Population Reports

SERIES H NUMBER 3 JANUARY 1975

BARRIER MElHODS
Department of Medical and Public Affairs, The George Washington University Medical Center, 2001 S Street, NW., Washington, D.C. 20009

Vaginal Contraceptives A Time for Reappraisal?

Vaginal chemical contraceptives deserve a second look. Until the advent of oral contraceptives and IUDs in the 1960s, creams, jellies, and suppositories were widely used, both with and without diaphragms and condoms. Then, vaginal contraceptive use declined. But in the last few years more effective foam preparations and more convenient packaging have been developed. This product improvement. coupled with the need for contraceptives that can be disseminated through nonmedical channels, suggests that vaginal contraceptives can still playa useful role in family planning programs. Vaginal chemical contraceptives, sometimes called spermicides or topical contraceptives, are made of relatively inert base materials which physically block sperm plus active spermicidal agents which chemically immobilize or destroy sperm . One of the oldest forms of contraception, these preparations remain the only method of birth control used exclusively by a woman which does not require medical intervention or produce systemic effects. Vaginal contraceptives, like condoms, can be distributed in many ways-by smal'l stores, bazaars, door-to-door salesmen, vending machines, as well as in clinics or registered pharmacies. The cost ranges from about $.02 (US) to $.45 (US) per application . The major drawback of vaginal methods is the relatively high failure rate. Compared with users of pills, IUDs, and even condoms, the users of vaginal contraceptives have a high incidence of accidental pregnancy. A US survey in 1970 showed that, among couples practicing contraception for the purpose of either delaying or preventing pregnancy, 31 percent of foam users experienced an unplanned pregnancy during the first 12 months of use as compared with 6 percent of the pill users, 8 percent of the IUD users, 17 percent of the condom users, and 33 percent of the rhythm users (135) (see Page H-39). Inconsistent Use a Problem The higher failure rates for methods like condoms, vaginal contraceptives, and rhythm are usually attributed to inconsistent use of the method rather than to failure of the method during use. As far as vaginal methods are concerned, recent clinical studies suggest that the new preparations, particularly foams in aerosol, or pressurized, containers, can provide substantial protection if used regularly and correctly. Low pregnancy rates-i.e., below five per 100

This report on vaginal chemical contraceptives was prepared by Raymond Belsky, B.S.E.E., and the staff of the Population Information Program, George Washington University (USA), on the basis of published papers, unpublished studies, and discussions with individual investigators. The assistance of S. A. Baker, Elizabeth Connell, E. C. Corderoy, John D. Cutler, Henry Elkins, Thomas Gingrich, Norman Hardy, H. D. Herbrand, Louis Keith, Richard Lincoln, Fuhmio Ohneda, Malcolm Potts, Edward Sargent, Jerome J . Siegel, AquilesJ. Sobrero, J. Joseph Speidel, and Armond M . Welch in reviewing this report is greatly appreciated. Frances G. Conn is Executive Editor. Comments, letters, and updated material are welcome.

woman-years of use-have been reported in several recent studies in the US (see Page H-45). There are other factors which limit wide-spread popularity and distribution of chemical contraceptives. As with all coitus-dependent methods, these preparations must be used almost immediately before intercourse, which interrupts lovemaking. They must be inserted high into the vagina, which some women may be reluctant to do. They must be reinserted for repeated acts of intercourse . They may cause mild burning or irritation in some women. In the tropics, many of these preparations require special protection against heat and humidity. Other difficulties, including cost, transportation, and promotion, inhibit commercial distribution, especially in the rural areas of developing countries. If, however, the wide-spread medical skepticism about nonprescription methods of fertility control could be overcome, these problems might also be solved. Certainly there are many parts of the world in which long standing folk

CONTENTS History ........... . .. ... ..... ...... . .... Mode of Action ....... .. . ............. .. Effectiveness .. . . . ........ . .. ..... . ..... Use and Distribution ................... , Venereal Disease Prophylaxis .. . ......... Bibliography ..... ... ........ . .... . .. . ... H-38 H-40 H-44 H-47 H-50 H-52

Part 1 of 3 parts - January 1975 mailing

H-37

Population Reports is published bi-monthly at 2001 S Street, N.W., Washington, D.C. 20009, USA, by the Population Information Program, Science Communication Division, Department of Medical and Public Affairs of The George Washington University Medical Center and is supported by the United States Agency for International Development, P. T. Piotrow, Ph.D., Director. Application to mail at second class postage rates is pending at Washing ton, D.C.

B.C. Aristotle described the use of oil of cedar and frankincense in olive oil to block the cervical os. Peppermint juice mixed with honey was mentioned by Dioscarides in the 1 st century AD. Soranos, in his 2nd century classic Gynaecology, lists oil, honey, cedar gum, various fruit acids, and astringents like alum (76). Since environments that are either strongly acid or strongly alkaline are hostile to sperm, these early paste and chemical barriers probably did have some effect in limiting fertility. Salt in an 8 percent solution, for example, is highly spermicidal. During the middle ages, rock salt and alum were frequently used as vaginal contraceptives. Indian writers in the 8th century described rock salt dipped in oil or honey as a contraceptive. Moslem physiCians in the 12th century recommended suppositories or tampons containing rock salt, alum, or various fruit and herb juices. In Europe, a sponge moistened with diluted lemon juice and inserted into the vagina was cited in 1732 as an effective traditional fnethod (76) . Coitus interruptus was widely practiced by the rural population in Europe during the 18th and 19th centuries. As the rapid population growth which accompanied the In-

traditions support vaginal contraception, making this approach more acceptable at first than more modern techniques. Useful Adjunct Methods No one today would advocate a family planning program emphasizing vaginal contraceptives as the primary method of fertility regulation. The question is whether these preparations fit into modern family planning programs in association with other methods and, if so, how. For example, vaginal contraceptives are sometimes recommended for use with the IUD during the first few months after insertion and with condoms during the most fertile time of the month. During lactation they can reinforce the contraceptive effect of breastfeeding . The lack of systemic reaction makes vaginal contraceptives suitable for women who have had side effects with oral contraceptives or IUDs. For young couples, vaginal methods can provide a simple introduction to contraception. At the other end of the age spectrum, women approaching menopause may find many of these products provide welcome vaginal lubrication as well as protection against a late pregnancy. At all ages women who have intercourse infrequently or women who have forgotten to take oral contraceptives regularly can find in vaginal contraceptives the occasional protection that is needed. Laboratory tests have shown that all vaginal contraceptives currently in use inhibit, in varying degrees, the growth of venereal disease organisms. Clinical studies now underway in the United States will determine whether in practice women using vaginal preparations can expect similar protection against VD. Most important from the point of view of current distribution facilities, vaginal contraceptives require no supervision by health personnel. Convenient packaging and simple graphic instructions are possible . In short, although vaginal chemical preparations will certainly never replace oral contraceptives, sterilization, IUDs, and condoms, they can serve as a convenient back-up or alternative techniques.

HISTORY
The insertion of pastes, jellies, and various mixtures into the vagina in order to prevent conception is surely among the oldest and simplest methods of fertility control. As early as the 19th century B.C. the Egyptians were mixing honey, natron (sodium carbonate), and crocodile dung to form a vaginal contraceptive paste. In the 4th century H-38

Fig. 1. Examples of Various Vaginal Contraceptives Top row (I-r): Antemin Cream (UK), Immolin CreamJel (USA), Neo Sampoon Loop Foam Tablets (Japan), CCC Foam Tablets (Japan) Middle row (I-r); Emko Foam (USA), Delten Foam (USA). C-Film (Switzerland) Bottom row (I-r): Rendells Suppositories (UK). CCC Jelly (Japan), Gynomin Foaming Tablets (UK)

dustrial Revolution brought people to the cities, additional forms of contraception became accessible t hrough the marketplace. The first com merc ial vaginal contraceptive w as developed in 1885 by Walter Rendell, an English pharmacist. who prepared a suppos itory of soluble cocoa butter plu s quinine sulfate (7). (Quinine sulfate was re placed by hydroqu inone, a more potent spermicide , in 1939 when it was discovered tha t the sperm icidal effect of quin ine su lfate was impaired by cocoa butter.) In the late 19th century, Anni e Besant, t he Engli sh feminist leader who chall enged laws prohibiting the distribution of contrace ptive information, was recom mend ing a sponge soaked in Quin ine solution as a spermicida l vaginal barrier. Several Dutc h physicians in the late 1880s recommended va gina l pl ugs made fro m soap. In 1895, W. P. Chu nn in the United States suggested vaginal suppositories of cocon ut butter with boric acid, tann ic acid, or bichlori de of merc ury (76). Together w ith coitus interruptus, these vaginal methods, both homemade and commercial, w ere wide ly used before t he development of latex rubber permitted mass manufacture of che ap reliable condoms. Grad ual recogn itio n by the medi cal profession of th e need f or more reliab le f orms of contraception spurred the development of sper micidal je llies to be used with the dia-

phragm, invented in 1882 by Dr. W ilhelm M ensinga, and of cream bases for use either alone or with devices f itted by physician s. During t he 1920s and 1930s, n umerous vaginal suppositories an d foaming tablets, many containing organo-met all ic compounds such as mercury, quin ine, chinosol, lactic acid, bori c aci d, or bu rnt alu m, were marke ted in the United Stat es and Europe. Beca use many physician s still refused to advise on or recommend birth co ntro l, vagin al contraceptives w ere sold primarily over the counter or by mail to consumers who were not prot ected by any official standa rds of safety or effectiveness. Today in ma ny part s of t he w orld homemade vagina l methods and simple spermi cides are still used. A tampon of cotton waste and m ust ard oil , for exa mple, is popular in so me regio ns of India, and douch es of Coca-Co la, w h ich is moderat ely acid and sperm icida l, have rep ortedly served the same purpose elsewh ere (130,132).

Surface Active Agents Compared w ith the volume of research required in recent years to develop steroidal contraceptives and IU Ds, rela tively little study has been devoted to sperm icidal prepa rations. The modern trend has been toward vagi nal contraceptives which combine a spermicidal agent of proven

50 ~---------------------------------------------------------------------,
Percent intending to delay pregnancy who failed to do so .

o
40

Percent intending to prevent pregnancy who fail ed to do so. Percent intending to delay or prevent pregnancy who failed to do so.

30

20

10

o
Pill IUD Condom Diaphragm Foam Rhythm Douche Method
Fig. 2. Percent of Couples Failing to Delay or Prevent an Unwanted Pregnancy in the First Year of Exposure, by Method and Intent. Source: Ryder (135).

H39

potency with a base material, or vehicle, as it is usually called, that will dissolve or disperse rapidly throughout the vagina and not irritate either the woman or her partner. At the same time, concern for toxicity and consumer safety has led some manufacturers to eliminate possibly hazardous compounds, such as mercury and hydroquinones, from vaginal contraceptive products. Other substances which offer greater surface action and are less likely to be irritating, absorbed systemically, or harmful to a fetus have been substituted. A critical development in the early 1950s was the discovery that surface active agents (surfactants) such as nonylphenoxy polyethoxy ethanol (nonoxynol-9) were effective spermicides. Unlike many of the earliest commercial formulations, these are neither strongly acidic nor irritating to the vagina. They are increasingly used as the principal active ingredients in modern preparations (see Table 1).

Hotay developed a water-soluble plastic (polyvinyl alcohol) film as a base for the spermicide cetyl pyridinium bromide (CPB). He called this C-film (72). With nonoxynol-9 as the spermicide, C-film is now patented by USV Pharmaceutical Corporation and licensed for manufacture and sale by a British, a Swiss, and an Italian drug firm. Studies are being conducted in a number of European countries, and C-film is sold in Britain as an adjunct contraceptive method.

MODE OF ACTION
There are four basic types of chemical contraceptives used vaginally-creams, jellies, and pastes, which are squeezed from a tube; suppositories; foams, either in tablet form or pressurized containers; and soluble films (see Table 2). Each preparation has two components: a relatively inert carrier base or vehicle and an active spermicidal agent. All operate both mechanically, by forming a barrier to delay sperm progression, and biochemically, by immobilizing or destroying the sperm which have been blocked. Products squeezed from a tube include creams, jellies, and pastes. These diHer mainly in physical characteristics. Jellies a nd pastes are made from a variety of water-soluble bases, such as gelatin or gum tragacanth. The base material and spermicide incorporated within it liquify at body temperatures and disperse rapidly when they come in contact with vaginal secretions. About four or five grams of jelly or paste are squeezed from the tube into a special applicator used to insert the product into the vagina. Creams, on the other hand, are made from water-insoluble fats, such as stearates or glycerin, which are compounded into an emulsion with the active spermicide dissolved in the aqueous portion (72). These preparations tend to remain wherever they are discharged into the vagina and not to disperse further. Thus correct positioning of the applicator is important. Creams provide protection within two to three minutes after application. Like jellies, they are packaged in tubes and require special applicators. Suppositories, sometimes called pessaries or vagitories, are either water-soluble gelatin-based or water-insoluble wax-based. They are designed to dissolve at body temperature, releasing active agents which, if placed high in the vaginal canal, will coat the cervix and vagina. For optimal effectiveness, most suppositories should be inserted about 15 minutes before coitus. Spermicidal action then lasts about 20 minutes to one hour. Special packaging is required to prevent damage from heat and humidity. Foam products are available in tablet form or in pressurized containers. Foam tablets usually consist of tartaric acid and bicarbonate of soda with a powder base in which the spermicide is incorporated. In the presence of vaginal secretions carbon dioxide is released, generating foam. This takes from three to ten minutes depending on the product. Some manufacturers recommend moistening the tablet with a small amount of saliva or water before inserting it, so that foaming action is hastened. As the foam carrying the spermicide disperses over a broad surface area of the vagina, it produces a discernible amount of heat. No special applicator is needed, but moisture-proof packaging is required.

Application and Packaging Not only the ingredients themselves, but also the methods of application and packaging have been changed and improved. In the early 1930s chemical suppositories and foaming tablets were inserted with the fingers. By the late 1940s plastic applicator tubes with plungers were developed so that jellies could be inserted high in the vagina. When vaginal creams were introduced in the mid-1950s, the same applicator design was used. In recent years, single-dose tampon-shaped applicators, pre-filled at the factory and disposable after use, have been developed. In the late 1950s Joseph Sunnen, a St. Louis manufacturer and family planning enthusiast, developed Emko, a vaginal contraceptive foam containing nonoxynol-9 and benzethonium chloride in a pressurized container. It was first marketed in 1961. Ortho Pharmaceuticals followed with Delfen contraceptive foam in 1963. The first foams came in glass bottles. Because foam could not be discharged directly into the vagina, single-dose applicators like those for creams and jellies were included. The applicator had to be filled just before coitus, sincefoam in the applicator lost its stability and became liquid after several hours. Most foams are still applied this way. In 1970 Emko introduced a single-dose applicator which the user can fill as much as one week in advance. The preparation is transferred from the can to the applicator as a liquid which, when applied, becomes foam in the vagina. Emko marketed a tampon-shaped container-applicator in 1974. Factory-filled with six premeasured doses, it remains ready for use indefinitely and produces foam upon application. The cost is high, about $1 .80 (US) for six applications, but it may be reduced in time. In Japan, the Eisai Company has developed small foam tablets with a new surface active agent, p-methanylphenyl polyoxyethylene (8.8) ether, commonly called TS-88. The tablets are round with a hole in the center and look somewhat like white Life-Saver candies. They foam quickly and have a strong spermicidal effect. Water-soluble contraceptive fi 1m is the newest form of vaginal contraceptive. In Hungary several years ago H-40

Table 1-Active Ingredients in Selected Vaginal Contraceptives, 1973-1974 Surface active agents 1
o
It) It)

Bactericides

Acids

(5

.;; .,

> x o

(5

c:

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o

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>

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.!!!

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~

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...

C,

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~ ...

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en

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N

.
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1J

Brand name, Manufacturer, and Country

Jellies: CCC (Yamanouchi Pharmaceutical Co. Ltd., Japan) Koromex-A (Holland-Rantos Co., Inc., USA) Lorophyn (Eaton Laboratories, Inc., USA) Orthogynol 2 (Ortho Pharmaceuticals, USA) Patentex (Patentex GmbH, GFR) Preceptin (Ortho Pharmaceuticals, USA) Ramses Contraceptive Vaginal Jelly (Schmid Laboratories, I nc., USA) Creams and Pastes: Antemin (Coates & Cooper Ltd., UK) Conceptrol (Ortho Pharmaceuticals, USA) Delfen Cream (Ortho Pharmaceuticals, USA) Immolin (Schmid Laboratories, Inc., USA) Suppositories: Lorophyn (Eaton Laboratories, Inc., USA) Rendells (W.J. Rendell Ltd., UK) SynA-gen (Dr. Herbrand KG, G FR) Foaming tablets: Antibion (Patentex GmbH, GFR) Gynomin (Coates & Cooper Ltd., UK) Neo Sampoon Loop (Eisai Co. Ltd ., Japan) Semori (LuitpoldWerk, GFR) Speton (Temmler-Werke, GFR) Syn-A-gen (Dr. Herbrand KG, GFR) Aerosol foams: Delfen Foam (Ortho Pharmaceuticals, USA) Emko Foam (The Emko Co., USA) Patentex (Patentex GmbH, GFR) Soluble film: Cfilm (USV International, Belgium)

.!!! -S .., C

o ..

0 c:

., - .. .. 0
[rl c:

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.,

o c. -

o u

'E
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1J

>x 0 o c: c: > ., x ~ 0 c. c: >-0 c: z

~i c: ...
~

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Isurface active agents may also possess bactericidal properties. 2use with diaphragm recommended by manufacturer .

SOU RCE: Physician's Desk Reference , 1973; American Medical Association Bureau of Drugs; product labels and in serts; and personal communications with manufacturers.

HAl

Pressurized foam products, com m only called aerosol foams, consist of an o il and water e m ulsion stored under gas pressure. The liq uefied gas prop ellant, w hen re leased, prod uces the foam . Depend ing on the type of contain er, the foa m is eith er released into an applicator or, in newer desig ns, disc harged d irectly into th e vagina, where the foam disperses w idely and provides immediate protection . Some foams can be inserted as much as one hour before coitus.

trated for m , some of t hese agents may also be effective aga inst comm on vaginal infections such as tr ichomoniasis or monol iasis, but t her e is no evidence th at th ey have a significant bact er icidal effect i n norm al contraceptive use.

Soluble films use polyvinyl alcohol and gly cerine, sodium carboxy methyl cel lulose (CMC), or rice paper to carr y spe rm icides. C-f il m is a four em sq uare piece of transparent, w ater-sol uble, paper-l ike plastic impregnated with nonoxyno l- 9 . It requires no special applicator but is fo lded once and inserted into t he vagina by hand. C-fi lm should be placed in th e vagi na 30 m inutes befor e coitus (98) .

Highly acidic agents most likely to be used as sperm icides inc lude lactic acid, boric acid, tartaric and citr ic acids, and g u m acacia , w hi ch w as a lso used in anci ent Greecefor blocking t he cervix. So meti mes small quant ities of acidic agents ar e used in addition to other spermicida l ingredi ents.

Quality Control and Safety Spermic ides pose gen uin e proble m s in drug regu lat ion . Ma ny prod ucts now in use were introd uced before any nati on developed soph isticated regu latory authorit ies_ In Britai n, for exam p le, most products have a license " as of right " fro m th e Com m ittee for Safety of Medicines, which w ill revi ew them according to a set timetab le. Altho ugh some tes ts for spermicidal effectiveness have bee n devel oped, few tests have been made to evalu ate safety. Lack of reported adver se effects du r ing past use is the prim ary arg ument for t he safet y of existin g form u lations, but any new prod ucts, such as C-film, wi ll u ndoubtedly be subj ected to m uch closer scr uti ny. Biologically, a spermiCide could damage the genetic ma te ria l in the sperm head without killing the sperm and lead to abnormalities after fertilization , or it could be absorbed in m inute quantities and damage the woman or the developing fetus. The former is unproven and the latter has been investigated only w ith regard to certain mercury com pounds. Although th ere are no studies or data showing that ph enyl mercuric acetate (PMA) or any other compounds used in vaginal contraceptives have adversely affected human users, there are ample data proving the toxic ity and teratogenicity of other mercury compounds such as methyl mercury (110,118,156,176). Moreover, there is at least one Japanese study which showed fetal abnormalities in albino mice ranging from three to five times higher than in control groups when a portion of a contraceptive tablet containing PMA was introduced in the vagina on the seventh day of pregnancy. In addition to these fetal abnormalities, which involved primarily the central nervous system, pathological changes suggestive of acute mercury poisoning were observed in the livers and kidneys of the mothers (113). To avoid this danger altogether and also to avoid the necessity of extensive testing to guarantee safety, a number of manufacturers have substituted surface active agents for the organo -metallic compounds that were used initially. In the USA, the Food and Drug Administration (USFDA) has established an advisory panel, chaired by Dr. Elizabeth Connell, to review the safety, effectiveness, and labelling of over-the-counter drugs for human use including overthe-counter contraceptives and other vaginal drug products (168). Although the panel has reached nofinal conclusions, the following standards have been promulgated by the USFDA "to determine general recognition that a category of OTC drugs is safe and effective ... " (1 67).
(i) Safety means a low incidence of adverse reactions or significant side effects under adequate directions for use and warnings against unsafe use as well as low potential for

Althou gh Lagap SA. the Sw iss m an ufacturer, suggests in its packa ge i nsert that C-fil m can al so be placed over t he peni S before coitus li ke a condom , this techn ique is not con sidered highly effective (1 ).

Other fil ms are made of different substances . For example, one Italia n con tr acept ive film uses r ice pa per as its base; an India n f ilm uses ure a as th e spermi cide althou gh its poten cy is doubtful (70, 13 2 ). Befo re us e soluble fi lm contra cep tives must be protect ed against hum idity and moisture. Biochemical Acti o n The ingredients w hich determine a particular product's spermicidal or biochemical action may be predominately surface active, bactericidal, or hi gh ly acidic. Frequ ently two or more of these ingredients are co mb ined in a s ingle product (see Table 1).

Surface active agents are believed to attach themselves to the spermatozoa , inhibiting oxygen uptake and fructolysis (the splitting up of fructose -sugar). Their primary action is in breaking down the sperm wall (15). The simplest explanation, as Hardy and Wood put it, is that "they reduce the surface tension at the cell surface and thus indirectly kill the spermatozoa by osmotic imbalance" (72). Among the most commonly used surface active agents are : nonylphenoxy polyethoxy ethanol (nonoxynol-9), pdiisobutyl phenoxy polyethoxy ethanol, methoxy polyoxyethylene glycol 550 laurate, and p-methanylphenyl polyoxyethylene (8.8) ether (TS-88) (see Table 1).

The bactericidal agents used most frequently as spermi cides are phenyl mercuric acetate (PMA), quinine compounds , quartenary compounds, and ricinoleic acid and its compounds. They act by combining with the sulfur and hydrogen bonds within the spermatozoa, thus disrupting their metabolism (72). Actually the distinction between surface active and bactericidal is not always clear since some bactericides act by altering the surface characteristics and potency of bacteria (13,17 ,37). Surfactants and bactericides together often have a synergistic effect, making the combined product a more effective spermicide than any one of the ingredients alone . Administered under direct medical supervision at frequent intervals or in concenH-42

harm which may result from abuse unde r conditions of widespread availability. Proof of safety shal l consist of adequate tests by methods reaso nably applicable to show the drug is safe under the prescri bed, r ecommended, or suggested conditions of use . This proof shall include results of significant human experience during marketing . General recognition of safety shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data.

by partially controlled or uncontrolled studies, documented clinical studies by qualified experts, and reports of significant human experience du ring marketing . Isolated case reports, random experience, and reports lacking the details which perm it scientific evaluation will not be considered . General recognition of effectiveness shall ordinarily be based upon published studies which may be corroborated by unpublished studies and other data. (iii) The benefit-to-risk ratio of a drug shall be considered in determining safety and effectiveness .

(ii) Effectiveness means a reasonable expectation that, in a significant proportion of the target population, the phar macological effect of the drug, when used under adequate directions for use and warnings against unsafe use, will provide clinically significant relief of the type claimed . Pro of of effectiveness shall consist of controlled clinical investigations, unless this requirement is waived on the basis of a showing that it is not reasonably applicable to the drug or essential to the validity of the investigation and that an alternative method of investigation is adequate to substa ntiate effect iveness . Investigations may be corroborated

(iv) An aTC drug may combine two or more safe and effective active ingredients and may be generally recogn ized as safe and effective when each active i ng redient ma kes a con tr ibution t o the claimed effect(s); w he n combining of th e act ive ing redients does not decrease the safety or effectiveness of any of the individua l active ingredients; an d w hen the combination , when used under adequate directions for use and warnings against unsafe use, provides rational concurrent therapy for a significant proportion of the target population.

Table 2-Major Characteristics of Various Types of Vagi nal Chemical Contraceptives

Recomm ended minimum interval bet w een appll ca tio n and co itus 2 23 minutes

Type of Product

Frequentlv Used Base Materials

Frequently Used Act ive Ingred ients l

Packaging

Mode of Application

Duration of Spermicidal Eff ectiven8$S2

Jelly and Paste

Polyethylene glycol Gelatin Gu m tragacan th

Diisobutylphenoxy polyethoxy ethanol POlyoxyethylenenonyl phenol Phenyl mercuric acetate (PMA) Nonoxynol-9

Tube

Plastic appl icator

15 minutes 1 hour

Cream

Stearates Stearic acid Glycerin Refined cocoa butter Stearines Soap Glycerin

Tube or single dose container Individual foil packages

,

Plastic applicato r

2-3 minutes

10 minutes 1 hour 20 m inutes1 hour

Suppesitories

Nonoxynol-9 Polyethyleneglycol of monoisoctyl phenol ether Polysaccharidepolysuffuric acid ester TS88 Nonoxynol-9 Chinosol Polysacch ar ide polysulfuric acid ester Chloramine Sodium dichlorosulphamidobenzoate Nonox ynol-9 Benzethonium chloride

Manual insertion or with inserter

3-15 minutes

Foaming tablets

Bicarbona te of soda Polyethylene glycol Glycerin Tartaric acid

Vial or indio vidual foil pac k

Manual insertion

3-10 minutes

30 minutes 1 ho ur

Aerosol foam

Hydrocarbon and freon Polyethylene glycol Glycerin Polyvinyl alco hoi Glycerine Rice paper Sodium car boxymethyl icellulose (CMC)

Aluminum or glass container

I

Plastic appl icator, single or mul tiple dose

None

30 minutes 1 hour

Soluble film

Nonoxynol -9

Plas tic pouch contain ing cardboard ma tch book-l i ke packet

Manual insertion after folding

30 minutes

N .A .

Isee also Table 1. 21nterval between appl ication and coitus and duration of spermic idal effectiveness vary among products of the same type. Also, researchers' recommendations for the same product may vary . N.A. = Not Available.

H43

(v) Labeling shall be clear and truthful in all respects and may not be false or mlsleading in any particular. It shall state the intended uses and results of the product; adequate directions for proper use; and warnings against unsafe use, side effects, and adverse reactions in such terms as to render them likely to be read and understood by the ordinary individual, including individuals of low comprehension, under customary conditions of purchase and use. (vi) A drug shall be permitted for OTe sale and use by the laity unless, because of its toxicity or other potential for harmful effect or because of the method or collateral measures necessary to its use, it may safely be sold and used only under the supervision of a practitioner licensed by law to administer such drugs.

vagina can determine whether the spermicidal agent, however potent in vitro, will function effectively in vivo . Best results were achieved with aerosol foams and creams . Using a point scoring method to evaluate contraceptive effectiveness at time periods ranging from a few seconds to eight hours after coitus, they found that only Delfen Cream (Ortho) and Emko Foam provided full protection after two injections of semen (87) (see Table 3). Sobrero's independent studies also confirm that, even though foam apparently disappears during coitus, the spermicide is well distributed. It forms a highly potent coating or film which sperm must traverse if they are to penetrate the cervical canal (151). Other formulations were less effective, Johnson and Masters found (86). Jellies did not disperse rapidly or thoroughly through the vagina, were excessively fluid, and sometimes caused irritation. Foam tablets varied widely in their dispersal capability, and some users complained of vaginal irritations such as burning and itching sensations. Suppositories often did not melt completely, causing an insufficient distribution of the contraceptive within the vagina (86).

EFFECTIVENESS
Determining the effectiveness of spermicidal preparations is a complex and sometimes controversial process. It begins in the laboratory and continues through animal, clinical, and even survey data to measure the actual use-effectiveness of vaginal products as compared with other contraceptives. Even then there is disagreement about the best way to evaluate coitus-related methods since it is more often the user than the product which is responsible for failure.

Measuring Effectiveness Even more difficult than measuring the efficacy of the vehicle and spermicide as separate components is the attempt to measure the efficacy of the composite product in actual use. With coitus-dependent contraceptives such as the condom, diaphragm, and vaginal chemical preparations, consistent use in each and every act of intercourse is more important than any other factor. Therefore, a distinction is sometimes made between theoretical (or physiologica I) effectiveness and use-effectiveness. Theoretical effectiveness measures the intrinsic capability of a specific contraceptive, when used correctly without human error or negligence, to prevent conception. Rates of theoretical effectiveness measure only "method failures" and are based on Iy upon pregnancies which occurred during regular

During the first stage of testing, the manufacturer usually undertakes in vitro tests for spermicidal potency, toxicity, local reactions, and possible carcinogenic properties. These are followed by comparable tests in animals, usually rabbits, since, in its sensitivity to spermicides, the rabbit vagina has proved more like the human vagina than those of other laboratory animals (46,152). After the spermicide and base are combined, further tests measure the time required for dissolution, foaming, and product dispersal. Only then are clinical trials initiated, both with and without sexual activity.

To measure in vitro the potency of the spermicidal ingredients,various special tests have been devised. Baker in the 1930s developed one of the earliest tests, involving 48 different operations (7,8) . Other variations were developed by Brown and Gamble (20,59,60,61,62), Sander and Cramer (137), Millman (111), Davidson (36), Carruthers (24), and Harris (73). Many of these are now incorporated in the International Planned Parenthood Federation Agreed Test for Total Spermicidal Power (90,130). The IPPF test approves preparations if 1.0 ml of a 1 :11 solution immobilizes all sperm in 0.2 ml of semen within 40 seconds after the semen and spermicide are mixed . Each product must pass the test three times using semen from three different donors or five times uSing semen from six different donors (90,130).

Table 3-Comparison of Product Contraceptive Effectiveness by Point Scoring Method* Commercial Contraceptive Product Delfen Cream Emko Foam Lanesta Gel Lactikol Creme Lactikol Jelly Durafoam Tablets Lorophyn Suppositories Perfect performance score 1st Insemination 180 180 170 176 168 159 164 180 2nd Insemination 180 180 180 144 162
72

3rd Insemination 148 130 130 100 61 3 2 180

Total Points 508 490 480 420 391 234 222 540

There is considerable question, however, whether spermicidal potency measured in vitro has any relationship to the clinical effectiveness of the preparation (2,102). Studies by Johnson and Masters, for example, suggest that the distribution and mechanical function of vaginal contraceptives can alter spermicidal potency. After observing simulated coitus photographed intravaginally, they concluded that the manner in which the base material spreads in the

56 180

'One point is allotted for each vaginal specimen showing all sperm immobilized; six specimens were taken from each of 30 subjects after each insemination. SOURCE : Johnson and Masters (87) .

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Table 4-Effectiveness of Vaginal Chemical Contraceptives in Selected Major Studies Published Since 1960a
RefarAuthor and Date

ance
N'umber

Brand 01 Preparation

Location 01 Study

Characteristics of Population Studied

Number

Woman-

01 Women

Months 01 Use

Average Duration 01 Use (in Monthsl

Number of

Failure Rates (Pregnancies per 100 Woman-Y earsl

Method Failure Method and User Failure 7.75

Pregnancies

JELLIES Margolis, Cavanaugh, and Erns 1962 Kasabach 1962 Frank 1962

104

Lan.sta -Gel

USA

Young clinic patients contacted monthly Clinic patients

259

3,250

12 .5

21

N.A .

88 54 162

Koromex A

USA USA

195 684 462

2,058 6,594 4,987

10.6 9.6 10.8

36 127 150

7.58 N.A . N.A.

20.99 23. 1 36.09

Korome)( A
Koromex. Lactikol, Lorophyn, Ortho-Gynol,

Urban clinic patients; 3 mo. contact

Young , married, low income, rUfal;

Tietze. Pai, T aylar, IndGamble 1961

Puena
Rico

3 mo. contact

and Precept in
CREAMS Rovinsky 1964 Tyler 1965 134 164 Dellen Dellen (full dosel Dellen (half dosel Dellen (hall dosel Syn-A-gen USA USA Medically indigent 251 508 164 425 2,915 6,783 2,748 4,071 11 .6 13.3 16.8 9.5 22 35 9 19 3.70 . 71 .44 2.06 9.06 6.19 3.93 5.60

clinic patients
Clinic patients, in mid-1950s Same as above Combined sta tistics, 6 investigators in 19505
Belgium

SUPPOSITORIES God.ts 1973 FOAM TABLETS

64

N.A .

56

1,344

24

N .A.

1.79

FuruSlwl et al 1968
Ishihama .,d Inoue 1972 Tyler 1965

58 82 164

Neo Sampoon Loop

Japan

Clinic patients,
most aged 25-35

124 587

1,058 8,955 11,096 1,749

8 .5 15.3 7.0 7.3

2 24 133 32

0 0.67 4.22 N.A.

2.27 3.22 14.38 21.96

Neo Sampoon Loop

Dellen

Japan
USA USA

Farmers' wives,
most aged 25-35

Combined statistics, 1590 11 investigators in 1950s "Poorly motivated" clinic patients; 3 mo . contact Young, low income, rural, married
240

Dingle and Tietze 1963

Tietza, Pai, Taylor, and Gamble 1961 AEROSOL FOAMS Bushnell 1965

39

Durofoam

162

Fomos

Puerto Rico

166

1,565

9.4

50

N .A.

38.34

21 23

Emko Emko

USA USA

"Intelligent,

130 1778

2,737 17,200

21 . 1 9 .7

4 45

0 N.A.

1.75 3.14

motivated" "Low motivated and disadvantaged"; 3 mo. contact

Mostly medically

Carpenter .nd Martin 1970 Bernstejn 1971

Kleppinger 1965

14

Emko

USA

2932

28,322

9.7

94

3.05

3.98

indigent; 3 mo . contact
91 Dellen USA

Clinic patients; 3 mo. contact

Hospital and clin ic patients; ' -3 mo. contact

138

1,116

8.1

2.15

7.53

Tietze and Lewit 1967 Paniagua. Vaillant.

end Gambia 1961 SOLUBLE FILM

160

Emko

USA

779

5,572

7.1

N .A.

N.A .

28.3

127

Emko

Puerto Rico

Low income, urban, Catholic, married ; contact each mo .

N .A . N.A .

142

1,723

12.1

42

N.A .

29.25

128

Cl ilm

Europe
Egypt

716 91

5,194 1,638

7.3 18.0

23
10

N.A . N .A .

5.31 7.33

Pariser 1974

N.A. = not available. aAlthough many studies of vaginal chemical contraceptives were conducted before 1960, changes of ingredients in some brands make the results of some early studies inapplicable to the products as now formulated . bAfter one year, as calculated by life table method. All other rates are calculated by the Pearl Formula .

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contraceptive practice . Since the rates attributed to method failure in existing studies range from .4 (164) to 7.6 (88) per 100 woman-years, t he theoretical effectiveness of vaginal co ntracept ives would appear to be fairly high (see Table 4).

Neo Sampoon Loop foam tablets, which are manufactured in J apan , resulted in pregnancy rates as low as 3.2 in a recently reported study including 587 Japanese farmers' wives (82). Other studies utilizing foam tablets, however, have reported failure rates as high as 38.3 per 100 womanyears (see Table 4).

Use-effectiveness measures what act ually happens in practice, that is, w hen careless or inconsistent use are considered togethe r with "method failure." It is a more valid meas ure t ha n theoretica l effectiveness. Use-effectiveness rates were origin ally calculated by t he Pearl form ula - the number of pregnancies per 100 woman-years of exposureand thus may be biased either by the relatively h igh failure rates of short-time users or by the relative ly low fa il ure rates of long-time users. A more sophisticated method , li fe table analysis, wh ich measures discontinuation rates over a specifi ed length of time (extended use-effectiveness), is comi ng into wider use .

A multi-center study of C-fi lm, sti ll u npublished. reported an overall pregnancy rate of 5.3 per 100 woman -years after 5194 woman-months of use (128). On the other hand, C-f il m fail ed a tes t by the British Family Planning Association because nine pregnancies occurred among 45 women du ring 175 cycles, for a pregna ncy rate of 62 per 100 woman years. This is about th e same as the rate which mig ht be expected among women who use no contraception . Users f ound that the quick-dissolving film tended to adhere to sticky fingers and was therefore difficult to insert (1 ,148).

Cli nica l trials sh ow a great var iation in th e effectiveness rates of vaginal contraceptives. These trials have taken place over a 40-year time period, using different types of vag inal contraceptives, different test populations, and different procedures for record keeping and fol low-up (1 1. 41 , 42, 44, 45, 50-53 , 63 , 65 -67, 74, 75, 92 , 129, 139. 155, 159, 163. 171. 174, 178, 179). Furthermore. studies of use- effectiveness were sometimes biased when irregu lar users or t hose w ho discon ti nued t he method w ere excluded from the fina l calculations. Therefore, most of the re sults are not comparab le w ith one another and certa inl y do not provide conclusive evidence of th e efficacy of vagi nal methods or of one brand formulatio n as against another brand .

Nevert hel ess. some poi nt s do eme rge from recent, larger studies, w hich are summ arized in Table 4. (Al so see refs_ no. 10,26.55, 103,108,109,1 16,122,124,140.150.) Pregnancy rates range from about two per 100 woman -years in several relat ively small clin ica l studies to a high of nearly 40. Th e largest number of consistently low failure rates (less than five per 100 years of exposu re) are reported in rece nt research wi th Emko and Delfen fo ams in developed areas-either among private patients, or those attending Pla nned Parenthood cli nics who se lected foams volun tarily, or in other programs w ith continu ing follow -up. In several US studies , fo r example. women were introduced to the product by fami ly planning outreach w orkers of similar eth nic and social backgro unds who communicated to potential users their own confidence in the product (14, 21, 23,91 ,1 27, 164 ).

It has long been known that use-eff ectiveness is related to experience with t he meth od and to th e stage of fa m ily fo rmation in w hich the couple find themselves. A recent US study by Professor Norman Ryder of Princeton based on survey data has provided f urther insight into the reasons for contracept ive failur e. Regardless of the specific method used, contraceptors who w ere t ryi ng to prevent further pregn anCies entirely were much more successful t han contraceptors tryi ng mere ly to delay or space pregnancies. Of th ose using foams to prevent births, 22 percent experi enced an unw anted pregnancy compared with 36 percent of those seeki ng me rely to delay birth s. But in t he entire study 31 percent of those w ho used foams experienced un intended pregnancies, compared with 6 percent of t hose using pi lls, 8 percent using IUDs, 17 percent using con doms, 23 percent using diaphragms, 33 perce nt using rhythm , and 45 percent using a douche (135) (see Fig. 1).

Over the last decade, va gina l contrace pt ives have been cri ticized or more often si mply ignored by those in the fa mily planni ng fi eld because of t he hig h fa ilure rates. On the one hand, many experts believe t hat theoretical and use -effect iveness shoul d not be differentiated, that is, all fai lures should be considered method failures sin ce intermitten t use of a contraceptive met hod actually refl ects dissatisf action with it (70,9 9,157 ).

Tw o studies, how ever, contradict the low rates oth er resea rch ers have found with foams. Tietze and Lewi t reported a pregnancy rate of 28.3 after 12 mo nths for 779 US w ome n using Emko foam. This ra te, calculated by the life table method, is lower than t he pregnancy rate in the same study for women who used jellies or crea ms alon e (36 .8) but hi gher t han that of women w ho used diaphrag ms wit h je lly (17.9) (160). In a Puerto Rica n study, Pan iagua et 81 reported a failure rate w ith Emko f oam of almost 30 per 10 0 woman-years (127) (see Tab le 4). These rates are high in comparison to oral contraceptive or IUD pregnancy rates.
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On the other han d, some experts argue that those who ch oose vaginal methods toda y instead of more effective co ntracepti ves may have ambivalent vi ews about preventing pregn ancy. Therefore they may unconsciously ch oose and use a method carelessly, wi th resulting high pregna ncy rates. Although contraceptive effectiveness is very important in some circumstances, in other cases, for exa mple w here abortion is readily available, different fac tors may w eig h m ore heavily in a couple's choice. Even if rel atively ineffective, a method which is easy to secure and use may double or triple the i nterval between births and thus meet individual or comm unity needs more readily than a highly effective, sophisticated met hod which requires the supervision of trained medical personnel (13 6) .

Moreover, for t he infrequent user or for women w ho need temporary protection after IUD removal or omission of several pills or for women who prefer not to use orals or IUDs, vaginal contracept ives, especially foam, provide a reasonable a ltern ative comparable to condoms. Altho ugh not as effective as condoms, they do not require th~same degree of mal e cooperation as do condoms, nor do they dimin ish penile se nsi tivity as condoms are sometimes alleged to do.

fou nd that use of foa m had increased from 3.3 perc ent in 1965 to 6.1 percent in 1970. By comparison , in 1973 about 10 mi llion women in the US used oral contraceptives (131 ) and th ree to fo ur million, IUDs (97 ,166).

USE AND DISTRIBUTION

The Internationa l Pl anned Parenthood Directory of Con traceptive s (71) lists co ntraceptives marketed th roughout t he world, in cl udi ng brand nam es, ma nufacturers, and dist ributors of vaginal contraceptives . These inclu de 65 products in tubes (creams, je llies, or pastes), 35 su ppositories, 33 foam tab lets, and s ix pressu rized foa ms. Alt hough aerosol foams are probably the most effective of t hese, no more th an five f irm s manufacture them beca use of the large investment in equipment th at is necessary. In t he USA and Brit ain the num ber of vagi nal products on the market has decl ined steadily since t he 1950s, wi th only about one t hird as many produ cts listed in 1971 as two decades before (7 2). Assessing the act ual use and distribution ofthe se products is difficult (68). Si nce prescriptio ns are not required, women who sel ect th ese methods are not likely to seek the advice of physicians, and, in t urn, phYSicians and famil y pla nn ing programs do not generally recommend or dispense vaginal co nt racepti ves un less orals, IUDs, or steri lization are co ntraindicated. On t he w hole, use of vagi nal methods is f ar less tha n th at of orals, IUDs, sterilization, or condoms, wh ich have repla ced vaginal methods in most developed cou ntries. Use of ae rosol foams and foam table ts, however, is increasing as compared to jellies and cre ams, and it may increase f urther in many co untries if t hese products are more r ead ily available and more vigorously pro moted. An Internationa l Pl an ned Parenthood Federation survey estimated that 1,0 41 ,500 ,000 doses of spermicides were distributed in 1971 in t he 73 cou ntries w here IPPF affi liate s w ere able to provi de informat ion (7 8). Two-th irds of these were in Western Europe . If 100 doses provide one year's protection for the average couple (177), the IPPF figure could mean that about 10.4 milli on w omen in those 73 countries we re regular users of va ginal contraceptives. However, the use of vaginal cont racept ives is often irregular, and probably many more women use them , though not regul arl y. Estimates vary about the use of vaginal contraceptives in the USA and other developed coun tries. Accordi ng to one drug manufacturer's estimate about four million US w omen now use them (112). Another manufacturer has estimated there are more tha n two million current US use rs of foam (142) . The 1970 US National Ferti lity St udy placed the number of US users of contrace ptive foa m at about 1.5 million in that year (135) . The study, based on a survey of over 5000 couples in which the wife was under 45,

One po int is cl ear . The use of vaginal contracept ives has declined substantial ly since oral contraceptives and IUDs were intr odu ced in the early 1960s. In 1969 in Japan, where aborti ons were readily availabl e and orals and IUDs w ere not legal, about 9 percent of ma rried wom en of reproducti ve age used jelli es or foa m tablets (1 23). Elsewhere, use of vaginal contraception in recent years probably has not exceeded 5 or 10 percent of th e populat ion of repro ductive age . In Melbourne, Australi a, a retrospective survey of once-married wome n under 60 living w ith their husbands showed that the use of sperm icides as t he main method of fa m ily plan ning decli ned f rom 20 percent in the 1930s and 1940s to 2 to 3 percent in th e late 1960s. From 1965 on, over 30 pe rcent of these Melbournewom en were using orals (2 2). In Europe , a 1971 survey of family planning attitudes and practices ind icated that only 1 percent of t he married w omen in Great Britain w ere then using vagi nal ch em ical methods and even few er in Italy, Bel giu m, France, and W est Germany (81). A bout 5 percent in Britain were using spermicides together with diaphragms or condoms (18).

Promotion and Sa les Before the 1960s, the major US manufactur ers con cen tr ated their sales effort on persuading ph YSicians to recomme nd specific vagi na I contraceptives for use together with diaphragms fi tted by phYSicians . Thus the most effective vagina l preparati on s were not promoted directly to the consumer market, but indirectly through the medical profeSSion.

More recently, as t he di ap hragm has been replaced by other methods and as pu bl ic discussion of family pla nning has made direct advertising and pharmacy display of nonprescription contraceptives more acceptable, some manufacturers have undertaken more vigorou s promot ion and distribution of va gina l contraceptives . In the USA, for exa mple, the Emko Company, which produces no co ntra ceptives except foam, has taken the lead in public advertising , and now supplies 40 percent of the domestic foam market. The Ortho Pharmaceutical Corporation, on the

The International Planned Parenthood Federation will provide upon request a full description of the Agreed Test of Spermicidal Power and a list of products which have passed the test . The IPPF Directory of Contraceptives (1971) is also available. Contact: The Medical Department International Planned Parenthood Federation 18-20 Lower Regent Street London SW1 Y 4PW United Kingdom

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other hand, which manufactures and distributes all types of vaginal and oral contraceptives as well as many other medical supplies, promotes its products primarily to physicians. During 1973, Ortho produced about 55 percent of the foam products sold in US pharmacies as well as about 80 percent of the jellies and creams (80). In recent years vaginal contraceptives, particularly aerosol foam and cream products, have been advertised in women's magazines and in some general interest magazines. In order not to offend public sensitivities, however, most advertisements describe the product in such vague terms that the message may not be conveyed clearly to the consumer. Moreover, some douches and other vaginal products are similarly advertised in such ambiguous terms that consumers may think these products also have contraceptive value, even though they do not. In the USA many state laws prohibit contraceptive advertisements. US television accepts advertisements for vaginal sprays and vaginal douches which are used for cosmetic purposes but does not accept advertisements for vaginal contraceptives. There are fewer restrictions on contraceptive advertising in Europe and Japan, where advertisements appear in both newspapers and magazines, but not on television. In Sweden, foam is advertised widely, even at cinema performances. Most developing countries accept family planning advertisements which do not mention specific types of contra-

ceptives. India, Korea, Sri Lanka, Jamaica, and Kenya have permitted advertisements for condoms, but so far vaginal preparations have not been promoted in the same way. Sales of vaginal contraceptives are generally permitted through any retail outlet, although some US states and a few countries attempt to limit distribution to registered pharmacies. In certain European countries, such as Germany, Sweden, Denmark, and the United Kingdom, vaginal contraceptives can be purchased in specialty shops which sell products associated with sex. Mail order sales are important in Germany and in some other countries. Sales in Developing Countries Several studies of contraceptive distribution through the commercial sector have been made in developing countries. In nine country surveys the Westi nghouse Popu lation Center interviewed fertile urban couples who had cash incomes. In Turkey, Pakistan, and Panama, users of foams / creams or other products amounted to 4 percent of those interviewed. For Jamaica, the figure was 2 percent. Except in Pakistan, these users were all supplied through commercial channels. In Iran, Korea, the Philippines, Thailand, and Venezuela, vaginal products were rarely used (172, 173). A somewhat similar survey by Arthur D. Little Inc . (5) noted that vaginal contraceptives constituted "a minor volume of all contraceptives sold through commercial

Table 5-Retail Prices of Selected Vaginal Contraceptive Products in Selected Countries, 1974
Approximate Retail Price in uS$ (as of June 1974) $4.00 $2.89 - $3.25 Number of Applications 30 30

Product Name

Country of Sale UK, F inland, South Africa USA, Canada

Annual Sales or Number of Users 1 million users, USA & Canada 20,000 users, UK 40,000 users, Finland $50,000 (US), UK 42,200 tubes, South Africa $14,100 (US), UK

Emko Foam

Gynomin foam tablets

$ .75 $1.10 $ .37 + taxes $2.63 $2.51 $2.11 1.72 1.10 1.48 1.20 1.95 1.80 2.40 1.90 $ .05 $1.85 - $2.72

12 12 56 10 6 20 20 20 20 20 20 20 20 20 12 6

UK South Africa UK UK USA Philippines Thailand Hong Kong Singapore South Vietnam Guatemala EI Salvador Dominican Republic Panama Peoples Republic of China Europe (5 countries) Africa (5 countries) Asia (11 cou ntries) Central America (10 countries) South America (2 cou ntries)

Duragel Conceptrol cream Conceptrol cream premeasured Neo Sampoon Loop tablets

1,000,000 tubes, Japan 530,000 tubes, Asia 55,000 tubes, Africa and Middle East

90,000 tubes, Latin America

Peoples Republic Tablets Syn-A-gen/A-gen 53 suppositories

N.A. 5 million suppositories

SOURCE: Data from manufacturers. Data on Peoples Republic Tablets from Ohneda (120).

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channels" in Colombia, Iran, and the Philippines. "The reasons for the sma II vol ume," accordi ng to the study, were " lack of consumer demand, restriction on distribution to the drug network, and lack of product availability. The authors do not believe that drug firms are likely to increase their efforts to promote these products because of lack of potential consumer demand for them" (5). Promotion, however, appears to increase consumer demand. In 1972 a four-month pilot project that provided pamphlets for pharmacists in Colombia to distribute with information on orals, condoms, and suppositories produced a 63 percent increase in suppository sales, an 81 percent increase in condom sales, and a 26 percent increase in orals sales. Even in drugstores which did not distribute the pamphlets, suppository sales increased by 39 percent (6). An analysis of contraceptive distribution in Nigeria, Ghana, Kenya, and Uganda during 1970 showed sales of 288,000 vaginal foam tablets in Nigeria and 204,000 in Ghana, with smaller amounts sold in Uganda and Kenya . There were some tube cream sales in all four countries (16) . Since suppositories have been used traditionally by the Yorubas in Nigeria as abortifacients and since in the minds of some men vaginal methods are less likely than pills or IUDs to encourage women to be unfaithful (125), a still larger market may exist in Africa for these products. Black noted that, "In West Africa, in particular, 'chemical sellers: or patent medicine dealers, felt this market was being held back by inadequate importation of products rather than by lack of demand." Manufacturers are "unwilling to make any significant promotional investments in view of the threat to the markets from the increasing flood of subsidized contraceptives, as supplied through bilateral aid and distributed by family planning organ izations" (16). Such evidence, although far from conclusive, suggests that a market may exist for vaginal products, but that these products so far have not been vigorously promoted. Nor have the most effective formulations been the most widely marketed.

Table 7-New Acceptors of Vaginal Products in 11 Government and/or Family Planning Association Programs, 1971
New Acceptors of Vaginal Preparations 54,389 1,081 73,306 4,635 99 2,479 4,033 93,375 146 670 97 Acceptors of Vaginal Preparations as Percent of Total Acceptors 43 33 22 17 14 9 9 7 6 5 5

Country

Total New Acceptors

Bangladesh Barbados Pakistan Ghana Sierra Leone Jamaica Puerto Rico USA St. Lucia Ecuador German Federal RepUblic

127,051 3,265 329,245 27,217 701 26,632 44,660 1,263,837 2,390 13,722 2,100

SOU RCE : Huber (78).

Costs Retail prices vary considerably according to the type of vaginal product and the type of distribution outlet. In general, aerosol foams and premeasured doses of cream are the most expensive, tubes of cream are in the middle range, and jellies and foam tablets are the least expensive. Retail costs per application range from about $.02 (US) to $.45 (US) (see Table 5 for selected prices) . AJapanese manufacturer has reported that foam tablets are sold in the Peoples Republic of China for the equivalent of about one-half cent per tablet (120) .

Table 6-Deliveries of Vaginal Chemical Contraceptives Financed by US Agency for International Development, by Fiscal Year and Continent, 1971-1974 1
1971 Latin America 2 Foam Jelly Asia Foam Jelly Africa Foam Jelly TOTAL Foam Jelly 58,945 27,580 10,153 10,092 119,260 14,580 188,358 52,252 1972 64,684 72,232 4,394 34,368 127,794 14,076 196,872 120,676 1973 49,983 90,120 4,664 35,976 100,470 11,988 155,117 138,084 1974 47,931 41,912 406,975 42,120 40,258 8,496 495,164 92,528

Bulk costs paid by international donor agencies are, of course, lower than retail prices, but in all instances the costs of vaginal contraceptives, like those of condoms, are increasing . In fiscal 1973 the US Agency for International Development (USAID) paid $.95 (US) for a 90 gram aerosol container of Emko with applicator. In 1974 the price was $1 .10 (US). Since 1.2 grams are required for protection, the per application cost is approximately one and one-half US cents. The cost to USAID for 50 grams of Delfen foam with applicator is $1 .30 (US) . With slightly less than one gram needed for protection, the per application cost is approximately two US cents. UNICEF has recently purchased Neo Sampoon Loop foam tablets at about $.65 (US) for 20 tablets, or about three US cents for each application (121) . These prices should be compared with the current cost to USAID of approximately three US cents for a single condom (114) and approximately $.13 for a month's supply of oral contraceptives (38) when purchased in quantity.

USAID Shipments At present the distribution of vaginal contraceptives through family planning programs is not substantial. USAID, which is the principal source of subsidized contraceptive supplies, has not stressed vaginal contraceptives in its bulk purchasing because of a deliberate program decision to give first priority to the most effective methods.

lAlso, 4000 containers of vaginal tablets delivered to Africa in 1974. Foams in number of 90 gram units or equivalent; jellies in number of tubes. 21 ncludes Caribbean . SOURCE : US Agency for I nternational Development, Commodity Reports System, December 1974.

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For example, between fiscal years 197 1 and 1974, USA ID supplied about one mill ion 90gra m units or t he eq uivalent of aerosol foams, approximately half of that in 1974 (see Table 6). USAID suppl ied about 400,000 tubes of jelly over th e same four -year period . Until 1974, the largest shipments of foam were consigned to Africa, w he re shortages of med ical personnel may have delayed t he spread of IUDs and ora l contraceptives, bu t in 1974 shipments to A sia increased a hundredf old . Abo ut 300,000 units were sent t o Ba ngl adesh f or its new family plann ing program . Pakistan, which stepped up its program, rece ived about 100,000 units.

family planning aSSoCiations, IPPF supplied 16 ti mes as many foam tablets in 1974 as in 1971 (see Table 8 ). This increase is caused in part by requests from new programs in the Phil ippines and in Indonesia , but it may also be the res ult of vigorous promotion by the Ei sai Company of Japan of the new Neo Sa mpoon Loop foam tablets. To supply th ese requests, the IPPF purch ases contra ceptives directly from the manufacturers as w ell as obt ai ning them from USAID .

Program Distribution The Internati ona l Planned Parenthood Federation (lPPF) has gathered data on the choi ce of vaginal aerosol fo am, foam tablets, je ll ies, and creams by patients In c li nics and other fami ly plann ing program facilit ies (78). A n extensive study based on detailed questi onna ires fro m 98 countries re vealed that in 1971 there were either no new acceptors or an unknown number of acceptors of vaginal methods re ported in 65 country progra ms. These figures, of course, may be attr ibutable to program decis ions and to the non availa bility of va gi nal preparat ions as well as to individual cons umer choice. Of the 33 countries where government and lor pri vate fa mi ly planning progra ms d id re cord new acceptors of va gina l preparati ons, on ly 11 showed 5 perce nt or more accepting these methods (see Table 7). IPPF-supported clinics have not experienced any great increase in the use of jell ies, creams or aerosol foam s since 1971. even t hough the use of ot her methods has grow n substant ially. Foam tablets, on the ot her hand, have become more popular. In response to requ ests from local

Si nce most fa mily planning adm inistrators have not emphasized the use of vag inal contraceptives, t he present level of dema nd for these prod ucts, although not high, probably reflects the conti nuing preference of some individuals and a few fami ly planning clin ics. Th e growing interest in non cl inical distr ibution by midwives, retai l outlets, bazaars, pedd lers, and the like- although so fa r focused pr imarily on condoms and pills- may eventu ally contribu te to wider use of self-ad ministered vag ina l contraceptive methods.

VENEREAL DISEASE PROPHYLAXIS

If cu rrent rese arch is successfu I, vaginal contraceptives may be shown to offer an additiona l benefit as a VD prophylactic. Stu di es now being carried out by Drs. Cut ler, Singh, and associates at the Universi ty of Pittsburgh are directed toward the identif ication of vag inal preparations with bot h contracepti ve and prophylactic prope rti es (13, 17,30,3 1,32,33,34,95, 143, 144,145,146).

Initial in vitro tests have compared 20 products which are now in use on the basi s of their effect on Ne isseria gonorrhoeae and Trepo ne ma pa ll id um (syph ilis). They were

Table a-Vaginal Chemical Contracept ives Provided by t he International Planned Parenthood Federation, by Calendar Year and Area, 1971 1974, and Scheduled Deliveries, 1975 (by number of containers)
Product and Area JELLI ES/CR EAMS Africa Asia leIti n America and Caribbean TOTA L FOAM TABLETS Africa Asia leIti n America and Caribbean TO TAL AEROSOL FOAMS Africa Asia Latin America and Caribbean TO TAL Used 1971 Used 197 2 Used 1973 Est imated Usage 1974
16,204 42,396 32,020 90,620 23,856 286,820 28,940 339,616 13,9 46" 51 ,600 36,000 101,546
a

To Be Deli ve red 1975

7,530 16,150 41,984 65,664

To tal

11 ,900 21 ,083 13,432 46,415 4,208 3,93 1 12,913 21,052 17,336 17,661 43,667 78,664

11,981 26,936 20,048 58,965 17,265 19,341 1,689 b 38,295 15,014 c 12,311 34,017 61,342

13,913 30,242 26,856 71,011 20,751 114,606 2,540 137,897 11,490 54 ,639 35,017 101,146

61,528 136,807 134,340 332,675 124,080 477,998 148,482 750,560 65,170 155,061 207,947 428,178

58,000 53,300 102,400 213,700 7,384 18,850 59,246 85,480

aexclud ing Tunisia bexcl uding Trinidad and Tobago cexcl uding Philippines and Sabah SOURCE : Internat io nal Planned Parenthood Federation, Report to Donors, September 1972,1973, and 1974 (82,83,84).

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Table 9- Lowest Concentration of 20 Contraceptives Requ ired to Inhibit the Growth of N. Gonorrhoeae by Two Methods3
Time-Exposure Method Conce ntration Contraceptive IParcent)b 10 50 10 1 20 50 50 50 50 20 10 50 10 10 10 10 1 10 1 50 pH
1

Plate-Dilution Method Concentration IPe rcen t) 10 10 10 10 10 20 20 20 20 20 10 10 50 10 10 10 1 10

1

Growth after Exposure IMin .)

5
-

pH

Growth

10
-

Cartane Vagina l Jelly Contra Creme Co ntra Foam Cooper Crem e Delfen Cream Delfan Foa m Em ko Concentrate Em ko Concent rate +A Emko Co ncentrate +8 Emko Co ncent rate + Spermic ide Emko Fo am Im molin Vag inal Koromex A Vaginal J elly Lanesta Gel Lorophyn Suppo sitories Miiex Crescent Ortho Creme Orthogynol Jelly Preceptin Gel Ramslls Vaginal

4.6 6.9 7.5 6.7 5.2 4.9 7.4 7.1 7.2 7.0 7.3 4.9 6.0 5.6 5.7 5.7 6.2 5.5 5.6 6.7
6

+ +

+ -

+ -

+ -

+ -

+
-

+ + +
-

+ + +

50

7.5 7.5 7.5 7.6 7.6 7.6 7.5 7.2 7.2 7.3 7.4 7.5 7.5 7.5 7.5 7.5 7.4 7.4 7.4 7.5

aBacterial suspension for these experiments contained about 10 CFU per 0.1 ml, the inoculated Thayer-Martin selective medium plates were incubated at 37C. in CO 2 incubator. bOnl y 50,20, 10, and 1 percent dilutions in physiological saline solution were tested. cpH of media after adding the contraceptive at different concentrations. dResults from duplicate plates. SOURCE: Singh, Cutler, and Utidjian (145).

analyzed according to the length of time required to kill the VD organisms and the minimum concentration that was effective against them.

A vaginal preparation which offers both contraception

and VD prophylaxis might be a major step in preventing the spread of VD. Such an agent would be the first female contraceptive method to offer the kind of dual protection, even to a limited degree, against both venereal disease and pregnancy which has long been provided by the condom (35).

In 1-,5-, and 1O-minute time exposure tests three contraceptives-Cooper Creme, Ortho Creme, and Preceptin Gelat a 1 percent dilution inhibited the growth of N. gonorrhoeae bacteria. Eight of the contraceptives were effective at 10 percent concentration. In a plate-dilution test, Ortho Creme and Preceptin Gel were effective at a 1 percent concentration, and eleven others, at a 10 percent concentration (see Table 9) (145).

Table 10-Dilutions of Contraceptives Required to Immobilize T. Pallidum Suspension within 1 to 1.5 Minutes
Concentration Number of Ipercent) Contraceptives 1
10

In tests of the effectiveness of various vaginal contraceptive products against syphilis, an Emko concentrate and Ortho Creme at a 1 percent concentration immobilized T. pallidum, the spirochete responsible for syphilis, within 1 to 1.5 minutes; 12 preparations were effective at a 10 percent concentration, three at 20 percent, and two at 50 percent (see Table 10) (145).

Name of Contraceptive Emko Concentrate +8, Ortho Cream Certane Vaginal Jelly, Contra Foam, Cooper Creme, Delfen Cream, Delfen Foam, Emko Concentrate, Emko Concentrate +A, Finesse, Immolin Vaginal Cream-Jel, Lorophyn Suppositories, Orthogynol Jelly, Preceptin Gel Contra Creme, Lanesta Gel, Ramses Vaginal Jelly Koromex A Vaginal Jelly, Milex, Crescent Jelly

2 12

Preliminary results of these tests have been encouraging and further in vitro and in vivo tests are planned. Progress in this area is especially important for several reasons: public health measures have had limited success in controlling the spread of venereal disease (147,175); gonorrhea is becoming more resistant to penicillin therapy (101,147,153,154); syphilis, although not resistant to penicillin, is infecting more and more people, an increasing proportion of whom react advetsely to the drug.

20 50

3 2

SOURCE: Singh, Cutler, and Utidjian 1145).

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89. KI RALY, K. The venereal disease problem around the w orld. In : Ep idem ic venereal disease. Proceedings of the Second Intern ational Ven er eal Disease Symposi um, St. Louis, April 19 72 . New York, Pfizer, Inc., 1973 . p. 124 -1 26 . 90. KLEI NMA , R. D., ed. Intern ationa l Planned Pare nthood Federation M edical Handbook, 2nd ed. Lond on, Int ern ational Planned Pa renth ood Feder ation, 1964. 106 p. 91. KLEPPING ER, R. K. A va ginal cont racept ive foam. Pennsylvania M edical J o urn al 68 : 31- 34 . April 1965. 92. KOPP, M. E. Birth control in practice. A nalysis of ten tho usand case histories of the Birth Control Clinical Research Bureau. New York, Robert M . M cBri de & Cmpany, 1933 . 212 p. 93 . KRAUS, S. J. Complications of gonococca l in fection. M edical Cli nics of Nort h America 56(5): 11 15-1125 . 1972 . 94 . LAUG, E. P. and KUNZE, F. M . The absorption of phenylmercuric acetate from the vaginal tract of the rat. J ournal of Pharm acology and Experimen tal Th erap eutics 95(4): 460-464. April 1949 . 95. LEE, T. Y., UTIDJ IAN , H. M . D" SINGH, B., CARPENTER, U., and CUTLER, J. C. The potential impact of chemical prophylaxis on t he incidence of gonorrhoea. Br itish Journal of Venereal Diseases 48(5): 376-380. October 1972 . 96 . LEHFELDT, H. , SOBRERO, A. J. , and INGLIS, W. Spermicidal effect iven ess of che mical co ntraceptives used w ith a cer vical ca p. A merican Journal of Obstetrics and Gynecology 8 2(2): 446 -44 8 . August 196 1. 97. LEVIN, L. S. (Interconti nental Medical Stat istics). Personal communication, April 3, 19 74 . 98 . LICHTMAN, AS ., DAVAJAN, V., and TUCKER, D. C-fi lm: a new vaginal contraceptive. Contraception 8(4): 291 -297. Octo ber 1973. 99 . LINCOLN, R. Personal communication, October 8, 1974. 100 LONG, J . H , CAREY, M. L., HELLEGERS, A E. , and PENTECOST, M. P. The vaginal douche: observ ations on some of its effects. W estern Journal of Surgery, Obstetrics and Gynecology 71(3): 122- 127. May-June 1963. 101. LUCAS, J . B. The national venereal disease problem. Medical Clinics of North America 56(5): 1073-1086 . 1972 . 102. MacLEOD, J., SOBRERO, A J., and INGLIS, W . In vitro assessment of commercial contraceptive jellies and creams: positive correlation between laboratory tests and clinical use awaits further investigation . Journal of the American Medical Association 176(5): 427-431. May 6 , 1961 . 103. MARCUS, S. A clinical study of a new contraceptive creamjet. Journal of American Medical Women's As sociation 16(5): 383-385. May 1961 . 104. MARGOLIS, A J ., CAVANAUGH , A T., and EMS , M . Contraception with gel alone. Fertility and Sterility 13(3): 265-269. 1962 . 105. MARTIN, J . B. Tolerance to repeated application of a foam contraceptive in the human vagina . Clinical Medicine 69(9). September 1962. (Reprint) 3 p. 106. MASTERS, W. H. and JOHNSON, V. E. Human sexual response. Boston, Little, Brown and Company, 1966. 366 p. 107. MATSUMOTO, Y. S., KOIZUMI, A , and NOHARA T. Condom use in Japan. Studies in Family Planning 3(10): 251 -255 . October 1972 . 108. MEARS, E. Chemical contraceptive trial : II. Journal of Reproductive Fertility 4: 337-343. 1962. 109. MEARS, E. and PLEASE, N. W. Chemical contra ceptive trial. Journal of Reproductive Fertility 3: 138-147. 1962. 110. MILLER, V., KLAVANO, P. A, and CSONKA, E. Absorption, distribution and excretion of phenylmercuric acetate. Toxicology and Applied Pharmacology 2 : 344-352 . May 1960. 111. MILLMAN , N. A critical study of methods of measuring spermicidal action. Annals of the New York Academy of Sciences 54: 806-824. 1952. 112. MORIARITY, P. (Ortho Pharmaceuticals) Personal communication, March 19, 1974.

1 13. MU RAKAMI, U. , KAM EYAMA, Y., and KATO, T_ Effects of a vaginally applied contraceptive w ith phenyl mer curi c acetate upon dev eloping embryos and their mother anim als. In : Annual report of t he Research Inst itute of En vi ronm ent al M edicine. Japan, Nagoya Un iversi ty, 195 5 . p. 88- 99 . 114. NA KAM URA, G. and PEDERSEN , H. (U.S . Age ncy for International Development). Personal communicati on, November 18, 1974. 115. NAKANO, E. and FURUSE, I. Spermat ozoicid al acti vity of p-menth an ylphenyl polyoxyet hylen e (8.8) ether (TS-88). In: Neo Sa mpoon Loop Tablets. To kyo, Eis ai Company Lid., undated. p. 17-24 . 116. NAGANO, M . The results of a fie ld-test on the contr ace ptive ta blet with TS-88 as t he main ingredient. Clin ical Gynecology & Obst etrics 22(5). Repri nted in : Neo Sampoon Loop Tablets_ Tokyo, Eisa i Company ltd., undated . p. 27-3 7. 117. NAGANO , M . Res ults of vagina l cytodiagnosis on long-term users of a contr aceptive ta blet co nta ining a surface active agent p-metha ny lph enl po lyoxyethylene (8 .8 ) ethe r (TS-8 8) as an act ive in gredie nt. In : Neo Sa mpoo n Loop Tablets. Tokyo, Eisai Com pa ny Ltd ., undated . p. 4 1-46 . 118. NE LSON, N., BYERLY, T. C., KOLBY E, A . C., J r., KURLAND, L. T. , SHAPIRO, R. E., SHIBKO, S. I., STICKEL, W. H. , THOM PSON, J . E. , Van Den BERG, L. A ., and WE ISSLER, A Hazards of mercu ry, Speci al report to the Secret ary' s Pesticide Advisory Committee, [U S] Department of Health, Education, and Wel fare, November 1970 . Environmental Research 4(1): 1-69 . 19 7 1. 119. O'BRIEN, J . E and TH OM S, R. K. The in vit ro effect of sodium lauryl sulfate on vagi nal pathogens. Journal of Pharmaceutical Sciences 44(4): 24 5 -247. April 1955 . 120. OHNEDA , F. (Eisai Company). Personal communication, September 10, 1974. 121 . OHNEDA, F. (Eisai Company) . Personal communication, November 15, 1974. 122. OHTANI. Y. and KAWAGOE, T. A study of the contraceptive effect and side effects of a surface active agent, E-1 36. Clinical Obstetrics and Gynecology 22(8) Reprinted in : Neo Sampoon Loop Tablets. Tokyo, Eisa i Company Ltd., undated . p. 61- 71 . 123. OKAZA KI, Y. Family planning . In : Mainichi Newspapers, ed . Family planning in Japan. Opinion survey by the Mainichi Newspapers. Tokyo, J apanese Organization for International Cooperation in Family Planning , 1970. p. 97-126. 124. OKUYAMA, M., UCHIDA, S., and AIHARA, R. Contracept ive effect and phys ical feeling with the use of a surface active agent, E-136 (Neo -Sampoon Loop Tablets). In: Neo Sampoon Loop Tablets. Tokyo, Ei sai Company Ltd ., undated. p. 83-90 . 125. OLUSANYA, P. O. Nigeria. Cultural barriers to family plan ning among the Yorubas. Studies in Family Planning No. 37, January 1969. p. 13-1 6 . 126. PALMER, B. (Schmidt Laboratories Inc .). Personal communication, November 12, 1974. 127. PANIAGUA, M. E., VAILLANT, H. W., and GAMBLE, C. J. Field trial of a contraceptive foam in Puerto Rico. Journal of the American Medical Association 177(2): 125-129. July 15, 1961. 128. PARISER, G. C-film use-effectiveness studies. 1972 / 1973. Paris, USV International , 1974. (Unpublished) 129. PEARL. R. The natural history of population . New York, Oxford University Press, 1939. 416 p. 130. PEEL, J . and pons, M . Textbook of contraceptive practice. London, Cambridge University Press, 1969. 297 p. 131. PIOTROW, P. T. and LEE, C. M. Oral contraceptives-50 million users. Population Report, Series A. No. 1. Washington, D.C., George Washington University Medical Center, Population Information Program, April 1974. 26 p. 132.

pons, M . Personal communication,

October 11 , 1974.

133. RAWLS, W . E. and GARDNER, H. L. Herpesvirus and cervical cancer. In : Greenblatt, R. B., ed . Medical gynecology. San Juan, Pu erto Rico, Searle & Company, 1972. p. 23 -29. 134. ROVINSKY, J . J. Clinical effectiveness of a contraceptive cream. Obstetrics and Gynecology 23(1): 125-131. January 1964. 135. RYDER, N. B. Contraceptive failure in the United States. Family Planning Perspectives 5(3): 133-142. Summer 1973.

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136. SANDBERG . E. C. and JACOBS. R. I. Psychology of the misuse and rejection of contraception . Medical Aspects of Human Sexuality 6(6): 34-70. June 1972. 137. SANDER. F. V. and CRAMER. S. D. A practical method for testing the spermicidal action of chemical contraceptives. Human Fertility 6(5): 134-137. October 1941. 138. SANHUEZA. H. Personal communication. April 23. 1974. 139. SEIBELS. R. E. The effectiveness of a simple contraceptive method. Human Fertility 9(2): 43-47 . June 1944. 140. SHAPIRO. L. H. A new contraceptive aerosol foam . Obstetrics and Gynecology 26(3): 420-423. September 1965. 141 . SIEGEL. J. J. (Emko Company). Personal communication. March 15. 1974. 142. SIEGEL. J. J. (Emko Company). Personal communication. November 1. 1974. 143. SINGH. B. Anti-VD effect of spermicides. [Response to Letter to the Editor] Medical Aspects of Human Sexuality 7(9): 268. September 1973. 144. SINGH. B. Personal communication. February 21. 1974. 145. SINGH. B . CUTLER. J. C. and UTIDJIAN. H. M . D. Studies on development of a vaginal preparation providing both prophylaxis against venereal disease and other genita l infections and contraception. II: Effect in vitro of vaginal contraceptive and non-contraceptive preparations on Treponema pallidum and Neisseria gonorrhoeae. British Journal of Venereal Diseases 48(1): 57-64. February 1972. 146. SINGH. B. CUTLER. J. C. and UTIDJIAN. H.M .D. Studies on the development of a vaginal preparation providing both prophylaxis against venereal disease. other genital infections and contraception. III: In vitro effect of vaginal contraceptive and selected vaginal preparations on Candida albicans and Trichomonas vaginalis. Contraception 5(5): 401 -411 . May 1972. 147. SMARTI. W . H. and LIGHTER. A. G. The gonorrhea epidemic and its control. Medical Aspects of Human Sexuality 5: 96-115. January 1971. 148. SMITH. M . VESSEY. M . P. BOUNDS. W . and WARREN. J . C-film as a contraceptive. [Letter to the Editor] British Medical Journal 4(5939) : 291 . November 2. 1974. 149. SNOWDEN. R. Social and personal factors involved in the use-effectiveness of the IUD. In : Goldsmith. A. and Snowden. R. eds. Proceedings of the Family Planning Research Conference. Exeter. England. September 27-28. 1971 . Amsterdam. Excerpta Medica. 1972. (Internationa l Congress Series No. 260) p. 74 -81 . 150. SOBRERO. A. J . Evaluation of a new contraceptive. Fertility and Sterility 11(5): 518-524. 1960. 151 . SOBRERO. A. J . Personal communication. October 6.1974 . 152. SOBRERO. A. J . Vaginal chemical products . In: Calderone. M . S . ed. Manual of family planning and contracept ive practice. 2nd ed. Baltimore. Williams & Wilkins Company. 1970. p. 275282 . 153. SPARLING. P. F. Antibiotic resistance in Neisseria gonorrhea . Medical Cl1 inics of North America 56(5) : 1133-1144. 154. SPARLING. P. F. Penicillin. In : Epidemic venerea l disease. Proceedings of the Second International Venereal Disease Symposium. St Louis. Missouri. 1972 . New York. Pfizer. Inc . 1973. p. 58-63 . 155. STROMME. W . B. and ROTHNEM. M. S. Clinical experience w ith a new gel-alone method of contraception. Annals of the New York Academy of Sciences 54: 831-844. 1952. 156. STRYKER. J . M . SPARBER . S. B . and GOLDBERG. A. M. Subtle consequences of methylmercury exposure: behavioral deviations in offspring of treated mothers . Science 177: 621-623. August 18. 1972. 157. SWYER. G.1. M . Collection and evaluation of data on contraception . International Journal of Fertility 13(4): 366-372 . October-December 1968. 158. THOMAS, H. H. Vaginal contraception-a necessity. Pacific Medicine and Surgery 73 : 74-78. February 1965. 159. TIETZE, C. The clinical effectiveness of contraceptive meth ods. American Journal of Obstetrics and Gynecology 78(3): 650656. September 1959.

160. TIETZE. C. and LEWIT, S. Comparison of three contraceptive methods : diaphragm with jelly or cream. vaginal foam. and jelly/ cream alone. Journal of Sex Research 3(4): 295-311 . November 1967. 161 . TIETZE , C. Relative effectiveness. In: Calderone, M . S., ed. Manual of family planning and contraceptive practice . 2nd ed. Baltimore, Williams & Wilkins Company, 1970. p. 268-274. 162. TIETZE, C. PAL D. N. TAYLOR, C. E. and GAMBLE. C. J . A family planning service in rural Puerto Rico. American Journal of Obstetrics and Gynecology 81 : 174-182. January 1961 . 163. TYLER. E. T. Clinical test of the cream-alone method. In : Best. W . and Jaffe, F. S., eds. Simple methods of contraception. New York, Planned Parenthood Federation of America, 1958. p. 23-26 . 164. TYLER. E. T. Current deve lopments in systemic contraception . Pacific Medicine and Surgery 73 : 79-85. February 1965. 165. TYLER. E. T. Vaginal chemical methods. In: Calderone, M . S. ed. Manual of family planning and contraceptive practice . 2nd ed . Baltimore. Williams & Wilkins Company. 1970. p. 428432 . 166. U.S . DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE. CENTER FOR DISEASE CONTROL. IUD safety: report of a nationwide physician survey. Morbidity and Mortality 23 (26): 1-2. July 5. 1974. 167. U.S. FOOD AND DRUG ADMINISTRATION. Over-thecounter contraceptives and other vaginal drug products . Federal Register 38(94): 12840-12842. May 16, 1974. 168. U.S. FOOD AND DRUG ADMINISTRATION. Procedures for classification of over-the-counter drugs. Federal Register 37(92): 9464-9475 . May 11. 1972 . 169 . U.S. FOOD AND DRUG ADMINISTRATION . Summary mi nutes of the meetings of the Panel on OTC Contraceptives and Other Vaginal Drug Products from August 2. 1973, to September 21, 1974. 170. WARNER . M . P. To lerance studies with a new contraceptive gel. Journal of the American Medical Womens Federation 14: 412 -414. May 1959. 171 . WESSELS. M. Vag inal insufflation of a powder as a method of contraception . Human Fertility 6(5): 152-153. October 1941 . 172. WESTINGHOUSE POPULATION CENTER . Distribution of contraceptives in the commercial sector of selected developing countries . Summary report . Columbia, Md ., Westinghouse Popula tion Center. April 1974. 135 p. 173. WESTINGHOUSE POPULATION CENTER. Survey of patterns of contraceptive distribution in Pakistan. 1973 . Columbia, Md . Westinghouse Population Center, 1973 . 68 p. 174. WHITEHILL. J . L. and WETZEL. P. The acceptability and effectiveness of foam powder. Human Fertility 6(5): 151-153. October 1941 . 175. WILLCOX, R. R. A world look at venereal diseases. Medical Clinics of North America 56(5) : 1057-1061. 1972. 176. WILSON. J . Birth defects and the environment. New York, Academic Press, 1973. 305 p. 177. WISHIK. S. M. Indexes for measurement of amount of contraceptive practice. Paper presented at meeting of expert group on assessment of acceptance and use-effectiveness of family planning methods. United Nations Economic Commission for Asia and the Far East. Bangkok. Thailand. June 11-21. 1968. 31 p. 178. WOLF, L.. OLSON, H. J . and TYLER. E. T. Observations on the clinical use of cream -alone and gel-alone methods of contraception . Obstetrics and Gynecology 10(3): 316-321. September 1957. 179. WULFF, G. and JONAS. H. S. Conception control : a clinical evaluation of the Preceptin -Gel method . American Journal of Obstetrics and Gynecology 72(3): 549-556. September 1956. 180. ZUSPAN, F. P. BIBBO, M . GARDNER, H. L.. HESSELTINE. H. C., KEETIEL, W . C. LANG. W. R., and WElD. G. L. Management of patients with vaginal infections : an invitational symposium. Journal of Reproductive Medicine 9(1): 1-16. July 1972.

GWU -SCD -75-01 P H-55

Publications of the Population Information Program Department of Medical and Public Affairs The George Washington University Medical Center 2001 S Street. N. W . Washington. D. C. 20009 U. S. A.

ORAL CONTRACEPTIVES Series A A-l, Oral Contraceptives-Fifty Million Users INTRAUTERINE DEVICES Series B B-1, Copper IUDs-Performance to Date STERILIZATION Series C Female C-l, C-2, C-3, C-4 , C-5, Laparoscopic Sterilization- A New Techn ique Laparoscopic Sterlization II; What Are The Problems? Colpotomy-The Vaginal Approach Laparoscopic Sterilization with Clips Female Sterilizat ion by Mini-Laparotomy

Series D Male D - l , Vasectomy-Old and New Techniques D-2. Vasectomy-What Are The Problems? LAW AND POLICY Series E E- l, Eighteen Months of Legal Change E-2 , World Plan of Action and Hea l th Strategy Approved PREGNANCY TERMINATION Series F F-l, F-2 , F-3. F-4 , Five Largest Countries Allow Legal Abortion on Broad Grounds M enstrual Regulation- What Is It? Uterine Aspiration Techniques Menstrual Regulation Update

PROSTAGLANDINS Series G G - l , Clinical Use of PGs in Fertility Control G-2, Fertility Contro l Research Maps and Directory G-3, A Review : Modulation of Autonomic Transmission by Prostaglandins G-4 , "Prostaglandin Impac t" for Menstrual Induc tion G -5, Physiology and Pharmacology of PGs in Parturition BARRIER METHODS Series H H-l , Condom - An Old Method Meets a New Social Need H-2, The Modern Condom-A Quality Product for Effective Contraception H-3, Vaginal Contraceptives - Reappraisal PERIODIC ABSTINENCE Series I 1 - 1, Birth Control Without Contraceptives FAMILY PLANNING PROGRAMS Series J J -1, Family Planning Programs and Fertility Patte rns J -2, World Fertility Trends, 1974 J-3, Advanced Training in Fertility Management INDEX 1972-1973

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