Obstentrics_Williams

Obstentrics_Williams. Septate anomalies are associated with diminished fertility and increased risks for adverse pregnancy outcomes that include miscarriage, preterm delivery, and malpresentation (Chan, 201i1a; Ghi, 2012). Hysteroscopic septal resection has been shown to improve pregnancy rates and outcomes (Mollo, 2009; Pabu:cu, 2004). From their metaanalysis, Valle and colleagues (20l3) reported a 63-percent pregnancy rate and 50-percent live birth rate following resection. his malformation is a mild deviation from the normally developed uterus. Although some studies report no increased adverse associated outcomes, others have found excessive secondtrimester losses, preterm labor, and malpresentation (Chan, 2011a; Mucowski, 2010; Woelfer, 2001). Treatment with Cerclage


Obstentrics_Williams

Obstentrics_Williams. Treatment with Cerclage Some women with uterine anomalies and repetitive pregnancy losses may beneit from transvaginal or transabdominal cervical cerclage (Golan, 1992; Groom, 2004). Others with partial cervical atresia or hypoplasia may also benefit (Hampton, 1990; Ludmir, 1991). Candidacy for cerclage is determined by the same criteria used for women without such defects, which is discussed in Chapter 18 (p. 354).


Obstentrics_Williams

Obstentrics_Williams. During the 1960s, a synthetic nonsteroidal estrogen-diethylstilbestrol (DES)-was used to treat pregnant women for threatened abortion, preterm labor, preeclampsia, and diabetes. he treatment was remarkably inefective. Later, it was also discovered that women exposed as fetuses had increased risks of developing several specific reproductive-tract abnormalities. hese included vaginal clear cell adenocarcinoma, cervical intraepithelial neoplasia, small-cell cervical carcinoma, and vaginal adenosis. Afected women had identiiable structural variations in the cervix and vagina that include transverse septa, circumferential ridges, and cervical collars. Uteri potentially had smaller cavities, shortened upper uterine segments, or T-shaped and other irregular cavities (see Fig. 3-5) (Kaufman, 1984).


Obstentrics_Williams

Obstentrics_Williams. These women sufer impaired conception rates and higher rates of miscarriage, ectopic pregnancy, and preterm delivery, especially in those with structural abnormalities (Kaufman, 2000; Palmer, 2001). Now, more than 50 years after DES use was proscribed, most afected women are past childbearing age, but higher rates of earlier menopause, cervical intraepithelial neoplasia, and breast cancer are reported in exposed women (Hatch, 2006; Hoover, 2011; Troisi, 2016).


Obstentrics_Williams

Obstentrics_Williams. he fallopian tubes develop from the unpaired distal ends of the mlillerian ducts. Congenital anomalies include accessory ostia, complete or segmental tubal agenesis, and several embryonic cystic remnants. The most common is a small, benign cyst attached by a pedicle to the distal end of the fallopian tube-the hydatid of Morgagni. In other cases, benign paratubal cysts may be of mesonephric or mesothelial origin. Last, in utero exposure to DES is associated with various tubal abnormalities. Of these, short, tortuous tubes or ones with shriveled fimbria and small ostia are linked to infertility (DeCherney, 1981). The pregnant uterus may infrequently show exaggerated flexion. Mild or moderate lexion is typically inconsequential, but congenital or acquired extremes may lead to pregnancy complications.


Obstentrics_Williams

Obstentrics_Williams. The pregnant uterus may infrequently show exaggerated flexion. Mild or moderate lexion is typically inconsequential, but congenital or acquired extremes may lead to pregnancy complications. Antlexion describes forward angling of the uterine fundus in the sagittal plane relative to the cervix. Exaggerated degrees usually pose no problem in early pregnancy. Later, however, particularly when the abdominal wall is lax such as with diastasis recti or ventral hernia, the uterus may fall forward. In extreme cases, the fundus lies below the lower margin of the symphysis. Sometimes, this abnormal uterine position prevents proper transmission of labor contractions, but this is usually overcome by repositioning and application of an abdominal binder.


Obstentrics_Williams

Obstentrics_Williams. Retrolexion describes posterior uterine fundal angling in the sagittal plane. A growing retrolexed uterus will occasionally become incarcerated in the hollow of the sacrum. Symptoms include abdominal discomfort, pelvic pressure, and voiding dysfunction or retention. During bimanual pelvic examination, the cervix will be anterior and behind the symphysis pubis, whereas the uterus is appreciated as a mass wedged in the pelvis. Sonography or MR imaging can aid the clinical diagnosis (Gardner, 2013; Grossenburg, 2011; van Beekhuizen, 2003).


Obstentrics_Williams

Obstentrics_Williams. With continued uterine growth, the incarcerated uterus can spontaneously resolve over 1 to 2 weeks. An indwelling urinary catheter or intermittent self-catheterization may be needed in the interim to empty the bladder. Persistent cases require manual repositioning. For this, after bladder catheterization, the uterus can usually be pushed out of the pelvis when the woman is placed in a knee-chest position. Often, this is best accomplished by digital pressure applied through the rectum. FIGURE 3-7 Anterior sacculation of a pregnant uterus. Note the markedly attenuated anterior uterine wall and atypical location of the true uterine fundus. Rood, 2014). Conscious sedation, spinal analgesia, or general anesthesia may be necessary. Following repositioning, the catheter is left in place until bladder tone returns. Insertion of a soft pessary for a few weeks usually prevents recurrent incarceration.


Obstentrics_Williams

Obstentrics_Williams. Lettieri and colleagues (1994) described seven cases of uterine incarceration not amenable to these simple procedures. In two women, laparoscopy was used at 14 weeks' gestation to reposition the uterus using the round ligaments for traction. Alternatively, in case series, advancing a colonoscope or colonoscopic insulation was used to dislodge an incarcerated uterus (Dierickx, 2011; Newell, 2014; Seubert, 1999).


Obstentrics_Williams

Obstentrics_Williams. Rarely, sacculation may form as extensive lower uterine segment dilatation due to persistent entrapment of the pregnant uterus in the pelvis (Fig. 3-7). In these extreme cases, sonography and MR imaging are typically required to deine anatomy (Gottschalk, 2008; Lee, 2008). Cesarean delivery is necessary when sacculation is marked, and Spearing (1978) stressed the importance of clariying the distorted anatomy. An elongated vagina passing above the level of a fetal head that is deeply placed into the pelvis suggests a sacculation or an abdominal pregnancy. The Foley catheter is frequently palpated above the level of the umbilicus! Spearing (1978) recommended extending the abdominal incision above the umbilicus and delivering the entire uterus from the abdomen before hysterotomy. This will restore correct anatomical relationships and prevent inadvertent incisions into and through the vagina and bladder. Unfortunately, this may not always be possible (Singh, 2007). As a inal caveat, a


Obstentrics_Williams

Obstentrics_Williams. restore correct anatomical relationships and prevent inadvertent incisions into and through the vagina and bladder. Unfortunately, this may not always be possible (Singh, 2007). As a inal caveat, a true uterine diverticulum has been mistaken for uterine sacculation (Rajiah, 2009).


Obstentrics_Williams

Obstentrics_Williams. he uterus commonly rotates to the maternal right during pregnancy. Rarely, uterine rotation exceeds 180 degrees to cause torsion. Most cases of torsion result from uterine leiomyomas, miillerian anomalies, fetal malpresentation, pelvic adhesions, or laxity of the abdominal wall or uterine ligaments. Jensen (1992) reviewed 212 cases and reported that associated symptoms may include obstructed labor, intestinal or urinary Anterior wall complaints, abdominal pain, uterine sacculation hypertonus, vaginal bleeding, and hypotension.


Obstentrics_Williams

Obstentrics_Williams. Anterior wall complaints, abdominal pain, uterine sacculation hypertonus, vaginal bleeding, and hypotension. Most cases of uterine torsion are found at the time of cesarean delivery. In some women, torsion can be conirmed preoperatively with MR imaging, which shows a twisted vagina that appears X-shaped rather than its normal H-shape (Nicholson, 1995). As with uterine incarceration, during cesarean delivery, a severely displaced uterus should be repositioned anatomically before hysterotomy. In some cases, an inability to reposition or a failure to recognize the torsion may lead to a posterior hysterotomy inci sion (Albayrak, 2011; Picone, 2006; Acitll P, Aden MI; lhe hisrory of female genital (rael malformation classiica rions and proposal of an updau'd s,slcm. Hum Reprod Update 17:693, 2011 AksgJacdc , JUlll A: Testicular �unction and lertiliry in men and Klinefelter syndrome: a review. Ellr J Endocrinol 168(4):R67, 2013


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Obstentrics_Williams. AksgJacdc , JUlll A: Testicular �unction and lertiliry in men and Klinefelter syndrome: a review. Ellr J Endocrinol 168(4):R67, 2013 Albayrak M. 3eni:m A, Ozdemir I. Cl al: Deliberate posterior low transverse incision at cesarean section of a gr.\'id uterus in 180 degrees of [OTsion: a case report. J Reprod Med 56(3-4): 181, 20 II Alborli S, Asejah H, Amini \1, cr al: Laparoscopic mClfoplasry in bicornuate and didelphic uteri: feasibility and outcome. Arch Gynecol Obslet 291 (5), I 167. 2015 NJen JW, Cardall S. Kitdjarukhajon M, '1 al: Incidence of ovarian mal descent in women with mulleriln dun anomalies: evaluation by MRI. A)R 198(4),W381. 2012 Am�ric;tn College of Obstetricians and Grnecologisrs: Mlillerian agenesis: , diagnOSIs, management. and Ireatment. CommiHee Opinion No. 562. May 2013, Reairmed 2016


Obstentrics_Williams

Obstentrics_Williams. Am�ric;tn College of Obstetricians and Grnecologisrs: Mlillerian agenesis: , diagnOSIs, management. and Ireatment. CommiHee Opinion No. 562. May 2013, Reairmed 2016 American Fertility Society: 111e American Fertility Society classiications of �dn�(al adhesions, distal tubal occlusion. mbal occlusion secondary to tubal Ilgallon, mbal pregnancies, \liillerian anomalies and intrauterine adhesions. Fertil Steril 49:944. 1988 Auchus R): Management considerations for thc adult with congcniral adren,11 h),p·rplasia. Mol Cdl Endocrinol 408: 190. 2015 Bermelon�, ��:m�nez, Ten p, et �I: l'hree-dimensional ultrasound in the diag �10SISnol lllullenan duct anomalies and concordance with magnetic resonance . Imagtng. Ultrasound Obstct G)'nccol 35: 593, 2010 Blanton EN, Rouse 0): Trial oflahor in women with transverse vaginal septa. Obstet Gynecol JOI:IIIIO, 2003 Bradshaw KD: Anatomical disorders, In Hoffman BL, Schorge )0, Bradshaw


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Obstentrics_Williams. Blanton EN, Rouse 0): Trial oflahor in women with transverse vaginal septa. Obstet Gynecol JOI:IIIIO, 2003 Bradshaw KD: Anatomical disorders, In Hoffman BL, Schorge )0, Bradshaw KD. ct al (eds): Williams Gynecology, 3rd ed. New York, �IcGraw-Hill Education. 20n16 Byne ), Nussbaum-Bbsk A. Taylor WS, et al: Prevalence of �Hil1erian duct anomalies deteCled at ultrasound. Amn) Med Gener 94(1):9. 2000 Calogero E, Giagul1i VA. Mongiol LM, et al: Klineflter syndrome: cardio vascular abnormalities and metabolic disorders.n) Endocrinol Invest 40(7): 705.n2017 Chan V, )ayaprakasan K, Tan A. et al: Reproductive outcomes in women with cOllgellitalnuterine anomalies: a systematic review. Ultrasound Obstet Gynecol 38(4):rnt. 20n1lna Chan V. )ayaprakasan K. Zamoran), et al: The prevalence of conueniral uterine anomalies in unsdecled and high-risk populations: a syste'.ttic review. Hum Rcprod Update 17(6):761, 201lb


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Obstentrics_Williams. Chan V. )ayaprakasan K. Zamoran), et al: The prevalence of conueniral uterine anomalies in unsdecled and high-risk populations: a syste'.ttic review. Hum Rcprod Update 17(6):761, 201lb Dabirashrai H. Mohammad K. Moghadami-Tabri.i N: Ovarian malposition in women with uterine anomalies. Obstet Gynecol 83:293. 1994 Deans R, 3anks F. liao LM. et al: Reproductive outcomes in women with cla� sic bladder exstrophy: an observational cross-sectional srudy. Am J Obstct Gynecol 206(6):496.e I. 2012 DeChcrney AH. Cholst I. Nafcolin F: StrucUire and funcrion of the f.111opian tubes following exposure o diethylstilbestrol (DES) during gesmtion. Fenil Steril 36(6):74n1, 1981 Deutch TO, Abuhamad AZ: 111e role of 3-dimensional ultrasonography and magnctic resonance imaging in the diagnOSiS of l11illlerian ducr anol11alies: a review of the literature. ) Ultrasound Me<l r(3):413. 2008 Die�ickx I. V�n Holsbeke C, Mesens T, et al: Colonoscopy-assisted reposi


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Obstentrics_Williams. Die�ickx I. V�n Holsbeke C, Mesens T, et al: Colonoscopy-assisted reposi CIon ufthe IIlcarcerared u[crus in mid-pregnancy: a repOrl offour Cases and a literature review. Eur) Obstet G'necol Rcprod Bioi 158(2):153.n201 J Di ?piezionS�rdo A. Campo R. Gordts S, et al: 111e comprehensiveness of the . ESHRE/ESGE classiication of female genital tract congenital anomalies: a systematic review of cases not classiied by [he AFS system. Hum Reprod 30(5),n104.n2015 Dondcrwinkel PF. Dort )1'. Willemsen N: The uniconltate uterus: clinical implications. Eur) Obstet Gynccol Reprod Bioi 47(2): 135. 1992 Dove CK. Harvey SM, Spalluro LB: Sonographic indings of early pregnancy in the rudimentary hon of a uniconuatc uterus: 1 rwo case rcpon. Clin Imaging 47:25, 2017 Dreisler E. Srampe Sorensen S: Mlillerian duct anomalies diagnosed by salinc contraSt sonohystcrography: prevalence in a general population. Fenil Steril 102(2),525. 20n14


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Obstentrics_Williams. Dreisler E. Srampe Sorensen S: Mlillerian duct anomalies diagnosed by salinc contraSt sonohystcrography: prevalence in a general population. Fenil Steril 102(2),525. 20n14 Dy GW, Willihnganz-Llwson KH. Shnorhavorian M, er al: Successful preg nancy in paci'rHS with exst'Tophy-epispadias complex: a Universiry of Iash ington experience.n) Pediatr Urol II (4):213.eI. 2015 Edelman AB. Jensen )T, Lee OM. et al: Sliccessfulnmedical abortion of a pregnancy within a noncommunicating rudimentary ucerine hon. Amn) Obstel Gynccol J89:886, 2003 .swara)R, Kielb S, Koyle MA. et al: The recommendations of the 2015 American Urological Association (Iorking Group on Genitourinary COil genitalism. Urology 88: I, 20I6 l'edele L, Bianchi S, Agnoli B. et al: Urinary tract anomalies associated with unicornuate merus.n) Urol 155:84;'. 1996 Fedele L, Bianeli S. Zaneonato G, et II, Laparoscopie removal ofthe eavitared nOllcommunicating rudimetllary UTerine horn: surgical aspects in 10 c;lses.


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Obstentrics_Williams. Fedele L, Bianeli S. Zaneonato G, et II, Laparoscopie removal ofthe eavitared nOllcommunicating rudimetllary UTerine horn: surgical aspects in 10 c;lses. Fenil Steriln83(2):432. 2005 Friedler S. Grin L. Liberti G. et al: The reproductive parential of patients with Mayer-Rokitansky-Kiister-Hauser syndrome using gestational surrogacy: a systematic review. Reprod Biomed Online 32{ln):54, 2016 Gardner CS, Jafe TA, Hertzberg BS, et al: The incarcerated uterus: a review of MRI and ultrasound imaging appearances. A)R Am ) Roentgenol 201(1),223.n2013 Ghi T, De �'usso F, Maroni E. et at: 'fhe pregnanc)' outcome in women with incidental diagnOSiS of septate uterus at irst trimester scan. Hum Reprod 27(9),267. 2012 Golan A, Langer R. Neuman M. et al: Obstetric outcome in women with congenital uterine malformations. ) Reprod 'ed 3-:233. 1992


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Obstentrics_Williams. Golan A, Langer R. Neuman M. et al: Obstetric outcome in women with congenital uterine malformations. ) Reprod 'ed 3-:233. 1992 Gonschalk E�1. Siedenropf )P, Schoenbon I, ct 31: Prenatal sonographic and ..lRl indings in a pregnancy complicated by uterine sacculation: case reporr and review of [he litera Hire. Ultrasound Obstet GynecoIn32(4):582 ' 2008 Graupera B. Pascua! MA, Hereter , C[ al: Accuracy of three-dinensionalnultrasound compared with magnetic resonance imaging in diagnosis of miillerian duct anomalies using ESHRE-ESGE consensus on (he classiication of con genital anomalnies of the female genital tracr. Ultr..lsound Obsret Gynecol 46(5),616.n2015 Greaves R. Hunt RW, Zacharin ..l: Transient anomalies in genital appear .n ance In some extremely preterm female infants may be the result of foeral programming causing a surge in LH and the over activation of the pituirary gonadal axis. Clin Endocrinol (OxO 69(5):76, 2008


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Obstentrics_Williams. Greenwell T), Venn SN, CreighlOn SM. et al: Pregnancy after lower uri nary tract reconstruction for congenital abnormalities. B)U Int 92:773 Grimbizis GF, Camus M. Tarlanis Be. et al: Clinical implications ofurerine malformations and hysteroscopiC treatment resulrs. Hum Reprod Update -(2),161. 2001 Grimbizis GF, Di Spi'/jo Sardo A. Saravetos SH. CI al: The 1·hes.110niki ESHRElESGE consensus on diagnosis of female genital anomalies. Hum Reprod 31(1):2, 2016 Groom J1. Jones SA, Edmonds OK. et al: Preconception tran.1bdomina! cervicoisthrnic cerclage. Amn) Obstet GYllecol 191 (I ):230, 2004 Gross"nburg N), Delane' AA, B�rg TC: Treatment of a [ate second-trimester incarcerated uterus using ultrasound-guided manual reduction. Obstet GYlleco1n1n18(2 Pt 2):436, 201n1 Haddad B, Louis-Sylvestre e. PoilOut P, et al: Longitudinal vaginal septllm: : rerroSp!ctive sllId}, of 202 cases, Em ) Obstet Gynecol Reprod Bioi ,4(2),19.• 1997


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Obstentrics_Williams. Haddad B, Louis-Sylvestre e. PoilOut P, et al: Longitudinal vaginal septllm: : rerroSp!ctive sllId}, of 202 cases, Em ) Obstet Gynecol Reprod Bioi ,4(2),19.• 1997 Hal�-Craggs �A, Kirkh:lnl A. Creighton SM: Renal and urological abnormali ties occunng with mlillerian anomalies.n) Pcdiatr UroI9(1):27. 2013 Hampton HL. M�ks GR. Bates GW, et al: Pregnancy after successful vagino plasty and cervical stenting for partial atresia of the cervix. Obstet Gynecol -6;900, 1990 Hatch EE, Troisi R, (Iise LA. et al: Age at natural menopause in women exposed 10 diethylstilbestrol in lItero. Am J Epidemiol 164:682. 2006 Heiner Z. Dmochowska A. Szemraj ). et al: A novel mutation (c. 341 A>G) in the SRY gene in a 46,XY female palient with gonadal dysgenesis. Gene 526(2):46-,I2013 Hoover N, H'er M, Pfeifer RM, er al: Adverse health exposed in lItero ro diethylstilbestrol. N r..led 365: 1304,n2011


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Obstentrics_Williams. Hoover N, H'er M, Pfeifer RM, er al: Adverse health exposed in lItero ro diethylstilbestrol. N r..led 365: 1304,n2011 Hua ..t, Odibo AO, Longman RE. et al: Congenital lIterine anomalies and adverse pregnanc), outcomes. Amn) Obstel Groecol 205(6):558.e I, 20II Hughes lA, HVuk C, Ahmed SF. et a!: Consensus statement on management ,nof lntCrSex disorders. J Pediatr Urol 2:! 48, 2006 Hillson )M, Crover SR. O'Connell M, et al: Malformation syndromes associated with disorders of sex development. Nat Rev Endocrino! 10(8);476. 2014 Jensen )G: Ulerine torsion in pregnancy. Acta Obstet Gynecol Scand 71:260, )ian� )F. �lle W. Deng Y. Ct al: Gonadal malignancy in 202 female patients With dlsorders of sex development comaining Y-chromosome ma[crial. Gynecol EndocrinoIn32(4):338. 2016 )oh�1 NS, Bogri� S, �llIshtaq I: Neonatal imperforate hymen causing obstruc tion of The lITtnary tracL Urology ;'3(4):750. 2009


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Obstentrics_Williams. Gynecol EndocrinoIn32(4):338. 2016 )oh�1 NS, Bogri� S, �llIshtaq I: Neonatal imperforate hymen causing obstruc tion of The lITtnary tracL Urology ;'3(4):750. 2009 Johannesson L. )iirvho!1l1 S: Uterus transplanration: current progress and future prospects. lilt) (Iomens He.I,h 8:43. 2016 Jones ME, Boon we, Mcinnes K, et aJ: Recognizing rare disorders: aromarase deiciency. Nat C1in Pom Eodoerino! lvletab 3(5):414, 2007 Kaufman RH, Adam E, Hatch EE, ct al: Cominued follow-up of pregnancy outcomes in diethylstilbestrol-exposed ofspring. Obstet Gynecolo96(4):483, 2000 Kaufman RH, Noller K, Adam E, et al: Upper genital tract abnormalities and pregnancy outcome in diethylstilbestrol exposed progeny. m J Obstet Gynecol 148: 973,o1984 Kenney PJ, Spirt SA, Leeson MD: Geniwurinary anomalies: radiologic-anatomic correlations. Radiographies 4(2):233, 1984


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Obstentrics_Williams. Khati Nj, Frazier A, Brindle A: The unicornuate uterus and its variants: clinical presentation, imaging indings, and associated complications. J Ultrasound Med 31(2):319, 2012 Kriplani A, Kachhawa G, Awasthi 0, et al: Laparoscopic-assisted uterovaginal anastOmosis in congenital atresia of uterine cervix: follow-up srudy, J Minim Invasive GynecoIo19(4):477, 2012 Kumar N, Tayade S: Successful pregnancy outcome in an untreated cse of concomitant transverse complete vaginal septum with unicornuare uterus, J Hum Reprod Sci 7(4):27, 2014 Lee SW, Kim MY, Yang JH, et al: Sonographic indings of uterine sacculation during pregnancy. Ultrasound Obstet GynecoIo32(4):595, 2008 Lettieri L, Rodis JF, McLean DA, et al: Incarceration of the gravid uterus. Obstet Gynecol Suv 49:642, 1994 Ludmir J, Jackson GM, Samuels P: Transvaginal cerclage under ultrasound guidance in cases of severe cervical hypoplasia. Obstet Gynecol 78: 1067, 1991


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Obstentrics_Williams. Obstet Gynecol Suv 49:642, 1994 Ludmir J, Jackson GM, Samuels P: Transvaginal cerclage under ultrasound guidance in cases of severe cervical hypoplasia. Obstet Gynecol 78: 1067, 1991 Ludwin A, Ludwin I, Pitynski K, et al: Diferentiating between a double cervix or cervical duplication and a complete septate uterus with longitudinal vaginal septum. Taiwan J Obstet Gynecol 52(2):308, 2013 Matthews 0, Bath L, Hagler W, et l: Hormone supplementation for pubertal induction in girls. Arch Dis Child 102(10):975,o2017 McCann-Croshy B, Chen MJ, et al: Non-classical congenital adrenal hyperplasia: targets of treatment and transition. Pediatr Endocrinol Rev 12(2):224, 2014 McCann-Crosby B, Sutton VR: Disorders of sexual development. Clin PerinawIo42(2):395,o2015 Miller L, Auchus RJ: The molecular biology, biochemistry, and physiology of human sterOidogenesis and its disorders. Endocr Rev 32(1):81, 2011


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Obstentrics_Williams. Mollo A, De Franciscis P, Colacurci N, et al: Hysteroscopic resection of the septum improves the pregnancy rate of women with unexplained infertility: a prospective controlled trial. Ferri! SteriIo91(6):2628, 2009 Moore L, Persaud V, Torchia MG: he urogenital system. In The Developing Human. Philadelphia, Saunders, 2013, P 272 Mucowski SJ, Herndon CN, Rosen MP: The arcuate uterine anomaly: a critical appraisal of its diagnostiC and clinical relevance. Obstet Gynecol Surv 65(7),449,o2010 Murphy C, Allen L, Jamieson A: Ambiguous genitalia in the newborn: an overview and teaching tool. J Pediatr Adolesc GynecoIo24:236, 2011 Nahum G, Stanislaw H, McMahon C: Preventing ecropic pregnancies: how often does transperiwneal transmigration of sperm occur in efecting human pregnancy? BJOG 111:706,o2004 Nahum GG: Rudimentary uterine horn pregnancy: the 20th-century worldwide experience of 588 cases. J Reprod Med 47: 151, 2002


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Obstentrics_Williams. Nahum GG: Rudimentary uterine horn pregnancy: the 20th-century worldwide experience of 588 cases. J Reprod Med 47: 151, 2002 Newell SO, Crofts JF, Gram SR: The incarcerated gravid uterus: complications and lessons learned. Obstet Gynecol 123(2 Pt 2 Suppl (2 Pt 2 Suppl 2))A23,o2014 Nicholson K, Coulson Cc, McCoy MC, er al: Pelvic magnetic resonance imaging in the evaluation of uterine torsion. Obstet Gynecol 85(5 Pt 2),888, 1995 Nielsen J, Wohlert M: Sex chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in rhus, Denmark. Birth Defects Orig Artic Ser 26:209, 1990 Nistal IvI, Paniagua R, Gonzalez-Peramato p, et al: Perspectives in pediatric pathology, chapter I. normal development of testicular structures; from the bipotemial gonad to the fetal testis. Pediarr De\' PathoIo18(2}:88, 2015a


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Obstentrics_Williams. Nistal M, Paniagua R, Gonlez-Peramato P, et al: Perspectives in pediatric pathology, chapter 5. gonadal dysgeneSiS. Pediatr Dev PathoIo18(4):259, 2015b Ocal G: Current concepts in disorders of sexual development. J Clin Res Pediatr EndocrinoI3(3): \05,o2011 Oppelt P, Renner sr, Brucker S, et al. The VCUAM (Vagina Cervix Uterus Adnex-associated Malformation) Classiication: a new classiication for genital malformations. Ferril Sterilo84: 1493,o2005 Pabw:cu R, Gomel V: Reproductive outcome after hysteroscopic metroplasfY in women with septate uterus and othervrise unexplained infertility. Ferril Sterilo81:o1675,o2004 Pados G, Tsolakidis 0, Athanatos 0, et aI: Reproductive and obstetric outcome after laparoscopic excision of functional, non-communicating broadly attached rudimentary hon: a case series. Eur J Obstet Gynecol Reprod Bioi 182,33,o2014 Palmer JR, Hatch EE, Rao RS, et al: Infertility among womcn exposed prenatally to diethylstilbestrol. Am J Epidemiol 154:31G, 2001


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Obstentrics_Williams. Palmer JR, Hatch EE, Rao RS, et al: Infertility among womcn exposed prenatally to diethylstilbestrol. Am J Epidemiol 154:31G, 2001 Pellerito JS, lvlcCarthy S�'I, Doyle MB, et al: Diagnosis of uterine anomalies: relative accuracy of MR imaging, endovaginal sonography, and hysterosalpingography. Radiology 183:795, 1992 Picone 0, Fubini A, Ooumerc S, et al: Cesarean delivery by posterior hysterotomy due to torsion of the pregnant uterus. Obstet Gynecol 107(2 Pt 2),533, 2006 Puscheck EE, Cohen L: Congenital malformations of the uterus: the role of ultrasound. Semin Reprod Med 26(3):223, 2008 Rackow BW, Arici A: Reproductive performance of womcn with miillerian anomalies. Curr Opin Obstet Gynecol 19(3):229, 2007 Rajiah P, Eastwood KL, Gunn ML, ct aI: Uterinc diverticulum. Obstct Gynecol 113(2 Pt 2):525, 2009


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Obstentrics_Williams. Rajiah P, Eastwood KL, Gunn ML, ct aI: Uterinc diverticulum. Obstct Gynecol 113(2 Pt 2):525, 2009 Ral K, Eisenbeis S, Henninger V: Typical and atypical associated indings in a group of 346 patients with Mayer-Rokitansky-Kuester-Hauser syndrome. J Pediatr Adolesc Gynecol 28(5):362, 2015 Reichman 0, Laufer MR: Congenital uterine anomalies afecting reproduction. Best Pract Res Clin Obstet GvnaecoIo24(2):193, 2010 Reichman 0, Laufer MR, Robinson 3K: Pregnancy outcomes in unicornuate uteri: a review. Fertil Sterilo91(5): 1886,o2009 Roberts CP, Rock JA: Surgical methods in the treatment of congenital anomalies of the uterine cervix. Curr Opin Obstet Gynecol 23(4):251, 2011 Rock JA, Roberts CP, Jones HW Jr: Congenital anomalies of the uterine cervix: lessons from 30 cases managed clinically by a common protocol. Fertil Steril 94(5),1858,o2010 Rolen AC, Choquette AJ, Semmens JP: Rudimentary uterine horn: obstetric and gynecologic implications. Obstet Gynecol 27:806, 1966


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Obstentrics_Williams. Rolen AC, Choquette AJ, Semmens JP: Rudimentary uterine horn: obstetric and gynecologic implications. Obstet Gynecol 27:806, 1966 Rood K, Markham KB: Torsion of a term gravid uterus: a possible cause of intrauterine growth restriction and abnormal umbilical artery Doppler indings. J Ultrasound Med 33(10):1873, 2014 Saravelos SH, Cocksedge A, Li TC: Prevalence and diagnosis of congenital uterine anomalies in women with reproductive failure: a critical appraisal. Hum Reprod Update 14(5):415,o2008 Seubert DE, Puder KS, Goldmeier P, et al: Colonoscopic release of the incarcerated gravid uterus. Obstet Gynecol 94:792, 1999 Singh MN, Payappagoudar J, Lo J: Incarcerated retroverted uterus in the third trimester complicated by postpartum pulmonary embolism. Obstet Gynecol 109A98, 2007 Spearing GJ: Uterine sacculation. Obstet GynecoIo51:IIS, 1978


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Obstentrics_Williams. Spearing GJ: Uterine sacculation. Obstet GynecoIo51:IIS, 1978 Speiser PW, Azziz R, Baskin LS, ct al: Congenital adrenal hyperplasia due to steroid 2 I-hydroxylase deiciency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 95(9):4133, 2010 Tongo], Zhu L, Lang J: Clinical characteristics of 70 patients with HerlynWerner-Wunderlich syndrome. Int J Gynaecol Obstet 121 (2): 173, 2013 Troisi R, Hatch EE, Palmer JR, et al: Prenatal diethylstilbestrol exposure and high-grade squamous cell neoplasia of the lower genital traCt. Am J Obstet Gynecol 215(3):322.el, 2016 Valle RF, Ekpo GE: Hysteroscopic metroplasty for the septate uterus: review and meta-analysis. J Minim Invasive GynecoIo20(1):22, 2013 Van Beekhuizen HJ, Bodewes HW, Tepe EM, et al: Role of magnetic reso nance imaging in the diagnosis of incarceration of the gravid uterus. Obstct Gynecol 102:1o134,o2003


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Obstentrics_Williams. Van Beekhuizen HJ, Bodewes HW, Tepe EM, et al: Role of magnetic reso nance imaging in the diagnosis of incarceration of the gravid uterus. Obstct Gynecol 102:1o134,o2003 Williams CE, Nakhal RS, Hall-Craggs A, et al: Transverse vaginal septae: management and long-term outcomes. BJOG 121(13):1653,o2014 Woelfer B, Salim R, Banerjee S, et al: Reproductive outcomes in women with congenital uterinc anomalies detected by three-dimensional ultrasound screening. Obstet GynecoIo98:1099, 2001 Worley KC, Hnat i'vID, Cunningham FG: Advanced xtrauterine pregnancy: diagnostic and therapeutic challenges. Am J Obstet Gynecol 198:287.e 1, 2008 WU QY, U N, Li W, et al: Clinical, molecular and cytogenetic analysis of 46,X testicular disorder of scx developmcnt with SRY-positive. BMC Urol 14:70,o2014 REPRODUCTIVE TRACT ...........................49 BREASTS....................................... 53 SKIN .......................................... 53


Obstentrics_Williams

Obstentrics_Williams. REPRODUCTIVE TRACT ...........................49 BREASTS....................................... 53 SKIN .......................................... 53 METABOLIC CHANGES. . . . . . . . . . . . . . . . . . . . . . . . . . . 54 HEMATOLOGICAL CHANGES ...................... 57 CARDIOVASCULAR SYSTEM ....................... 60 RESPIRATORY ............................64 URINARY SYSTEM ............................... 65 GASTROINTESTINAL TRACT .......................68 ENDOCRINE SYSTEM ................... ...... .. 68 MUSCULOSKELETAL SYSTEM ...................... 72 CENTRAL NERVOUS SYSTEM . . . . . . . . . . . . . . . . . . . . . . 72 The matenal organism reacts to a greater or lesser extent under the inluence of pregnancy, but naturaly the most characteristic changes are observed in the generative tract, and especialy the uterus, which undergoes a very marked increase in size. -J. Whitridge Williams (1903)


Obstentrics_Williams

Obstentrics_Williams. -J. Whitridge Williams (1903) In the irst edition of this textbook, Williams devoted only 10 pages to the physiology of pregnancy, and half were focused on uterine growth. Many gestational changes begin soon after fertilization and continue throughout pregnancy. Equally astounding is that the woman is returned almost completely to her prep regnancy state after delivery and lactation. Most pregnancy-related changes are prompted by stimuli provided by the fetus and placenta. Virtually every organ system undergoes alterations, and these can appreciably modiy criteria for disease diagnosis and treatment. hus, an understanding of pregnancy adaptations is essential to avoid misinterpretation. Moreover, some physiological changes can unmask or worsen preexisting disease.


Obstentrics_Williams

Obstentrics_Williams. In the nonpregnant woman, the uterus weighs approximately 70 g and is almost solid, except for a cavity of 10 mL or less. During pregnancy, the uterus is transformed into a thin-walled muscular organ of suicient capacity to accommodate the fetus, placenta, and amnionic luid. he total volume of the contents at term averages 5 L but may be 20 L or more! hus, by the end of pregnancy, the uterus has achieved a capacity that is 500 to 1000 times greater than the nonpregnant state. The corresponding increase in uterine weight is such that, by term, the organ weighs nearly 1100 g.


Obstentrics_Williams

Obstentrics_Williams. During pregnancy, uterine enlargement involves stretching and marked hypertrophy of muscle cells, whereas the production of new myocytes is limited. Fibrous tissue also accumulates, particularly in the external muscle layer, together with a considerable rise in elastic tissue content. The walls of the corpus considerably thicken and strengthen during the first few months of pregnancy but then gradually thin. By term, the myometrium is only 1 to 2 cm thick, and the fetus usually can be palpated through the soft, readily indentable uterine walls. Uterine hypertrophy early in pregnancy probably is stimulated by the action of estrogen and perhaps progesterone. Thus, similar uterine changes can be observed with ectopic pregnancy. But after approximately 12 weeks' gestation, uterine growth is related predominantly to pressure exerted by the expanding products of conception.


Obstentrics_Williams

Obstentrics_Williams. Within the uterus, enlargement is most marked in the fundus. The extent of uterine hypertrophy is also influenced by the position of the placenta. Namely, the myometrium surrounding the placental site grows more rapidly than does the rest. The uterine musculature during pregnancy is arranged in three strata. The irst is an outer hoodlike layer, which arches over the fundus and extends into the various ligaments. The middle layer is a dense network of muscle fibers perforated in all directions by blood vessels. Last is an internal layer, with sphincter-like ibers around the fallopian tube orifices and internal cervical os. Most of the uterine wall is formed by the middle layer. Here, each myocyte has a double curve so that the interlacing of any two cells forms a figure eight. This arrangement is crucial and permits myocytes to contract after delivery and constrict penetrating blood vessels to halt bleeding.


Obstentrics_Williams

Obstentrics_Williams. For the first few weeks, the uterus maintains its original piriform or pear shape. But, as pregnancy advances, the corpus and fundus become globular and almost spherical by 12 weeks' gestation. Subsequently, the organ grows more rapidly in length than in width and becomes ovoid. By the end of 12 weeks, the enlarged uterus extends out of the pelvis. With this, it contacts the anterior abdominal wall, displaces the intestines laterally and superiorly, and ultimately reaches almost to the liver. With uterine ascent, it usually rotates to the right, and this dextrorotation likely is caused by the rectosigmoid on the left side of the pelvis. As the uterus rises, tension is exerted on the broad and round ligaments.


Obstentrics_Williams

Obstentrics_Williams. With the pregnant woman standing, the longitudinal axis of the uterus corresponds to an extension of the pelvic inlet axis. The abdominal wall supports the uterus and maintains this axis, unless the wall is lax. When the pregnant woman lies supine, the uterus falls back to rest on the vertebral column and the adjacent great vessels.


Obstentrics_Williams

Obstentrics_Williams. Beginning in early pregnancy, the uterus contracts irregularly, and these may be perceived as mild cramps. During the second trimester, these contractions can be detected by bimanual examination. In 1872, J. Braxton Hicks first brought attention to these contractions, which now bear his name. hese appear unpredictably and sporadically and are usually nonrhythmic. Their intensity varies between 5 and 25 mm Hg (Alvarez, 1950). Until near term, these Braxton Hicks contractions are infrequent, but their number rises during the last week or two. At this time, the uterus may contract as often as every 10 to 20 minutes and with some degree of rhythmicity. Correspondingly, uterine electrical activity is low and uncoordinated early in gestation, but becomes progressively more intense and synchronized by term (Garield, 2005; Rabotti, 2015). This synchrony develops twice as fast in multiparas compared with nulliparas (Govindan, 2015). Late in pregnancy, these contractions may cause some


Obstentrics_Williams

Obstentrics_Williams. by term (Garield, 2005; Rabotti, 2015). This synchrony develops twice as fast in multiparas compared with nulliparas (Govindan, 2015). Late in pregnancy, these contractions may cause some discomfort and account for so-called false labor.


Obstentrics_Williams

Obstentrics_Williams. The delivery of most substances essential for fetal and placental growth, metabolism, and waste removal requires the placental intervillous space to be adequately perfused (Chap. 5, p. 94). Placental perfusion depends on total uterine blood low, but simultaneous measurement of uterine, ovarian, and collateral vessels is not yet possible, even using magnetic resonance (MR) angiography (Pates, 2010). Using ultrasound to study the uterine arteries, uteroplacental blood low has been measured to increase progressively during pregnancy-from approximately 450 mUmin in the mid trimester to nearly 500 to 750 mU min at 36 weeks (Flo, 2014; Wilson, 2007). hese measures are similar to uterine artery blood flow estimates ascertained indirectly using clearance rates of androstenedione and xenon-133 (Edman, 1981; Kauppila, 1980). These values also mirror older ones-500 to 750 mUmin-obtained with invasive methods (Assali, 1953; Browne, 1953; Metcalfe, 1955). Logically, such massively increased


Obstentrics_Williams

Obstentrics_Williams. (Edman, 1981; Kauppila, 1980). These values also mirror older ones-500 to 750 mUmin-obtained with invasive methods (Assali, 1953; Browne, 1953; Metcalfe, 1955). Logically, such massively increased uteroplacental blood flow requires adaptation of the uterine veins as well. The resultant increased venous caliber and distensibility can result in uterine vein varices that in rare instances may rupture (Lim, 2014).


Obstentrics_Williams

Obstentrics_Williams. As noted irst from animal studies, uterine contractions, either spontaneous or induced, lower uterine blood flow proportionally to contraction intensity (Assali, 1968). A tetanic contraction yields a precipitous fall in uterine blood flow. In humans, three-dimensional power Doppler angiography has also demonstrated reduced uterine blood low during contractions Gones, 2009). Using a similar technique, resistance to blood low in both maternal and fetal vessels was found to be greater during the second stage of labor compared with the first (Baron, 2015). Given that baseline uterine blood low is diminished in pregnancies complicated by fetal-growth restriction, these fetuses may tolerate spontaneous labor less efectively (Ferrazzi, 2011; Simeone, 2017).


Obstentrics_Williams

Obstentrics_Williams. The vessels that supply the uterine corpus widen and elongate yet preserve their contractile function (Mandala, 2012). In contrast, the spiral arteries, which directly supply the placenta, vasodilate but completely lose contractility. This presumably results from endovascular trophoblast invasion that destroys the intramural muscular elements (Chap. 5, p. 91). It is this vasodilation that allows maternal-placental blood low to progressively rise during gestation. Given that blood flow increases proportionally to the fourth power of the radius of the vessel, small increases in vessel diameter result in tremendous augmentation of uterine artery blood low. For example, in one study, the uterine artery diameter grew from only 3.3 mm to 3.7 mm between 22 and 29 weeks' gestation, but mean velocity increased 50 percent, from 29 to 43 cm/sec (Flo, 2010).


Obstentrics_Williams

Obstentrics_Williams. The downstream fall in vascular resistance is another key factor that accelerates low velocity and shear stress in upstream vessels. In turn, shear stress leads to circumferential vessel growth. Nitric oxide-a potent vasodilator-appears to play a central role in regulating this process and is discussed later (p. 63). Indeed, endothelial shear stress and several hormones and growth facrors all augment endorhelial nitric oxide synthase (eNOS) and nitric oxide producrion (Crummer, 2009; Lim, 2015; Mandala, 2012; Pang, 2015). Facrors include estrogen, progesterone, activin, placental growth facror (PIG F), and vas cular endorhelial growrh factor (VEGF), which is a promoter of angiogenesis. As an impo((am aside, VEGF and PIGF signaling is attenuated in response to excess placenral secretion of their soluble recepror-soluble FMS-like yrosille kinase I (sFlt-I). An ing PIGF and VEGF concentrations and is importanr in pre eclampsia parhogenesis (Chap. 40, p. 716).


Obstentrics_Williams

Obstentrics_Williams. Normal pregnancy is also characterized by vascular refrac mriness CO the pressor efects of infused angiotensin II, and rhis raises ureropiacenral blood Aow (Rosenfeld, 1981,e2012). relaxin and certain adipocyrokines (Vodsrrcil, 201e2). Chemeri1 is an adipocycokine secreted by several rissues, including the placenra (Garces, 2013; Kasher-Meron, 2014). Irs concentra tion rises as gestadon advances and serves ro increase human umbilical eNOS activity, which mediates greater blood Aow (Wang, 2015). Anorher adipocyrokine-viotil-raises VEGF cells derived from the placemal amnion (Astern, 2013). Orher adipocyrokines include lepfin, resistin, and 1diponectin, which (Pole', 2014).


Obstentrics_Williams

Obstentrics_Williams. Last, cenain micro RNA species mediate vascular remodeling and uterine blood low early in placentation (Sama, 2015). In particular, members of the miR-1e7-92 clusrer and miR-34 are important in spiral artery remodeling and invasion. Abnormalities of micro-RNA function have been reported in preeclampsia, fetal-growth rescriction, and gestational diaberes.


Obstentrics_Williams

Obstentrics_Williams. As early as 1 momh after conception, the cervix begins to soften and gain bluish mnes. These result from increased vascularity and edema of the entire cervix, from changes in the collagen necwork, and from hypertrophy and hyperplasia of the cervical glands (Peralra, 2015; Srraach, 2005). Alrhough rhe cervix contains a small amollnt of smooth muscle, its major componenr is connective (issue. Rearrangemem of rhis collagen-rich tissue aids rhe cervix in retention of the pregnancy until term, in dilatation to aid delivery, and in posrpartum repair and reconstitution ro permir a subsequenr successful pregnancy (Myers, 2015). As derailed in Chapter 21 (p. 409), cervical ripening involves connective tissue remodeling (har lowers collagen and proreoglycan concentrations and raises warer comenr compared wirh rhe nonpregnanr cervix.


Obstentrics_Williams

Obstentrics_Williams. Cervical glands undergo marked proliferation, and by the end of pregnancy, they occupy up to one half of the entire cervical mass. This normal pregnancy-induced change promprs an extension, or eversion, of (he proliferating columnar endocervical glands onto the ecrocervical portio (rig. 4-1). This tissue appears red and velvety and bleeds even with minor trauma, such as with Pap tesring. FIGURE 4-1 Cervical eversion of pregnancy as viewed through a colposcope. The eversion represents columnar epithelium on the portio of the cervix. (Used with permission from Dr. Claudia Werner.)


Obstentrics_Williams

Obstentrics_Williams. FIGURE 4-1 Cervical eversion of pregnancy as viewed through a colposcope. The eversion represents columnar epithelium on the portio of the cervix. (Used with permission from Dr. Claudia Werner.) The endocervical mucosal cells produce copious amounts of tenacious mucus thar obstruct the cervical canal soon after conception (Bastholm, 2017). This mucus is rich in immunoglobulins and cytokines and may acr as an immunological barrier to prorec( the uterine conrents against infection (Hansen, 2014; Wang, 2014). Ar labor onser, if not before, this mucus plug is expelled, resulting in a bloody show. Moreover, the cervical mucus consistency changes during pregnancy. Speciically, in most pregnant women, as a result of progesterone, when cervical mucus is spread and dried on a glass slide, it shows poor crysrallization, termed beading. In some gravidas, as a resulr of amnionic Auid leakage. an arborization of ice-like crystals, calledening, is seen microscopically.


Obstentrics_Williams

Obstentrics_Williams. HistOlogically, basal cells near rhe squamocolumnar junction can be prominenr in size, shape, and staining quality in pregnancy. 111ese changes are considered ro be estrogen induced. In addition, pregnancy is associated with bO[h endoccrvical gland hyperplasia and hypersecretory appearance-the Arias-Stela raction-which can make diferenriating these from truly atypical glandular cells during Pap test evaluarion particularly diiculr (Rosai, 2015). Ovularion ceases during pregnancy, and maturation of new follicles is suspended. The single corpus luteum found in graVidas functions maximally during the irst 6 to 7 weeks of pregnancy--4 ro 5 weeks postovulation. Thereafter, ir contributes relarively linie to progesrcrone production. Surgical removal of the corpus luteum before 7 weeks prompts a rapid fall in matenal serum progesrerone levels and spontaneous abortion (Csapo, 1973). Afrer this time, however, corpus lureum excision ordinarily does nO[ cause abortion.


Obstentrics_Williams

Obstentrics_Williams. An extrauterine decidual reaction on and jusr beneath the ovarian surface is common in pregnancy and is usually observed ar cesarean delivery. 1l1ese slighdy elevated clear or red patches bleed easily and may, on irst glance, resemble freshly torn adhesions. Similar decidual reactions arc seen on the uterine serosa and other pelvic, or even extrapelvic, abdominal organs (Bloom. 2010). These areas arise from subcoelomic mesenchyme or eniomcrcioric lesions that have been stimulated by progesterone. They histologically appear similar to progestin-stimulated intrauterine endometrial stroma (Kim. 2015). The enormous caliber of the ovarian veins viewed at cesarean delivery is starding. Hodgkinson (1953) found that the diametcr of the ovarian vascular pedicle increased during pregnancy from 0.9 em to approximately 2.6 em at term. Again, recall that Aow in a tubular structure increases exponentially as the diameter enlarges.


Obstentrics_Williams

Obstentrics_Williams. This protein hormone is secreted by the corpus lureum, the decidua. and the placenta in a pattern similar to that of human chorionic gonadotropin (hCG) (Chap. 5. p. 102). Relaxin is also expressed in brain, hean, and kidney. Ie is mentioned here because its secretion by the corpus lureum appears to aid many maternal physiological adaptations, such as remodeling of reproductive-tract connective tissue to accommodate labor (Conrad. 2013; Vrachnis. 2015). Relaxin also appears importam in initiating augmented renal hemodynamics, lowering serum osmolality, and increasing arterial compliance, which are all associated with normal pregnancy (Conrad. 2014a). Despite its name, serum relaxin levels do nOt contribute to greater peripheral joint laxity or pelvic girdle pain during pregnancy (Aldabe. 2012; Marnach. 2003; V0l1estad. 2012).


Obstentrics_Williams

Obstentrics_Williams. These benign ovarian lesions reAect exaggerated physiological follicle stimulation, which is termed hyperreactio luteinalis. These usually bilateral cystic ovaries are moderately to massively enlarged. The reaction is usually linked to markedly elevated serum heG levels. Logically, theca-Iurein CYStS are found frequenrlywith gestational trophoblastic disease (Fig. 20-3. p. 391). They also can develop with the placentomegaly that can accompany diabetes, anti-D alloimmunization, and multi fetal gestation (Malinowski, 2015). Hyperreactio luteinalis is associated with preeclampsia and hyperthyroidism, which may contribure to elevated risks for fetal-growth restriction and preterm birth (Cavorerro. 2014; Lynn. 2013; Mlinowski. 2015). hese cystS also are encountered in women with otherwise uncomplicated pregnancies. In these cases, an exaggerated response of the ovaries to normal levels of circulating heG is suspected (Sarmento Gon,alves. 2015).


Obstentrics_Williams

Obstentrics_Williams. Although usually asymptomatic, hemorrhage into the CYStS can cause acme abdominal pain (Amoah. 2011). Maternal virilization may be seen in up to 30 percent of women, however, virilization of the fetus has only rarely been reported (Malinowski. 2015). Maternal indings that include temporal balding, hirsutism, and clitoromegaly are associated with massively elevated levels of androstenedione and testosterone. The diagnosis typically is based on sonographic findings of bilateral enlarged ovaries containing multiple cysts in the appropriate clinical settings. The condition is self-limited and resolves following delivery. Its management is reviewed by Malinowski (2015) and discussed further in Chapter 63 (p. 1199). The fallopian rube musculature, rhat is, the myosalpinx, undergoes little hypertrophy during pregnancy. The epithelium of the mdosnpinxsomwhat Ranens. Decidual cells may develop in rhe stroma of the endosalpinx, but a continuous decidual membrane is not formed.


Obstentrics_Williams

Obstentrics_Williams. Rarely, a fallopian tube may twisr during uterine enlarge� mem (Macedo, 2017). This torsion is more common with comorbid pararubal or ovarian cysts (Lee, 2015). During pregnancy, greater vascularity and hyperemia develop in the skin and muscles of the perineum and vulva, and the underlying abundant connective tissue softens. This augmented vascularity prominently afects the vagina and cervix and results in the violet color characreristic of Chadwick sign.


Obstentrics_Williams

Obstentrics_Williams. Within the vagina, the considerably elevated volume of cervical secretions during pregnancy forms a somewhat thick, white discharge. The pH is acidic, varying from 3.5 to 6. This pH results from increased production of lactic acid by lactobacillus acidophi/us during metabolism of glycogen energy stores in the vaginal epithelium. Pregnancy is associated with an elevated risk of vulvovaginal candidiasis. particularly during the second and third trimesters. Higher infection rates may stem from immunological and hormonal changes and from greater vaginl glycogen stores (Aguin. 2015). The vaginal walls undergo striking changes in preparation for the distention that accompanies labor and delivery. These alterations include considerable epithelial thickening, connective tissue loosening, and smooth muscle cell hypertrophy.


Obstentrics_Williams

Obstentrics_Williams. Pelvic Organ Prolapse Quantiication (POP-Q) and threedimensional sonography studies show that vaginal suppOrt changes across pregnancy. In particular, vaginal lengthening, posterior vaginal wall and hiatal relaxation, increased levaror hiaral area, and greater irst-trimester vaginal elastase activity are all associated with uncomplicated spontaneous vaginal delivery (Oliphant. 2014). The larger hiatal area persists in women who deliver vaginally compared with women delivering by prelabor or early-labor cesarean delivery. However. all women show greater hiatal distensibility after delivery, which is potentially a facror in later pelvic floor dysfunction (van Veelen, 2015).


Obstentrics_Williams

Obstentrics_Williams. In women with apical vaginal prolapse. the cervix, and occasionally a portion of the uterine body, can protrude variably from the vulva during early pregnancy. With further growth. the uterus usually rises above the pelvis and can draw the cervix up with it. If the uterus persists in its prolapsed position, symptoms of incarceration may develop at 10 to 14 weeks' gestation (Chap. 3, p. 46). s a preventive measure. [he urerus can be replaced early in pregnancy and held in position with a suitable pessary.


Obstentrics_Williams

Obstentrics_Williams. Attenuation of anterior vaginal wall suppOrt can lead to prolapse of the bladder, that is, a cystocele. Urinary stasis with a cystocele predisposes to infection. Pregnancy may also worsen coexistent stress urinary incontinmce (SUi), likely because urerhral closing pressures do nor risc suiciently to compensate for altered bladder neck support. Urinary incontinence afects nearly 20 percent of women during the first trimester and nearly 40 percent during the third trimester. Most cases stem from SUI rather than urgency urinary incontinence (Abdullah, 2016a; Franco, 2014; Iosif, 1980). In primigravidas, maternal age greater than 30 years, obesity, smoking, constipation, and gestational diabetes mellitus are all risk factors associated with SUI development during pregnancy (Sangsawang, 2014).


Obstentrics_Williams

Obstentrics_Williams. Attenuation of posterior vaginal wall support can result in a rectocele. A large defect may fill with feces that occasionally can be evacuated only digitally. During labor, a cystocele or rectocele can block fetal descent unless they are emptied and pushed out of the way. Rarely, an enterocele of considerable size may bulge into the vagina. If the mass interferes with delivery, the hernia sac and its abdominal contents are gently reduced to permit fetal descent.


Obstentrics_Williams

Obstentrics_Williams. In early pregnancy, women often experience breast tenderness and paresthesias. Mter the second month, the breasts grow in size, and delicate veins are visible just beneath the skin. he nipples become considerably larger, more deeply pigmented, and more erectile. Mter the first few months, a thick, yellowish luid-colosrum-can often be expressed from the nipples by gentle massage. During the same months, the areolae become broader and more deeply pigmented. Scattered through each areola are several small elevations, the glands of Montgomey, which are hypertrophic sebaceous glands. If breasts gain extensive size, skin striae similar to those observed in the abdomen may develop. Rarely, breasts can become pathologically enlarged-referred to as gigantomastia-which may require postpartum surgical reduction (Fig. 4-2) (Eler Dos Reis, 2014; Rezai,i2015).


Obstentrics_Williams

Obstentrics_Williams. For most normal pregnancies, prepregnancy breast size and ultimate volume of breast milk do not correlate, as multiple factors influence milk production (Hartmann, 2007). These FIGURE 4-2 Gigantomastia in a woman near term. (Used with permission from Dr. Patricia Santiago-Munoz.) factors and gestation breast changes are further discussed in Chapter 36 (p. 656). Skin changes are common, and Fernandes and Amaral (2015) described dermatological changes in more than 900 pregnant women. They found at least one physiological cutaneous change in 89 percent of the women examined. Dermatologic pathologies during pregnancy are found in Chapter 62.


Obstentrics_Williams

Obstentrics_Williams. Beginning after midpregnancy, reddish, slightly depressed streaks commonly develop in the abdominal skin and some times in the skin over the breasts and thighs. These are called striae gravidarum or stretch marks. In multiparas, glistening, silvery lines that represent the cicatrices of previous striae fre quently coexist. In one study of 800 primiparas, 70 percent their breasts; and 41 percent on their hips and thighs (Picard, 2015). The strongest associated risk factors included younger maternal age, family history, and prepregnancy weight and weight gain during pregnancy. The etiology of striae gravi darum is unknown, and there are no preventive steps or defini tive treatments (Korgavkar, 2015).


Obstentrics_Williams

Obstentrics_Williams. Occasionally, the muscles of the abdominal walls do not withstand the tension of the expanding pregnancy. As a result, rectus muscles separate in the midline, creating diastasis recti of varying extent. If severe, a considerable portion of the anterior uterine wall is covered by only a layer of skin, attenuated fascia, and peritoneum to form a ventral hernia.


Obstentrics_Williams

Obstentrics_Williams. This develops in up to 90 percent of women and is usually more accentuated in those with darker complexion (Ikino, 2015). Of speciic sites, the pigmented skin line in the midline of the anterior abdominal wall-the linea alba-takes on dark brownblack pigmentation to form the linea nigra. Occasionally, irregular brownish patches of varying size appear on the face and neck, giving rise to chloasma or melasma gravidarum-the mask of pregnancy. Pigmentation of the areolae and genital skin may also be accentuated. Mter delivery, these pigmentary changes usually disappear or at least regress considerably. Oral contraceptives may cause similar alterations (Handel, 2014).


Obstentrics_Williams

Obstentrics_Williams. he etiology of these pigmentary changes is incompletely understood, however, hormonal and genetic factors play a role. For example, levels of melanocyte-stimulating hormone, a polypeptide similar to corticotropin, are elevated remarkably throughout pregnancy, and estrogen and progesterone also are reported to have melanocyte-stimulating efects . Angiomas, called vascular spiders, are particularly common on the face, neck, upper chest, and arms. These are minute, red skin papules with radicles branching out from a central lesion. he condition is often designated as nevus, angioma, TABLE 4-1. Additional Energy Demands During Normal Pregnancya Rates of Tissue Deposition Energy Cost of Pregnancy Estimated from Basal Metabolic Rate and Energy Deposition aAssumes an average gestational weight gain of 12 kg. bEfficiency of food energy utilization for protein and fat deposition estimated as 0.90. Adapted from the World Health Organization, 2004.


Obstentrics_Williams

Obstentrics_Williams. bEfficiency of food energy utilization for protein and fat deposition estimated as 0.90. Adapted from the World Health Organization, 2004. or telangiectasis. Palmar eythema is encountered during pregnancy. Both conditions lack clinical significance and disappear in most gravidas shortly after pregnancy. hey are likely the consequence ofhyperestrogenemia. In addition to these discrete lesions, increased cutaneous blood flow in pregnancy serves to dissipate excess heat generated by the augmented metabolism. hroughout life, the human hair follicle undergoes a pattern of cyclic activity that includes periods of hair growth (anagen phase), apoptosis-driven involution (catagen phase), and a resting period (telogen phase). Based on a study of 116 healthy pregnant women, the anagen phase lengthens during pregnancy and the telogen rate increases postpartum (Gizlenti, 2014). Neither is exaggerated in most gravidas, but excessive hair loss in the puerperium is termed telogen fluvium.


Obstentrics_Williams

Obstentrics_Williams. In response to the greater demands of the rapidly growing fetus and placenta, the pregnant woman undergoes metabolic changes that are numerous and intense. By the third trimester, maternal basal metabolic rate rises by 20 percent compared with that of the nonpregnant state (Berggren, 2015). This rate grows by an additional 10 percent in women with a twin gestation (Shinagawa, 2005). Viewed another way, the additional total pregnancy energy demand associated with normal pregnancy approximates kcal (World Health Organization, 2004). This is stratified as 85, 285, and 475 kcal/d during the irst, second, and third trimester, respectively (Table 4-1). Of note, Abeysekera and coworkers (2016) reported that women accrue fat mass during pregnancy despite the increased total energy expenditure and without signiicant change in energy intake. This suggests more eicient energy storage.


Obstentrics_Williams

Obstentrics_Williams. Most of the normal weight gain in pregnancy is attributable to the uterus and its contents, the breasts, and expanded blood and extravascular extracellular fluid volumes. A smaller fraction results from metabolic alterations that promote accumulation of cellular water, fat, and protein, which are so-called maternal reserves. The average weight gain during pregnancy approximates 12.5 kg or 27.5 Ib, and this value has remained consistent across studies and over time (Hytten, 1991; Jebeile, 2016). Weight gain is considered in urther detail in Table 4-2 and in Chapter 9 (p. 165). In pregnancy, greater water retention is normal and mediated in part by a drop in plasma osmolality of 10 mOsm/kg. This decline develops in early pregnancy and is induced by a reset of osmotic thresholds for thirst and vasopressin secretion (Fig. 4-3) TABLE 4-2. Weight Gain Based on Pregnancy-Related Components Total 650 4000 8500 12,500 Modified from Hytten, 1991l. Weeks of pregnancy


Obstentrics_Williams

Obstentrics_Williams. TABLE 4-2. Weight Gain Based on Pregnancy-Related Components Total 650 4000 8500 12,500 Modified from Hytten, 1991l. Weeks of pregnancy FIGURE 4-3 Mean values (black line) ± standard deviations (blue lines) for plasma osmolality (Posm) measured at weekly intervals in nine women from preconception to 16 weeks. LMP = last menstrual period; MP = menstrual period. (Redrawn with permission from Davison JM, Dunlop W: Renal hemodynamics and tubular function in normal human pregnancy. Kidney Int 18:1o52, 1980.) (Davison, 1981; Lindheimer, 2001). Relaxin and other hormones are thought to playia role (Conrad, 2013). At term, the water content of the fetus, placenta, and amnionic luid approximates 3.5 L. Another 3.0 L accumulates from expanded maternal blood volume and from uterus and breast growth. Thus, the minimum amount of extra water that the average woman accrues during normal pregnancy approximates 6.5 L. This corresponds to 14.3 lb.


Obstentrics_Williams

Obstentrics_Williams. Clearly demonstrable pitting edema of the ankles and legs is seen in most pregnant women, especially at the end of the day. This fluid accumulation, which may amount to a liter or so, results from greater venous pressure below the level of the uterus as a consequence of partial vena cava occlusion. A decline in interstitial colloid osmotic pressure induced by normal pregnancy also favors edema late in pregnancy (0ian, 1985). Longitudinal studies of body composition show a progressive accumulation of total body water and fat mass during pregnancy. These two components as well as initial maternal weight and weight gained during pregnancy are highly associated with neonatal birthweight (Lederman, 1999; MardonesSantander, 1998). "Over-nourished" women are more likely to deliver oversized neonates, even when glucose tolerant (Di Benedetto, 2012).


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Obstentrics_Williams. The products of conception, the uterus, and maternal blood are relatively rich in protein rather than fat or carbohydrate. At term, the normally grown fetus and placenta together weigh about 4 kg and contain approximately 500 g of protein, or about half of the total pregnancy increase. The remaining 500 g is added to the uterus as contractile protein, to the breasts primarily in the glands, and to maternal blood as hemoglobin and plasma proteins.


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Obstentrics_Williams. Amino acid concentrations are higher in the fetal than in the maternal compartment and generally result from facilitated transport across the placenta (Cleal, 2011; Panitchob, 2015). This greater concentration is largely regulated by the placenta through an incompletely understood process. In particular, placental transport is variable for individuals and for diferent amino acids. For example, tyrosine is a conditionally essential amino acid in the preterm neonate but not in the fetus (Van den Akker, 2010, 2011). The placenta concentrates amino acids into the fetal circulation and is also involved in protein synthesis, oxidation, and transamination of some nonessential amino acids (Galan, 2009).


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Obstentrics_Williams. Maternal protein intake does not appear to be a critical determinant for birthweight among well-nourished women (Chong, 2015). Still, recent data suggest that current recommendations for protein intake may be too low. These guidelines are extrapolated from nonpregnant adults and may underestimate actual needs. Stephens and colleagues (2015) prospectively analyzed maternal protein intake and metabolism. They estimated average requirements of 1.22 g/kg/d of protein for early pregnancy and 1.52 g/kg/d for late pregnancy. These levels are higher than the current recommendation of 0.88 g/kg/d. The daily requirements for dietary protein intake during pregnancy are discussed in Chapter 9 (p. 167). Normal pregnancy is characterized by mild fasting hypoglycemia, postprandial hyperglycemia, and hyperinsulinemia (Fig. 4-4). his elevated basal level of plasma insulin in normal 1 PM 6 PM 12 M SAM MEALS: SAM t t t


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Obstentrics_Williams. FIGURE 4-4 Diurnal changes in plasma glucose and insulin in normal late pregnancy. (Redrawn from Phelps, 1981o.) pregnancy is associated with several unique responses to glucose ingestion. Speciically, after an oral glucose meal, gravidas demonstrate prolonged hyperglycemia and hyperinsulinemia and a greater suppression of glucagon (Phelps, 1981). This cannot be explained by an increased metabolism of insulin because its half-life during pregnancy is not changed appreciably (Lind, 1977). Instead, this response relects a pregnancy-induced state of peripheral insulin resistance, which ensures a sustained postprandial supply of glucose to the fetus. Indeed, insulin sensitivity in late normal pregnancy is 30 to 70 percent lower than that of nonpregnant women (Lowe, 2014).


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Obstentrics_Williams. The mechanisms responsible for this reduced insulin sensitivity include numerous endocrine and inlammatory factors (Angueira, 2015). In particular, pregnancy-related hormones such as progesterone, placentally derived growth hormone, prolactin, and cortisol; cytokines such as tumor necrosis factor; and hormones derived from central adiposity, particularly leptin and its interplay with prolactin, all have a role in the insulin resistance of pregnancy. Even so, insulin resistance is not the only factor to elevate postprandial glucose values. Hepatic gluconeogenesis is augmented during both diabetic and nondiabetic pregnancies, particularly in the third trimester (Angueira, 2015).


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Obstentrics_Williams. Overnight, the pregnant woman changes from a postprandial state characterized by elevated and sustained glucose levels to a fasting state characterized by decreased plasma glucose and some amino acids. Plasma concentrations of free fatty acids, triglycerides, and cholesterol are also higher in the fasting state. his pregnancy-induced switch in fuels from glucose to lipids has been called accelerated starvation. Certainly, when fasting is prolonged in the pregnant woman, these alterations are exaggerated and ketonemia rapidly appears.


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Obstentrics_Williams. he concentrations of lipids, lipoproteins, and apolipoproteins in plasma rise appreciably during pregnancy (Appendix, p. 1259). Increased insulin resistance and estrogen stimulation during pregnancy are responsible for the maternal hyperlipidemia. Augmented lipid synthesis and food intake contribute to maternal fat accumulation during the first two trimesters (Herrera, 2014). In the third trimester, however, fat storage declines or ceases. his is a consequence of enhanced lipolytic activity, and decreased lipoprotein lipase activity reduces circulating triglyceride uptake into adipose tissue. his transition to a catabolic state favors maternal use oflipids as an energy source and spares glucose and amino acids for the fetus.


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Obstentrics_Williams. Maternal hyperlipidemia is one of the most consistent and striking changes of lipid metabolism during late pregnancy. Triacylglycerol and cholesterol levels in very-low-density lipoproteins (VLDLs), low-density lipoproteins (LDLs), and highdensity lipoproteins (HDLs) are increased during the third trimester compared with those in nonpregnant women. During the third trimester, the average level of total serum cholesterol is 267 ± 30 mg/dL, ofLDL-C is 136 ± 33 mg/dL, ofHDL-C is 81 ± 17 mg/dL, and of triglycerides is 245 ± 73 mg/dL (Lippi, 2007). After delivery, the concentrations of these lipids, lipoproteins, and apolipoproteins decline. Breastfeeding drops maternal triglyceride levels but increases those of HDL-C. The efects of breastfeeding on total cholesterol and LDL-C levels are unclear (Gunderson, 2014).


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Obstentrics_Williams. Hyperlipidemia is theoretically a concern because it is associated with endothelial dysfunction. From studies, however, endothelium-dependent vasodilation responses actually improve across pregnancy (Saarelainen, 2006). Ihis is partly because increased HDL-C concentrations likely inhibit LDL oxidation and thus protect the endothelium. hese indings suggest that the increased cardiovascular disease risk in multiparas may be related to factors other than maternal hypercholesterolemia. This peptide hormone is primarily secreted by adipose tissue in nonpregnant humans. It plays a key role in body fat and energy expenditure regulation and in reproduction. For example, leptin is important for implantation, cell proliferation, and angiogenesis (Vazquez, 2015). Leptin deiciency is associated with anovulation and infertility, whereas certain leptin mutations cause extreme obesity (Tsai, 2015).


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Obstentrics_Williams. Among normal-weight pregnant women, serum leptin levels rise and peak during the second trimester and plateau until term in concentrations two to four times higher than those in nonpregnant women. Among obese women, leptin levels correlate with adiposity (Ozias, 2015; Tsai, 2015). In all cases, leptin levels fall after delivery, relecting the significant amounts produced by the placenta (Vazquez, 2015). Leptin participates in regulating energy metabolism during pregnancy. Interestingly, despite the rise in leptin concentrations during pregnancy, reduced leptin sensitivity to food intake during pregnancy has been described (Chehab, 2014; Vazquez, 2015). This "leptin resistance" may serve to promote energy storage during pregnancy and for later lactation.


Obstentrics_Williams

Obstentrics_Williams. Higher leptin levels during pregnancy may be disadvantageous under certain situations, such as in maternal obesity. Leptin functions as a proinflammatory cytokine in white adipose tissue, which may dysregulate the inlammatory cascade and lead to placental dysfunction in obese women (Vazquez, 2015). In addition, abnormally elevated leptin levels have been associated with preeclampsia and gestational diabetes (Bao, 2015; Taylor, 2015). Fetal leptin is important for the development of several organs that include the pancreas, kidney, heart, and brain. Fetal levels correlate with maternal body mass index (BMI) and birthweight. Lower levels are linked to fetal-growth restriction (Brifa, 2015; Tsai, 2015).


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Obstentrics_Williams. Dozens of hormones with metabolic and/or inflammatory functions are produced by adipose tissue. Adiponectin is a peptide produced primarily in maternal fat but not in the placenta (Haghiac, 2014). Adiponectin levels inversely correlate with adiposity, and it acts as a potent insulin sensitizer. Despite reduced adiponectin levels in women with gestational diabetes, directed assays are not useful for predicting diabetes development (Hauguel-de Mouzon, 2013). Ghrelin is a peptide secreted principally by the stomach in response to hunger. It cooperates with other neuroendocrine factors, such as leptin, in energy homeostasis modulation. Ghrelin is also expressed in the placenta and likely has a role in fetal growth and cell proliferation (Gonzalez-Dominguez, 2016). Angelidis and associates (2012) have reviewed the many functions of ghrelin in the regulation of reproductive function.


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Obstentrics_Williams. Viatin is a peptide that was first identified as a growth fac tor for B lymphocytes, but it is mainly produced within adipose tissue. Mumtaz and colleagues (2015) propose that elevated levels of visfatin and leptin impair uterine contractility. Such findings may provide a physiological basis for the observation that maternal obesity raises the risk for dysfunctional labor.


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Obstentrics_Williams. During normal pregnancy, nearly 1000 mEq of sodium and 300 mEq of potassium are retained (Lindheimer, 1987). Although the glomerular filtration rate of sodium and potassium is increased, the excretion of these electrolytes is unchanged during pregnancy as a result of enhanced tubular resorption (Brown, 1986, 1988). Although total accumulations of sodium and potassium are elevated, their serum concentrations are diminished slightly (Appendix, p. 1257). Several mechanisms may explain these lower levels (Odutayo, 2012). In the case of potassium, it possibly involves the expanded plasma volume of pregnancy. With respect to sodium, osmoregulation is altered and the threshold for arginine vasopressin release is lowered. his promotes free water retention and diminished sodium levels.


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Obstentrics_Williams. Total serum calcium levels, which include both ionized and nonionized calcium, decrease during pregnancy. his reduction consequent decline in the amount of circulating protein-bound nonionized calcium. Serum ionized calcium levels, however, remain unchanged (Olausson, 2012).


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Obstentrics_Williams. he developing fetus imposes a significant demand on maternal calcium homeostasis. For example, the fetal skeleton accretes approximately 30 g of calcium by term, 80 percent of which is deposited during the third trimester. his demand is largely met by a doubling of maternal intestinal calcium absorption mediated partly by 1,25-dihydroxyvitamin D3• hese higher levels of vitamin D are possibly stimulated by a twofold rise in PTH-related peptide levels produced by several tissues including the placenta (Kovacs, 2006; Olausson, 2012). To help compensate, dietary intake of suicient calcium is necessary to prevent excess depletion from the mother. A list of all recommended daily allowances is found in Table 9-5 (p. 167). his is especially important for pregnant adolescents, in whom bones are still developing. Unfortunately, a lack of robust data prevents drawing firm conclusions regarding the utility of calcium and vitamin D supplements during pregnancy (De-Regil, 2016).


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Obstentrics_Williams. Serum manesium levels also decline during pregnancy. Bardicef and colleagues (1995) concluded that pregnancy is actually a state of extracellular magnesium depletion. Compared with nonpregnant women, both total and ionized magnesium concentrations are significantly lower during normal pregnancy (Rylander, 2014). Serum phosphate levels lie within the nonpregnant range (Larsson, 2008). Although calcitonin is an important regulator of serum calcium and phosphate, the importance of calcitonin as it relates to pregnancy is poorly understood (Olausson, 2012).


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Obstentrics_Williams. Iodine requirements increase during normal pregnancy for several reasons (Moleti, 2014; Zimmermann, 2012). First, maternal thyroxine production rises to maintain maternal euthyroidism and to transfer thyroid hormone to the fetus prior to fetal thyroid functioning. Second, fetal thyroid hormone production increases during the second half of pregnancy. This contributes to greater maternal iodine requirements because iodide readily crosses the placenta. hird, the primary route of iodine excretion is through the kidney. Beginning in early pregnancy, the iodide glomerular iltration rate increases by 30 to 50 percent. In sum, because of greater thyroid hormone production, fetal iodine requirements, and augmented renal clearance, dietary iodine needs are higher during normal gestation. lthough the placenta has the ability to store iodine, whether this organ functions to protect the fetus from inadequate maternal dietary iodine is currently unknown (Burns, 2011). Iodine deiciency is discussed


Obstentrics_Williams

Obstentrics_Williams. placenta has the ability to store iodine, whether this organ functions to protect the fetus from inadequate maternal dietary iodine is currently unknown (Burns, 2011). Iodine deiciency is discussed later in this chapter (p. 71) and in Chapter 58 (p. 1126). At the other extreme, maternal supplements containing excessive iodine have been associated with congenital hypothyroidism. his stems from autoregulation in the thyroid gland-known as the Wof-Chaikof fect-to curb thyroxine production in response to iodide overconsumption (Connelly, 2012).


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Obstentrics_Williams. With respect to most other minerals, pregnancy induces little change in their metabolism other than their retention in amounts equivalent to those needed for growth. An important exception is the considerably greater requirement for iron, which is discussed subsequently. he well-known hypervolemia associated with normal pregnancy averages 40 to 45 percent above the nonpregnant blood volume after 32 to 34 weeks' gestation (Pritchard, 1965; Zeeman, 2009). In individual women, expansion varies considerably. In some, accumulated volume rises only modestly, whereas in others blood volume nearly doubles. A fetus is not essential, as augmented blood volume develops in some with hydatidiform mole. Pregnancy-induced hypervolemia serves several functions.


Obstentrics_Williams

Obstentrics_Williams. Pregnancy-induced hypervolemia serves several functions. First, it meets the metabolic demands of the enlarged uterus and its greatly hypertrophied vascular system. Second, it provides abundant nutrients and elements to support the rapidly growing placenta and fetus. Third, the expanded intravascular volume protects the mother, and in turn the fetus, against the deleterious efects of impaired venous return in the supine and erect positions. Last, it safeguards the mother against the adverse efects of parturition-associated blood loss.


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Obstentrics_Williams. Maternal blood volume begins to accrue during the irst trimester. By 12 menstrual weeks, plasma volume expands by approximately 15 percent compared with that prior to pregnancy (Bernstein, 2001). Maternal blood volume grows most rapidly during the midtrimester, rises at a much slower rate during the third trimester, and reaches a plateau during the last 6.5 � 6.0 ! 5.5 5.0 4.0 3.5 • Twin pregnancy• Singleton pregnancy 3.0 7 -6 -ls 5E 4)E) 3�'5r� 2:� Menses First Second Third Postpartum


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Obstentrics_Williams. FIGURE 4-6 Estimated daily iron requirements during pregnancy in a 55-kg woman. (Modified from Koenig, 2014.) (n 10) and singletons (n 40). Data shown as medians. (Data from Thomsen, 1994.) several weeks of pregnancy (Fig. 4-5). Blood volume accrues even more dramatically in twin gestations. During blood volume expansion, plasma volume and erythrocyte number rise. Although more plasma than erythrocytes is usually added to the maternal circulation, the increase in erythrocyte volume is considerable and averages 450 mL (Pritchard, 1960). Moderate erythroid hyperplasia develops in the bone marrow, and the reticulocyte count is elevated slightly during normal pregnancy. These changes are almost certainly related to an elevated maternal plasma erythropoietin level.


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Obstentrics_Williams. Because ofgreat plasma augmentation, both hemoglobin concentration and hematocrit decline slightly during pregnancy (Appendix, p. 1255).s aresult, whole bloodviscositydecreases (Huisman, 1987). Hemoglobin concentration at term averages 12.5 g/dL, and in approximately 5 percent ofwomen it is below 11.0 g/dL. Thus, a hemoglobin concentration below 11.0 g/dL, especially late in pregnancy, is considered abnormal and usually due to irondeficiency anemia rather than pregnancy hypervolemia.


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Obstentrics_Williams. The total iron content of normal adult women ranges from 2.0 to 2.5 g, or approximately half that found normally in men. Most of this is incorporated in hemoglobin or myoglobin, and thus, iron stores of normal young women only approximate 300 mg (Pritchard, 1964). Although the lower iron levels in women may be partly due to menstrual blood loss, other factors have a role, particularly hepcidin-a peptide hormone that functions as a homeostatic regulator of systemic iron metabolism. Hepcidin levels rise with inlammation, but drop with iron deficiency and several hormones, including testosterone, estrogen, vitamin D, and possibly prolactin (Uu, 2016; Wang, 2015). Lower hepcidin levels are associated with greater absorption ofiron via ferroportin in enterocytes (Camaschella, 2015).


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Obstentrics_Williams. Of the approximate 1000 mg ofiron required for normal pregnancy, about 300 mg is actively transferred to the fetus and placenta, and another 200 mg is lost through various normal excretion routes, primarily the gastrointestinal tract. These are obligatory losses and accrue even when the mother is iron deficient. The average increase in the total circulating erythrocyte volume-about 450 mL-requires another 500 mg. Recall that each 1 mL oferythrocytes contains 1.1 mg of iron.


Obstentrics_Williams

Obstentrics_Williams. As shown in Figure 4-6, because most iron is used during the latter halfofpregnancy, the iron requirement becomes large after midpregnancy and averages 6 to 7 mg/d (Pritchard, 1970). In most women, this amount is usually not available from iron stores or diet. Thus, without supplemental iron, the optimal rise in maternal erythrocyte volume will not develop, and the hemoglobin concentration and hematocrit will fall appreciably as plasma volume rises. At the same time, fetal red cell production is not impaired because the placenta transfers iron even if the mother has severe iron-deficiency anemia. In severe cases, we have documented maternal hemoglobin values of 3 gldL, and at the same time, fetuses had hemoglobin concentrations of 16 gldL. The mechanisms of placental iron transport and regulation are complex (Koenig, 2014; McArdle, 2014).


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Obstentrics_Williams. Ifthe nonanemic pregnant woman is not given supplemental iron, then serum iron andferritin concentrations decline atermidpregnancy. Importantly, hepcidin levels drop early in pregnancy (Hedengran, 2016; Koenig, 2014). s noted, lower hepcidin levels aid iron transfer into the maternal circulation via ferroportin in enterocytes. Lower hepcidin levels also augment iron transport into the fetus via ferroportin in syncytiotrophoblast. With normal vaginal delivery, 500 to 600 mL of blood is typically lost, and thus not all the maternal iron added in the form of hemoglobin is spent (Pritchard, 1965). he excess hemoglobin iron becomes stored iron.


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Obstentrics_Williams. Pregnancy is associated with suppression of various humoral and cell-mediated immunological functions (Chap. 5, p. 95). his permits accommodation of the "foreign" semiallogeneic fetal graft that contains antigens of both maternal and paternal origin (Redman, 2014). he tolerance that exists at the maternal-fetal interface remains a great unsolved medical mystery. This tolerance is complex and involves certain immune system adaptations and crosstalk among the maternal microbiome, uterine decidua, and trophoblast. In particular, areas of the uterus that were previously considered sterile are colonized with bacteria. In most cases, these microbes are believed to be commensal and play a tolerizing and protective role. Indeed, commensal organisms may inhibit the proliferation of certain pathogens. Several reviewers have described these relationships (Mor, 2015; Racicot, 2014; Sisti, 2016).


Obstentrics_Williams

Obstentrics_Williams. tection at the maternal-fetal interface involves the expression of the trophoblast. Recall that all cells of the body express a "badge" immune responses. For most cells of the body, this "badge" is known as MHC Class Ia. However, it is uncommon for two unrelated individuals to share compatible MHC class Ia. This creates a potential problem for reproduction because half of the fetus is composed of paternally derived antigens. To circumvent this problem, trophoblast cells express a form of MHC that does not vary between individuals. This "nonclassic" MHC is known as human leukocyte antigen class Ib and includes HLA-E, HLA F, and HLA-G. Recognition of these HLA class Ib proteins by natural killer cells residing within the decidua inhibits their activ ity and promotes immune quiescence (Djurisic, 2014).


Obstentrics_Williams

Obstentrics_Williams. Another immune adaptation that promotes tolerances stems from important changes in CD4 T lymphocyte subpopulations in pregnancy. First, Th1-mediated immunity shifts to h2-mediated immunity. Indeed, an important antiinlammatory component of pregnancy involves suppression ofT-helper (Th) 1 and T-cytotoxic (Tc) 1 cells, which lower secretion of interleukin-2 (IL-2), interferon-a, and tumor necrosis factor (TNF). Moreover, suppressed Th1 response is thought to be a requisite for pregnancy continuation. It also may explain pregnancy-related remission of some autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and Hashimoto thyroiditis-which are cell-mediated immune diseases stimulated by h1 cytokines (Kumru, 2005). With suppression of Th1 cells, there is upregulation of Th2 cells to increase secretion of IL-4, IL-10, and IL-13 (Michimata, 2003). hese h2 cytokines promote humoral, or antibody-based, immunity. hus, autoimmune diseases mediated mainly by autoantibodies,


Obstentrics_Williams

Obstentrics_Williams. cells to increase secretion of IL-4, IL-10, and IL-13 (Michimata, 2003). hese h2 cytokines promote humoral, or antibody-based, immunity. hus, autoimmune diseases mediated mainly by autoantibodies, such as systemic lupus erythematosus, may lare if the disease is already active in early pregnancy. But, the transition to an antibody-mediated immunity is an important defense during pregnancy and early puerperium. In cervical mucus, peak levels of immunoglobulins A and G (IgA and IgG) are significantly higher during pregnancy, and the immunoglobulin-rich cervical mucus plug creates a barrier to ascending infection (Hansen, 2014; Wang, 2014). Similarly, IgG is transferred to the developing fetus in the third trimester as a form of passive immunity, ostensibly in anticipation of birth. Further, immunoglobulins secreted into breast milk during lactation augment neonatal defenses against infection.


Obstentrics_Williams

Obstentrics_Williams. Other subpopulations of CD4 T lymphocytes serve mucosal and barrier immunity. These specific CD4-positive cells are known as h17 cells and Treg cells. h17 cells are proinflammatory and express the cytokine IL-17 and the retinoic acid receptor-related orphan receptors (RORs). Treg cells express the transcription factor forkhead box protein-3 (FOXP3) and confer tolerizing activity. here is a shift toward Treg CD4 cells in the first trimester, which peaks during the second trimester and falls toward delivery (Figueiredo, 2016). his shift may promote tolerance at the maternal-fetal interface (La Rocca, 2014). In particular, failure of these CD4 T lymphocyte subpopulation alterations may be related to preeclampsia development (Vargas-Rojas, 2016).


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Obstentrics_Williams. nonpregnant values, and upper values approach 15,000/jLL (Appendix, p. 1255). During labor and the early puerpe rium, values may become markedly elevated, attaining levels of 25,000/LL or greater. The cause is unknown, but the same response occurs during and after strenuous exercise. The leuko cytosis possibly represents the reappearance of leukocytes previ ously shunted out of active circulation. The distribution of lymphocyte cell types is also altered during pregnancy. Speciically, B lymphocytes numbers are unchanged, but the absolute numbers of T lymphocytes rise and create a relative increase. Concurrently, the ratio of CD4 to CD8 T lymphocytes does not change (Kuhnert, 1998).


Obstentrics_Williams

Obstentrics_Williams. Many tests performed to diagnose inlammation cannot be used reliably during pregnancy. For example, leukocyte alkaline phosphatase levels-used to evaluate myeloproliferative disorders-are elevated beginning early in pregnancy. he concentration of C-reactive protein, an acute-phase serum reactant, rises rapidly in response to tissue trauma or inflammation. Median C-reactive protein levels in pregnancy and labor are higher than for nonpregnant women (Anderson, 2013; Watts, 1991). Of nonlaboring gravidas, 95 percent had levels of 1.5 mg/ dL or less, and gestational age did not afect serum levels. Another marker of inlammation, the erythrocyte sedimentation rate (ESR), is increased in normal pregnancy because of elevated plasma globulins and ibrinogen levels. Complement actors C3 and C4 levels also significantly rise during the second and third trimesters (Gallery, 1981; Richani, 2005). Last, concentrations ofprocalcitonin, a normal precursor of calcitonin, increase at the end of the


Obstentrics_Williams

Obstentrics_Williams. also significantly rise during the second and third trimesters (Gallery, 1981; Richani, 2005). Last, concentrations ofprocalcitonin, a normal precursor of calcitonin, increase at the end of the third trimester and through the irst few postpartum days. Procalcitonin levels rise with severe bacterial infections but remain low in viral infections and nonspecific inlammatory disease. However, measured levels poorly predict development of overt or subclinical chorioamnionitis after premature rupture of membranes (Thornburg, 2016).


Obstentrics_Williams

Obstentrics_Williams. During normal pregnancy, both coagulation and fibrinolysis are augmented but remain balanced to maintain hemostasis (Kenny, 2014). Evidence of activation includes increased concentrations of all clotting factors except factors I and III (Table 4-3). Of procoagulants, the level and rate of thrombin generation throughout gestation progressively increase (McLean, 2012). In normal nonpregnant women, plasma ibrinogen (factor 1) averages 300 mg/dL and ranges from 200 to 400 mg/dL. During normal pregnancy, the fibrinogen concentration rises approximately 50 percent. In late pregnancy, it averages 450 mg/dL, with a range from 300 to 600 mg/dL. his contributes greatly to ap <.05. Data shown as mean ± standard deviation. PlT = partial thromboplastin time; tPA = tissue activator. Data from Uchikova, 2005. the striking increase in the ESR. Also, levels of factor XIIIibrin stabilizing oetor-signiicantly drop as normal pregnancy advances (Sharief, 2014).


Obstentrics_Williams

Obstentrics_Williams. Data from Uchikova, 2005. the striking increase in the ESR. Also, levels of factor XIIIibrin stabilizing oetor-signiicantly drop as normal pregnancy advances (Sharief, 2014). The end product of the coagulation cascade is ibrin formation, and the main function of the fibrinolytic system is to remove excess ibrin (Fig. 41-29, p. 784). Tissue plasminogen activator (tP A) converts plasminogen into plasmin, which causes ibrinolysis and produces ibrin-degradation products such as D-dimers. Although somewhat conlicting, most evidence suggests that fibrinolytic activity is reduced in normal pregnancy (Kenny, 2014). As reviewed by Cunningham and Nelson (2015), these changes favor ibrin formation. Although this is countered by increased levels of plasminogen, the net result is that pregnancy is a procoagulant state. Such changes serve to ensure hemostatic control during normal pregnancy, particularly during delivery when a certain amount of blood loss is expected.


Obstentrics_Williams

Obstentrics_Williams. Several proteins are natural inhibitors of coagulation, including proteins C and S and antithrombin (Fig. 52-I, p. 1005). Inherited or acquired deficiencies of these and other natural regulatory proteins-collectively referred to as thrombophiliasaccount for many thromboembolic episodes during pregnancy. hey are discussed in Chapter 52 (p. 1006).


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Obstentrics_Williams. Activated protein , along with the cofactors protein Siand factor V, functions as an anticoagulant by neutralizing the procoagulants factor Va and factor VIlla. During pregnancy, resistance to activated protein C grows progressively and is related to a concomitant drop in free protein S levels and greater factor VIII concentrations. Between the irst and third trimesters, activated protein C levels decline from 2.4 to 1.9 V/mL, and free protein S concentrations diminish from 0.4 to 0.16 V/ mL (Cunningham, 2015; Walker, 1997). Antithrombin levels decrease by 13 percent between midpregnancy and term and fall 30 percent from this baseline until 12 hours after delivery. By 72 hours after delivery, there is a return to baseline Games, 2014).


Obstentrics_Williams

Obstentrics_Williams. Normal pregnancy promotes platelet changes. In one study, the average platelet count declined slightly during pregnancy to 213,OOO/1L compared with 250,000/1L in nonpregnant controls (Boehlen, 2000). hrombocytopenia deined as below the 2.5th percentile corresponded to a platelet count of 116,OOO/1L. Lower platelet concentrations are partially due to hemodilution. Also, platelet consumption is likely augmented and creates a greater proportion of younger and therefore larger platelets (Han, 2014; Valera, 2010). Further, levels of several markers of platelet activation rise with gestational age but drop postpartum (Robb, 2010). Because of splenic enlargement, there may be an element of "hypersplenism," in which platelets are prematurely destroyed (Kenny, 2014).


Obstentrics_Williams

Obstentrics_Williams. By the end of normal pregnancy, the spleen enlarges by up to 50 percent compared with that in the irst trimester (Maymon, 2007). Moreover, Gayer and coworkers (2012) found that splenic size was 68-percent greater compared with that of nonpregnant controls. he cause of this splenomegaly is unknown, but it might follow the increased blood volume and/or the hemodynamic changes of pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Changes in cardiac function become apparent during the irst 8 weeks of pregnancy (Hibbard, 2014). Cardiac output is increased as early as the ifth week and reflects a reduced systemic vascular resistance and an increased heart rate. Compared with prepregnancy measurements, brachial systolic blood pressure, diastolic blood pressure, and central systolic blood pressure are all signiicantly lower 6 to 7 weeks from the last menstrual period (Mahendru, 2012). he resting pulse rate rises approximately 10 beats/min during pregnancy. Nelson and associates (2015) found that for both normal and overweight women, heart rate increased signiicantly between 12 and 16 weeks' and between 32 and 36 weeks' gestation. Between weeks 10 and 20, plasma volume expansion begins, and preload rises. his augmented preload results in signiicantly larger left atrial volumes and ejection fractions (Cong, 2015).


Obstentrics_Williams

Obstentrics_Williams. Ventricular performance during pregnancy is inluenced by both the decrease in systemic vascular resistance and changes in pulsatile arterial low. Multiple factors contribute to this overall altered hemodynamic function, which allows the physiological demands of the fetus to be met while maintaining maternal cardiovascular integrity (Hibbard, 2014). hese changes during the last half of pregnancy and efects of maternal posture are summarized in Figure 4-7. As the diaphragm becomes progressively elevated, the heart is displaced to the left and upward and is rotated on its long axis. As a result, the apex is moved somewhat laterally from its usual position and produces a larger cardiac silhouette in chest radiographs. Furthermore, gravidas normally have some degree of benign pericardial efusion, which may enlarge the


Obstentrics_Williams

Obstentrics_Williams. FIGURE 4-7 Left ventricular stroke volume across pregnancy compared with 12-week postpartum (nonpregnant) values for normal-weight women in the supine and lateral positions. (Data from Nelson, 201o5.) cardiac silhouette (Enein, 1987). These factors make it dii cult to precisely identiy moderate degrees of cardiomegaly by simple radiographic studies. graphic changes, and the most common is slight left-axis devia tion due to the altered heart position. Q waves in leads II, III and avF and lat or inverted T-waves in leads III, V1-V3 may also occur (Sunitha, 2014). During pregnancy, many of the normal cardiac souns are modiied. hese include: (1) an exaggerated splitting ofthe irst heart sound and increased loudness ofboth components, (2) no deinite changes in the aortic and pulmonary elements of the second sound, and (3) a loud, easily heard third sound (Cut forth, 1966). In 90 percent of gravidas, they also heard a sys expiration in others and that disappeared shortly after delivery.


Obstentrics_Williams

Obstentrics_Williams. A soft diastolic murmur was noted transiently in 20 percent, and continuous murmurs arising from the breast vasculature in 10 percent (Fig. 49-1, p. 950). Structurally, the expanding plasma volume seen during nor mal pregnancy is relected by enlarging cardiac end-systolic and end-diastolic dimensions. Concurrently, however, septal thick ness or ejection fraction does not change. This is because the dimensional changes are accompanied by substantive ventricu lar remodeling, which is characterized by left-ventricular mass expansion of 30 to 35 percent near term. In the nonpregnant state, the heart is capable of remodeling in response to stimuli such as hypertension and exercise. Such cardiacplasticiy likely as that in exercise, and pathological hypertrophy-such as with hypertension (Hill, 2008). Stewart and colleagues (2016) used cardiac MR imaging to prospectively evaluate cardiac remodeling during pregnancy.


Obstentrics_Williams

Obstentrics_Williams. Stewart and colleagues (2016) used cardiac MR imaging to prospectively evaluate cardiac remodeling during pregnancy. Compared with the first trimester, left ventricular mass increased signiicantly beginning at 26 to 30 weeks' gestation, and this continued until delivery (Fig. 4-8). This remodeling is concen tric and proportional to maternal size for both normal and over weight women and resolved within 3 months ofdelivery. Certainly for clinical purposes, ventricular unction during pregnancy is normal, as estimated by the Braunwad ventricuar unction graph (Fig. 4-9). For the given illing pressures, cardiac ..I3 .g 90 ; ..c)> .J=80