Effects of uremia and chronic hemodialysis on the reproductive cycle

Effects of uremIa and chronic hemodialysis on the reproductive cycle :\ () R M:\

J, (; () () n W I :\.

C :\ R L () \':\ L E :\ T I,

J,

E D W :\ R D 1I.\ L L,

~I

~I

J)

l>,

~I,

l> ,

ELI A, FRIEDM:\:\, M,D, Brook/pI, Nell' },,,,k Abnormal mt'liltrual pattnn. in '.!'.! a'"'''''' :t"h (h',,'I/( ,,'nal fll/lul( tlI~ p."o,t,d, lrl 4 o{ thtle WOllltn. ol'ulat<"-l f,"'(/lOn a II. ""Iuulnr Th,,, "I Ih, 4 ILllIIun ,ubjuttd to the ululator)'Itudy u''''e ,to" Inl! ",I/",Ienan" hn,,,,dial)J" Ihoapy and the fourth patiellt

\lud;~cl

had

\t'{

~rt' rr1lai fallur,.

but a

tIl

'1'(-": InA: rruduai

manag""tnl Dilly, Thi 'lUlu" of Ihr ""nll.ual abn"""al,l) ", all '.!'/ a VIII"" It'll.< corrt/ated wilh Ih, d'I!"r o{ rl'na/ fllllu,r a. ,.I",,,,I,d b) cr,alin,n, c1,a"mt'#. ePltlOf,;enOUf and/or ,j!i'cli:·,. ()l'uliJlory Cyrl'f u"" dt'rlJondfd/,d i,. ont' U.'O"!illl receil'i'lK mainl"lalla hOllodialj'.;1 Ihoap) On Iht ba.;. uf Ih.". of Ihr {our paranleters studi'll, anoth" u'omall f,ct'i:·tnR ma,nt'"tHUI' h,.modial,\ ,i., th,.,t.l.p)' p/Obabl}' ul'ulalrd, Clml.aapl;;, thnaPl ,. ru"",,","det/ for /L'O",,,, in tll~ ch;/dbearinK £IKe Kruup .urinn!! lIIa;nl"IIlIIo hrmot/Ill/) ." Ih''''(11

P R I () R TO 196!l, tllt're was no t·tf('('\i\'(' therapy availahle for tt'IlIlinal irn'\'I'Isihlt, renal failure other than r('nal homotransplantation. With the advt'nt of maintl'lIann' hemodialysis therap)" a feasiblt" allt'matin' Illt'thod of prolong-atioll of life has ('m('rgt'd, '" Patients under!!;oin!!; helllodialysis lIlay n'tulIl to normal patterns of life and ellgagl' in sexual activity. In this institution, 18 patit'nts unut'rgoing ('hronic maintt'llan('c hemodialysis for terminal renal failul'l' WI'I'(' qut'stiolll'd regarding reslImption of sexual activity. Of these 18 patients, I4 t'1I!!;agt'd in !'I'gular sexual intercourse. Therefore, the t1l1'ol'etical possibility of pl't'gnallcy exists for WOIllen in the ('hildbearing agt' group n'C!'I\'IIlg maintenanct' hemodialysis therapy. The I){)t('ntial

complicatioll' invok ..d in managing such a \l,llit'llt throughout pn'gll:lIK), "writ serious c(lllSidl'latic.n, Foll!' of tht' first Ii palit'llts begun on /IIainlt'nann' IIt'/IIo:\iah,is Wert' women in the childllf'aring agt' group. Each reported men,tmal irn'gularitil's coincident with the de\'('IOPIlII'llt of un'mic symptollls (i.e., nausea, vOlniting. \\'I'akrlt'ss, anorexia, weight loss, fluid rt'!t'nlion', As n'nal function deteriora!c'd, till'S(' symptoms progressed and amen01'1'111':1 ('nsllt'd, :\lIIenolTlwa had been pres(,lit fW1I1 2 to !I Illonths whell dialytic therapy was institult'd. Within 2 months of initial dialysis thl'r;lpy, IIl1'nslrual pl'riods returned in tll('S(' 4 WOlllt'n, and in 3 of the 4, irregular IIl1'nstrllal periods han' been sustained, with longt'r than norlllal inlt'l'\'als, The purp0S!' of the pn's('nt study was to ascertain wlll,t1lt'r I hI'S(' IIwnsll'lIal periods represented ovulatory cydt'~ amI to characterize the nature' anel exlt'nt of IIlt'nstrllal aberrations in dHonically lIrl'lIli(' wOlllen. Historical and dink,,1 data were collected n·l.(anlinl.( IIIl' ('ourS(' of chronic renal disease in 19 additional WOlllt'n with ('hronic renal

From the Depa,tmenlJ o{ M,dic;ne and Obstelrics and (;y,ltcolol!)', Stal, flnil'usily uf New Yurk, Downllale Medical Centn, and the KingJ Counly 1I0spitai Centu. This study war suppo,ud in pa" b)' United States Public IItalth Snl'ia G,ant ell ,1.1-44C and a Ueuarch Fellowship (Dr, Goodwin) I,om the NtJtionalln,
528

Volume 100 Number 4

Ovulation and uremia and chronic hemodialysis

failure . (Table I). Particular attention was given to obstetric and ~ynl'colo~ic histories, and to the chronologie relationship between abnormal mellstrual cycles and the statlls of renal function. Materials and methods The Helllodialysis Cellter has been in operation for 30 months. Patiellts are accepted for maintenance hemodialysis only when it can be dClilonstrated that their lives cannot be slistained by optimal Illedical management (i.e., 40 Gill. protein diet, dietary sodium balanced to maximal urinary sodium loss, transf usions, alpha-Ill ethyl DOPA, and aluminulll hydroxide or aluminum carbonate gl'l, as indicated). Thus, all patients accept['(1 into the Hemodialysis Center have had a chronic debilitated condition and are terminally ill. Helllodialysis is performed twice a w('('k for a total of 24 to 28 hours per w('('k , \ltilizin~ the two-layered modified Kiil dialyzer. All patients recelvmg maintenance hemodialysis function as active outpatients. Of the 22 patients un(\t>rgoing maintenance hemodialysis, only 4 are women of childbearing age. Three of these 4 women submitted to the study. OvulatOlY function was assessed in these 3 women. Another woman, being treated by conselvative medical means was also studied. Celvical mucus drying patterns (fern test) and viscosity (spinnbarkeit) and vaginal cytology were studied every 3 to 4 days for a 60 day period in each patient. Basal body temperature determined orally was charted daily by the patients throughout the study period. These parameters for the evaluation of ovulatory function are widely accepted and have been comprehensively reviewed recently.s Case reports Case 1. J. B., aged 34 years, had menarche at 13 ycars of age followed by regular Illensti'ual pcriods. Hl'r only pregnancy, in 1955, complicated hy hyp<'J'tt'nsion (hlood pressure 160/100 mm. Hg) and ~+proteinuria in the third trimester, resuited in the deliVl'ry of a live infant at term by cesarean sl'ction. The patient ·expcrienced clinical bouts of acute pyelonephritis

529

( fever, dysuria, fbnk tcnderness, pyuria, and hact"rillria ) in 1958 and 1960. Anemia (hemo. glohin 10 Gill. per IO() III I. ), easy fatigability, anorexia, and oligonH'norrhea d('\'('lop,'d in 1962 within a 2 month interval. Contrart('d kidneys were d.'monstratcd by intrawnous pyelography, and the diagnosis of chronic pyelonf' phritis was mad.,. An1t'norrlwa developed in S('ptember, 1963 . The patient continued to work as a hook. k('eper until JUIl<" 1964, when she was hospital. izpd for grand mal St'izur('s. Vomiting, anor('xia, It'thargy, and reversal of slt'l'p pattern had dt'. ve\opt'd 0\'1'1' the prect'ding w('ek. Laboratory findings on admission were: hematocrit 24 volumes pCI' ('Cllt, blood ul'l'a nitrogl'n 118 mg. per 100 mI., and senllll creatinine 6.7 Illg. per 100 ml. l'eritone;i1 dialysis was performed for 5 days, and the patient discharged with a hlood urt'a nitrogen of 33 mg. per 1()() ml. and sl'rurn creatinine of 4.4 mg. pCI' 100 011. One month following the initial peritoneal dialysis therapy and aftpr a 9 month period of amenorrhea, the palient had a menstrual period of normal quantity and duration. Peritoneal dialysis was required on five subsequent occasions between August and November, 1964, because of seizures, circulatory overload, and azotemia (blood urea nitrogcll ranging between 120 and 150 mg. per 100 1111.). Percutanl'ous renal biopsy showed chronic pyt'lol1l'phritis. Maintenance hemodialysis therapy was institutt'd in November, 1964, when the endogenous creatinine clearance decreased to less than 2.5 ml. per minute. The patient's management by hemodialysis has been uncompli. cated over the ensuing 26 months. Hemodialysis was done twice weekly for a total of 26 hours per week, and on the basis of six consecutive hemodialyses, the average blood urea nitrogen in milligrams per 100 m!. was 72.5 predialysis and 10.5 postdialysis with an 86 per cent reduction, while the average serum creatinine in milligrams per 100 ml. was 11.8 predialysis and 3.5 postdialysis with a 70 per cent reduction. One month after hemodialysis therapy was started, the patient became asymptomatic and within 2 months she resumed full activity. Two months after maintenance hemodialysis was initiated, a menstrual period occurred, followed by regular monthly menstrual flow through June, 1965. During the present study, the interval between consecutive menstrual periods was 65 days. Vaginal smears, fern patterns of cervical mucus, spinnbarkeit, and basal body temperature indicated, concurrently, that ovulation occurred 30

530

Goodwin et 01 .

Table I. :\[t'llstrual

Alit.

Cyrll'S

alld rt'nal functioll in 2~

WOlll(,1I

Pati~llt

Agt

Diagnosis

I. J. B." 2. C . S.· 3. r-i . P." 4. B.M" 5. A ...q 6. KD·t 7. E. T.t 8. E.~q 9. R. H.t 10. I. P. I I. R. T.t 12. B. L. 13. R.C. 14. E. H. 15. E. B. 16 .. L . C .t 17. R. R. 18. E.C. 19. C . L. 20. D.D. 21. S. B. 22. L.D. 23. E.W.

34 30 38

Chrunic pyelonephritis Chronic glollleruioneph ri tis Chronic pyelonephritis Chronic glomeruloneph ri tis Chronic glollle rulunt'ph ritis Chronit' glollleruinneph ritis Chronic glomerulonephritis E"l'ntial hypertension Polycystic kidney diseasl' Chronic glomerulonephritis Diabetic nephropathy Bilateral cortical necrosis Polycystic kidney disease Lupus erythematosus Chronic glomerulonephritis Chronic glomerulonephritis Chronic pyelonephritis Chronic pyelonephritis Chronic pyelonephritis Chronic pyelonephritis Essential hypertension Lupus erythematosus Chronic glomerulonephritis

23

45 H 26 45 51

23

39 16 52

47 45 43

50 18 24 44 35 46 34

·Ovulator)· function studit·d. Sre c:a)1! rrports. tEffrcti ..·(, crl"3tinint' cll'arancr ~ f'ndog("n()u~ + twier w('('kly Kiil

Frluu .. q < I."'), It~~n '" CoY''''''

J. 010,1.

with chronic rl'nal failure being treat.

- - - -Lt

Duration of diU(1!/!

6 15 17 16 5 2 6 4 12 3 5 II 20 2

5

16

6 4

2 3 3

4

16

years years years months years years years years years years years months years years years months months years years months years months years

Parity

1-0-0-12-0-0-2 2-0-3-2 2-0-3-1 0-0-0-0 1-0-3-1 0-0-0-0 2-0-0-1 1-0-0-1 1-1-1-2 1-1-2-2 1-1-1-1 2-0-1-2 2-0-0-2 ..,-1-1-6 3-0-0-3 2-0-0-2 0-0-0-0 1-0-0-1 3-0-0-3 4-1-0-5 1-0-0-1 3-0-1-3

hC"modi3Iy~is.

:Patiem 5, A.A., hystereclomy 15 yr .... ago for leiomyoma •. Patient 6, N. D., hystrrectomy .. yean ago aft.r spontan. treatment . Parirnt 8, E. M., hYilt'rtctomy ... yrar5 ago for mcnomr.tronh~gia . Patient 9. R. H., hysterrctomy 25 years ago for ht)cl, 3 yean ago. Patif'nt 16, L. G .• anu'norrhra for 4 months prior to institution of maintrnanre prritonral dialysit thtrapyo .1"0 IEfrecti\'e cnatiuine draran("r.

=

tndugt'nons + twice weC'kly pt'l"itont31 dia'y~i~.

days prior to mellstruation. The inteIY'als of menstrual periods since JUlie, 1965, have been 13050-65-37-45-31-38, and 65 days. After the interval of 130 dilYs, dialysis time was increased by 2 hours per week. Case 2. C. S., aged 30 years, had menarche at age 14 years, followed by regular menstrual periods. Acute glomrrulonephritis occurred in 1951 with clinical recovery. The palient had uncomplicat"d trrm pn'gnanrif's ill 1959 and 1960. ,Nephrotic syndrome df'vrloprd in july, 1962 (imasi-\rca, 4 +prot<'itluria, Sf'rum ch(Jk~terol 528 "'-:n, mg. pf"rl~,OO mI., sC'rulll albumin 1.5 to 2.5 Gm. per \00 ,ill.). Intrawtlous pyelograph)' was normal, hemoglohin 14.4 Gm. per 100 011., blood urea nitrogrn \0 mg. p.-r 100 mI., and SenllTl creatinine 1.8 mg. prJ' lOa ml. Urinalysis showed gnlnlll~'r and h)'aliup ('asts. Cortisonr, 25 mg. per day orally. was given for apprnximatdy G 1I10nths with dillical remission. The palit'nt 'remained a.s ymptolllatic ulllil April, 196·1, when at 4}/.l months' gf'stalilln shc dC'velopcd mild hypertension (blood prcssme 150/100 111m. IIg), anemia

(hemoglobin 10 Gm. per 100 mI.), and azotemia (blood urea nitrogen 38 mg. per 100 mI.). One month later, she aborted spontaneously. Bilateral tubal ligation was performed in the puerperium. Anorexia, 2+ edema, weight loss, and hypomenorrhea developed in March, 1965, and in july, 1965, amenorrhea developed_ Peritoneal dialysis was required on two occasions, in August and Septemher, 1965, because of oliguria (urine output lC'ss than 500 mI. per day), azotemia (blood urea nitrogen 150 mg_ per 100 m!.), and asterixis. An open renal biopsy showed chronic glomerulonephritis, and in October, 1965, maintenance hemodialysis thrrapy was begun. The endogenous creatinine clearance was less than 1 ml. per minute, Hemodialysis was done twice weekly for a total of 24 hours per week, and on the basis of six conseruti\'e hemodialyses, the average blood urea nitrogen in milligrams per 100 ml. was 71.3 predialysis and 15.0 postdialysis with a 79 per cent reduclion, while the average serum creatinine in milligrams per 100 m!. was 14.1 predialysis and 5,2 postdialysis with a 63 per cent

VuiUIllf' Ion i'iurnhC"f ..

Ovulation and uremia and chronic hemodialysis

Kings COllllt)' Hospital Cmter In/nt'al /,om on," 0/ u,emic rymptom, to on.!et 0/ m~nJt'ual i"tgula,itirr

2

Cu,,,,,t

< II month month < 2 month~

No possible correlation No pos~ible correlation No possible correlation No possible correlation No pm.ibl .. correlation Never irregular 3 months 1 month Always irregular Never irregular 3 months 1 month I month Never irregular Never irregular I month 6 we.,ks 2 months Unknown

<

< <

----- -----

nOUf 'f,atl1UII'

Cu,,,n'men,',ual patt"n

Irrt'gular Irrt'gular Irr.,gular Amt'norrht'a Am.,norrht'a Amt'norrhra Amenorrhea Amt'norrhra Amenorrht'3 Regular Irregular Irregular Irr.,gular Regular Amenorrhea Irregular Irregular R.,gular Regular Am.,norrhea Irft'gu!ar Irregular lrr.,gular

month~

-----~"d,,!:,-

531

cI,a,anrt

(ml

":In

It It It 1-2 It It

It

1-2 6-8 16 20 4-5 5 60 1-2§ !-2§ 5-8 13

24

:1 5 4 5

!of;l,ntcnanct' hf'modi,llysis !ofaintr-nanct" hel1lodi,dysis !ofainlrnan,"c ht'modial)"sis Mrdiral man;lgement !ofainlrn,tIIl"<- hem"dialysis !ofaint .. nance ht'modialysis Maintrnanct' hemodialysis Mt'dical manag.'ment Mrdiral managrmrnt Mt'di,"al managrmcnt Mt'diral manag,'m"nt Mtdical managrment Mrdical manag.'ment Mtdical managl'lIlent Maintenance peritoneal dia,lysis Maint .. nanet' paitoneal dialysis Mnfical managelllent M.-diral managcrnrnt Mnf iGI I management M.-di("dl managrment Mnfi'-'ll manac:elllent Mrdicll managrmrnt ____M.-dic~_1 _~l~naC:f'I!'~nt

------

.s

'·liun. Patient 7, E. T., .Itt'r • year pc-riod of amrnorrhra had ~ rrifULt, rnf'll,tru.11 prrind \\ilh hrl h,\r p.·rirnnt"al dialysjJ sllual bll'cding. Patienl 11, R. T., diab~tt"S IIItliitu! for 20 yta,s. P.tit'llt 11, E. H., lJ'ltmic lupus trytlwnl.llO\u'J diaJrno~d

reduction, Six weeks" after hemodialysis therapy was started, the patient had a normal mrnstrual period, was asymptomatic, and had resumed full activity as a housewife, Subsequrnt interval~ between menstruation were 46-47-128-30, and 31 days. During the 128 day interval the patient had several episodes of infection of her arteriovenous shunt. During the present study, the interval between sllccessive menstrual periods was 47 day"s. The fern pattern, spinnbarkeit, and basal body tempt'ratllre findings suggrsted that ovulation occurred 30 days prior to menstruation. Thr cytoln!;ic findings, however, were inconclusi\'e, Case 3, N'. P., agcd 38 years, had mcnarche at age 18 years followed by regular menstrual periods. She WilS wcll until 1949 whrn, during the third trinll'ster of her first prrgnancy, she drve\oped clinical findings of acute pydonephritis (fever, flank tendernes.~, pyuria, bacteriuria, and leukocytosis), which was respomive to antibiotic therapy, The pregnancy proceeded uneventfully to term, Thc following pregnancy, in

19S0, was cornpli.-.1tt'd b)" n'cunl'lIt bouts of py"c1onf'l'hriti, and trrl1lill"t"<1 in spnntanrous abortion at 5 month,' gl'station. Duing her third prl'gnanq", in 19:»1, urinary tract infection recurred, requiring 6 month, of antibiotic therapy, but resulting in t~ ddiwry of a healthy infant at (('rill. In latl' 1951, th.· patient had a self-induCt·d anortion at 6 wrl'h of gl'st;ltion. In 1959, the di;'gnosis of chronic pyelonephritis was made on the b",i, of int", Illitlt,nt bacteriuria. contracted kidn.'}s on r.. trograd,~ pyt·logr;lphy, and bilatt'ral r.. f1ux on cyst ..~:;r;lphy. Th(' piltient's blood un'a nitrogm wa~ S9 mg, p,'r \00 ml. in June. 19ti:~. Thr fifth p"'glliln.-y tl'flllinated in spontan('ou~ ahoninn at 2 months' gestation in July. 19GI, at whi.:h tillll' th .. blood urt'a nitrogl'n wa~ 7tj 1I1~" pn- 1001111. Oligllhypomenorrhea, wra"'\f's~, Ij,th:u·J:)'. p;lfestlll'sias in thl' extremitics. and an"tIJia (hrlllo~l .. bin 8 Gill. per 100 mI.) d"Hlol",d in j\ll\O', 19(0. 011(' mOllth hlter, thl' patil'nt l'X(W"riell('('d an exacerbation of pyelonephritis with blood url'a nitrogell elevation to 160 mg. pt'r 100 nil. and serull\ creatininc rise

532

Goodwin et

f,·bruary I;, 1968

01.

10 17 IlIg, p('(' I()() 1111. Followin,l( a ti \'TI'k comsl' of anlibiolic tht'rapy, Iht.' blood III'1'a ninOl(I'n dl'nl'asl'd til HH mg, pIT I III) 1111., till' "'1'11111 creatinine III 11.5 IIIg, Iwr 11111 1111. In SI'PII'lIIll1'r, II)t;:), till' palil,Ilt's hlood III'1 'a nitrllgl'n 1'''''' III 13", IlIg, 1"'1' I flO Ill!. and 1'I'lIIailll'd ill Ihal LU'gl' ,~uhseqlll'IIt1y ill spil(' of h~drati(lll and anlihiolil ' th(' rap)' and anll'llIl1Tllt'a dl ' \'I'lolled , l'C'rillllll"al dialysis was Iwrfornll'd lin Iwo (KTasions, in i\'''''I'lIIlwr and 1>1'I'c'lIIll1'r, I"ti,'), rt'spc'('( in'''', I,..· ('allst' of kthar,gy prllrillls, wt'akIH',ss, O('('lIlt hlolld in Ihl' SIIlIII, alwllIia, alld sc 'nliH lTC'atinilll' in till' rangl' of 17 to :2() Illg, pl'!' I ()() ml. ]\I<'nstrual pC" rinds "f normal quanlily and duration fllllowl'd hOlh lH'rilOlll'al dialySt~s, Maillll'llan('(' hC'IlIIl' dialysis tlwrap}' was lH'gun in DI'('I'II1I)('r, Illt{" with Ihe ('ndng-I'nolls cl'I'alinilll' clt-arall .... ""s,, than :2 1111. pl'r Illinllll' , Ilt'lllodialysis was dOllc' twirl' w('('kly for a total of 2H hours pn wl' .. k, alld on tilt' basis of six (,Oll,,'('ut ive 11I'1llo
Am .

J.

()h, • .

"(;yntt.

phritis , Th,· P,ltic'llI had re .... il't,d no dialysis tlII'Lq'\ , ;\t th,· ,t;11"I IIf til!' study, thl' pati,'nt's en dog. l'llttl" rJ"'''ltillinc' c IC',1ra11O c' rangl'd from 5 to 6 ml. Ih'r Illinllt'·, »lII"ilH~ th .. slUdy period, the ill!"r\'" I Iwt" ("'11 ,'"",,'''Ul in' 1ll"I1suuai bleedings \\ 3' ,'III <'1' milllll<'. R","lts of tilt' SIlIYt'Y of ~:l Hr<'mic women an' slllllll1;rri/l'(l ill '1',11>1" I.

Comment There is scarcity of information in the litt'ratllrt' regarding modifications of the sc'xllal Cyell' sccondary to urt'lttia. Board and aSS
Volume 100 Number 4-

Ovulation and uremia and chronic hemodialysis

In the present study, ondation has bCl'1I documented in aile of :~ wOIl1('n 011 lllaintenance in terllli Uellt hemodialysis thl'rapy (J. B.), and th('n~ was sllggrstin' ('vidl'IICC of ovulation in another (C. S.) . The abnormally long secretory phase of these cyell'S cannot be explained. Chronic urelllia and maintenance helJlodialysis th(,rapy may haw, indcpendently or in cOlljunction, interfered with thc corpus luteulll function. althollgh it cannot bl~ excluded that thl' parameters chosen for d(,tection of ovulation Illay hav(' been altered by the sallle factors. The third patient (N. P.) probably did not ovulate. An extended period of observation for the last 2 patients may detect ovulation, sinre til(' intervals of ovulatory cycles in hemodialysis patients may bc quite variable. Thc fourth patient studied (B. M . ) , who had advanced renal failure and was lIot rC'c('iving dialysis therapy, did not ovulate during the study. That amenorrlwa developt'd in H. M. during the study and has Iwrsisted would telld to support this conclusion. The findings in these 4 patients indira!!' that not only dol'S urell1ia affect the female reproductive cyell', but that treatment of uI'I'llIia by chronic maintenance hemodialysis lIlay Illodify these (,fferts. The return of menstrual periods in Patients J. n.) c. S., and N. P., correlat('d with a disappearance of other manifestations of uremia. Since the Ilt'rVOllS, cardiovascular, hematopoil'tic, skeletal, integumentary, and respiratory systems are known to undergo pathologic changes secondary to urelllia, it is not surprising to find that the female reproductive system is also affected. In an attempt to correlate menstrual abnonnalities with degree of renal dysfunction , clinical, and historical data in 23 uremic women with primary renal disease were reviewed (Tabl(, I). While the number of patients is admitt('dly small, certain generalizations might be lIIade. Patients with chronic renal failure tend to develop menstrual irregularities coim·jdent with the development of other symptoms of uremia (Le., nausea, vomIting, anorexia, weakness, lethargy, weight loss, fluid retention, and pruritus).

533

SYlllptoms of urt'lllia usually appear when the endogenolls creatinine clearance falls to the range of 10 to 15 ml. pCI' minute. Patit'lIlS have irregular menstrual periods until the endogenous creatinine clearance decreases to about 4 ml. per minute or less, at which point arllel10rrhea develops. Representative examples of this cited correlation follow. I. E. C., aged 18 years, has chronic pyelonephritis s('(,(lIldary to congenital abnormalities or th(~ genitourinary tract. In 1964 a right Ilf'phr('c. tomy was performed b('cause of hydronephrosis. At pres('nt, hf'r f'ndogf'nous creatinine clearance is 13 m\. per minute and she continu('s to have J't·gular monthly menstrual periods. The patiC'nt has received no dialysis therapy. 2. B. 1", agC'd 16 years, in March, 1966, dev('loped prl'matul'e separation of the placenta in th(' eighth month of pregnancy. Anuria followed and was slIstained for 3 months. Cortical necrosis was found on rl'nal biopsy. Thc patient was tr('ated with intermittcnt maintenance hemodialysis two to three times per week throughout the period or anllria, utilizing the Kolff twin-coil dialyzer. In June, 1966, urine flow rcturned and hemodialysis therapy was discontinued. With ('ardul balancing of salt intake to urinary sodium C'xcretioll, the endogenous creatinine clearance incn'ased gradually to thc present level of 4 to 5 Ill\. per minute in September, 1966. Amenorrhea which had pC'rsisted during the interval of anuria was Slip planted by irregular menstrual periods when her creatinine clt'arance exceeded 4 mi. per minute. The pattern of menstrual cycles noted in women undergoing chronic maintenance hemodialysis approximates that seen in women with cndogenous creatinine clearances in the range of 10 to 15 ml. per minute (Table I). Hemodialysis utilizing the Kiil dialyzer produces a creatinine clearance of 50 to 60 m\. per minute.· Since the patients undergo hcmodialysis twice weekly, the net effect is the clearance of 100 to 120 m!. per minute of creatinine per week, or 15 to 16 m\. per minute daily. The asymptomatic status of the 3 patients undergoing maintenance hemodialysis who were studied correlates with thc clinical status of stable outpatients with chronic renal failure having en-

534

Goodwin el 01.

dogenous C'reatillillf' cJt'aranC'es in the salll~ range. It is known that urt'lllia has an a(kersf' efTert upon prl'gn:lllC'y and thl' concept LIS. In a series of paticnts with renal failure mllected by ~rackayO OWl' a 10 year spall, there was a 39 per cellt fetal mortality rate. In his series, no patients with a blood urea level above 60 mg. pl'r 100 ml. was delivered of a live birth. Others haw reported a fetal mortality rate ahove 60 pcr cent in urcmic patients. 6 • 13 Tenncy and Dand row 17 reviewed the dinical coursc of 55 womcn with renal disease and pregnancy. In 20 patit'nts, the pregnancy terminatcd in spontaneous premature labor. Seven pregnancies resulted in stillbirths, 3 in superimposed pre-eclampsia, and one in prelllature separation of th~ placenta. In 5 of the 7 stillhirths observed prior to labor tl1£'re was arrested uterine growth for 2 to 3 weeks prior to intrauterinc death. Tenney and I>androw 17 recollllllcnclcd that uremic \\'olllen be delivered at 36 weeks because of the low salvage of term babies. Of the term babies, SOllie died during labor and others during the neonatal period. In contrast, of 169 women with hypertension and/or pre-eclampsia, there were only 5 spontaneous premature labors. Whether the poor fetal prognosis in uremic women also applies to wOlllen on maintenance hcmodialysis is sp('culativc. Howe\'cr, since these pati('nt!\ may ovulate, serious consideration should be given to the place of contraceptive thcrapy in tht' over-all management of these wOlllcn who are in the childbearing age group. Whcreas there are a few reports in th(' lit('rature on thc use of hemodiaiysis tllC'rapy during pregnancy, I, 1, 8, 18, 18 none spl'cifically is pertinent to the . management of a patit'nt maintained by chronic hemodialy~is throll~hollt pr('gnancy. Although it is unknown wh('ther prl'gnancy from onset to t(Tm would complicate the clinical managPIJl('nt of a patil'nt fl'ceiving maintp.nance int(~rlllittl'lIt helllodialysis therapy, it SCCIIIS likely that at a rnHlIIIIlllll, additional psychological stress would be placed upon patient anc! family. Many qllestiom remain regimling altera-

Am.

F("hlu;'q' I:;, I~;n Oh~r. &: G)'IIC'e.

J.

tions of the scxual cycle in women with chronic renal failure and the efTcct of hemodialysis therapy on these alterations. Detailed study of estrogen-progesterone balance and gonadotropin l('vels may shed significant light upon this problem. It is not known whetht'r the germinal epithelium undergoes change secondat)· to chronic uremia. Since the number of women of childbearing age maintained by hemodialysis in a given institution is likely to be relatively small, it is highly desirable that studies similar to the one reportcd herein be conducted by other dialysis centcrs. Summary Ovulatory function was studied in 4 women with terminal irreversible chronic renal failure, 3 of whom were receiving maintenance hemodialysis therapy. Ovulation was deJllonstrated in onc paticnt, and there was suggestive evidcncc of ovulation in a second patient. Findings in the third patient were inconclusive. Ovulation was not shown in the fourth patient, who was receiving medical management alone. Both peritoneal dialysis and hemodialysis may alter the effects of uremia on the reproductive cycle. Abnonnalitics of menstrual cycles correlate with the degree of renal insufficiency. Contraceptive therapy is recommended for women of childbearing age undergoing maintenam."" hemodialysis therapy for the following reasons: (I) the possibility of ovulatory cycles, (2) the uncertainty of medical and psychological effects of pregnancy, and (3) the high fetal mortality rate in women with chronic renal failure. The Dialysis Unit is a collahorative v('nture of the Departments of Mt'dkinc and Surgc'ry ( Urology) . Th" authors rxpn'ss thpir gralilllClt- to Dr. Stt'pl ... n St·It,,·r for assistant'e in obtaining sprrinWIIS, 10 Drs. Gl'rald Thomson, R. Krith Wah'rhousr, I hlrold :McDonald, Jr., Edmund BUllS, L. Iladl.i-I'r~ic. Robert Krain, and StcphclI Sdll.t'r, who assisted in conducting the hcmodialyscs, and to Miss Katht'rinc Whcch'r and Mrs. Kay Leu for their valuahle technical assistance.

VllltiflIr

lun

Numh .. !" 4

Ovulation ond uremIa and chronic hemodialysis

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Cuu,d. ~1. :\. J. 83: 372.1960. 1-1. Sdm·i,wr. C. E .. and ~aht'r. ]. F.: Uremia, Sprin'lfi.-Jd , lIIi,lO;I. 1961. Charles C Thomas. P.bIisht'r. IS . Scllwcit/. M. B., Seftd. H. C ., and Isaacson, C.: South Afri can ~1. J. 35: 341, 1961. 16. SO'pnnwo. ~l. :\. 0 ., Armstrong. M . J., and McGeown. ~f.: Lane"t 2: 1009, 1966. 17 . Tmnq·. B, and Dandrow, R. V.: AM. JOan. &. C,·:.;rc: 81: 8,1961. 18. Thril. G. B .. Powell, M . R., and Doolan, P. D.: ="eurnlog)' I: 138, 1961.

Cla,klon .~"Inue B'Nklyn. N,w rod: 1/20.1

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