A multicentred phase III comparative clinical trial of depot-medroxyprogesterone acetate given three-monthly at doses of 100mg or 150 mg: II. The comparison of bleeding patterns

A" MULTICENTRED .....~................................~0.~ .. .....D , ~

PIIASE III COMPARATIVE EDR 0X~r;RO~~~~~E~

C] Ac,

G__IVE,N _T~aREE-HOI~'~T~tlL'x"A T ...... DP_-sES. ....... O F IO0m Mt~..:_~, II. THE COMPARISON OF BLEEDING PATTERNS =

__

~ . . . . . . . .

....

_ ~ - - - - : -

WORLD HEA

-

~_

...........

.

~

...................

°~

~

.

~

.

~-~

I{ ORGANI Z AT ION

Task Force on Long-Act~_ng Systemic Agents for Fertility Regulation Special P r o s t a t e of Research, Development and Research Tra~.nJn~ ~n H u m a n Reproduction

S Sa~d and K. Omar Department of Obstetrics aud Gynaecology, Shatby i-laternlty llospital, University of Alexandr~_a, Alexandria, Egypt Suporn KoetsawaL,g, Orawan K~ riwat and Yuwadee Sr~satayapan Fam~_ly Plannl Research Unit, Sir~_raj Hospital, I.laha~dol University, Bangkok, Thailand A. K"a zt and F. Ajmal Nat~_onal Research Institute of Ferttlity Pak~_stan

Control,

Karacl,[,

H. H. Wynter Advanced Trainlng and Researc|, Uttlr. i_n Fertility Management, Un[verslty of the West Indies, Kingston, Jamaica A. Pretnar-Darov~c Un~vers~.ty Cl~n.~_c of Obstetrics Yugoslavia

al~d Gynaecolo~-¢,

LjubLjana,

I. B. Ben~tez, J. de la Cruz, aud K. Ape!o Reproductive B~.ology Centre, Department of Obstetr4~cs and Gynaecology, College of Medicine, Un[vers~.ty of the Philippines, Man~_la, t,te Phll~.pp~nes L. Kovacs and S. Koloszar Department of Obstetr~cs and Gynaecology, Un~vers£ty Aedtcal 3cI~ooi of Szeged, 3ze~ed,

Hungary

C. d'Arcangues, B. Busca, P. E. llall and D. Maehln* Special Programme of Research, Development and Research Training ~_n lluman Reproduction, World Health Organ!_zation, Geneva, 3wi tz erland * al~o Med~.cal Statistics and Computing, Unlvursity of Southampton, Southampton, Un~ted K~ngdom Reprint requests and address for correspondence: Catherine d'Arcangues, pecial Program of search, Development and Resear Traini i~ Human Reproduction, Health Organization, 1211 Geneva 27 Switzerland

World

S u b m i t t e d f o r publication February 25, 1987 A c c e p t e d f o r p u b l i c a t i o n June 29, 1987

J U N E 1987 VOL. 35 NO. 6

591

CONTRACEPTION

AS ST ~%C T A mul~Ic~ntered pt~asu I I I c l i n i c a l trial was cot,ducKed In seven c u u n E r i e s to c o m p d r ~ Kwu dosages o~ d e p o t - m u d r o x y p r o g e s K e r o n e ace~at~ (~IPA), iOC~ng a n d 1 5 ~, ~ i v ~ n e v e r y 919 d a y s . Contraceptive efficacy and side-~fects of b o ~ n r e g i m e n s w ~ r e r e p o r t e d previously. Tl~e~£ e t £ ~ c K oi, v a g i n a l bleeding patterns i s ti,e on j e e r o~ E n i s |)aper. A t o ~ a ± o f 1 2 i 6 wo~aen w e r e ~ a n d o m l y assigned to a d o s e g r o u p and l l b o of t h e m p r o v l d e d a me**sEruax dlary. Tl~e c o m p a r ' i s o n o~ Ehe 01ee~in~ patterns is m a d e u s i n g a ~O--ddy r ~ f e c e n c e period approacl% and f o l l o w i n g the g u i d e l i n e s puDiisned by %4|{0. In a d d i K i o n , tlle ±ongesE bie~dins/spoE£ing" episode a n d Ki]e ± o n z e s E bleeding/spo~ing-free in£e~'val a r e c a i c u ± a t e d over The en£ire diary

The only dlr~e~=nce £ou,~d D e ~ w e C n t~,e E w o n o s e g r o u p s is a higher incidence o~ a m ~ n o r r h e a wi~ ~i~e ± D 0 m ~ ~-egimen. Ove~all, ti,ere is a lli~h d e ~ rec o~ cu~,si s ~ e n c y be ~ w e e n ~ne r e a s o n s ~ i v e n by i n d i v i d u a l ~;omen r u t d i s c o n E i n u i n ~ Ehe c o ~ = r a c e p ~ I v e meEnod and Klleir v a g i n a ± b l e c d a n & pa~~r~, during tnu 90 days preceding discontinuation. ~4owever E h e d a ~ a r e v e a l e d l a r g e o e t w e e n - c e n t r e differences, Dot~, i,l t ~ incidence of s p e c i f i c patterns, and in tl,e id~nKiflca£1on oy w o m e n 0£ D l e c d i n ~ ~ ) r o D l e m s as r e a s o n s Z o r dlscontinud~ion. T~,is last p u i n t s u g g e s t s t h a t ~i~e i i f e - - ~ a b l e analysis u~,derestimat~s £11e E r u e i ~ , c i d c n c e of m e n s t r u a l irr~u±acit[~s. C o ~ n m ~ n E s o n Else ~ f ~ r c s c e period eila±ysi~ method are ~ u d e . INYI[ODUC f ION The mosL significant proDlem in u s i n g d e p o t - m e d = o x y p r u g e s t e r o n e ~ce£at~ (UPIPA) as a c o t i ~ r a c e p E i v e is Ene i r r e ~ u ± e r i ~ y o~ m ~ n s s r u a ± D i e e d i n g i~ i n d u c e s . Previous suudies ,.I," 2) ~,ave silown E~,at ti~e incidence of a m e n o r r h e a and Infrequent oleeding increases wl~h dsraEion of t ~ e a E m e n E a n d EtlaK, aE o n e y e a c , 35/. or w o m e n experience amenorri~ea ~or a whole 5 months in3ecnion inK erval~ approxitaa£ely 1 0 & o~ w o m e n ~ x p ~ r i e n c e prolonged episoaes of D l e e ~ i n ~ , w h i l e l,eavy b±eeding is rare. In a n a t t e m p ~ Eo decrease tt~e incidence o f s i d e - - e f f e c t s of t h i s coneracep~ive me~llod by r e d u c i n g the sE~roid load, ehe World Health c j r g a n i z a t i o n ' s Task. F o r c e o n L o n g - - A c t i n g S y s u e m i c A g e n t s for Fertility Regulation undertook a large phase Iii mu±Eicencred clinical ==ial comparing two r e g i m e n s of D~IPA- 1 5 O m ~ vs i O O m g g i v e n intramuscu±arly e v e r y ~llree m o n = h s . T h e f i r s = p a r t of t h e s t u d y results has been published previous±y k3) a n d h e r e a f t e r is r e f e r r e d c o as P a p e r I. There was iiggle difference in efficacy De=ween =he c~o dosages; the side-effects were also similar excepc for amenorrnea wiEh a life-table disconti~,uation r a t e at o n e y e a r or 7.2/~ f o r ~ h e I O 0 m g r e g i m e n , v e r s u s 12.5~-" f o r E h e 150rag d o s e .

592

JUNE

1987

L. 35

. 6

CONTRACEPTION

Huwever, d i s c o n t i l l u d t l o ~ f o r amellorrllea w a s v ~ r y m u c h c e n t r e relate~" it w a s mot'e e v i O e n t in Alexandria, Karachl, L j u b l j a n a and Smeged. in c o n t r a s t , very few women discontlnued for amenorrhea in BangKoK, Ki,tgsKon and .-lanila. Ploreover, in t h e t w o E a s t - A s i a n c~n~r,zs, i~ w a s llOt~d t~lat a g r e a t e r n u m b e r of w o m e n h a d disconti~,ued £ u r ' n o n - m e d i c a l r e a s o n s ' o r i~ad b e e n l o s t to foiio~¢-up, tl]an in Erie otl~er c ~ n K r e s , it w a s s u g g e s t e d that such differences mzg~,u r e f l e c t K n e c o u n s e l l i n g =.,iven i n e a c h c l i n i c , cultural differences in t h e t o l e r a n c e to a m e n o r r n e a or the f e a r of possible pregnancy suspected f r o m ~ h e a b s e n c e of b l e e d i n g . This paper presents a d e ~ a i l e d atlaiysis of t t a e m e n s t r u a l diaries recorded by 1 1 5 0 (~5.17~) of tl,~ w o m e n r e c r u i t e d to ~l,e t r i a l , to verity the observations sutamaris,_,d a b o v e . The vaginal bleeding patterns induced by boti] r e g i m e n s a r e comp'ared, a n d t h e irregularities experienced oy d i f f e r e n t eEnnic groups are identified. To assess cultural differences in tolerance of menstrual irregularities, the r d l a t i o n s l ~ i p b e t w e e n o i e e d i n g p a t t e r n s and the subjects' reasons rot discontinuation is a l s o i n v e s t i g a t e d . The analysis follows guidelines recently proposed Dy W H O (4) a n d comment is m a d e on t h e i r u s e f u l n e s s . TERIAL5 Design _- ~

....

of

.........

: .....

AND

I.~THODS

tlle s t u d y ..........=

-

; -

...........

The preparations u s e d z n tlae s t u d y w e r e IU g and 1 5 g d o s e ~ of D~po-Provera K kdepot-medro>~yprogeseeconu aceuatc, UAPA2 formulated i n Ira! a q u e o u s S O l U t i o n aS a m i c r o c r y s t a i l i n e ~uspension. D e t a i l s of the s t u d y desi~n= , s u b O u c t s~l.2c~ion a n d ~ o i ± o w - u p |~ave .been p r e s e n t e d in P a p e r I. A E o t d ± of 1 1 1 6 w o m e n e n t e r e d ti,e s~udy in seven centres distributed worLdwldc; of tilese, iiSb provided a menstrual d i a r y w i t h d a i l y r e c o r d of ~lle o c c u r r e n c e of bl~eding, spotting or n e i t h e r . ~ l e e d l n g w a s d e f i n e d as 'any b ± o o d y vaginal discharge EhaK q u i r e s Ene u s e of s u c h p r o t e c t i o n as pads or tampons'; and spoe~ing as 'any bloody vaglna± discharge t h a t is not sufficient to r e q u i r e p r o t e c t i o n ' . If a w o m a n d e c i d e s to l e a v e the E r i a ± in r a i d - c o u r s e , she w a s asked her ason for discontinuation. Her answer s then classified i n t o one of s e v e c a i c a t e g o r i e s : a vaginal bleedi problem further detailed a s "'heavy b l e e d i ", " p r o l o n g e d bleedi ", "Xrr~gular Dleedin~", "spotting" or " ' a m e n o r r n e a " ; "'other m e d i c a l " r e a s o n , t h a t is u n r e l a t e d to vaginal bleedin:g; a " ~ e s i r e ~ o r pregnancy"; or a " n o n - m e d i c a l " reason. The subjects who remained in the grial for the full four injection intervals w e r e list.ed a s havi r e a c h e d ~he " e n d of s t u d y " , wi~ile t h o s e w n o d i d n o t r e t u r n K s t h e c l i n i c w e r e l i s t e d a s " I 0 s t to follow-up". Statistical .

.

.

.

.

.

.

.

.

.

.

The diaries

J

.....

-

-

Proceaures .........

.__

_ . = = . ~ ,

. . . . .

_ ...............

..........

comparison of is m a d e u s i n g

.

b±eeding patterns obtained from the tile r e f e r e n c e p e r i o d a p p r o a c h f i r s t

1 9 8 7 V O L . 35 N O . 6

menstrual suggested

593

CONTRACEPTION

by R o d r i g u e z ~t~ ... 9_~ ..I" (5) a n d following = h e g u i d e l i n e s pubiisl,ed oy Wild t4). ItI sumtsary t h e m e n s t r u a l d i a r y is d i v i d e d i n t o 4 r e ~ r ~ n c e p e r l o d s of 90 days s t a r t i n ~ on Ei,e day o f f l r s t I n o e c t i o n and f i n i s h i t , g 3 D O d a y s l a t e r at t h e |.appr ima£~) annxversary of ~ h e f i r s t in jut=ion.

for

F o r eacl, w o m a n each re£erence --

-

-

-

the f o ± i o w i n ~ p~riod"

summary

statistics

are

calcuiaEed

n u m b e r of u l e e d i /spotting days n u m o e r of b l e e d i n . g / s p o u = i n g episodes n~ean l e ~ g £ h of b l e e d i n g / s p o t t i n ~ episodes mea~, leng~la of o i e e d l n g / s p o t t i n g - - f r e e intervals n u m b e r of s p o t t i n g days n u m b e r of s p o t t i n g - o n l y episodes

F o r tl,os~e d i a r i e s w h i c n a r e n o t c o m p l e t e d ~oz" 360 days, for exampl~ from wom~n WhO refused in3ectlons or w e r e l o s t to f o l l o w - u p , a ~ e d u c e ~ ~un~ber of r ~ f e r e n c e p~riods is consequently available. T h~ m i n i m u m l e n g t h of u s a b l e d i a r y i n a n y r e f e r e n c e p e r i o d is t a k e n as d O d a y s ; f o r t h e s e s n o r t d i a r i e s ~ the n u m b e r s of d a y s a n d episodes are calculated on a proporEionaEe basis. F o r e x a m p l e if a w o m a n ~,as 2 b l e e d i n g e p i s o d e s i n 7 0 d a y s o~ d i a r y , s h e is c r e ~ i ~ e d with 2 X 90/70 = 2.b episodes f o r tl,e r e f e r e n c e period. %4i~i,in a r e f e r e n c e period, a l l ~_-venKs a r e £a~.en a s c o m p l e t e ~ v e n if o n l y o n e d a y ± o or truncated b y ~ h e ~0--day l i m i t . Because s u b j e c t s w i ~ n no b l e e d i n g nor spo~tin& Et~rou~n0u£ an e n t i r e relerence period would dominate the s u m m a r y s t a t i s t i c s on ± e n g t n s of epasodes and intervals, they ac~ omitted f r o m t|lose E w o c a l c u l a t i o n s i n tn~ c o m p a r i s o n of t h e d o s a g e g r o u p s . For eacl~ s u m m a r y s t a t i s t i c , ~|~e m ~ d l a n a interquartiie r a n 6 e are c a l c u l a t e d for a l l tae w o m e n in a d o s e g r o u p .

first

In a d d i t i o n injection,

discontinuatlon

~o t h e r e f e r e n c e p e r i o d s d e f i n e d f r o m tt,e d a ~ e of the menstrual d i a r y 90 d a y s p r i o r to ~lle d a y of f r o m study is a l s o s u m m a r i s e d £or e a c h w o m a n .

A modification o£ T h e b o x - w h i s k e r plot proposed Dy T u k e y k6# is u s e d to i ± l u s T r a E e Ehe v a r a a t i o n in summary statistics f r o m Kne menstrual diaries by r e f e n e e p e r i o d a n d d o s a g e grou~. Classica!ly, ~ne m o x - w n i s r diagram ili~_is~rates t h e m i n i m u m , lower quartile, median, upper quartile and m im v a l u e s of a p a r t i c u l a r variable. The modification a d d s t h e 5Eh and 95~I~ p e r c e n t i l e s . In a d d i t i o n to the ~lle p e r t i c u l a r in~eres=

reference period statisticS, a n d b e c a u s e of i n e x t r e m e patter~,s, =he l o n g e s t bleeding/spotting--free i n t e r v a l and tile l o n g e s t b l e e d i n g / s p o t t i n g episode recorde~ i n t~,~ w ~ u l e d i a r y are c a l c u l a t e d for each ~an. For some subjects s u c h v a l u e s w i l l De c e n s o r e d 0y d i s c o n t i n u a t i o n .

594

J

1987

L. 3 5 N O . 6

CONTRACEPTION

S e v e n uieedit,~ l,atterns a r e d e ~ I n e a as s u g g e s t e d in the W~IO guidellnes (4) ill]d, eac|l wolaatl is c l a s s i f x e d i n t o o n e of ~ h e s e s e v e n 'Ciltllcaliy itul)Ortattt' g r o u p s in e a c h r e ~ e r ~ n c e p e r i o d f o r wlxlclt she |tas p r o v i d e d a compiet,a d i a r y . T h e s e p a t t e r n s ar~ d e ~ e r m l n ~ d over a 9U--day r e f e r e n c e p e r x o d as f o l l o w s : -

-

--

no Oleuoit,~ c,troughout the r~aference p ~ r l o d ; p r o i o n & e d b L ~ u d i s ~ : dE least o n e u i e e d l n g / s p o t ~ I n g episod~ i d s ~ i n g m o r e £1l~ln lq d a y s ; f r e q u e n t b l e v d l n ~ " n|ore ~nd|| 5 b l e u d l n g / s p o ~ I n ~ episodes; zntr,~quent o i e u d i n & : X Or 2 U l e e d l n ~ / S p o ~ t i n & episodes; irt'eSUidr bi~din~: 3 £ O b b l e e d i l l ~ / s p o t ~ I n ~ e p i s o d e s and less ~l,au 3 b l e e d i n g / s p o t t i n g - f r e e i n t e r v a l s of 1 4 d a y s or more; comblnations of the a D o v ~ c a t e g o r i e s ; a n d n o n e o£ ~ t , e a b o v e : a p a t t e r n c o n s i d e r e d as ' a c c e p t a b l e ' w l c h 3 ~o 5 b l e e d i n g / s p o t , i n & uplso~s, n o n e L o n g e r t h a n I~ d a y s a r i d at l e a s e 3 b i e e d x n B / s p o t t l n g - f r e e i n t e r v a l s of i4 d a y s or more. SULTS

I.

Comparison

of

low

aud

n i g h d o s e DrIP A

T a o l e i c o m p a r e s ~lle s u m m a r y s ~ a ~ I s c l c s f o r e a c h r e ~ e r e n c e ' A g roups . The p e r x o d f o l l o w i n g ~ i r s t i n D e c t i o n bj l o w a n d higtl D~.IP n u m o e r of d i a r i e s u s e d ~ o r the comparisot~ i S i n c i u d e d . The data s u g g e s t a r e d u c t i o n wit1, t i m e in the n u u b e v of O i e e d l n ~ / s p o t c l n ~ d a y s ) spottit, G d ~ y s and b l ~ d i n ~ / s p o t ~ I n S ~pisodes and ~h~ir l~n&th w i t h a c o r r e s p o n d i n . ~ X n c r ~ a s e in ~he iengEtl of b l e e d i n g / s p o ~ E i n g r r ~ e i n t e r v a l s !n s u c c e s s i v e ~ e Z e r ~ n c e p e r l o d s . No difference b e t w e e n ~ne ~ o d o s e ~ r o u p s is d e m o n s t r a t e d by K h ~ s e s u m m a r y s~a£iscics, i~o~vur, a daf~erence is s h o w n in t~l~ n u m b e r o~ w o m e s w i ~ n no b i e e d i n & or s p o t t i n g d u r i n g a r e f e r e n c e p e v l o d . Their t,utaD~-s are ~ i v e n in T a b l e I a n d rurti~er e £ a D o r a t e d xn T a b l e II. F i g u r e I s n o w s tl~e m o d i f i e d b o x - w ~ i s K e r p l o t of n u m D e r of ble~din&/spoEtin~ d a y s by re£e,_'ence p e r i o d and d o s a g e g ~ o u p a n d i l i ~ s ~ r a ~ e s ~txe ~ m e trend discussed aoove. T a o i e If s n o w s ci,e p e r c e n t a g e of w o m e n in e a c h d o s a g e M r o u p experivncin~ clinically important bleeding pa~tern irre~ularltles, iu eactL s u c c ~ s s l v ~ r ~ r e r e n c e p e r i o a , i n l o w anO n i ~ n d o s e ~ r o u p s r e s p e c t i v e l y , 8 9 . o a n d 88.~-~ 0 £ w o m e n h a d ' c l i n i c a l l y i m p o r t a n t ' bxeedlng digturoances itl tile first re~erence period. Tt,e corr~spondin~ f i g u r e s Zor ~he f o u r t h r e f e r e n c e p ~ r l o d w e r e 9 3 . o a n d 90.4;& s u ~ e s E i n 4 chat t i l e i n c i d e n c e o~ a r r ~ & u i a r l t i e s d i d not d e c r e a s ~ w i t h e x p e r i e n c e of E h e i n j e c t a b l e , even ~nough the mos~ 'unacce@~aole' patterns would r~sult in early di~conKinuatlons. The m o s t c o m m o n s u c h pa~cert, was l u f r e q u e n ~ b l e e d i n g w h i c h is e x p e r i e n c e d by a i m o s ~ one--tlliL°d of tnc w o m e n ~llrou3hout t h e s t u d y period (co~oinin~ ~lle Z r o u p s " i n f r e q u e n t , and prolonged plus i n f r ~ q u ~ n ~ in T a o l e ll). "£ner~ is a d ~ c r e a s e w i t h t i m e i n the

J U N E 1987 V O L . 35 N O . 6

5

O~

X O

bJ t~

i

100 150

Table I

578 575

26.5 25.9

5.0 5.9

L_

Interquartile Range

2,0 2.0

18.0 18.0

3.0 3.0

27.2 30.0

[nterquartlle Range

523 (55) 512 (63)

23.0 21.0

5.2 5.0

Hedlan

1.0 1.0

l.O 8.0

3.0 3.0

15.0

15.0

Hedian

Reference Period I days 1-90

"

23.9 26.5

5.0 5.0

375 (In3) 343 (i36)

25.0 24.6

5.5 5.0

0 0

3.0 1.0

1.0 1.0

4.0

6.0

.

.

.

.

.

.

24.5 24.9

4.0 4.1

Interquart£1e Range

.

409 393

1.0 1.0

i0.0 8.0

3.0 3.0

16.5 12.0

Interquartlle Range

!

23.7 24.3

3.8 3.5

212 (149) zgt (~66)

27.6 28.0

4.0 4.0

lnterquarrlle Range

1.0 1.0

7.1 6.O

3.0 2.0

II.0 10.6

[ Rangelnterquattlle

361 . 357

Hedlan

HI

0 0

1.0 O.0

1.0 1.0

3.0 3.0

Median

Reference Period IV days 2?0-360

Number of such women Indicated in parentheses.

287 (122) 225 (Z68)

26.3 26.6

5.0 4.0

Hedian

•.

Hedtan

Reference Period I11 days 18i-270

. . . . . . . .

Interquarttle Range

1.0 2.0

14.0 13.0

2.0 3.0

19.0

20.0

l

h~terquarttle Range

478 419

Hedtan

0 0

5.0 4.0

2.0 2.0

8.0

tI.O

Hedian

Reference Period li days 9O-IJO

Comparison of lou and high dose,,OHPA using reference p,ertod analysis

+ fi/S - bleeding or spotting * Excludes women uho had no bleeding~spotting for the whole reference period.

Number of diaries f o r analysis*

I00 150

I00 i50

Number of d i a r i e s {o~ attalysis

r~

I00 150

N~mber of spottingonly episodes

Hean length of S/S-free interval*

I00 150

Nutnber of spotting days

lO0 150

I00

150

Number of B/S episodes

Nean length of Sls episode*

100 150

Number of 61S days+

°"

dose (~g)

OO -,4

t~ ~D O~

Z

O

"0 -]

Z H > C3

0

CONTRACEPTION

Table Nuraber o f woraen r ( p e r e e n t a g e )

II

experiencing

d,ifferent

types

of

in each reference p erlod bY D~IPA dose See 'seatlsgical

procedures'

for the d e f i n l ~ i o n

D~'tPA

Reference

dose

Bleeding Patter=*

(rag)

I .1-90

1

II 91-180

of each pattern

Period IIl 181-270

j* . . .

IV

271-360

irregular

i00 150

92 (15.9) 86 (15.0)

60 (12.6) 41 ( 8 . 6 )

43 (IO. 5) 39 (9.9)

46 ( 1 2 . 7 ) 33 ( 9 . 2 )

I:ifrequen~

100 150

171 (29.6) 149 (25.9~

157 (32.8) 148 (30.9)

134 (32.S)

103 (28.5) 102 (28.6)

107

(27.2)

27

I00 150

48 55

(8.3) (9.6)

32 42

(6.7) (8.d)

24

(6.6) (6.1)

i00 150

10

(i.7) (1.4)

II 3

(2~J) (0.6)

I i

(0.3)

(0. 2 )

(0.3) (0.6)

100 150

71 (12.3) 74 ( 1 2 . 9 )

23 25

(4.8) (5.2)

18

(4.4)

(3.3)

(1.4)

13

100 150

4~ 54

(8.3) (9.4)

42 34

(8.8) (7.1)

19 17

(4.6) (4.3)

Prolonged and frequera~

100 150

27 22

(4.7) (3.8)

i0 10

(2.1) (2.1)

6 4

(1.5) (1.o)

(0.6) (i.I)

No bleeding

iO0

150

51 ( 8 . 8 ) 60 (10.4)

100 (20.9) 133 (27.8)

122 (29.8) 168 ( 4 2 . 7 )

1 4 9 (41.3) 166 (46.5)

"Dnacceptable' patterns (total)

100 150

518 (89.6) 508 (88.3)

435 (91.O) 436 (91.0)

370 (90.5) 373 ( 9 4 . 9 )

338 (93.6) 344 (96.4)

'Acceptable' patterns

IOO 150

60 (10.4) 67 (11.7)

Frequent Prolonged alone Prolonged irregular

and

Prolonged,and

infrequent

8

J U N E 1987 V O L . 35 N O . 6

43 43

(9.0) (9.0)

39 20

(9.5) (5.1)

17 18

(4.7) (5.0)

(1.4) 15 14

23 13

(4.2) (3.9)

(6.4.) (3.6)

597

CONTRACE

ION

Reference period

100mg

150rag

~

~I~'. . . . . . . . . .I.. ........... i, ~-............................... i, ................

III

IV

f .............................................. --I

0

.....................

30

................

!

......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

60

i

O•

90

30

60

90

Days

Key

" 90 days

0 ° I

l 1,,,!.,ol l

Lower Upper Maximum Ouartiles 5% 95%

Minimum

Fig 1. N u m b e r o f b l e e d i n g / s ~ t t i n g days ~ r

598

referen~ ~riod

by D M P A dose.

J U N E 1987 V O L . 35 N O .

6

CONTRACEPTION

cat~.orles of p r o l o n g e d bleeding, D o ~ % alou~a a n d c o m b i n e d ) accounting for the experience of 25~: or w o m e n i n r e f e r e n c e p e r i o d I ~o a p p r o x l m a £ e l y 7/. in r e f e r e n c e p e r i o d IV. It is c ± ~ a r K n a t no bleedin)~ is e x p e r i e n c e d Dy an i n c r e a s i n ~ proportion of subjec~s wi~h e a c h s u c c e s s i v e z n j e c ~ l o n and a f f e c t s a l a r ~ e r proporti0** of w o m e n r e c e i v i n g lligh a o s e D~I . This ~ppears to oe t]~e o n l y d i f f e r e n c e b ~ t w e e n t l l d two d o s e s . 0

Ke£~tionshi~ _ p between discon~ i n u a z ~on

~

~ . =

.....

_ ....... - ~

.................

. . . .

~

bleedin~

................. ~

............ ~

~,, ~

patu~cns

aria r e a s o n s ~

-

~

~

~

-

-

for

........-, ..........

Taoi,a ii£ sl~o~s Ki~e s ~ m m a r y s E a = i s T i c s for ~ne 90 days prior to dlscon~i~ua~ion by r e a s o n g i v e n by ~ e sub3ec~ for dlscon~Lnua~ion. ~4omen ~ i v i n g 'amenowrl,ea' as E n e i r d i s c o n t i n u a t i o n reason have IDng~r m~an bleedln~/spoKKing--free intervals than women d3sconKinulng f o ~ o~l~er r e a s o n s . S~n~i±arly t h o s e a ~ s c o n E i n u i n g for 'heavy' "or 'pro±on~d' b±eedin~ ~lave a. muc|', ~igiler n u m b e r of b l e e d i n g / s p o t t l n g d a y s and t h o s e d l s c o n t i n u i n g f o r 's v o c a i n g ' s a v e the ~lishest n u m o e r of s p o t t i n g d a y s . Thus ~ne diaries s u p p o r t =he p a t t e r n s o f menstrual D i e e d i n g i.apli~d uy ~ile d i s c o n t i n u a t i o n r e a s o n s at l e a s t in tl,ese r e s p e c E s . T h e w o m e n in ~lle h i g h d o s e & r o u p w h o c o m p l e t e d Ki,e s ~ u d y n a v e a ~nean b l e e d i n g / s p o t t i n g - f r e e interval s i m i l a r ~o ~ h o s e w h o d i s c o n t i n u e d f o r a m e n o r r n e a in ~ h a ~ s a m e , r o u p yet wlttl ~reater DeKween--sub3ecE VartaDik key. Tt~ose ~n,J a r e l o s t ~o f o l l o w - u p !,ave m o r e b l e e d i n g / s p o = ~ I n g days, bl~ed[ng/spo~Ein~ el)isodcS a n d s p o t t i n g d a y s a n ~ io er b l e e d i n g / ~poK tin G e p i s o d e s t h a n El,ose w h o c o m p l e t e tl~e s t u d y . This is e s p e c x a l l y so ~n ~,,e l o w d o s e z r o u p . Tner~ is a s i m i l a r but less pronounced p a t t e r n in tt,~ ' o t t ~ r m e d i c a l ' a n d ' n o n - m e d i c a l ' d i s c ot~t i n u a t ion ~ r o u p ~ . T a b l e lii a i ~ o s n o w s tl~e meax~tls a u d i n T e r q u a r t i l e ra es of T h e longest ble~ding/spo~cing-free i n t e r v a l of e a c h e n t i r ~ d i a r y b y d o s e atld reasotl f o r discoiIKit, u a t i o n . £ne ~omen who complained of ~menorr|~ea **ave l o n g D i e e d l n 6 / s p o = ~ i n g - - f r e e i n t e r v a l s , the f e w w h o disconcinded for spotting n a v e En~ stlortes~ i n = e r v a l s witl,out b l e e d i n g or s p o t t i n g ) and ~he w o m ~ n d i s c o n ~ i n u i n ~ for ott%~r r e a s o n s ~ave ~,~e£medlate values. ~o~v~r t~ lenities o~ ~ne i n t e r v a l s a m o n g the w o m ~ n w h o r e c e i v e d a i l 4 i n 3 ~ c ~ i o n s a r e s i m i l a r Ko t h o s e of ti,= w o m e n w h o d i s c o n t i n u e d for ~menorrl,~a. Figure 2 shows the distriDu=ion of s u b j e c t s by l o n ~ e s t bleeding/spotting--free inKerva± aud ion~es~ ole~dlng/spotting e p i s o d e f o r the t h r e e d i s c o n t i n u a t i o n groups ' o T h e r tnedical' ) ' o t h e r non--medical' and '±osK to f o l ± o ~ - u p ' . IK a l s o i n d i c a t e s t h ~ arD ary l i m i t s f o r a m e n o r r h e a ~9(J d a y s ) a n d ie Kh of bleeding/spo~ti e p i s o d e %ib d a y s ) wt,ic'it w e r e p r e v i o u s l y c h o s e n to define the 'clinically important' bieeedin~ patterns. Thus of a t o t a l of £88 w o m e n wit1, o n e of ~i,~se d i s c o n t i n u a t i o n ~-easons, 121 (b4~i) f a l l o u t s i d e at l e a s t o n e of t h e s e b o u n d a r i e s w i E h 'unacceptable' bleeding paK~ecns, a n eletnenK o f i n z o n a a ~ i o n which w a s not e v i d e n t f r o m K n e l t s t a k e d d i s c o n = i n u a t i o n reason. This may

JU

1987 V O L . 35 N O . 6

599

O~

oz

UJ

r-,

Oo -4

Z

t.,

g

O~

~'----

IOO t~o

Heart lengtl| oK ~,lS-tre++ Intervals

i

lOO 150

3ut 357

No. of diaries I 100 for analysis | 150

(3,u)

o.5 (7.2)

b+J

5,5 (~.P,)

5,G (L.J)

LU (5.J) 2.U (b.])

Ib 5

L4

14

40

37

Z4.0 LZO.~) ZL.U ~lb.3 2Z.5 LU.B) 34.0 (38.0; 2b.0 432.5 22.5 (25.8;

7.4 (u.5~ tl, J LI/.H) 7.B (it.3; i t ) t2l.+)~

ILl (l.l.')i 62 (4Z.5) t t . l LL~s.~)

O,3 it.B) U.u (3.0;

tO,O 42t,8) 24.0 (ZLO)

2.t H.73 5.t, (2.0)

17,0 (~G.4J 5. t U L g )

2.0 0,~) 4.3 (5.1)

1,o (t,OJ 0+5 (Z.3)

37.3 (6LI} 41,5 (2L5; 42.5 (70.0) 27,5 (29.2)

:s.u (u.~) 3.8 (0.6)

o,o H.O) o.u (hO;

L o (6.0? 5.5 (I0,57

.t.o (3.0) 2.0 ~2.32

7,0 ~iLO) 9.U (~.5

32 60

22 zo

li

LUB.5(S9.O) 73.5 475,5) ~4.0 4b~.o) XOS.5~Bg.B) 83.5 463.8) bo.o (hL53

90.,) (U) 90.0 40)

0 CO)

0 (o) 0 tOJ

(J.u;

l.U (15.8) I.~ (9,4)

2.0

5.5 U9,U) 6.0 (15.63

~eSiges Predna~y

Z~.5 0 7 d )

z~b

51.

25 2~

bO.O ~38.0~ 59.5 (62.8) 59.5 tu~.~J

4Z,5 L70.S) bS.0 (70.J;

t~.U) t7.6)

u.u ( L ~ ;

8.u (i3.5; J.5 LI3.~;

J.O ~J.U/ 2.0 (2.~/

~,u iV,2) 4.7 3.0 (7.83 LJ

O,U LI.O) O.u ( l..u.~

2,0 LIJ.3~

I+U U I . O J

1.o {2.u; 1.o 43.o;

8,0 (22.02 3,5 ( £ 2 . J }

Lost to

Fur 1u~-up

k Note: d e f i n i t i o n s of heavy, prolonged, e t c . . , sere the discontinuation reasons given by the subjects and not the d e f i n i t i o n s used [ o r Table [1, * * Aled£an and incerquarCiZe range

!

tUS,OLtlT,O) t36,0(i3G,O)

4~.5 (b4.2) BT.O ~b3.o)

1,6 (.5.0) LO (4,8j

LUJi)

o (o; u (o)

(3,87 8.0 42.3; (,5,3} 7,5 0 . 5 )

i,O {7,0) it,5 riO.S) 12LO (U),~; 2%5 ~12,5) ,,).5 (27, ~q 0.~ LG,V; IG.O (4Lu/ 28,U (37.~2 21.U (3J.J) 144.0 ( i t , o )

3.0 3.0

o tO) 0 (0) o (o)

4.0 43.5/

oG.5 ( I 8 . 8 ) +SLO (17.8)

Othec

Hedtcal

Ameno f rlle a

Hi ,;ed i ng

Spotting

I r ret~ol,lr Iticed I ng

grul,mged

7.0 (lb. 3) 8.U ¢,l t,3)

1,0 (LOb i.o L2,o}

Longest U/S-feet tO0 Interval !150

Enthe diary:

lleav] Bleeding

**LU 41LU; 43,5 (29.0) uO, U (30.3) 3'/.5 rio.o) t.O (tU,O3 ,iLO (5~.53 53.0 ¢39.5) )7.2 t2~.3)

End o[ shady

RIiASUt;GIVEN FOK DISCOSII~UATLOH*

mid tm+gest blee:llnc/sp,Jtttng-I tee tntcrv,tL ot entice diary by dhcuncttmattoa reason

flU0 [ O.u (t.tJ) 0.0 1.50 } 0.o ( t.o,~

~lOO ! I~O

I

!IOO i l.sU

Huan ien~;th of B/S eptsode~

spot t big-only episodes

Humber ul

sp~t t h~/; days

llumber o[ l~/S e~)lsodes

I~u~.~beroI B/~ days

to d ~,,qCOll~[ Ilai|L~ OH

Immediatel~ ~ lo¢

Reference perlud eL 9U days

i (',"g/

D;IPA ]dose

___

T,thie lit

1'.2ra_'~+"cYL+i::t..'~.o-#L .r.t:+.,'Lc,.eJ'.j,/:ji~:l)+~+mv,t_l_+tL+l~_t,rlor co dtsco,,tt,maclon

0 Z

>

0 Z ,../

CONTRACEPTION

9O

l

I

[

"other medt~l"

I

I

30

.

I. 1

e

•

LP

"

I

~

D

•

15

i

I

o

I

oo I

e

Q

~

o

0 1 °0° I O

OO

I

|o

0

o

o

~

'

-

'

~

~

~

~

~

,=

i

90

~80

2~0

3~0

o

90

o

~n

"

I

'non-medi

I o

-

o~

0

~

•

60

I . i

30

I

I

•

i

•

O 4I

15

1"

o i n d i ~ t e s 14 o ~ e r v a t i o n s

Q

oi~ °o

~

ml

s e~

I

o

o

e

o

0

0 O

I

0

90

0

•

•

0 B

1~

270

360

90 f 1 1 "

1 I I

=

30 D

LD

I

=°

15 B

."

LI~

H 0

"lost to f o l l o w - u p '

0

O OBBO O

O• I

g

•

I O

OB

0

O 0 0

~0

•

90

~

270

3~0

Longest bleeding/spotting-free interval (days) Fig 2. Longest bleeding/~ tting-fr interval and I o n ; e ~ bl ding/s episode of d i s ~ n t i n u e r s for "other m~d i ~ I " or 'n o n - m e d i ~ l " r sons or "lost t o follow-up'. Both dose g r o u ~ ~ m b i n e d .

JU

1987 VOL.

35 NO.

6

tting

601

CONTRACEPTION

exl)la~ta ti,~ o 0 s ~ c v m t l u ~ , ma~Ic i n l'aper 1 t~,a~ Etae c c n t r c s wit|, l o w ~ r discontinuation r a t ~ s [ o r 'a~u~t%orrh,za' w e r e ~ h o s ~ w i t h g r e a t e r diseonE1|luaE1on r d t ~ s t o t ~llose £ n r ~ e r ~ a s o n s unrelated Eo b l e e d i n g . 3.

C e n t rc O i f f ~ r e n c e s

T~ae m e d i a n u u r a t l o ~ t oi' l o n g e s n Oleedzng/spoEting-~r~e intervals I,.~ sl,own Dy oct, K re i n T a b l e iV. Tn£s table confirms t|]e l e s s e r d~r~e of '~ln~no~'c~-,~a' i n ~ l c ±~U~I~ O A g r o u p as s u g g e s t e d Dy t h e discon~inuaci0n r a t e r ~ p o r t e d in P a p e r I. In = n o s e cetltr~s f o r w h i c n £ Itcre we re no o r f ~ d i s c on ~ i n u a ~ i otis f o r ' d m e u o r r n e a ' ~1o%4eve r ~ilere i s c o n s l d e r a D l e variation i:, n]edian l o n ~ e s ~ bleedlng/spo~tingIt%terval 'f~is is i n d i c a K c u Dy t h e i n ~ e r q u a r t i l e r a n g e whict~ v a r i e s f r o m b W d ~ y s in i.iani±a, to 1 1 4 d a y s in K i n g s t o n f o r t h e ±0Chug D~-IPA group. C e n T res witll h z ~ n m e d ± d n d u r a t i o n s of l o n g e s t bieeding/spotting-fre~ intervals suci~ a s A l e x a n l r i a and B a n g k o k nave very dif~er~n~ cumulative discontit~uation r~,zs ~or dmenor~'hea. Tt,is is also =rue for Ljubljana a n d ~-lanila w n u i~ave l o w m e d i a n d u r a t i o n s of b l e e d Ing/sl, o KL i n G - r r~ c ~.ntervals. T a u l e V g i v e s t~,e m e d i a n ± o n g e s E D±eeding/spotting-frCe interval by c e n t r e a n d d i s c o n = i n u a t i o n reason. For ~hose women WhO completed ~ h e s t u d y , ti~aE is r ~ c c i v ~ d a l l f o u r it,j e c t i o n s , tllere are considerable wiEhln,ce~tre and b e t w e e n - - c e n t r e d i f f e r e u c e s . Slmi[ar~y, ~l,~ce is inuc|, v ~ r i d b x ! i E y ' - o ~ s w ~ e n c~ntr~s ataon~ wotaen ~¢I,o dlsconKinue ~or 'ocn~- medical reasons' and 'other non-medical rc~so~s'. There appeac E u DC n o l a r g e b e ~ w ~ e n - - c ~ n K r ~ d i z ~ e t ' e n c e s amon 6 wo n w t l o a c e l o s t Ko f o ± i o w - u p . T a D ± c VI p r o v i d e s d e ~ a i l s or tile d a ~ r i o u ~ l o n oy c e n a r = ot tttosc subjects ld~nKified ill Fl/:ure Z as h a v i n g 'on ceptable' oleeding puKcerr, s DuE w~,o d i s c o n t i n u e d En~_~ir p a r E i c i p a E i o , l it, tile s c u e y £ o r reaso:~s unrel.lted to ui~editlg ~ r o u p e d under ' o t h e r m e d i c a l ' , '0 5 h e r no[,-~acdlcal' o , _ - ' i o s E ~ o follow--up' c a ~ e $ o r i e s . Among ~nesc groups, 54/o o~ d i s c o n ~ i t , u e r s nave 'unaccepcaDie' IOugesc bleedlug/spoc~ing episod,_~ a n d / o r i o t l ~ s K DieediO~/SpotCl --lreu i n t e r v a l as d ~ i n e d previously i n F i g u r e 2. H o s t o~ t h e m k O 0 ~ ) c o m e f r o m ~ang6.og a n d i.lanila, in 5 a n 6 k o K , tll~ most ~requen~ irregularity is e l o n g e s = b/eeding/spoE~ing-free in=erval of 9 0 d a y s o r m o r e e x p e r i e n c e d by 3 1 (bS./~) o f the d i s c o n ~ i n u e r s in t h e s e c a t e g o r i e s . In c o n t r a s t , in Manila, Ene m o s = f r e q u e n t irregularity is a longes~ b±eeding./spot tin~ episud~ of 1 5 d e y s o r m o r e e x p e r i e s c e d Dy 2 5 (567~) of ~ n e discon=inuers in t h e s e = n r e e g r o u p s . DI S C d S S ION i.

Clinical

trial

In s e v e n d i f f e r e n t countries, 1glo women were randomly assigned to =Ilree--moncnly r e g i m e n s of U;.'l o f 100rag o r 150rag a n d 1 1 ~ 6 Q95.1./~) of K n ~ m p r o v i d e d a menstrual diary. These data offer a unique opportunity Ko compare ~ne e f f e c t s of b o t h r e g i m e n s on vaginal bleeding patterns, ~o i d e n t i f y p o s s i D l e ethnic differences in drug response and =o a s s e s s the p e r c e p t i o n of m e n s t r u a l irreguiariKies in vacious cul~ures.

602

J U N E 1987 V O L . 35 N O . 6

CONTRACEPTION

Duratlon

of

Table IV bleudln~/~pOttlnl:-free

Longest

in{ervals by centre

B/S-free

interval

Cumula ~ ive

Centre

Alexandria Bangkok

Karaclai

1 O0

99,3

0.0 0.0

90

I I09"0

I

1 O0

92 90

1

I 86.0 107.3

93

.L4 0 .

e

6~'0 75.0

I

78.5 66.0

22 0 20.4

71.0 88.5

!

69,0 82.5

1.1 2.4

]61.5 70.5

i

6b.5 77.3

13.3

i00 150

53 52

I

Manila

1 O0 150

95 96

!

Szeged

I00 150

96 92

of P a p e r

6,0 ~'3 8 !.8 0.0

Ljubljana

* From Table i l I

89.0 89.0

Z 51.0

114.0 153.3

51 5b

100

0

]

ZS0

Kingston

18.0 26.8

! 00 150

ZS0

99

184.0 136,0

[137.0 151.0

I

99

l

I07.0

179.0

4.7

I.

J U N E 1987 V O L . 35 N O . 6

603

O~

t~ t~

<

~D Oo ",4

X

l

13~ Ui.O(7~.U)

tub 90.0~81,3)

H~nJL4

~zeded

t t Heat,Ill attd l n t e r q u a r t ; i t e

s iduul)er of d i a r i e s

! .........

~2 V~.S(~8.0)

LJuULJJa~

Lu2.Oli3l.~)i

9b

8~ io~.0(zo~.u)

g~r~chs

gingttott

ILL tdo,O~£dU.U)

'13] rileY,Oft73,5)

Udti~kok

ALexandria

End ot s t u d y

r~nge

7 lu.O~.|8.0)

40.U

1

5 50.ul2~.0)

29.5(19.0)

2o.o(lb.o)

2O

2LS(t,t.o)

22.5(~0.8)

t~

i 25.0

Z3 20.0L25.J)

3 b2.0(~o.O)

2 z~5.5(37.0,1

13.0

t

l~ 2i.Sltu,O)

2L0 (?.O)

b

t$tee,t z.6

Lt,ez)~tt 4r

t) "23.0(22.5)

0

0

u

0

Slmttln6

#

13 91.0190.5)

IIG.O(Bb.O)

3

iiZ.0(48.8)

12 4G.0(32.3)

130.5(69.8)

b

II 70.0(~9.0)

L00.0

t

7

9.Lo(96.o)

2O

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CONTRACEPTION

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indicate

J U N E 1987 VOL. 35 NO. 6

. . . . . . . . . . . . . . . . . .

/, £~om ~ o ~ a i

numDcr

of

di~con~inuers.

CONTRACEPTION

'l',,e r ~ e r c n c ~ per~u~ analysis |~r~scn~cd i~ T a b l e 1 sl~ows a n overdll trc,~d Witl] ~ i m e t o w a r d s ± e s s D l u e d i n 6 a n d s p o K t i n ~ in boil, dos~ ~£oups" all m~dsures of bleedlllg dee,'ease wi£1~ £ i m c wi~l| a corresl, ondit,g it,crease in c | ~ e m e d i a n ± e ~ g t h of D ± c e d i n g / s p o t t i n g fr~u In~ccvul. t'~,is co;~[ i r m s ~ u ~i n d ~ n g s ot p~e.vious s t u d i e s of no impor~.ant ~t',.e 1 5 U m g eel/met, k k , 2 ) , ilowevcr Ta b l e I s u g g e s t s dift~r~nces D e ~ w u ~ a ~l~u ~wu d o s ~ ~ r o ups. In T a D l u 11 tl~u classlflcation of s u b j e c t s Dy t y p ~ o f Dleedi~,~ p a ~ , 2 r n f o r e a c h refe~'~nce perlou con~l~ms "i'~Dlc I in s n u w X n g a (lecr~ase w i ~ n t i m e of the four categories wi~n prolon&~d bieeding a n d of the catego~-y wittl £requ,_.-ll~ bl,me~lll;~ wi~ll a s i m u l ~ ! i e o u s i n c r e a s ~ i n tile c a t e g o r y Of a m e n o r the a. I~ t h i s ~ a b l e , h o w e v e r , a dosc-efZec~ is s e e n wz=|, a 4 6 . 5 % incidence of a m e n o r r h e a i n ~ n e higl, d o s e g r o u p a ~ a i n s t 41.3;~ i n t h e ± o w d o s e ~ r o u p in ~ n e f o u r K ~ r~fer~nce period. This re~±ects the resulgs r e p o r t e d in P a p e r I in w ~ i c h tnc o n l y s i g n i f i c a n t difference ue~we~n trite two r e g i m e n s w a s £ o u n d b e t w e e n tne c u m u l a t i v e discontinuation ra~es ~or am~norrnea. T h i s is f u £ ~ n e r c o n f i r m e d in each individual c e n t r e i n T ~ e l e I V wllere c ~ e t=edidn d u r a t i o n s of t h e long~s~ ~/S-free in~erva! a~e greatest in t h e i t O m g g r o u p s . T a b l e I I £ s n o w s a l~ign O e g r e ~ or c u n s i s L e ~ t c y D ~ w e e n the r e a s o n s - i v e n by i n d i v i d u a l women for discon~fnui~g tl~e c o n ~ r a c e p K i v e method a n d ~ll~ir v a g i n a l D i e e d i n ~ p a ~ t e r n duk'in G t n c 9 0 d a y s p r e c e d i n g discontinuation. Those women who ~omplained of h e a v y o r p r o l o n g e d bleeding had a lar~ numDe~ o~ D l e e d i n g / s p o ~ i n g days, ~ne ia£~er over fewer Dleeding/spoKtin~ ~pisodes Evidently ~here is a ±urge overLap between =nese two categories a s hi,is c l a s s i f i c a t i o n reflects t,~e w o m a n ' s o w ~ s ~ b j e c ~ i v e assessment of i,er v a g i n a l b l e e d i n g pat tern. T h o s e wo,netl w h o c o m p l a i n e d o~ s p o t ~ i t ~ t,ad r e c o r d e ~ cn~ ma3oriKy of t h e i r b l e e d i n g / s p o t , i n s e a y s a s s p o t t i n g a n d had Kne snorEes~ bleedln.-./spotE±n&-free int~rva± However, in t h e n i g n d o s e g r o u p i n p a r t i c u l a r , women who comp±et~d tne s t u d y o C C a S i O t l d l l y ilad l o n g e r o i e e d i n g / s p o E t i n g - - f r e e intervals t h a n E.~Lose wlao d i s c o n K i n u e d ~or 'amenorr|~ea'. Their ion.-es~o i n ~ e r v a ± w a s ~ r e a ~ e r , DuE £t~eir m e d i a n ± n K e c v a l l~ngt|, smaller, =nan ~or the disconKinuers for amino,rhea. T h i s is p a r t l y d u e to the s t u d y d e s i z n s i n c e a woiaa~, w h o r e t u r n s i~er d i a r y a ~ Kt,e e n d of K h e c l i n i c a l trial can no longer discontinue for amenorrnea. ~ut it also su$~ests a ~r~at variauill&y o£ De~taviour in r e s p o n s e ~o a given bleeding pattern. A similar ooservatiou w a s m a d e oy G r a y e t al. (7) w h o s u m m a r i z e d the menstrual d i a r i e s of a p r e v i o u s WHO mulLicentL'~ trial comparing D~A at,d n o r e £ 1 , i s t e r o n e e n a n E a E e . In Etlat t r i a l K n e r e w a s a s t r u n g association between discontinuation of Di-IP,k a n d ± o eSt bleeding-free i t I E e r V d l dui'ing the p c e c ~ d i n g Injection interval; o.7/. of w o m e n w h o experienced 1 5 to 7 ~ c o n s e c u t i v e e s wi~tlou~ O l e e d i n ~ d u r i n g a reference period alscontinued treatment; tiLLs p D ~ c e n t a g e r o s e to 20Zg f o r clause w o m e n wl,o e x p e r i e n c e d 79 ur more consecutive days wiKhout bl~edl~,~. They concluded t n a E w o ~ e n d o t,o~ f i n d p r o l o n g e d amenorrhea to±crab±e, b u t t h e i r d a t a w o u l d a l s o i m p l y K h a ~ h~O~ of ~ I ~ WOmeLl S a i l l KO/el'dted S U C h p r o ± o n z e d ±dc~. o£ b l e e d i n g .

606

JU

1987

L. 35 N O . 6

CONTRACEPTION

Ttlc dat,, o t tl~iS E[-ial r e v e a l e d £~1"~c bcEwu~t,-cc~t~rc di~er~tlc~s. TaD±~ iV s h o w s thdt w o m ~ n in L j u D i j a n a , :.lanila a n d S z ....~d d l d n o t c x i ) e r i e n c e m s i o n & b l e ~ d i n G / s l ~ o t t l t l g - f ~ intervals a s ~tlose it, A l e x a l l d r i a ~ dallgkok a n d K i n g s t o n . The underlying reason t o t suclt d i [ ~ e r c t l c ~ s i~ tioc &nOWlt Dot is p o s s i b l y |nt,i E [ ~ d c E o r i d l i n c l u d i i t g ctllnic d i f [ c r c n c c s in mt~tabolistn of DI.IPA wtllcl, txuVc en d~sci'i ued l ) f ~ v i o u s i y i ~). By c o m p a r i n g ~1~e I t t e - t a o t e dna±ysis atld Kilo m u t ~ s t r u a l d x a r l e s , 'laDle IV t,i&l|ligiIES sutnc turtt,er b e t w e e l , - c e n t r e di~ct'ell¢-es; i n a ± e X d l l d C i a and bdl,~kOk z o r ~xa~a}~ic, wola~n u x p e r i e n c e d lon~ oleedin6/spotExng-freu intervals but t l l ~ c u m u l a t i v e dlsconElnuation r ~ E e s fur a m e n o r r i l ~ d w ~ c ~ £ ~ . O g a~,d O&, r e s p ~ c ~ i v ~ l y ~ for tnu low d o s e ~ r o u p and 2o.d}~ a n d U% t o t ~ne llidl, d o s e g r o u p . At t h e other extreme kst'oups wittl l o w e c m e d l a r , lot~g~st B / S - ~ r ~ o xnterva±s) a silaildr c o m p a r i s o n cat, be m a d ~ between L3ubljana a n d clani±a. The c u m u l a t ivu d i s c o n E l t ~ u d t iot~ r a ~ s £ or d|nenot'rl,ea i n A ± e x a n d r i a i±d.O~{), B a n g ~ o k ~O~), LjuO±janm ('222~) a n d H a n i ± a (i.±%) in the hi~n d o s e &rout, d r ~ si:nllat" ~o gl-.>.&, Og, u . S & a n d 0X, r e s p e c t i v e l y , t,o t e d in d p e r v i o u s clinical t r i a l of 1 5 0 m ~ D[.IPA itl t h o s e t e n u r e s (~92. i'n~sc m a y r e f l e c t l o c a l c o t ~ d x E i o n s ot m e d i c a l support and counselling, as well ms cultural di£fercnces in tt-~e t o l e r a n c e Eo a~aenort'It.ea. In c n ~ i r c r o s s - - c u l t u r a l s t u d y of p d ~ t e r n s and perceptions of reel,situation, St,o w 0 e n a n d Utxris=iat% ( I 0 ) sl%owed ~|,aE E I , ~ r~si~onsc t o induced dmenorri,~a taay r a t l ~ [rotn r~dectiotl when It xmplics a £ac~% of f e m i n i E y , a n aose~Ice o~ c l ~ a n s i n , 3 o f tile dy, or a douD5 on Z~C~liiEy, Eo o v e r ~ l l a c c e p E a t l c c a~ ! o n Z mS ~tle p o s s i D i l i t ) ' O~ p r e g n a n c y is ~ a c l u d e d . T o try ~ n u e:¢~lain E h ~ d p p a r ~ n ~ contradlcttot, between tnc low discontinuation rates ~or 'amenorrnea' in ~an~.ok and Kingston, and c o so~a~ ~ x E e n E ~-idtli±a, atld t~l~ e v i d e n c e l o c ioilg D l ~ d l ~ l ~ / S p o ~ K i n g - f rec i n t e r v a l ± s , T a b l e V c o m p a r e s the groups of w o m e n ~ n o dlscOiiEtnued for dlr~er~ta£ c~asons i n ~ac~, c ~ n t r ~ , fller~ is so,he ~videncc El,at i n tl,ose t h r e e cetlKres, w o m e n %~t~o g a v e a n 'otller meuic~±' r~dSOn kme~ical reason utlr~lated ~0 va~ind± oleeding) for disconElnuaEiot, experienced long bleeding/spotting-tree intervals. IE is p o s s i b l e E n a ~ ~i,es,2 %1om~tl c o u l d IloE C o l ~ i ' a E ~ a m c n o ~ r | l ~ a out ~aVc a dirZer~n£ reason for discontinua=ion of m e t h o d use.

Fxgur~ 2 provides further support Eo t h i s i n t e r p c e t a t i o n oy i±±ustraEing Erie wide scatter of e v e n t s o u t s i d e 'acceptable' limits zor 5ubo~cEs wild d l s C O t I L i n u ~ d f o r 'o t h e r - m e d i c a l ' or ' n o n - - m e d i c a l ' r ~ a s o u s o r w ~ r e l o s t ao f o l l o w - - u p . Detailed analysis of E n c s e subjects in Table Vi confirm Enat n~ar±y two-thirds of ~ n e w u m ~ n i n K h e s ~ tllree d i s c o n E i n u a t i o L , o~roups h a v ~ ' u n a c c ~ p t a D l e ' Dleedlng p a r t e r r e s at~d it,at tj or ~llem c o m ~ f r o m ~a ko}~ o r [-lanlla. In Bangkok., Elter~ is e v i d e n c e t h a t the m a j o r i t y of Eiaese w o m e n experieac~d a m ~ n o r r l l e a , wtlil~ igl rlaniia m o r e S u D j ~ C t S experienced pro±onged bleedin&.

J U N E 1987 V O L . 35 N O

6

607

CONTRACEPTION

In K m n g s t o n , ~ne s~tuation is s i m i l a r t o Bangku+~ w i t h a l,i g h ~edlan ~or longes~./spoEting-free intervals for ~II subjects, c o [ ~ E r d s £ 1 n g W i E I I a I O W lit e--Edole d i s c o n t i n u a t i o n rake £or amenorrl,ea, in E h l s c a s e , h o w e v e r , =he res~!~s published in P a p e r t~avc s h o w n El~aE t|lls ceiltrc tams t|l~ l o w e s ~ c u ~ n u L a t i v ~ discontinuaL~o,x rate ~or all discontinuation reasons, and ~hece is i i E t i ~ evidc~|~c,_~ lrol~l T a b l e Vi EllaK s u b J e C t s w i K n 'unaccel)taDle' bleeding pa,cKerns d i s ~ z o n ~ i n d e d £ o r n o n - o i e e d i n ~ reasons. Overall, ~t~e tnetts~rual d i a r y a n a l y s i s confirms ~he life-~abie comparisons of d i s c o n t i n u a t i o n reasons presented in P a p e r I~ a n d stc~ngtllens their validity. IK t a i l s E o sl~ow any a d v a n K a g ~ in reducing the d o s e o f DHPA i n t e r m s of b l e e d i n g irregulariEies. However, it i n d i c a E e s tnaE women may disconEinue conEraception for bleeding r e a s o n s wtli±e s t a r i n g o t h e ~ d i s e , sugges=ing EnaT ~he life-tab±e analysis underesEimates Klle i n c i d e n c e of v a g i n a l Dleeding irregularities in e a c h g r o u p . 2

rl~l~od

of

analysis

Tile a n a l y s i s uses ~he reference period method and closely follows abe guidelines p u b l i s l % e d by W H O 1.4). T h e r e f e r e n c e period analysis i s s e t to s t a r e o n t h e f l r s ~ i n K ~ E i o n day and divides the diary inKo four 90-day periods. D a t a b e y o n d 5 6 0 d a y s is i g n o r e d . rlowev~r, the r ~ c o m m e n d e d sut~mary s t a t i s t i c s are ~OO nu~erous KO present individua±ly, so only Ehe st i n f o r m a t i v e ones are presented is ~ % i s p a p e r . A s Et~ese s E a E i s t i c s a l l a p p e a r to n a v e ske~ dls~riDuEions, ~he m e d i a n a n d t h e i n t e r q u a r ~ i l e range rather E|%an Eh~ taean a n d ~ n e s t a n d a r d devidEion are presented. It s h o u l d a l s o be e m p h a s i z e d that no formal ~a=istical tests n a v e o ~ e n u s e d in c o m p a r i n g £h~ d i f f e r e n t sumtaary s t a t i s t i c s from tl,e t w o g r o u p s . It is a n u n r e s o l v e d p r o b l e m a s Ko w h i c h T e s t s a r e D~sK s u i E ~ d f o r t h i s t y p e of a n a l y s i s wllicn i n v o l v e s m a n y comparisons of n o n - - i n d e p e n d e n ~ s T a t i s T i c s with unknown d i s £ ri D u K i o n a ± p r o p e r t i e s . Toe division of a m e n s t r u a l dlary i n s u c c e s s i v e rez e r e n c e periods implies Ehat many events (.bleeding/spotting episodes and D±eeding/spotKing--fr~e intervals) run across boundaries a are arDitrarily KruncaTed. To overcome This difficulty a n d D e c a u s e ~ of K n e i!,teres= i n e x t r e m e v a g i n a l b l e e d i patKerns, two addi=ional staKistics a r e calculated, the longest b±eeding/spo~ing-free interval and the longest oleeding/spo~ting e p i s o d e of a s u b j ~ c ~ s ' s entire didry. This still leaves Khe u n r e s o l v e d p r o b l e m of estimation with incompl.eEe diaries. F o r tills a n a l y s i s such censored daEa are regarded as complete. A iimiEation o£ the m e n s e m u a l d i a r y is i ± l u s E r a ~ e d in Figure 2 in =nat there is a coneencra=ion of ± o n g e s a b±eeding/spot=ing-free intervals aE ~ 0 d a y s . TNis reflects =he visit schedule imposed by rune 5 - m o n = n i y contracep=ive method on the ±e th of e v e n t s a n d t h e ~ i m e of d l s c o n t i n u a = i o n . Tile o v e r a ± ± e f f e c t of s u c h = r u n c a ~ i o n s on =he da=a is unclear and meri=s research.

608

J

E 1987 V O L . 35 N O . 6

I

CONTRACEPTION

Fit,ally, b~caust~ o f t l , ~ i m p o r t a n c e of amenorri,~a and b ~ c a u s e of ~he a b s e n c e of d l f f ~ r e n c e s D ~ t w e e n £|]~ Ewo d o s e s in o~|]er a s p e c t s of v a g i n a l D l e e d ~ n g , m a r c e.nl)nasls llas b ~ e n |)±aced on a n a l y s i n g ttte , ~it,~ ' c ± i n i c a l l y i m p o r t a n T ' D l e e d i n g p a t t e r n s and the e v e n t s O roups m e a s u r e d ovur t l , c ~ n E l r e d i a c y tl,an on £11~ r ~ e r e ~ l c e p e r l o d a n a l y s i s itself FE

i

e

O

3 ~

',i "

WttO S p e c i a l P r o g r a m m e o r R e s e a r c h , D e v e l o p m e n t and R e s e a r c h T r a i n i u 3 in liuman R e p r o d u c ~ z o n ; Taste F o r c e on g o n g - A c t i n g A g e n t s for F e r t i l m t y R e g u i a t l u n . Mu±tinationai comparative clinlcal e v a l u a t i o n of t w o ± o n g - a c ~ i n g i n j e c t a b l e c o n t r a c e p t i v e steroids: N o r e t h i s ~ e r o n e e n a n t h a t e and , n e d r o x y p r o g e s ~ e r o n e acetate. 2. ~ l e e d i n g pat t e r n s and s i d e - e f f e c t s . Con~racep=ion i7. 5 9 9 - 4 0 o ~ 1 9 7 ~ ) W h O b p c c i a ± P r o g r a m m e of R e s e a r c h , D e v e ± o p m e n T and l(esearcn T r a i n i u g i n zluman R e p r o d u c t i o n ; T a s k F o r c e o n L o n g - A c ~ i n g A g e n t s for F e r t i l i t y _~.egulaKion. MuiKinationa± compafativ~ clinical t r i a l of l o n g - a c t i n g i n j e c t a b l e c o t , K r a c e p ~ i v e s - n o n e t h i s t e r o n e e n a n T n a t e ~ i v e n in t w o d o s a g e r e g i m e n s and d e p o t - m e d r o x y progestecon~ acetate. F i n a l report. C o t , ~ r a c e p ~ i o n 2~: l--i0 < 19~33) %4ti0 b p ~ c i a i P r o g r a m m e of R e s e a r c h , D e v e l o p m e n t and R e s e a r c h T r a i n i n g in lluman R e p r o d u c t i o n ; T a s k F o r c e on L o n g - A c T i n g A g e n t s lot Fertility RegulaTion. A mul~inationai p h a s e III c o m p a r a t i v e c l i n i c a l t r i a l of d e p o E - m e d r o x y p r o g e s T e r o n e acetate given ti~r~-montl,ly at d o s e s of IO g or I b U m ~ " £. Contrac~ptlve ~rficacy and side-effects Contraception 54- 2 2 3 - 2 3 5 k±~80).

WtiO S p e c i a l Programlne of R e s e a r c h , u e v e ± o p m e n t a n d R e s e a r c h T r a i n i n g in H u m a n R e p r o d u c t i o n . T|~e a n a l y s i s of v a g i n a l D i e e d l n g p a t t e r n s i n d u c e d by ~ e r t i l i ~ y r e g u ± a t i n g laethods. Cont racepcion 34:253-260 k±980). O

t~.ouri~uez G, F a u n d e s - - L a t h a m A and A t k i n s o n uE. An a p p r o a c h co The a n a l y s i s of m e n s t r u a l p a t t e r n s in the c r i t i c a l evaluatJ-'n of contraceptives. Stud. Faln. P ± a n n . 7- 49_--51 (197~) T u k e y JW. Exploratory rlass (1977).

6~

7 ~

Q

JU

Data

Ana±ysis.

Addison-Wesley,

Reading,

Gray , ParKer a n d D i e t h e l m P. Vaginal Dleedi d i s t u r b a n c e s a s s o c i a t e d w i t h Ene d i s c o n = i n u a ~ i o n of l o n g - a c t i n g in2ectaDle contraceptives. Br. J. Oh. Gyn. 88" 3 1 7 - 3 2 1 ( 1 9 8 1 ) B a s s o i S, G a r z a - F ± o r e s J, C r a v i o t o MC, D i a z - s a n c h e z V, F o t h e r b y K, Licil~enDur~ ~. and P e r e z - P a l a c i o s G. Ovarian fuuction following a single administration of depo=-medr yproges=erone acetate iO~A) a= d i f f e r e n t d o s e s . F e r = i ± . and S t e r i ! . ~2" 210-222 (1984)

1987

L. 35 N O . 6

609

CONTRACEPTION

610

9.

WHO Ex.pandted P r o g r a m m e of R e s e a r c h , D e v e l o p m e n t , and R e s ~ r c l l T r a i n i n , ~ i n tiuman R e p r o d u c t i o n ; Task Force on L o n g - A c t i t : ~ S y s t e m i c A ~ e n ~ s tor tl~e R e g u l a t i o n o~ F e r t i l i t y . ~ul~ir:~:~ional c o m p a r a t i v e c l i n i c a l e v a l u a t i o n of ~wo ± o n ~ - a c ~ i n g i n j e c t a b l e c o n ~ r a c e p E i v ~ s~eroids: ~4orethisEerone enantl~a~e and m=d roxyp roges te tone aceEate. I. Use--effectiveness. C o n t r a c v p t i o n 15" 5 1 3 - 5 5 3 ~±977)

i0.

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C h r i s t i a n B, E d i t o r s . Pa~=erns C r o o m lleim, U o n d o n ~.1983)

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