Risks & benefits of combined oral contraceptive pills
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Transcript of Risks & benefits of combined oral contraceptive pills
Benha University Hospital, Egypt ABOUBAKR ELNASHAR
In the 1960s the pill' was launched.
Thanks to Pincus & Rock
The most important method
Over 100 million women using oral contraceptives
world-wide
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Combined Oral Contraception
How does it work?
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Types
A. High estrogen dose
1. Anovlar 1
{EE 50 ug + Norethindrone acetate 1000 ug}
2. Primovlar
{EE 50 ug + Norgestrel 1500 ug}
ABOUBAKR ELNASHAR
B. Low estrogen dose
It became popular during the 1970s in UK &
the 1980s in USA, but many of the original
studies were carried out before 1980.
a. Second generation:
Microvlar 30
{EE 30 ug + levonorgestrel 150 ug}
ABOUBAKR ELNASHAR
b. Third generation:
Gynera & Minulet
{EE 30 ug + Gestodene 75 ug}
Marvelon
{EE 30 ug + Desogestrel 150 ug}
Cilest
{EE 35 ug + Norgestimate 250 ug}
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C. Multiphasic
Triovlar & Trinordiol:
6 pills {EE 30 ug + levonorgestrel 50 ug}
5 pills {EE 40 ug + levonorgestrel 150 ug}
10 pills {EE 30 ug + levonorgestrel 125 ug}
ABOUBAKR ELNASHAR
Progestagen (ug) E.E (ug) Trade
name
Class
Norethisterone (1000)
Norgestrel (500)
50 Anovlar
Primovlar
High
Levonorgestrel (150)
Levonorgestrel (150)
Cyproterone acetate (2000)
Norgestimate (250)
Desogestrel (150)
Gestodene (75)
Drospirenone (3000)
35
30
Microvlar
Nordette
Dianette
Cilest
Marvelon
Gynera
Yasmine
Low
Norethisterone (1000) 20 Loestrine Lowest
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Steroid hormones
Estrogen
Mestranol
EE
Progestagen
Old: Norethisterone, Norethisterone
acetate, Ethindriol diacetate, Levonorgestrel
New: Norgestimate, Gestodene, Desogestrel.
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The current formulation
. decrease dose:
E: decrease 3 fold
P: decrease 10 fold
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. New P:
.Comparable with old P in regard to
BTB & amenorrhea.
.less androgenic,
.less adverse effects on lipid but
clinical significance is uncertain (Sperof,2002)
.Negligible impact on CHO
metabolism
ABOUBAKR ELNASHAR
Drug Interactions With Oral Contraceptive Medications Whose
Action May
Cause Contraceptive
Failure
Medications Which
May Increase
OC Activity
Medications Whose
Clearance Can
Be Decreased by OCs
Carbamazepine Acetaminophen Amitriptyline
Griseofulvin Erythromycin Caffeine
Oxcarbazepine fluoxetine cyclosporine
Phenobarbitol fluconazole Diazepam
Phenytoin Fluvoxamine Imipramine
Primidone Grapefruit juice Phenytoin
Rifampin Nefazadone Selegiline
Ritonavir Vitamin C Theophylline
St. John’s Wort
Topiramate ABOUBAKR ELNASHAR
ABOUBAKR ELNASHAR
Minor
N& V,
headache,
breast tenderness
25% discontinue
disappear immediately
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Unproven side effects
1. Melanoma
2. Hair loss
3. Cataract, intolerance to contact lenses
4. Agitation, Twitches
5. Joint pain
6. Respiratory infections, pneumonia
7. Mouth sores
8. Urinary tract problems
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Major
I. CVD,
II. Cancer
III. Liver disease
IV. Bowel disease
V. Reproduction
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I. CV risk
1. VTE
Relative risk of 3.2-4.1 of VTE compared with
non users.
The risk was unrelated to duration of use,
appeared within 4 months of starting the
COC & disappeared within 3 months of
stopping
(WHO, 1995).
ABOUBAKR ELNASHAR
The risk was higher with COCs containing third
generation progestagens than with those containing
second -generation progestagens. The relative risks
were 2.6, 5.3 & 5.7 for COCs containing
levonorgestrel, desogestrel & gestodene,
respectively. Sperof (1996):
.Thrombosis is an E dose related complication & P
has no impact on clotting parameters
.Observational study, biased, prescribed to women
at high risk, numbers are relatively small ( 20-30)
ABOUBAKR ELNASHAR
Some subsequent studies support these findings,
but others found no difference between COCs
containing second & third generation progestagens.
The absolute risk of women taking COCs containing
desogestrel or gestodene is very small & is much
less than the risk of VTE in pregnancy.
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VTE & factor V Leiden mutation.
Risk of VTE increases by 3to 4 x over the normal,
general incidence.
The minimal risk of venous thrombosis associated
with COCs does not justify the cost of routine
screening for deficiencies in coagulation system
ABOUBAKR ELNASHAR
If a patient has a family history of idiopathic
thromboembolism or develops a thromboembolic
complication while taking COCs
(Vandenbruck,1994): 1. Antithrombin III deficiency: Antithrombin III.
2. Protein C deficiency: Protein C
3. Factor V Leiden mutation: Activated protein C
ratio
4. Protein S deficiency: Protein S
5. Prothrombin gene mutation: Activated partial
throboplastin time
6. Antiphosolipid syndrome:Anticardiolipin Ab,
Lupus anticoagulant Ab
ABOUBAKR ELNASHAR
Other risk factors of CVD
Smoking, Increased age, hypertension, DM,
hyperlipaedemia.
No smoking: No increase risk of MI or stroke. No
increase death from CVD
< 15 cigarette/D: 3 fold increase in risk
>15 cigarette/D: 21 fold increase in risk.
OCP is safe , smoking is dangerous
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2. Myocardial infarction & stroke:
Low-dose COCs do not increase the risk of MI or
stroke in healthy nonsmokers, regardless of age (Sperof,2002).
No difference between 2nd & 3rd generation
products.
ABOUBAKR ELNASHAR
3. Hypertension
Low dose COCs cause a rise of about 1.0 mmHg in
diastolic pressure, but this is clinically unimportant (Shen et al, 1994).
The benefits of COCs outweigh the risks for a
women with mild hypertension ( Diastolic BP <100
mmHg) (Grade A)
ABOUBAKR ELNASHAR
II. Cancer risk 1. Hepatic adenoma: increase. Risk is related to duration & dose of pill. It may
regress with stop of pill. This is exceedingly rare in low dose
pills.
Hepatic carcinoma: no increase (WHO)
ABOUBAKR ELNASHAR
2. Cancer cervix:
Incidence increased from 0.9 per 1000 women-
years with 2 years to 2.2 per 1000 women-years
after 8 yr (Oxford Family planing Association Study).
COC increases the risk of cervical adenocarcinoma.
The relative risk was 4.4 for >12 yrs of use (Ursin et al,1994)
Pap smear is recommended
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3. Breast cancer:
Royal College study: No increase .
L.Angeles Study: increase: > 5 yr., <25 yr., < first full-term pregnancy.
In 1996, a reanalysis of 54 studies: During COCs use & for 10 years afterwards there
is a small increase. , the relative risk is 1.24 in
users & 1.07, 5-9 years after stopping.
The dose & type of hormone had little effect.
ABOUBAKR ELNASHAR
With the long latent period of breast cancer, this
study reflects the high dose era. There is evidence
that low dose COCs stimulate the breast less than
high -dose formulations
(Anderson et al,1989).
The effects of currently used COCs may be less than
those in this analysis & further studies are required.
ABOUBAKR ELNASHAR
4. Choriocarcinoma:
No increase
5. Malignant melanoma:
No increase
.
6. Prolactin-secreting adenoma:
No relationship. No reported cases of tumor growth.
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III. Liver disease
No association with gall bladder disease
(Oxford FPA study).
COCs may accelerate existing disease
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IV. Bowel disease
COCs increase the risk of both ulcerative coloitis
(relative risk 2.0)& Crohn s disease (relative risk 2.6)
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V. Effect on reproduction
1. Inadvertent use during pregnancy:
No increased risk of teraratogenesis
2. Reproduction after discontinuing COCs
A. Delay of fertility for 2 months on average.
B. No increase in spontaneous abortion.
3. Diminished quantity & quality of breast milk, but no
impairment of growth
4. Post pill amenorhea:
No evidence of cause & effect
ABOUBAKR ELNASHAR
ABOUBAKR ELNASHAR
.Largely ignored,
.Not dose dependent.
.They are attributed to suppression of ovulation.
.Women using low-dose COCs & women having
normal ovarian cycles are exposed to similar amounts
of E & P.
ABOUBAKR ELNASHAR
Benefits of Pill: risk reduction in %
(Drife,2000)
90%: Ectopic pregnancy
80%: Luteal ovarian cyst
50% :PID, Menorrhagia, Iron deficiency anaemia,
Follicular ovarian cysts
40%: Dysmenorrhea, Cancer ovary, Cancer
endometrium, Benign breast disease
20%: Solid ovarian tumors
15%: Fibroids (after 5 yr)
ABOUBAKR ELNASHAR
I. High efficacy
II. Protection against life threating diseases:
Ovarian carcinoma,
Endometrial carcinoma,
Colorectal cancer
PID,
Ectopic
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III. Decrease incidence of conditions that impair
quality of life:
menorhagia, dysmenorhea, functioning ovarian cyst,
benign breast disease
IV. Decrease incidence of:
Fibroid, endometriosis, toxic shock syndrome
V. Decrease incidence of :
Osteoporosis, rheumatic arthritis, thyroid disease,
peptic ulcer
ABOUBAKR ELNASHAR
I. Well documented evidence:
1. Protection against life threating diseases: Ovarian carcinoma, Endometrial carcinoma,, PID, Ectopic
2. Decrease incidence of conditions that impair
quality of life: menorhagia, dysmenorhea,, benign breast disease,
functional ovarian cysts, endometriosis, acne, hirsutism
II. Growing evidence Decrease incidence of: Colorectal cancer, Osteoporosis
III. Limited evidence Decrease incidence of: Fibroid,, toxic shock syndrome
, rheumatoid arthritis
ABOUBAKR ELNASHAR
I. High efficiency The most important health benefit of COCs is
effective prevention of pregnancy.
100% effective. Even where maternal mortality is
low, it is safer for a young woman to be on the pill
than to become pregnant
ABOUBAKR ELNASHAR
II. Protection against life threatening disease
1. Ovarian cancer: 40%
Use for as little as 6mo.
The longer duration, the greater is the protection.
Protection persists after stop.
ABOUBAKR ELNASHAR
2. Endometrial carcinoma:
Use for 1 yr.: decrease risk 50%.
The longer duration, the greater is the protection.
Protection persists after stop.
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Net effect of Ocs on the risk of cancer
(Schlesseman,1995)
For every 100,000 women from age 20-54 years
Non users Users for 8 years
Breast 2782 +151
Cervix 425 +125
Liver 20 +41
+ 277
Endometrium 438 -197
Ovary 369 -193
- 290
The net effect is negliable ABOUBAKR ELNASHAR
3. PID: 50%
It does protect against bacterial infection,
presumably because COCs thicken the cervical
mucous.
Decrease incidence & severity.
It protect against bacterial vaginosis & Trichomonas (Sperof,2002)
No effect on the risk of candidiasis or transmission
of viral agents such as herpes or HIV.
COCs increase incidence of cervical chlamydial
infection (cervical ectopy)
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4. Ectopic pregnancy:
90%reduction
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III. Decrease incidence of conditions that
impair quality of life?
1. Menorrhagia:50% decrease
2. Iron deficiency anemia.
3. Primary dysmenorhea
4. Premenstrual tension syndrome.
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5. Functioning ovarian cysts:
Follicular cyst (50%) & corpus luteum cyst (80%).
6. Benign breast disease (fibrocystic disease &
fibroadenoma):
After 2-4yr.
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IV. Decrease incidence of
1. Uterine fibroid:
Low dose OCP: no association (Oxford study).
OCP for 5yr.: decrease risk by 17%.
OCP for 10 yr.: decrease risk by 30% (Sperof,2002),
suggesting that the amount of estrogenic stimulation
provided by COC is less than during the normal
menstrual cycle.
2. Endometriosis
3. Toxic shock syndrome.
ABOUBAKR ELNASHAR
V. Decrease incidence of
1. Osteoporosis:
controversial. Recent study: prolonged use:
powerful protection.
2. Rheumatoid arthritis:
Decrease 50% (R. College study). Protection disappears when they are stopped.
Other studies: no effect.
ABOUBAKR ELNASHAR
3. Thyroid disease: (R College study).
Euthyroid swelling, thyrotoxicosis. Protection
disappears when pills discontinued
.
4. Peptic ulcer, earwax, acne.
ABOUBAKR ELNASHAR
Non contraceptive uses of COCs
Menorhagia
Mysmenorhea
Functional ovarian cysts
Endometriosis
Acne
Hirsutism
PCOS
Premenstrual tension syndrome
Menstrual migraine
Diet or exercise induced amenorrhea.
ABOUBAKR ELNASHAR
The WHO Guidelines (1996)
Category 1:
No risk. No restriction
Category 2:
Benefits > risks. Generally use the method
Category 3:
Risks > benefits. Relative contraindication
Category 4:
Unacceptable risk. Absolute contraindication.
ABOUBAKR ELNASHAR
Category 4 = Absolute contraindication
1. History of or recurrent ischemic heart disease
2. History of stroke
3. History of or current DVT or pulmonary embolism
4.Vascular disease
5. Complicated valvular heart disease (pulmonary
hypertension, atrial fibrillation, history of subacute
bacterial endocarditis).
ABOUBAKR ELNASHAR
6. Hypertension:
BP of 180/110 mmHg. BP of 160-179/100-109
mmHg warrants OC discontinuation in a current
user.
7. Smoking >20 cigarettes & age >35 yr
8. Major surgery with prolonged immobilization
9. Pregnancy
10. Breast feeding, <6 w postpartum
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11. Current breast cancer.
12. Benign or malignant liver tumors
13. Active viral hepatitis
14. Severe (decompensated) cirrhosis
15. Migraine headache with focal neurologic
symptoms.
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Category 3 = Relative contraindication
1. Hypertension
BP 160-179/100-109 mmHg
BP 140-159/90-99 plus other risk factors or no
monitoring
2. Smoking <20 cigarettes/d & age >35 yr
3. Diabetes with
retinopathy/nephropathy/neuropathy or with other
vascular disease or disease duration >20 yr
(Category 3/4 depending upon severity)
4. Genetic hyperlipidemias (category 2/3 depending
on type & severity)
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5. Postpartum <21 days
6. Breast feeding, 6 w to 6 mo (primarily breast
feeding)
7. Past breast cancer with no evidence for 5 yr
8. Unexplained suspicious vaginal bleeding (before
evaluation)
9. Mild liver cirrhosis
10. Long term use of enzyme inducing antibiotics or
anticonvulsants
11. History of OC-related cholestasis
12. Symptomatic biliary tract disease
ABOUBAKR ELNASHAR
Category 2 = Generally can be used
1. Superficial thrombophlebitis
2. Thalssemias
(COCs may induce metabolic disorders)
3. Undiagnosed breast mass.
4. Major surgery without prolonged immobilization
ABOUBAKR ELNASHAR
Category= Not a contraindications
1. Sickle cell disease:
androgenic P is beneficial. The risk of thrombosis is
theoretic (Sperof,2002) 2. Hypertension:well controlled patients
<35 & healthy (Sperof,2002)
3. Varicose veins.
4. > 35 yr.
5. Minor surgery.
6. Obesity
ABOUBAKR ELNASHAR
.
7. Benign ovarian tumors
8. Benign breast mass
9. Family history of breast cancer
10. History of cholicystitis, PET, gestational DM, ectopic
pregnancy, Trophoblastic disease.
11. Viral hepatitis carrier
12. Thyroid disease:
simple goiter, hyperthyroid, hypothyroid
ABOUBAKR ELNASHAR
.
13. Nulliparity
14. Tuberculosis.
15. Epilepsy:
COCs do not exacerbate epilepsy, but antiepileptic
drugs may decrease the effectiveness of COCs
no change or improvement.
16. Uterine fibroid:
low dose pills does not cause growth of fibroid &
bleeding decreases.
ABOUBAKR ELNASHAR
In healthy females: the non-
contraceptive benefits outweigh the
risks.
ABOUBAKR ELNASHAR
ABOUBAKR ELNASHAR