dramatically during the inal 6 to 8 weeks of normal pregnancy and are implicated in mechanisms that control the timing of human parturition (Smith, 2007; Wadhwa, 1998). CRH appears to promote myometrial quiescence during most of pregnancy but then aids myometrial contractions with parturition onset. Studies suggest that these opposing actions are achieved by diferential actions of CRH via its receptor CRHR1. In nonlaboring myometrium at term, the interaction of CRH with its CRHR1 receptor activates the Gs-adenylate cyclasecAMP signaling pathway. his results in inhibition of inositol triphosphate (IP3) and stabilization of (Ca2+)j levels (You, 2012). However, in term laboring myometrium, (Ca2+)j concentrations are augmented by CRH activation of G proteins Gq and Gi and prompts stimulation ofIP3 production and greater contractility.


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Obstentrics_Williams. As just described, cAvIP is an important mediator of myometrial relaxation. However, activation of guanylyl cyclase raises Physiology of Labor 407 intracellular cyclic guanosine monophosphate (cGMP) levels. This also promotes smooth muscle relaxation (Word, 1993). Intracellular cGMP levels are increased in the pregnant myometrium and can be stimulated by atrial natriuretic peptide (ANP) , brain natriuretic peptide (BNP) receptors, and nitric oxide (Telfer, 2001). All of these factors and their receptors are expressed in the pregnant uterus.


Obstentrics_Williams

Obstentrics_Williams. In addition to pregnancy-induced compounds that promote myometrial cell refractoriness, the activity of enzymes that degrade or inactivate endogenously produced uterotonins are strikingly increased in phase 1. Some of these degrading enzymes and their respective targets include PGDH and prostaglandins; enkephalinase and endothelins; oxytocinase and oxytocin; diamine oxidase and histamine; catechol O-methyltransferase and catecholamines; angiotensinases and angiotensin-II; and platelet-activating factor (P AF) and P AF acetylhydrolase. Levels of several of these enzymes decrease late in gestation (Germain, 1994). To ensure uterine quiescence, the synthesis in the decidua of prostaglandins, in particular PGF2', is markedly suppressed. Suppression of prostaglandin production here persists through out most of pregnancy, and suppression withdrawal is a prereq uisite for parturition (Norwitz, 2015).


Obstentrics_Williams

Obstentrics_Williams. Suppression of prostaglandin production here persists through out most of pregnancy, and suppression withdrawal is a prereq uisite for parturition (Norwitz, 2015). Phase 1 of parturition also promotes an environment of immune tolerance to protect the fetus. Namely, decidual stromal cells proactively ensure that fetal antigens do not elicit a maternal immune response. his stems from a reduced capacity to attract T cells. This limited ability derives in part from epigenetic silencing of T cell-attracting inlammatory chemokine genes (Erlebacher, 2013; Nancy, 2012; PrabhuDas, 2015).


Obstentrics_Williams

Obstentrics_Williams. The initial stage of cervical remodeling-termed soteningbegins in phase 1 of parturition. It is characterized by greater tissue compliance, yet the cervix remains irm and unyielding. Hegar (1895) irst described palpable softening of the lower uterine segment at 4 to 6 weeks' gestation, and this sign was once used to diagnose pregnancy. Clinically, the maintenance of cervical anatomical and structural integrity is essential for pregnancy to continue to term. Preterm cervical dilation, structural insuiciency, or both may forecast delivery.


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Obstentrics_Williams. Cervical softening results from increased vascularity, cellular hypertrophy and hyperplasia, and slow, progressive compositional and structural changes in the extracellular matrix (Mahendroo, 2012; Myers, 2015; Word, 2007). Key to matrix changes, collagen, which is the main structural protein in the cervix, undergoes conformational changes that alter tissue stifness and flexibility (Zhang, 2012). Speciically, collagen processing and the number or type of stable covalent cross-links between collagen triple helices is altered. Mature cross-links between newly synthesized collagen monomers are reduced due to diminished expression and activity of the cross-link-forming enzymes beginning in early pregnancy (Akins, 2011; Drewes, 2007; Yoshida, 2014). hese enzymes are lysyl hydroxylase and lysyl oxidase. Together, these early pregnancy changes contribute to greater tissue compliance.


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Obstentrics_Williams. Clinical evidence for the importance of matrix changes to cervical sotening is supported by in vivo mechanical evaluation of the cervix (Badir, 2013; Parra-Saavedra, 2011). he prevalence of cervical insuiciency is also higher in those with inherited defects in the synthesis or assembly of collagen or elastic ibers (Anum, 2009; Hermanns-Le, 2005; Rahman, 2003; Wang, 2006). Examples are Ehlers-Danlos and Marfan syndromes, discussed in Chapter 59 (p. 1151). Concurrent with matrix remodeling in the sotening period, genes involved in cervical dilation and parturition are actively repressed (Hari Kishore, 2012). PHASE 2: PREPARATION FOR LABOR To prepare for labor, the myometrial tranquility of phase 1 of parturition must be suspended-so-called uterine awakening or activation. This phase 2 of parturition is a progression of uterine changes during the last few weeks of pregnancy. Importantly, shifting events associated with phase 2 can cause either preterm or delayed labor.


Obstentrics_Williams

Obstentrics_Williams. Key factors in uterine activation are depicted in Figure 21-5. In species that exhibit progesterone withdrawal, parturition progression to labor can be blocked by administering progesterone to the mother. Whether progesterone administration in the absence of classic progesterone withdrawal in pregnant women can delay the timely onset of parturition or prevent preterm labor continues to be investigated. he possibility that progesterone-containing injections or vaginal suppositories may prevent preterm labor has been studied in several randomized trials conducted during the past 15 years. hese are discussed in Chapter 42 (p. 816), and their use in preventing recurrent preterm birth continues to be debated (Norman, 2016).


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Obstentrics_Williams. Classic progesterone withdrawal resulting from decreased secretion does not occur in human parturition. However, a mechanism for progesterone inactivation, whereby the myometrium and cervix become refractory to progesterone's inhibitory actions, is supported by studies using progesterone-receptor antagonists. Mifepristone is a classic steroid antagonist, acting at the level of the progesterone receptor. Although less efective in inducing abortion or labor in women later in pregnancy, mifepristone appears to have some efect on cervical ripening and on increasing myometrial sensitivity to uterotonins (Berkane, 2005; Chwalisz, 1994a).


Obstentrics_Williams

Obstentrics_Williams. The diverse mechanisms by which functional progesterone withdrawal or antagonism is achieved is an active area of research. These include: (1) changes in the relative expression of the nuclear progesterone-receptor isoforms, PR-A, PR-B, and PR-C; (2) diferential interaction of PR-A and PB-B with enhancers and inhibitors of gene expression; (3) alterations in PR activity through changes in the expression of coactivators or corepressors that directly influence receptor function; (4) local inactivation of progesterone by steroid-metabolizing enzymes or synthesis of a natural antagonist; and (5) microRNA regulation of progesterone-metabolizing enzymes and transcription factors that modulate uterine quiescence (Condon, 2003; Mahendroo, 1999; Mesiano, 2002; Nadeem, 2016; Renthal, 2010; Williams, 2012a). Taken together, these observations support the concept that multiple pathways exist for a functional progesterone withdrawal.


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Obstentrics_Williams. Phase 2 myometrial changes prepare it for labor contractions. his results from a shit in the expression of key proteins that control uterine quiescence to an expression of contraction-associated proteins, described earlier (p. 405) (Renthal, 2015). Of these CAPs, myometrial oxytocin receptors and gap junction proteins, such as connexin-43, markedly rise in number. These CAPs increase uterine irritability and responsiveness to uterotonins.


Obstentrics_Williams

Obstentrics_Williams. Another critical change in phase 2 is formation of the lower uterine segment from the isthmus. With this development, the fetal head often descends to or even through the pelvic inletso-called lightening. he abdomen commonly undergoes a shape change, sometimes described by women as "the baby dropped." It is also likely that the lower segment myometrium is unique from that in the upper uterine segment, resulting in distinct roles for each near term and during labor. This is supported by human studies that demonstrate diferential expression of prostaglandin receptors and CAPs within the upper-and lower-segment myometrial regions (Astle, 2005; Blanks, 2003; Sparey, 1999). Near term, elevated expression of the HoA13 gene in the lower myometrial segment compared with the upper segment also induces CAP expression and regionalized contractility of the lower segment (Li, 2016).


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Obstentrics_Williams. Because of its long-standing application for labor induction, it seemed logical that oxytocin must playia central role in spontaneous human labor. Myometrial oxytocin receptor levels do rise during phase 2 of parturition, and the level of oxytocin receptor mRNA in human myometrium at term is greater than that found in preterm myometrium (Wathes, 1999). However, it is unclear whether oxytocin plays a role in the early phases of uterine activation or whether its sole function is in the expulsive phase of labor. Most studies of regulation of myometrial oxytocin receptor synthesis have been performed in rodents. Disruption of the oxytocin receptor gene in the mouse does not afect parturition. This suggests that, at least in this species, multiple systems likely ensure that parturition occurs.


Obstentrics_Williams

Obstentrics_Williams. Progesterone and estradiol appear to be the primary regulators of oxytocin receptor expression. Estradiol treatment in vivo or in myometrial explants raises myometrial oxytocin receptor concentrations. This action, however, is prevented by simultaneous treatment with progesterone (Fuchs, 1983). Progesterone also may act within the myometrial cell to enhance oxytocin receptor degradation and inhibit oxytocin activation of its receptor at the cell surface (Bogacki, 2002). hese data indicate that one of the mechanisms whereby progesterone maintains uterine quiescence is through inhibition of a myometrial oxytocin response. Physiology of Labor 409


Obstentrics_Williams

Obstentrics_Williams. Physiology of Labor 409 Before contractions begin, the cervix must undergo extensive remodeling. his eventually leads to the cervix yielding and dilating from forceful uterine contractions. Cervical modiications during phase 2 principally involve connective tissue changes-termed cervical ripening. The transition from the softening to the ripening phase begins weeks or days before labor. During this transformation, the cervical matrix changes its total amounts of gycosaminogycans, which are large linear polysaccharides, and proteogycans, which are proteins bound to these glycosaminoglycans.


Obstentrics_Williams

Obstentrics_Williams. Many of the processes that aid cervical remodeling are controlled by the same hormones regulating uterine function. That said, the molecular events of each are varied because of diferences in cellular composition and physiological requirements. For example, the hormone relaxin regulates myometrial quiescence. It also regulates cervical ripening, but through cell proliferation and modulation of extracellular matrix components (Park, 2005; Soh, 2012). The uterine corpus is predominantly smooth muscle. In contrast, the cervix has a high ratio of ibroblasts to smooth muscle cells, and extracellular matrix contributes significantly to overall tissue mass. Recent studies in the nonpregnant human cervix report a spatial gradient of smooth muscle cells. Specifically, smooth muscle cells make up approximately 50 percent of stromal cells at the internal os but only 10 percent at the external os (Vink, 2016).


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Obstentrics_Williams. Collagen. The cervix is an extracellular-matrix-rich tissue. Constituents of the matrix include type I, III, and IV collagen, matricellular proteins, glycosaminoglycans, proteoglycans, and elastic ibers. Of these, collagen is largely responsible for the structural disposition of the cervix. During collagen assembly, multiple collagen triple-helical molecules are cross-linked to one another by the actions of lysyl oxidase to form ibrils. In addition, ibril size, packing, and organization determine the strength and mechanical properties of the cervix. These properties are regulated in part by collagen-binding proteoglycans such as decorin or biglycan, as well as matricellular proteins such as thrombospondin 2 (Fig. 21-9).


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Obstentrics_Williams. Higher turnover of collagen during pregnancy likely allows the gradual replacement of mature cross-linked collagen ibrils with poorly cross-linked ibrils, which yield greater collagen disorganization. his increased turnover, rather than loss of collagen to achieve cervical remodeling, is supported by mouse and human studies that document no changes in collagen content between nonpregnant states and term pregnancy (Akins, 201i1; Myers, 2008; Read, 2007; Yoshida, 2014). In further support, polymorphisms or mutations in genes required for collagen assembly are associated with an elevated incidence of cervical insuiciency (Anum, 2009; Rahman, 2003; Warren, 2007).


Obstentrics_Williams

Obstentrics_Williams. Glycosaminoglycans and Proteoglycans. Hyaluronan is a high-molecular-weight polysaccharide that functions alone, whereas most other glycosaminoglycans (GAGs) complex with proteins to form proteoglycans. Hyaluronan is a hydrophilic, space-illing molecule, and thus greater hyaluronan production during cervical ripening is thought to increase viscoelasticity, hydration, and matrix disorganization. Hyaluronan synthesis is carried out by hyaluronan synthase isoenzymes, and expression of these enzymes is elevated in the cervix during ripening (kgul, 2012; Straach, 2005).


Obstentrics_Williams

Obstentrics_Williams. Although not well deined, changes in proteoglycan composition are also suggested to accompany cervical ripening. At least three small leucinerich proteoglycans are expressed in the cervix-decorin, biglycan, and ibromodulin (Westergren-Thorsson, 1998). In other connective tissues, decorin interacts with collagen to regulate the packing, order, and strength of collagen fibrils (see Fig. 21-9) (Ameye, 2002). In addition to the cervix, these proteoglycans are expressed in the fetal membranes and uterus.


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Obstentrics_Williams. Inflammatory Changes. In phase 2, resident immune cells are localized to the cervical stroma, although a functional role for these cells in this phase of remodeling has been challenged. Microarray studies comparing gene to allow a gradual increase in mechanical compliance of the cervix, A collagen fiber is made up of many fibrils, Fibril size and packing are regulated in part by small proteoglycans such as ,,obefore and after cervical ripening decorln and by the denSity of collagen cross-links, In phase 1, fibril size is uniform and fibrils are veil organizedoalthough a decline in cross-link density aids softening, During cervical ripening show little rise in proinflammatory ,: ,o,


Obstentrics_Williams

Obstentrics_Williams. In phase 2, fibril size IS less uniform, and spacing between collagen fibrils and fibers is greater gene expression. In contrast, proinand disorganized, flammatory and immunosuppressive gene expression in the cervix after delivery increases markedly compared with that during cervical ripening (Bollapragada, 2009; Hassan, 2006, 2009). Further, detailed studies in mice provide evidence that leukocyte migration but not activation takes place before labor. Once labor is underway, activation of neutrophils, pro inflammatory M 1 macrophages, and tissue repair M2 macrophages in the cervix is augmented. This suggests a role for inlammatory cells in postpartum cervical remodeling and repair (Mahendroo, 2012). Induction of Cervical Ripening


Obstentrics_Williams

Obstentrics_Williams. Induction of Cervical Ripening No therapies prevent premature cervical ripening. In contrast, treatment to promote cervical ripening for labor induction includes direct application of prostaglandins PGE2 and PGF2'. Prostaglandins likely modiy extracellular matrix structure to aid ripening. Although the role of prostaglandins in the normal physiology of cervical ripening remains unclear, this property is useful clinically to assist labor induction (Chap. 26, p. 505). In some nonhuman species, the cascades of events that allow cervical ripening are induced by dropping serum progesterone concentrations. And in humans, administration of progesterone antagonists causes cervical ripening.


Obstentrics_Williams

Obstentrics_Williams. In addition to matrix changes, during pregnancy, endocervical epithelial cells proliferate such that endocervical glands account for a signiicant percentage of cervical mass. he endocervical canal is lined with mucus-secreting columnar and stratified squamous epithelia. These cells form both a mucosal barrier and a tight junctional barrier that protect against microbial invasion (Akgul, 2014; Blaskewicz, 2011; Timmons, 2007). The mucosal epithelium recognizes and deters pathogen invasion via expression of toll-like receptors that identiy pathogens and via antimicrobial pep tides and protease inhibitors. In addition, these epithelia express signals to underlying immune cells when a pathogenic challenge exceeds their protective capacity (Wira, 2005). • Fetal Contributions to Parturition


Obstentrics_Williams

Obstentrics_Williams. • Fetal Contributions to Parturition It is intriguing to envision that the mature human fetus provides the signal to initiate parturition, and evidence for fetal signaling is mounting (Mendelson, 2017). The fetus may give signals through blood-borne agents that act on the placenta or through secretion into the amnionic luid. Fetal growth is an important component in uterine activation in phase 2 of parturition. With uterine activation, stretch is required for induction of specific CAPs. Namely, stretch increases expression of connexin-43 and oxytocin receptors. Levels of gastrin-releasing peptide, a stimulatory agonist for smooth muscle, are also augmented by stretch in the myometrium (Tattersall, 2012).


Obstentrics_Williams

Obstentrics_Williams. Clinical clues for a role of stretch come from the observa preterm labor than singleton ones. And, preterm labor is also signiicantly more common in pregnancies complicated by hydramnios. Although the mechanisms causing preterm birth in these two examples are debated, a role for uterine stretch must be considered. Cell signaling systems that are inluenced by stretch to regulate the myometrial cell continue to be defined. his processmechanotransduction-may include activation of cell-surface receptors or ion channels, transmission of signals through extracellular matrix, or release of autocrine molecules that act directly on myometrium (Shynlova, 2007; Young, 2011).


Obstentrics_Williams

Obstentrics_Williams. The ability of the fetus to provide endocrine signals that initiate parturition has been demonstrated in several species. However, evidence suggests that it is not regulated in the same manner in humans. hat said, the human fetal hypothalamic-pituitaryadrenal-placental axis is considered a critical component of normal parturition. Moreover, premature activation of this axis is considered to prompt many cases of pre term labor (Challis, 2000, 2001). As in the sheep, steroid products of the human fetal adrenal gland are believed to have efects on the placenta and membranes that eventually transform the myometrium from a quiescent to a contractile state. A key component in the human may be the unique ability of the placenta to produce large amounts ofCRH 21-10).


Obstentrics_Williams

Obstentrics_Williams. A CRH hormone that is identical to maternal and fetal hypothalamic CRH is synthesized by the placenta in relatively large amounts (Grino, 1987; Saijonmaa, 1988). However, unlike hypothalamic CRH, which is under glucocorticoid negative feedback, cortisol instead stimulates placental CRH production. This ability makes it possible to create a feed-forward endocrine cascade that does not end until delivery. Maternal plasma CRH levels are low in the first trimester and rise from midgestation to term. In the last 12 weeks, CRH plasma levels rise exponentially, peak during labor, and then fall precipitously after delivery (Frim, 1988; Sasaki, 1987). Amnionic luid CRH concentrations similarly increase in late gestation. CRH is the only trophic hormone-releasing FIGURE 21-10 The placental-fetal adrenal endocrine cascade.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21-10 The placental-fetal adrenal endocrine cascade. In late gestation, placental corticotropin-releasing hormone (CRH) stimulates fetal adrenal production of dehydroepiandrosterone sul fate (DHEA-S) and cortisol. The latter stimulates production of placental CRH, which leads to a feed-forward cascade that enhances adrenal steroid hormone production. ACTH = adrenocorticotropic hormone. factor to have a speciic serum binding protein. During most of pregnancy, CRH-binding protein (CRH-BP) binds most maternal circulating CRH, and this inactivates it (Lowry, 1993). During later pregnancy, however, CRH-BP levels in both maternal plasma and amnionic luid decline, leading to markedly greater levels of bioavailable CRH (Perkins, 1995; Petraglia, 1997).


Obstentrics_Williams

Obstentrics_Williams. Petraglia, 1997). In pregnancies in which the fetus can be considered "stressed" from various complications, concentrations of CRH in fetal plasma, amnionic luid, and maternal plasma are greater than those seen in normal gestation (Berkowitz, 1996; McGrath, 2002). he placenta is the likely source of this elevated CRH concentration. For example, placental CRH content is four fold higher in placentas from women with preeclampsia than in those from normal pregnancies (Perkins, 1995).


Obstentrics_Williams

Obstentrics_Williams. Placental CRH is thought to play several roles in parturition regulation. It may enhance fetal cortisol production to provide positive feedback so that the placenta produces more CRH. Late in pregnancy-phase 2 or 3 of parturition-modiication in the CRH receptor favors a switch from cAMP formation to increased myometrial cell calcium levels via protein kinase C activation (You, 2012). Oxytocin acts to attenuate CRHstimulated accumulation of cAMP in myometrial tissue. CRH acts to augment myometrial contractile force in response to PGF2: (Benedetto, 1994). Finally, CRH stimulates fetal adrenal Cwsteroid synthesis, thereby increasing substrate for placental aromatization.


Obstentrics_Williams

Obstentrics_Williams. Some have proposed that the rising CRH level at the end of gestation relects a etal-placental clock (McLean, 1995). CRH concentrations vary greatly among women, and the rate of rise in maternal CRH levels is a more accurate predictor of pregnancy outcome than is a single measurement (Leung, 2001; McGrath, 2002). In this regard, the placenta and fetus, through endocrinological events, inluence the timing of parturition at the end of normal gestation.


Obstentrics_Williams

Obstentrics_Williams. Surfactant protein A (SP-A) produced by the fetal lung is required for lung maturation. SP-A is expressed by the human amnion and decidua, is present in the amnionic luid, and prompts signaling pathways in human myometrial cells (Garcia-Verdugo, 2008; Lee, 2010; Snegovskikh, 2011). he exact mechanisms by which SP-A activates myometrial contractility in women, however, remain to be clarified. One mode may be its efects on prostaglandins. Namely, SP-A selectively inhibits prostaglandin F2: in the term decidua, but SP-A levels drop in the amnionic luid at term (Chaiworapongsa, 2008). In addition to SP-A, the fetal lung makes the uterotonic agent platelet-activating factor (Frenkel, 1996; T oyoshima, 1995). This factor and SP-A playia role in fetal-maternal signaling for parturition (Gao, 2015).


Obstentrics_Williams

Obstentrics_Williams. Toward the end of pregnancy, fetal membranes undergo physiological aging termed cellular senescence (Menon, 2016). In human fetal membranes and animal models, stretch and oxidative stress induce senescent fetal membrane to manifest a form of sterile inflammation termed senescent-associated secretory Physiology of Labor 41s1 phenotype (SASP). This in turn propagates inlammatory signals that further weaken the fetal membrane and activate signals in the decidua and myometrium to initiate parturition. hus, as the functional necessity of fetal membranes declines at term, they are able to promote signals that contribute to parturition initiation.


Obstentrics_Williams

Obstentrics_Williams. Some evidence shows that pregnancies with markedly diminished estrogen production may be associated with prolonged gestation. These "natural experiments" include women with inherited placental sulfatase deiciency and fetal anencephaly with adrenal hypoplasia. The broad range of gestational length seen with these disorders, however, calls into question the exact role of estrogen in human parturition initiation. Other fetal abnormalities that prevent or severely reduce the entry of fetal urine or lung secretions into amnionic fluid do not prolong human pregnancy. Examples are renal agenesis and pulmonary hypoplasia, respectively. Thus, a fetal signal through the paracrine arm of the fetal-maternal communication system does not appear to be mandated for parturition initiation.


Obstentrics_Williams

Obstentrics_Williams. Some brain anomalies of the fetal calf, fetal lamb, and sometimes the human fetus delay the normal timing of parturition. More than a century ago, Rea (1898) observed an association between fetal anencephaly and prolonged human gestation. Malpas (1933) extended these observations and described a pregnancy with an anencephalic fetus that was prolonged to 374 days-53 weeks. He concluded that the association between anencephaly and prolonged gestation was attributable to anomalous fetal brain-pituitary-adrenal function. Indeed, the adrenal glands of the anencephalic fetus are very small and, at term, may be only 5 to 10 percent as large as those of a normal fetus. This is caused by developmental failure of the fetal zone that normally accounts for most of fetal adrenal mass and production of Cwsteroid hormones (Chap. 5, p. 104). Such pregnancies are associated with delayed labor and suggest that the fetal adrenal glands are important for the timely onset of parturition. PHASE 3: LABOR


Obstentrics_Williams

Obstentrics_Williams. This phase is synonymous with active labor, which is customarily divided into three stages. These compose the commonly used labor graph shown in Figure 21-4. he irst stage begins when spaced uterine contractions of suicient frequency, intensity, and duration are attained to bring about cervical thinning, termed facement. Several uterotonins may be important to the success of this stage of active labor (see Fig. 21-5). These have been shown to stimulate smooth muscle contraction through G-protein coupling. This labor stage ends when the cervix is fully dilated-about 10 cm-to allow passage of the term-sized fetus. The irst stage of labor, therefore, is the stage of cervical eacement and dilation. The second stage begins when cervical dilation is complete and ends with delivery. Thus, the second stage of labor is the stage of etal expulsion. Last, the third stage begins immediately after delivery of the fetus and ends with the delivery of the placenta. Thus, the third stage of labor is


Obstentrics_Williams

Obstentrics_Williams. stage of labor is the stage of etal expulsion. Last, the third stage begins immediately after delivery of the fetus and ends with the delivery of the placenta. Thus, the third stage of labor is the stage of placental separation and expulsion.


Obstentrics_Williams

Obstentrics_Williams. Body Anat.eI.O. Hist.eI.O. Active segmentI II E.O. � Pathological retraction ring (Sandi) Obliterated 1.0. Active segmentIII Passive segment PREGNANT UTERUS AT TERM UTERUS IN LABOR NORMAL EARLY FIRST STAGE UTERUS IN LABOR NORMAL SECOND STAGE UTERUS IN LABOR ABNORMAL SECOND STAGE -DYSTOCIA FIGURE 21-11 Sequence ofdevelopment ofthe segments and rings in the uterus at term and in labor. Note comparison between the uterus of a nonpregnant woman, the uterus at term, and the uterus during labor. The passive lower uterine segment is derived from the isthmus, and the physiological retraction ring develops at the junction ofthe upper and lower uterine segments. The pathological retraction ring develops from the physiological ring. Anat. 1.0. = anatomical internal os; E.O. = external os; Hist. 1.0. = histological internal os; Ph.R.R. physiological retraction ring. • First Stage: Clinical Onset of Labor


Obstentrics_Williams

Obstentrics_Williams. Ph.R.R. physiological retraction ring. • First Stage: Clinical Onset of Labor In some women, forceful uterine contractions that efect delivery begin suddenly. In others, labor initiation is heralded by spontaneous release of a small amount of blood-tinged mucus from the vagina. his extrusion of the mucus plug that had previously illed the cervical canal during pregnancy is referred to as "show" or "bloody show." Its passage indicates that labor is already in progress or likely will ensue in hours to days. Unique among physiological muscular contractions, those of uterine smooth muscle during labor are painful. Several possible causes have been suggested: (1) hypoxia of the contracted myometrium-such as that with angina pectoris; (2) compression of nerve ganglia in the cervix and lower uterus by contracted interlocking muscle bundles; (3) cervical stretching during dilation; and (4) stretching ofthe peritoneum overlying the fundus.


Obstentrics_Williams

Obstentrics_Williams. Of these, compression of nerve ganglia in the cervix and lower uterine segment by the contracting myometrium is an especially attractive hypothesis. Paracervical infiltration with local anesthetic usually produces appreciable pain relief with contractions (Chap. 25, p. 490). Uterine contractions are involuntary and, for the most part, independent of extrauterine control. Neural blockade from epidural analgesia does not diminish their frequency or intensity. In other examples, myometrial contractions in paraplegic women and in women after bilateral lumbar sympathectomy are normal but painless. Mechanical stretching of the cervix enhances uterine activity in several species, including humans. his phenomenon is the Ferguson relex (Ferguson, 1941). Its exact mechanism is unclear, and release of oxytocin has been suggested but not proven. Manipulation of the cervix and "stripping" the fetal membranes is associated with a rise in blood levels of prostaglandin F2. metabolites.


Obstentrics_Williams

Obstentrics_Williams. The interval between contractions narrows gradually from approximately 10 minutes at the onset of irst-stage labor to as little as 1 minute or less in the second stage. Periods ofrelaxation between contractions, however, are essential for fetal welfare. Unremitting contractions compromise uteroplacental blood flow suiciently to cause fetal hypoxemia. In active-phase labor, the duration ofeach contraction ranges from 30 to 90 seconds and averages 1 minute. Contraction intensity varies appreciably during normal labor. Speciically, amnionic fluid pressures generated by contractions during spontaneous labor average 40 mm Hg, but vary from 20 to 60 mm Hg (Chap. 24, p. 479).


Obstentrics_Williams

Obstentrics_Williams. Distinct Lower and Upper Uterine Segments. During active labor, the anatomical uterine divisions that were initiated in phase 2 ofparturition become increasingly evident (Figs. 21-11 and 21-12). By abdominal palpation, even before membrane rupture, the two segments can sometimes be diferentiated. he upper segment is firm during contractions, whereas the lower segment is softer, distended, and more passive. This mechanism is imperative because if the entire myometrium, including the lower uterine segment and cervix, were to contract simultaneously and with equal intensity, the net expulsive force would markedly decline. hus, the upper segment contracts, retracts, and expels the fetus. In response to these contractions, the segment -Passive segment--0evel of internal cervical os Cervix Level of external cervical os Vagina


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21-12 The uterus at the time ofvaginal delivery. The active upper segment retracts around the presenting part as the fetus descends through the birth canal. In the passive lower segment, there is considerably less myometrial tone. form a greatly expanded, thinned-out tube through which the fetus can pass. he myometrium of the upper segment does not relax to its original length after contractions. Instead, it becomes relatively fixed at a shorter length. The upper active uterine segment con tracts down on its diminishing contents, but myometrial ten sion remains constant. he net efect is to take up slack, thus maintaining the advantage gained in expulsion of the fetus.


Obstentrics_Williams

Obstentrics_Williams. Concurrently, the uterine musculature is kept in irm contact with the uterine contents. As the consequence of retraction, left of. hus, the upper part of the uterine cavity becomes slightly smaller with each successive contraction. Because of the successive shortening of the muscular fibers, the upper active second-stage labor (see Fig. 21-11). This process continues and immediately after delivery. Clinically, it is important to understand that the phenomenon of upper segment retraction is contingent on a decrease in the volume of its contents. For this to happen, particularly early in labor when the entire uterus is virtually a closed sac with only minimal cervical dilation, the musculature of the lower segment must stretch. This permits a greater portion of the uterine contents to occupy the lower segment. The upper segment retracts only to the extent that the lower segment distends and the cervix dilates.


Obstentrics_Williams

Obstentrics_Williams. Relaxation of the lower uterine segment mirrors the same gradual progression of retraction. Recall that after each contraction of the upper segment, the muscles do not return to their previous length, but tension remains essentially the same. By comparison, in the lower segment, successive lengthening of the fibers with labor is accompanied by thinning, normally to only a few millimeters in the thinnest part. s a result of the lower segment thinning and concomitant upper segment thickening, a boundary between the two is marked by a ridge on the inner uterine surface-the physiological retraction ring. When the thinning of the lower uterine segment is extreme, as in obstructed labor, the ring is prominent and forms a pathological retraction ring. This abnormal condition is also known as the Bandl ring, which is discussed further in Chapter 23 (p. 455).


Obstentrics_Williams

Obstentrics_Williams. Changes in Uterine Shape. Each contraction gradually elongates the ovoid uterine shape and thereby narrows the horizontal diameter. This change in shape has important efects on the labor process. First, there is greater etal xis pressure, that is, the smaller horizontal diameter serves to straighten the fetal vertebral column. This presses the upper pole of the fetus firmly against the fundus, whereas the lower pole is thrust farther downward. The lengthening of the ovoid shape has been estimated at 5 to 10 cm. Second, with lengthening of the uterus, the longitudinal muscle ibers are drawn taut. As a result, the lower segment and cervix are the only parts of the uterus that are flexible, and these are pulled upward and around the lower pole of the fetus. After the cervix is dilated fully, the most important force in fetal expulsion is produced by maternal intraabdominal pressure. Physiology of Labor 413


Obstentrics_Williams

Obstentrics_Williams. After the cervix is dilated fully, the most important force in fetal expulsion is produced by maternal intraabdominal pressure. Physiology of Labor 413 Contraction of the abdominal muscles simultaneously with forced respiratory eforts with the glottis closed is referred to as pushing. The force is similar to that with defecation, but the intensity usually is much greater. The importance of intraabdominal pressure is shown by the prolonged descent during labor in paraplegic women and in those with a dense epidural block. And, although increased intraabdominal pressure is necessary to complete second-stage labor, pushing accomplishes little in the first stage. It exhausts the mother, and its associated elevated intrauterine pressures may be harmful to the fetus.


Obstentrics_Williams

Obstentrics_Williams. s the result of contraction forces, two fundamental changesefacement and dilation-occur in the ripened cervix. For an average-sized fetal head to pass through the cervix, its canal must dilate to a diameter of approximately 10 cm. At this time, the cervix is said to be completely or ully dilated. Although there may be no fetal descent during cervical efacement, most commonly the presenting fetal part descends somewhat as the cervix dilates. Cervical facement is "obliteration" or "taking up" of the cervix. It is manifest clinically by shortening of the cervical canal from a length of approximately 3 cm to a mere circular oriice with almost paper-thin edges. The muscular fibers at the level of the internal cervical os are pulled upward, or "taken up," into the lower uterine segment. The condition of the external os remains temporarily unchanged (Fig. 2i1-13). FIGURE 21-13 Schematic showing effacement and dilation.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21-13 Schematic showing effacement and dilation. A. Before labor, the primigravid cervix is long and undilated in contrast to that of the mUltipara, which has dilation of the internal and external os. B. As efacement begins, the multiparous cervix shows dilation and funneling of the internal os. This is less apparent in the primigravid cervix. C. As complete efacement is achieved in the primigravid cervix, dilation is minimal. The reverse is true in the multipara. Efacement may be compared to a funneling process in which the whole length of a narrow cylinder is converted into a very obtuse, flaring funnel with a small distal circular opening. Because of growing myometrial activity during uterine preparedness for labor, appreciable efacement of a softened cervix sometimes is accomplished before active labor begins. Efacement causes expulsion of the mucous plug as the cervical canal is shortened.


Obstentrics_Williams

Obstentrics_Williams. Because the lower segment and cervix have less resistance during a contraction, a centrifugal pull is exerted on the cervix and creates cervical dilation (Fig. 21-14). As uterine contractions cause pressure on the membranes, the hydrostatic action of the amnionic sac in turn dilates the cervical canal like a wedge. The process of cervical efacement and dilation causes formation of the orebag of amnionic luid. This is the leading portion of fluid and amnionic sac located in front of the presenting part. In the absence of intact membranes, the pressure of the presenting fetal part against the cervix and lower uterine segment is similarly efective. Early rupture of the membranes does not retard cervical dilation so long as the presenting fetal part is positioned to exert pressure against the cervix and lower segment.


Obstentrics_Williams

Obstentrics_Williams. Referring back to Figure 21-4, recall that cervical dilation is divided into latent and active phases. The active phase is subdivided further into the acceleration phase, the phase of maximum slope, and the deceleration phase (Friedman, 1978). The duration of the latent phase is more variable and sensitive to extraneous factors. For example, sedation may prolong the latent phase, and myometrial stimulation shortens it. The latent phase duration has little bearing on the subsequent course of labor, whereas the characteristics of the accelerated phase are usually predictive of labor outcome. The first stage ends when cervical dilation is complete. • Second Stage: Fetal Descent


Obstentrics_Williams

Obstentrics_Williams. • Second Stage: Fetal Descent In many nulliparas, engagement of the head is accomplished before labor begins. hat said, the head may not descend further until late in labor. In the descent pattern of normal labor, a typical hyperbolic curve is formed when the station of the fetal head is plotted as a function of labor duration. Station describes descent of the fetal biparietal diameter in relation to a line drawn between maternal ischial spines (Chap. 22, p. 436). Active descent usually takes place after dilation has progressed for some time (Fig. 21-15). During second-stage labor, the speed of descent is maximal and is maintained until the presenting part reaches the perineal floor (Friedman, 1978). In nulliparas, the presenting part typically descends slowly and steadily. In multiparas, however, particularly those of high parity, descent may be rapid.


Obstentrics_Williams

Obstentrics_Williams. he birth canal is supported and functionally closed by the pelvic loor (Chap. 2, p. 21). The most important component of the loor is the levator ani muscle and the ibromuscular connective tissue that covers its upper and lower surfaces. he biomechanical properties of these structures and of the vaginal wall A B c Internal cervical as External cervical os \ Internal cervical os cervical os cervical os External cervical os FIGURE 21-14 Hydrostatic action of membranes in effecting cervical effacement and dilation, With labor progression, note the changing relations of the internal and external os in (A), (B), and(C), Although not shown in this diagram, with membrane rupture, the presenting part, applied to the cervix and the forming lower uterine segment, acts Similarly,


Obstentrics_Williams

Obstentrics_Williams. Physiology of Labor 415 its diminishing contents. Normally, by the time the newborn is completely deliv ered, the uterine cavity is nearly obliter ated. he organ consists of an almost solid mass of muscle, several centimeters thick, above the thinner lower segment. he uterine fundus now lies just below the level of the umbilicus .


Obstentrics_Williams

Obstentrics_Williams. in the area of the placental implantation 5.�2 c0 site (Fig. 21-16). For the placenta to accommodate itself to this reduced area, it thickens, but because of limited placen tal elasticity, it is forced to buckle. The resulting tension pulls the weakest layer decidua spongiosa-from that site. Thus, FIGURE 21-15 Labor course divided on the basis of expected evolution of the dilatation placental separation follows the disproand descent curves into three functional divisions. The preparatory division includes the portion created between the relatively latent and acceleration phases. The dilatational division is the phase of maximum slope of unchanged placental size and the reduced dilatation. The pelvic division encompasses both the deceleration phase and the second implantation site size. stage, which is concurrent with the phase of maximum slope of fetal descent. (Redrawm


Obstentrics_Williams

Obstentrics_Williams. stage, which is concurrent with the phase of maximum slope of fetal descent. (Redrawm Cleavage of the placenta is aided from Friedman EA: Labor: Clinical Evaluation and Management, 2nd ed. New York, greatly by the loose structure of the Appleton-Century-Crofts, 1978.) spongy decidua. As detachment proceeds, a hematoma forms between the separating change markedly during parturition. These result from altered placenta and the adjacent decidua, which remains attached to extracellular matrix structure or composition (Alperin, 2015; the myometrium. The hematoma is usually the result rather Rahn, 2008; Lowder, 2007). The levator ani muscle closes the lower end of the pelvic cavity as a diaphragm. Thereby, a concave upper and a convex lower surface are presented. The posterior and lateral portions of the pelvic Boor, which are not spanned by the levator ani muscle, are occupied bilaterally by the piriformis and coccygeus muscles.


Obstentrics_Williams

Obstentrics_Williams. The levator ani muscle varies in thickness from 3 to 5 mm, although its margins encircling the rectum and vagina are somewhat thicker. During pregnancy, the levator ani usually undergoes hypertrophy, forming a thick band that extends backward from the pubis and encircles the vagina about 2 cm above the plane of the hymen. On contraction, the levator ani draws both the rectum and the vagina forward and upward in the direction of the symphysis pubis and thereby acts to close the vagina.


Obstentrics_Williams

Obstentrics_Williams. In the first stage of labor, the membranes, when intact, and the fetal presenting part serve to dilate the upper vagina. he most marked change consists of stretching levator ani muscle fibers. This is accompanied by thinning of the central portion of the perineum, which becomes transformed from a wedgeshaped, 5-cm-thick tissue mass to a thin, almost transparent membranous structure less than 1 cm thick. hen the perineum is distended maximally, the anus becomes markedly dilated and presents an opening that varies from 2 to 3 cm in diameter and through which the anterior wall of the rectum bulges . • Third Stage: Delivery of Placenta and Membranes This stage begins immediately after fetal delivery and involves separation and expulsion of the placenta and membranes. As FIGURE 21-16 Diminution in size of the placental site after birth of the newborn. A. Spatial relations before birth. B. Placental spatial relations after birth.


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21-16 Diminution in size of the placental site after birth of the newborn. A. Spatial relations before birth. B. Placental spatial relations after birth. the neonate is born, the uterus spontaneously contracts around than the cause of the separation, because in some cases bleeding is negligible. FIGURE 21-17 Postpartum, membranes are thrown up into folds as the uterine cavity decreases in size. (Used with permission from Dr. Kelley S. Carrick.) The great decline in uterine cavity surface area simultaneously throws the fetal membranes-the amniochorion and the parietal decidua-into innumerable folds (Fig. 21-17). Membranes usually remain in situ until placental separation is nearly completed. These are then peeled of the uterine wall, partly by further contraction of the myometrium and partly by traction that is exerted by the separated placenta as it descends during expulsion.


Obstentrics_Williams

Obstentrics_Williams. After the placenta has detached, it can be expelled by increased abdominal pressure. Completion of the third stage is also accomplished by alternately compressing and elevating the fundus, while exerting minimal traction on the umbilical cord. The retroplacental hematoma either follows the placenta or is found within the inverted sac formed by the membranes. In this process, known as the Schultze mechanism of placental expulsion, blood from the placental site pours into the membrane sac and does not escape externally until after extrusion of the placenta. In the other form of placental extrusion, known as the Duncan mechanism, the placenta separates irst at the periphery and blood collects between the membranes and the uterine wall and escapes from the vagina. In this circumstance, the placenta descends sideways, and its maternal surface appears irst.


Obstentrics_Williams

Obstentrics_Williams. Late in pregnancy, during phase 2 of parturition, the number of myometrial oxytocin receptors grows appreciably (Fuchs, 1982; Kimura, 1996). his increase coincides with a greater uterine contractile responsiveness to oxytocin. Prolonged gestation is associated with a delay in the rise of these receptor levels (Fuchs, 1984). Oxytocin-literally, quick birt-was the irst uterotonin to be implicated in parturition initiation. his nanopeptide is synthesized in the magnocellular neurons of the supraoptic and paraventricular neurons. The prohormone is transported with its carrier protein, neurophysin, along the axons to the neural lobe of the posterior pituitary gland in membrane-bound vesicles for storage and later release. The prohormone is converted enzymatically to oxytocin during transport (Gainer, 1988; Leake, 1990).


Obstentrics_Williams

Obstentrics_Williams. In addition to its efectiveness in pharmacologically inducing labor at term, oxytocin is a potent uterotonin and occurs naturally in humans. Subsequent observations provide additional support for this theory: (1) the number of oxytocin receptors strikingly rises in myometrial and decidual tissues near the end of gestation; (2) oxytocin acts on decidual tissue to promote prostaglandin release; and (3) oxytocin is synthesized directly in decidual and extraembryonic fetal tissues and in the placenta (Chibbar, 1993; Zingg, 1995).


Obstentrics_Williams

Obstentrics_Williams. Although little evidence suggests a role for oxytocin in phase 2 of parturition, abundant data support its important role during second-stage labor and in the puerperium-phase 4 of parturition. Speciically, maternal serum oxytocin levels are elevated: (1) during second-stage labor, which is the end of phase 3 of parturition; (2) in the early puerperium; and (3) during breastfeeding (Nissen, 1995). Immediately after delivery of the fetus, placenta, and membranes, which completes parturition phase 3, irm and persistent uterine contractions are essential to prevent postpartum hemorrhage. Oxytocin likely causes persistent contractions.


Obstentrics_Williams

Obstentrics_Williams. Although their role in phase 2 of parturition in uncomplicated pregnancies is less well defined, a critical role for prostaglandins in phase 3 of parturition is clear (MacDonald, 1993). First, levels of prostaglandins-or their metabolites-in amnionic luid, maternal plasma, and maternal urine are increased during labor. Second, receptors for PGE2 and PGF2x are expressed in the uterus and cervix. Thus, if these tissues are exposed to prostaglandins, they will respond. Third, treatment of pregnant women with prostaglandins, by any of several administration routes, causes abortion or labor at all gestational ages. Moreover, administration of prostaglandin H synthase type 2 (PGHS-2) inhibitors to pregnant women will delay spontaneous labor onset and sometimes arrest preterm labor (Loudon, 2003). Last, prostaglandin treatment of myometrial tissue in vitro sometimes causes contraction, dependent on the prostanoid tested and the physiological status of the tissue treated.


Obstentrics_Williams

Obstentrics_Williams. During labor, prostaglandin production within the myometrium and decidua is an eicient mechanism of activating contractions. For example, prostaglandin synthesis is high and unchanging in the decidua during phase 2 and 3 of parturition. Moreover, the receptor level for PGF2x is augmented in the decidua at term, and this increase most likely is the regulatory step in prostaglandin action in the uterus. he fetal membranes and placenta also produce prostaglandins. Primarily PGE2, but also PGF2x, are detected in amnionic fluid at all gestational ages. As the fetus grows, prostaglandin levels in the amnionic fluid rise gradually. heir greatest


Obstentrics_Williams

Obstentrics_Williams. FIGURE 21-18 Sagittal view of the exposed forebag and attached decidual fragments after cervical dilation during labor. (Redrawn from MacDonald PC, Casey ML: Preterm birth. Sci Am 3:42, 1996.) elevation in concentration within amnionic luid, however, is demonstrable after labor begins. hese higher levels likely result as the cervix dilates and exposes decidual tissue (Fig. 21-18). hese higher levels in the forebag, compared with those in the upper compartment, are believed to follow an inflammatory response that signals the events leading to active labor. Together, the rise in cytokine and prostaglandin concentrations further degrade the extracellular matrix, thus weakening fetal membranes.


Obstentrics_Williams

Obstentrics_Williams. The endothelins are a family of 21-amino-acid pep tides that powerfully induce myometrial contraction (Word, 1990). The endothelin A receptor is preferentially expressed in smooth muscle, and when activated, it efects a rise in intracellular calcium. Endothelin-1 is produced in myometrium of term gestations and is able to induce synthesis of other contractile mediators such as prostaglandins and inflammatory mediators (Momohara, 2004; Sutclife, 2009). The requirement of endothelin-1 in normal parturition physiology remains to be established. Two G-protein-linked angiotensin II receptors are expressed in the uterus-AT1 and AT2. In nonpregnant women, the AT2 receptor predominates, but the ATI receptor is preferentially expressed in gravidas (Cox, 1993). Angiotensin II binding to the plasma-membrane receptor evokes contraction. During pregnancy, the vascular smooth muscle that expresses the AT2 receptor is refractory to the pressor efects of infused angiotensin II (Chap. 4, p. 63).


Obstentrics_Williams

Obstentrics_Williams. Physiology of Labor 41 7 PHASE 4: THE PUERPERIUM Immediately and for about an hour after delivery, the myometrium remains persistently contracted. This directly compresses large uterine vessels and allows thrombosis of their lumens to prevent hemorrhage. his is typically augmented by endogenous and pharmacological uterotonic agents (Chap. 27, p. 526). Uterine involution and cervical repair are prompt remodeling processes that restore these organs to the nonpregnant state. hese protect the reproductive tract from invasion by commensal microorganisms and restore endometrial responsiveness to normal hormonal cyclicity. During the early puerperium, lactogenesis and milk let-down begin in mammary glands (Chap. 36, p. 656). Reinstitution of ovulation signals preparation for the next pregnancy. Ovulation generally occurs within 4 to 6 weeks after birth. However, it is dependent on the duration of breastfeeding and lactationinduced, prolactin-mediated anovulation and amenorrhea.


Obstentrics_Williams

Obstentrics_Williams. Akgul Y, Holt R, Mummert M, et al: Dynamic changes in cervical glycosamino glycan composition during normal pregnancy and preterm birth. Endocrinology 153(7):3493,o2012 Akgul Y, Word A, Ensign LM, et al: Hyaluronan in cervical epithelia protects against infection-mediated preterm birth.] Clin Invest 124(12):5481, 20o14 Akins ML, Luby-Phelps K, Bank A, et al: Cervical softening during pregnancy: regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse. Bioi Reprod 84(5): 1 053, 2011 Alperin M, Lawley OM, Esparza MC, et al: Pregnancy-induced adaptations in the intrinsic structure of rat pelvic loor muscles. Am ] Obstet Gynecol 213(2):191 e191, 2015 Ambrus G, Rao CV: Novel regulation of pregnant human myometrial smooth muscle cell gap junctions by human chorionic gonadotropin. Endocrinology 135(6):2772, 1994