The Pill: 30 Years of Safety Concerns 
by Sharon Snider

When the birth control pill was introduced in 1960, it was a major medical
achievement that rewrote the future of women and family life. For the first 
time in history, it became possible for a woman to safely and effectively control
childbearing by taking a pill.

This year "the pill," as it is commonly referred to, is celebrating its 30th
anniversary. Since its introduction, it has been used by more than 60 
million women worldwide. It has proved to be, in the opinion of many, the 
most socially significant medical advance of the century. 

American women were quick to accept the pill. Within two years, 
approximately 1.2 million women were using it, within five years, 5 million,
and by 1973, about 10 million. In the early '80s, following reports of
possible harmful side effects, use of the pill dropped to 8.4 million.
Today, however, with safer, low-dose versions on the market, use is back up.
Approximately 10.7 million American women now use the pill. It is the most
popular method of non-surgical contraception. 

Concerns about side effects have
dogged the pill over the years. And rightly so. Doe the pill presented
society with problems unique in the history of medicine. As an FDA advisory 
committee on the pill noted in the mid '60s, never would so many people take
such a potent drug voluntarily over such a long period for a reason other 
than to cure disease. 

"Since probably no substance, even common table salt, and certainly no
effective drug, can be taken over a long period of time without some risk," 
the advisory committee warned, the pill's potential side effects "must be 
recognized and kept under continual surveillance."

Oral contraceptives have been kept under surveillance for 30 years. In fact,
over the years, more studies have been done on the pill to look for serious 
side effects than have been done on any other medicine in history, according
to FDA. 

Fears about blood clots, heart attack, and stroke, which spurred exhaustive 
research on oral contraceptives in the '60s and '70s, have largely been laid
to rest by the safer, low-dose birth control pills on the market today. 
Current research suggests that healthy, non-smoking women have little if any
greater risk of these serious health problems than do women who do not use
the pill. 

Questions about the pill's association with cancer, however, remain. Some 
widely reported recent studies support the hypothesis that in certain groups
of women the risk of breast cancer increases with oral contraceptive use. A 
larger number of studies, however, found no significant increased risk. Nor 
is it definitely known yet whether or not the pill causes cervical cancer in
some groups of women. So far, a cause-and-effect relationship has not been
established.

But the pill has been found to help prevent two major types of
cancer--cancer of the ovaries and cancer of the endometrium (the lining of
the uterus).

Last December, an FDA advisory committee, reviewing the relative risks and
benefits of today's birth control pills, recommended that the upper age 
limit of 40 then in use for the pill be lifted for healthy, non-smoking 
women, thereby making this popular, effective means of contraception
available until menopause.

How the Pill Was Developed

It was 1950 when Dr. Gregory Pincus, an American biologist, was invited by
the Planned Parenthood Federation of America to develop an ideal
contraceptive--one that Planned Parenthood stipulated would be "harmless, 
entirely reliable, simple, practical, universally applicable and
aesthetically satisfactory to both husband and wife." 

Planned Parenthood donated $2,100 to the project. Another $20,000 to $30,000
had to be raised from government and private sources before research could
get under way.

Within a few years, an oral contraceptive was being clinically tested in
6,000 women in Puerto Rico and Haiti. In 1960, the first commercially 
produced birth control pill, Enovid-10, was marketed in the United States.

What Dr. Pincus and colleagues developed was a pill containing estrogen and 
progestin, synthetic hormones similar to those produced naturally in a
woman's body. The pill works primarily by suppressing the release of eggs 
from a woman's ovaries. 

The first oral contraceptives contained 100 micrograms (mcg) to 175 mcg of
estrogen and as much as 10 milligrams (mg) of progestin--significantly
higher levels of both hormones than in today's pill. They were 99 percent 
effective if taken as directed--the highest rate of contraceptive protection
available except sterilization. 

Concerns About Side Effects 

Although the pill was widely welcomed, it wasn't long before concerns were
raised about possible serious side effects. 

As early as 1961, suspicions arose in the United States and England that the
pill might predispose some women to heart attack and stroke. Evidence of
blood clotting had been reported in a few women taking the pill. Blood clots
can cause life-threatening heart attacks and strokes. 

In 1965, spurred by further reports, FDA awarded a research contract to a 
scientist at the Johns Hopkins School of Hygiene and Public Health to 
investigate exactly how widespread the problem was. 

At the same time, the agency established its first advisory committee--the
Advisory Committee on Obstetrics and Gynecology--to review contraceptive
products and to find out what effect, if any, oral contraceptives had on
blood clotting. The committee was also directed to review existing data for 
clues to the pill's potential to cause cancer of the breast, cervix and 
endometrium.

In 1966, the advisory committee reported that it found "no adequate 
scientific data, at this time, to prove the pill unsafe for human use." 

FDA Calls for Study 

However, FDA expressed reservations about the pill's "very infrequent but 
serious" side effects and the lack of scientific data to adequately assess
those side effects. It called for a large, case-control study of the
relationship between oral contraceptives and blood clotting.

As for cancer, the advisory committee concluded the pill hadn't been in use 
long enough to draw valid conclusions about its carcinogenic effects. For 
example, it would be at least another 10 years before the risk of uterine 
cancer could be accurately assessed.

The advisory committee's findings on the possible relationship between the
pill and blood-clotting and cancer were supported by a World Health 
Organization scientific group, which independently had reached the same 
conclusions.

However, by 1968, amid further reports of blood clots and new evidence from 
British studies showing an increased incidence of blood clots among women 
taking the pill, FDA added information about the results of those studies to
the product labeling for oral contraceptives. A year later, the agency again
revised the labeling, this time to include the results of U.S. studies that 
supported the British findings. 

By 1969, ongoing research had revealed that the risks of blood clots, heart 
attack, and stroke were directly related to the amount of estrogen in the 
various versions of the pill. Research also showed that the same rate of
contraceptive effectiveness could be maintained with only 50 mcg of 
estrogen. By that time, 7.5 million women were using oral contraceptives--up
from 408,000 women in 1961. 

As the 1970s began, FDA issued a bulletin to doctors about the danger of
blood clots. It advised using the lowest effective dose of estrogen possible
when prescribing oral contraceptives. The agency also revised the product 
labeling once again to include the "lowest effective dose" recommendation.
And, for the first time, FDA required that information for patients about 
the drug's risks be included in every package of oral contraceptives. 

'Mini-Pill' Introduced

In the early 1970s, the "mini-pill," an oral contraceptive containing only
progestin, was introduced. Unlike the estrogen-progestin pill, which works
primarily by suppressing ovulation, the mini-pill works by creating changes 
in the cervix and uterus that make it difficult for sperm to unite with an
egg. Since mini-pills contain no estrogen, they pose few of the risks 
associated with the combination pill. However, mini-pills have two
drawbacks: They cause irregular bleeding in some women, and they have proven
to be less effective in preventing pregnancy. As a result, their use has
been limited. 

By the mid '70s, most women who used oral contraceptives were taking pills
that contained 50 mcg or less of estrogen--a considerable decrease over the 
100 to 150 mcg of the '60s. The amount of progestin in the pills had also 
decreased over the years from the original 10 mg to between 2.5 mg and 0.15 
mg. 

Between 1973 and 1974, FDA approved several low-dose pills containing as
little as 20 to 35 mcg of estrogen. Most pills prescribed today contain 30
to 35 mcg of estrogen and 0.5 mg to 1 mg progestin. 

In 1982, a new version of the pill, called the "biphasic" pill, was 
introduced. Two years later, three "triphasic" pills were introduced. These 
"multiphasic" oral contraceptives are low-dose pills in which the ratio of
progestin to estrogen changes during the 21 days the pill is taken. 

By 1986, use of high-dose estrogen pills had been drastically reduced--to 
3.4 percent of the oral contraceptive market. 

Nevertheless, some 400,000 women were still using high-dose estrogen pills. 
Most were between 30 and 39 years of age, the age group most at risk of 
serious side effects. 

High-Dose Estrogen Pills Withdrawn

In 1988, at FDA's urging, the three drug companies still manufacturing
high-dose estrogen oral contraceptives voluntarily withdrew from the market 
all remaining products containing over 50 mcg estrogen. 

The latest development in the 30-year saga of the pill was its approval last
year for use in healthy, non-smoking women over 40. The impact of this move,
in terms of the number of women who will choose to continue or start using
the pill after they turn 40, remains to be seen. But an estimated 1 million 
to 1.5 million women between 40 and 54, including the baby boomers, could be
affected. 

Today's Pill Safer

Today's oral contraceptives are considerably safer than the pill of the '60s
because they contain less estrogen and progestin. Over the years, the amount
of estrogen has been reduced to one-third or less of that in the first birth
control pills, and the progestin has been decreased to one-tenth or less. 

The risks of blood clots, heart attacks, and stroke have decreased
correspondingly for healthy, non-smoking women. There is a slightly 
increased risk of cardiovascular disease for women over 40 who use the pill,
but the benefits of contraception are considered to outweigh the risk in
most women, says Philip Corfman, M.D., of FDA's division of metabolism and
endocrine drug products.

Most side effects of the pill are not medically serious. The most common are
nausea, breakthrough bleeding (bleeding between menstrual periods), and mood
changes, including depression. Some women may also experience weight gain,
breast tenderness, and difficulty wearing contact lenses due to eye dryness.
These side effects, especially nausea, usually subside within the first 
three months of use.

Health Benefits 

In addition to its contraceptive effectiveness, the pill has proven to have 
significant health benefits. Studies show that the incidence of ovarian and 
endometrial cancers, benign cysts of the ovaries and breasts, and pelvic
inflammatory disease decreases with pill use. The pill also prevents heavy
and irregular menstrual periods, a common cause of anemia that leads to 
surgical procedures, including hysterectomy, in older women.

Whether these benefits will continue with the newer, low-dose pill remains
to be seen. The present benefits are associated with oral contraceptives
containing 50 mcg of estrogen. As yet, no scientific data are available on
the effects of those containing 30 to 35 mcg or less. 

Not Safe for All

As safe as today's pill is for most healthy, non-smoking women, it is still 
not safe for all women. The risk of serious illness and death increases 
significantly for certain groups: 
* Women who smoke--particularly those over 35 who are heavy smokers (more 
than 14 cigarettes a day)--have a significantly increased risk of heart 
attack and stroke. This risk increases with age. Women who use oral 
contraceptives are strongly advised not to smoke. 
* Women who are obese or have underlying health problems, such as diabetes, 
high blood pressure, or high cholesterol, also have a significantly 
increased risk of serious side effects from using the pill. 
* Women who have a history of blood clots, heart attack, stroke, liver
disease, or cancer of the breast or sex organs should not use oral
contraceptives. 

Women who become pregnant while on the pill should immediately discontinue
taking it because of a risk of birth defects in the child.

Uncertainties remain about whether the pill causes breast or cervical cancer
in some groups of women. Despite many studies over the years, there is still
insufficient evidence to definitely rule out these possibilities. 

While there are conflicting results among studies on breast cancer and the
pill, most investigations have found that women who have taken the pill have
no increased risk of developing breast cancer. However, the product labeling
on oral contraceptives recommends that women who use the pill and have a
strong family history of breast cancer or who have breast lumps or abnormal 
mammograms be closely monitored by their doctors. 

Some studies have found an increase in the incidence of cervical cancer in
women who use the pill, but this may not necessarily be related to the pill,
scientists say. 

One of the major problems of the studies to date, says Corfman, is that all 
the data reflect the effects of the higher-dose pills (those containing more
than 50 mcg of estrogen). No studies have been done on the low-dose pills,
and none are under way. The cancer-pill issue is very complicated and 
therefore difficult to study, and the research is expensive, he says. 

"We really need another breast cancer study on the low-dose pills," Corfman 
says. "We have the capability of finding out about breast cancer, but no one
is doing the research." 

Researchers may never find out whether the pill causes cancer of the cervix,
Corfman says, because the development of cervical cancer can be affected by 
numerous other factors, such as the age a woman begins having sex and the 
number of sexual partners. Corfman says he suspects, however, that such 
research would show that the risk of getting cervical cancer from the pill
is so small as to be outweighed by the benefits of contraception. 

Though some safety questions remain unsettled, for most healthy women the 
pill provides a safe, effective means of birth control with some possible 
beneficial health effects. 

Sharon Snider is a staff writer for FDA Consumer magazine who took the pill 
for nearly 15 years.