Premenstrual Syndrome

 
Premenstrual syndrome (PMS) affects 5-10% of reproductive-age women. Ovarian steroids play an
important role in symptomogenesis, since studies have shown that oophorectomy and gonadotropin-
releasing hormone (GnRH) agonists resolve symptoms. Whole blood serotonin (5-HT) has been
shown to be low during the luteal phase in patients with PMS.
Symptoms of Premenstrual Syndrome

Somatic
Mood
Appetite changes
Depression
Bloating
Hostility
Carbohydrate craving
Irritability
Fatigue
Mood swings
Headache
Negative world view
Hot flashes
Sadness
Insomnia
Behavioral
Mastalgia
Arguing
Cognitive
Decreased interest in anything
Confusion
Hyperphagia
Poor concentration

DSM-IV Criteria for Premenstrual Dysphoric Disorder

• Five or more symptoms

• At least one of the following four symptoms:
Markedly depressed mood, feelings of hopelessness, or self-deprecating thoughts
Marked anxiety, tension, feeling of being "keyed up" or "on edge"
Marked affective lability
Persistent and marked anger or irritability or increase in interpersonal conflicts
• Additional symptoms that may be used to fulfill the criteria:
Decreased interest in usual activities
Subjective sense of difficulty in concentrating
Lethargy, easy fatigability, or marked lack of energy
Marked change in appetite, overeating, or specific food cravings
Hypersomnia or insomnia
Subjective sense of being overwhelmed or out of control
• Other physical symptoms such as breast tenderness or swelling, headaches, joint or
muscle pain, a sensation of bloating, or weight gain
• Symptoms occurring during last week of luteal phase
• Symptoms are absent postmenstrually
• Disturbances that interfere withwork or school or with usual social activities and
relationships
• Disturbances that are not an exacerbation of symptoms of another disorder
Clinical evaluation of PMS
PMS involves an assortment of disabling physical and emotional symptoms that appear
during the luteal phase and resolve within the first week of the follicular phase. Symptoms of
PMS fall into four main categories: mood, somatic, cognitive, and behavioral.
No specific serum marker can be used to confirm the diagnosis. Premenstrual dysphoric
disorder is diagnosed when mood symptoms predominate symptoms of PMS.
The differential diagnosis includes hypothyroidism, anemia, perimenopause, drug and alcohol
abuse, and affective disorders. Common alternative diagnoses in patients complaining of PMS
include affective or personality disorder, menopausal symptoms, eating disorder, and alcohol
or other substance abuse. A medical condition such as diabetes or hypothyroidism, is the
 cause of the symptoms in 8.4%, and 10.6% have symptoms related to oral contraceptive (OC)
use.
Treatment of premenstrual syndrome
More than 70% of women with PMS will respond to therapy.
Symptomatic treatment
Fluid retention and bloating may be relieved by limiting salty foods. If 5 pounds or more
are gained during the luteal phase, diuretic therapy may be effective. Spironolactone
(Aldactone) is the drug of choice because of its potassium-sparing effects.The dose ranges
from 25-200 mg qd during the luteal phase.
Mastalgia. Support bras, decreased caffeine intake, nutritional supplements (evening
primrose oil or vitamin E, 400 IU), a low-fat diet, oral contraceptives, or non-steroidal anti-
inflammatory drugs (NSAIDs) are effective. Bromocriptine (Parlodel), 1.25-2.5 mg po each
day of the luteal phase may be effective.Side effects include dizziness and gastrointestinal
upset. Other therapies include danazol (Danocrine) 200 mg qd,and tamoxifen (Nolvadex), 10
mg qd for 3 months.
Sleep disturbances. Conservative measures include regulating sleep patterns, avoiding
stimulating events before bedtime, and progressive relaxation and biofeedback therapy.
Doxepin (Sinequan), 10-25 mg hs, also is effective.
Treatment for Premenstrual Syndrome

Serotonin-mediated
Fluoxetine ( Prozac) 5-20 mg qd
Sertraline ( Zoloft) 25-50 mg qd
Paroxetine ( Paxil) 5-20 mg qd
Fluvoxamine ( LuVox) 25-50 mg qd
Clomipramine ( Anafranil)25-100 mg qhs
Buspirone ( BuSpar) 25 mg qd in divided doses

GABA-mediated
Alprazolam ( Xanax) 0.25-0.50 mg tid

Mefenamic acid ( Ponstel) 250 mg tid with meals

Ovarian suppression
Ovulation suppression
Medroxyprogesterone ( Provera) 30 mg PO qd
Medroxyprogesterone acetate injection ( Depot-Provera) 150 mg IM q 3 months
Oral contraceptives
Total suppression
Leuprolide ( Lupron) 3.75 mg IM each month
Nafarelin ( Synarel) 400-800 pq intranasally qd
Danazol ( Danocrine) 200 mg qd-bid
Oophorectomy

Vitamin and mineral supplements

Calcium, 600 mg bid, may help decrease negative mood, fluid retention, and pain
Evening primrose oil, 500 mg tid
Magnesium may help decrease negative mood, fluid retention, and pain
Vitamin E, 400 IU qd

Other
Bromocriptine ( Parlodel), 1.25-2.5 mg po each day of the luteal phase for breast pain
Spirolactone ( Aldactone) 25-200 mg qd
Tamoxifen citrate ( Nolvadex),10 mg qd for 3 months for breast pain
Menstrual migraines often occur just before and during menses. Menstrual migraines are
treated with NSAIDs. Sumatriptan ( Imitrex), 50 mg po or 30-60 mg intramuscularly (IM);
 propranolol (Inderal), 80-240 mg in divided doses; or amitriptyline (Elavil), 25-100 mg, taken
before bedtime.
Syndromal treatment
Nonpharmacologic remedies include calcium (600 mg bid) and magnesium (360 mg qd),
possibly with the addition of vitamins.
SSRIs are appropriate for women with mood symptoms. Cyclical luteal phase administration
of fluoxetine (Prozac), 20 mg, or sertraline (Zoloft), 25-50 mg, has shown efficacy. Initially,
SSRIs should be restricted to the luteal phase of each cycle. If the patient's symptoms are not
ameliorated after a trial of 2-3 months, SSRIs can be given throughout the cycle.
Lifestyle Modifications That Help Relieve Premenstrual Syndrome

Moderate, regular, aerobic exercise (1-2 miles of brisk walking 4-5

times/week) may decrease depression and pain symptoms

Reducing or eliminating salt and alcohol, especially in the luteal phase;

eating small, frequent meas; increasing complex carbohydrates
Anxiolytics and antidepressants. Alprazolam (Xanax), 0.25-0.5 mg tid, given during the
luteal phase only may relieve anxiety. Dependence is possible, but restricting the agent to the
luteal period may help a subset of women.
Ovulation suppression
Less complex hormonal therapies include OCs and progestins. OCs (especially triphasic
formulations) may decrease the cyclical symptoms of PMS,although they may worsen
symptoms in a subset of patients.
Medroxyprogesterone acetate (Provera), 30 mg PO qd, may alleviate symptoms. Once the
symptoms resolve, drug therapy may be switched to medroxyprogesterone acetate injections
(Depot-Provera), 150 mg IM, every 3 months.
Ovarian suppression with GnRH agonists induces menopause. PMS symptoms will be
relieved, but patients experience menopausal side effects, including irritability, insomnia, hot
flashes, and vaginal dryness. To prevent osteoporosis, add-back therapy with estrogen and
progesterone is required.
Leuprolide (Lupron Depot), 3.75 mg IM each month, or nafarelin (Synarel), 400-800 pg qd
intranasally are effective. Conjugated equine estrogen, 0.625 mg, with medroxyprogesterone
acetate, 2.5 mg given daily will provide adequate estrogen for cardioprotection and shield the
bones from calcium breakdown.
Danazol, 200 mg qd-bid, is effective in decreasing the symptoms of PMS.Side effects include
hirsutism, acne, and weight gain.
Surgery. Oophorectomy is reserved for patients whose symptoms have resolved completely
for 4-6 monthswith GnRH agonists, who have completed child bearing, and who require more
than 5 years of long

Sexual Assault
Sexual assault is defined as any sexual act performed by one person on another without the person's
consent. Sexual assault includes genital, anal, or oral penetration by a part of the accused's body or by
an object. It may result from force, the threat of force, or the victim's inability to give consent. The
annual incidence of sexual assault is 200 per 100,000 persons, accounting for 6% of all violent crimes.
Approximately one in five women is sexually assaulted by the time she is 21 years of age.
Psychologic effects
A woman who is sexually assaulted loses control over her life during the period of the assault. Her
integrity and her life are threatened. She may experience intense anxiety, anger, or fear. After the
assault, a "rape-trauma" syndrome often occurs. The immediate response may last for hours or days
and is characterized by generalized pain, headache, chronic pelvic pain, eating and sleep disturbances,
vaginal symptoms, depression, anxiety, and mood swings.
The delayed phase is characterized by flashbacks, nightmares, and phobias.
 Clinical Care of the Sexual Assault Victim

Medical
Obtain informed consent from the patient
Obtain a gynecologic history
Assess and treat physical injuries
Obtain appropriate cultures and treat any existing infections
Provide prophylactic antibiotic therapy and offer immunizations
Provide therapy to prevent unwanted conception
Offer baseline serologic tests for hepatitis B virus, human
immunodeficiency virus (HIV), and syphilis
Provide counseling
Arrange for follow-up medical care and counseling

Legal
Provide accurate recording of events
Document injuries
Collect samples (pubic hair, fingernail scrapings, vaginal
secretions, saliva, blood-stained clothing)
Report to authorities as required
Assure chain of evidence
 
Medical evaluation
Informed consent must be obtained before the examination. Acute injuries should be stabilized. About
1% of injuries require hospitalization and major operative repair in, and 0.1% of injuries are fatal.
A history and physical examination should be performed. A chaperon should be present during the
history and physical examination to reassure the victim and provide support. The patient should be
asked to state in her own words what happened, identify her attacker if possible, and provide details of
the act(s) performed if possible.
Previous obstetric and gynecologic conditions should be sought, particularly infections, pregnancy,
use of contraception, and date of the last menstrual period. Preexisting pregnancy, risk for pregnancy,
and the possibility of preexisting infections should be assessed.
Physical examination of the entire body and photographs or drawings made of the injured areas
should be completed. Bruises, abrasions, and lacerations should be sought. Superficial or extensive
lacerations of the hymen and vagina, injury to the urethra, and occasionally rupture of the vaginal
vault into the abdominal cavity may be noted. Bite marks are common. If oral penetration has
occurred, injuries to the mouth and pharynx may be noted.
Pelvic examination should assess the status of the reproductive organs, collect samples from the
cervix and vagina, and test for Neisseria gonorrhoeae and Chlamydia trachomatis.
A Wood light should be used to find semen on the patient's body: dried semen will fluoresce. Sperm
and other Y-chromosome-bearing cells may be identified from materials collected from victims by
using fluorescence in situ hybridization with a DNA probe.
A serum sample should be obtained for baseline serology for syphilis, herpes simplex virus, hepatitis
B virus, and HIV.
Trichomonas is the most frequently acquired STD. The risk of acquiring human immunodeficiency
virus (HIV) is approximately < 1% during a single act of heterosexual intercourse, but the risk
depends on the population involved and the sexual acts performed. The risk of acquiring gonorrhea is
6-12%, and the risk of acquiring syphilis is 3%.
Hepatitis B virus is 20 times more infectious than HIV during sexual intercourse. Hepatitis B
immune globulin (0.06 mL of hepatitis B immune globulin per kilogram) should be administered
intramuscularly as soon as possible within 14 days of exposure. It is followed by the standard three-
dose immunization series with hepatitis B vaccine (0, 1, and 6 months), beginning at the time of
hepatitis B immune globulin administration.
Emergency contraception. If the patient is found to be at risk for pregnancy as a result of the assault,
emergency contraception should be offered. The risk of pregnancy after sexual assault is 2-4% in
victims not already using contraception. One dose of combination oral contraceptive tablets is given at
the time the victim is seen and an additional dose is given in 12 hours. Emergency contraception can
be effective up to 120 hours after unprotected coitus. Metoclopramide (Reglan), 20 mg with each dose
of hormone, is prescribed for nausea. A pregnancy test should be performed at the 2-week return visit
if conception is suspected.
Emergency Contraception Regimens

Trade Name Number of Pills Taken with Each Dose

Ovral 2

Lo-Ovral 4

Nordette 4

Levlen 4

Triphasil 4

Trilevlen 4

*Treatment consists of two doses taken 12 hours apart. Use of

metoclopramide (Reglan), 20 mg, before taking the contraception
will lessen the risk of nausea.
 
Screening and Treatment of Sexually Transmissible
Infections Following Sexual Assault

Initial Examination

Infection
• Testing for and gonorrhea and chlamydia from specimens from
any sites ofpenetration or attempted penetration
• Wet mount and culture or a vaginal swab specimen for
Trichomonas
• Serum sample for syphilis, herpes simplex virus, hepatitis B
virus, and HIV
Pregnancy Prevention
Prophylaxis
• Hepatitis B virus vaccination and hepatitis B immune globulin.
• Empiric recommended antimicrobial therapy for chlamydial,
gonococcal, and trichomonal infections and for bacterial
vaginosis:
Ceftriaxone, 125 mg intramuscularly in a single dose, plus
Metronidazole, 2 g orally in a single dose, plus
Doxycycline 100 mg orally two times a day for 7 days
Azithromycin ( Zithromax) is used if the patient is unlikely to
comply with the 7 day course of doxycycline; single dose of four
250 mg caps.
If the patient is penicillin-allergic, ciprofloxacin 500 mg PO or
ofloxacin 400 mg PO is substituted for ceftriaxone. If the patient
is pregnant, erythromycin 500 mg PO qid for 7 days is
 substituted for doxycycline.
HIV prophylaxis consists of zidovudine (AZT) 200 mg PO tid,
plus lamivudine (3TC) 150 mg PO bid for 4 weeks.

Follow-Up Examination (2 weeks)

• Cultures for N gonorrhoeae and C trachomatis (not needed if

prophylactic treatment has been provided)
• Wet mount and culture, if available, for T vaginalis
• Collection of serum sample for subsequent serologic analysis if
test results are positive

Follow-Up Examination (12 weeks)

Examination for infectious agents

• Serologic tests:
T pallidum
HIV (repeat test at 6 months)
Hepatitis B virus (not needed if hepatitis B virus vaccine was
given)
Emotional Care
The physician should discuss the injuries and the probability of infection or pregnancy with the
victim, and she should be allowed to express her anxieties.
Anxiolytic medication may be useful; loraze pam (Ati van) 1-5 mg PO tid prn anxiety.
The patient should be referred to personnel trained to handle rape-trauma victims within 1 week.
Follow-up Care
The patient is seen for medical follow-up in 2 weeks for documentation of healing of injuries.
Repeat testing includes syphilis, hepatitis B, and gonorrhea and chlamydia cultures. HIV serology
should be repeated in 3 months and 6 months.
A pregnancy test should be performed if conception is suspected. §

Sexually Transmissible Infections

Approximately 12 million patients are diagnosed with a sexually transmissible infection (STI)
annually in the United States. Sequella of STIs include infertility, chronic pelvic pain, ectopic
pregnancy, and other adverse pregnancy outcomes.
I. Clinical evaluation
Diagnosis and Treatment of Bacterial Sexually Transmissible Infections
Organism Diagnostic Methods Recommended Treatment Alternative
 
Direct fluorescent
Ofloxacin (Floxin)300 mg orally
antibody
2 times a day for 7 days or
Enzyme Doxycycline 100 mg orally 2
Erythromycin base 500 mg orally
Chlamydia immunoassay times a day for 7 days or
4 times a day for 7 days or
trachomatis Nucleic acid Azithromycin (Zithromax) 1 g
erythromycin ethylsuccinate 800
hybridization (DNA orally
mg orally 4 times a day for 7
probe)
days.
Cell culture
DNA amplification
Neisseria Gram stain of Ceftriaxone (Rocephin) 125 Spectinomycin 2 g IM or
gonorrhoeae endocervical smear mg IM or injectable cephalosporins given
Culture Cefixime 400 mg orally or single IM dose such as
DNA probe Ciprofloxacin (Cipro) 500 mg ceftizoxime 500 mg, cefotaxime
 orally or 500 mg, cefotetan 1 g IM, and
Ofloxacin (Floxin) 400 mg cefoxitin (Mefoxin) 2 g IM with
orally probenecid 1 g orally; or
plus quinolones given single oral dose
Doxycycline 100 mg 2 times a such as enoxacin 400 mg,
day for 7 days or azithromycin lomefloxacin 400 mg, or
1 g orally norfloxacin 800 mg
Primary and secondary syphilis Penicillin allergy in patients with
and early latent syphilis (<1 primary, secondary, or early
year duration): latent syphilis (<1 year of
benzathine penicillin G 2.4 duration): doxycycline 100 mg
Clinical appearance million units IM in a single orally 2 times a day for 2 weeks.
Dark-field dose. Penicillin allergy in patients with
microscopy Late latent syphilis or latent late latent syphilis or latent
Nontreponemal syphilis of unknown duration syphilis of unknown duration:
 
serologic test and late syphilis (gumma or doxycycline 100 mg orally 2
Treponema
Rapid plasma reagin cardiovascular syphilis, but not times a day for 4 weeks. (If
pallidum
VDRL neurosyphilis): Benzathine duration of infection is known to
Treponemal test penicillin G 7.2 million units be <1 year, administer for 2
MHA-TP total, as 3 doses of 2.4 million weeks.)
FTA-ABS units IM, at 1-week intervals. Neurosyphilis: procaine
Neurosyphilis: Aqueous penicillin 2.4 million units IM
penicillin G, 18-24 million daily, plus probenecid 500 mg
units a day, as 3-4 million units orally 4 times a day, both for 10-
IV q4h for 10-14 days. 14 days
 
Diagnosis and Treatment of Viral Sexually Transmissible Infections
Organism Diagnostic Methods Recommended Treatment Regimens
First clinical episode: Acyclovir 400 mg orally 5 times a
day for 7-10 days, or famciclovir 250 mg orally 3 times a
day for 7-10 days, or valacyclovir 1 g orally 2 times a day
for 7-10 days.
Recurrent episodes: acyclovir 400 mg orally 3 times a day
Clinical appearance
Herpes simplex for 5 days, or 800 mg orally 2 times a day for 5 days or
(confirm with culture)
virus famciclovir 125 mg orally 2 times a day for 5 days, or
Cell culture
valacyclovir 500 mg orally 2 times a day for 5 days
Daily suppressive therapy: acyclovir 400 mg orally 2 times
a day, or famciclovir 250 mg orally 2 times a day, or
valacyclovir 250 mg orally 2 times a day, 500 mg orally 1
time a day, 1,000 mg orally 1 time a day
Human papilloma Clinical appearance of External warts: Patient may apply podofilox 0.5% solution
virus condyloma papules or gel 2 times a day for 3 days, followed by 4 days of no
Cytology therapy, for a total of up to 4 cycles, or imiquimod 5%
cream at bedtime 3 times a week for up to 16 weeks.
Treatment area should be washed with mild soap and water
6- 10 hours after application. Provider may administer
cryotherapy with liquid nitrogen or cryoprobe, repeat
every1-2 weeks; or podophyllin resin 10-25% in compound
tincture of benzoin in small amounts to each wart, repeat
weekly if necessary; or TCA or bichloracetic acid 80-90%
in small amounts to each wart, repeat weekly if necessary;
or surgical removal.
 Vaginal warts: cryotherapy with liquid nitrogen, or TCA
80-90%, or podophyllin 10-25%
Enzyme immunoassay
Western blot (for
confirmation of
Human immuno
enzyme Antiretroviral agents
deficiency virus
immunoassay)
Polymerase chain
reaction
Centers for Disease Control and Prevention. 2005 Guidelines for the treatment of sexually transmitted
diseases. MMWR 2005;47(RR-1)
 
 
Treatment of Pelvic Inflammatory Disease

Regimen Inpatient Outpatient

Cefotetan (Cefotan) 2 g intravenously every

Ofloxacin (Floxin) 400 mg orally twice a
12 hours; or cefoxitin (Mefoxin) 2 g
day for 14 days
A intravenously every 6 hours plus
plus metronidazole 500 mg orally twice a
doxycycline 100 mg intravenously or orally
day for 14 days.
every 12 hours.

Ceftriaxone (Rocephin) 250 mg

intramuscularly once; or cefoxitin 2 g
Clindamycin 900 mg intravenously every 8
intramuscularly plus probenecid 1 g
hours plus gentamicin loading dose
orally; or other parenteral third-
B intravenously or intramuscularly (2 mg/kg
generation cephalosporin (eg,
of body weight), followed by a maintenance
ceftizoxime, cefotaxime) plus
dose (1.5 mg/kg) every 8 hours.
doxycycline 100 mg orally twice a day
for 14 days.
 
II. Chlamydia Trachomatis
A. Chlamydia trachomatis infection is the most prevalent STI in the United States. About 4 million
cases occur annually. The incidence of infection is two to three times higher among African-American
women compared with white women. Chlamydial infections are most common in women age 15-
19years is recorded.
B. Routine screening of asymptomatic, sexually active adolescent females undergoing pelvic
examination is recommended. Annual screening should be done for women age 20-24 years who are
either inconsistent users of barrier contraceptives or who acquired a new sex partner or had more than
one sexual partner in the past 3 months. Women age 25 years and older who meet both criteria should
be screened annually. Women with mucopurulent cervicitis, women undergoing induced abortion,
women attending STI clinics, and women in detention facilities also should be screened.
III. Gonorrhea
A. Gonorrhea has an incidence of 800,000 cases annually. Rates of gonorrhea are highest in the
southeastern United States and in large cities. Rates are higher among African Americans than among
whites or other racial groups.
B. Routine screening for gonorrhea is recommended among women at high risk of infection,
including prostitutes, women with a history of repeated episodes of gonorrhea, women under age 25
years with two or more sex partners in the past year, and women with mucopurulent cervicitis.
Women with gonorrhea also should be tested for chlamydia and offered testing for HIV infection.
IV. Syphilis
A. Over the past five decades, syphilis has decreased dramatically in the United States, with a current
incidence of 100,000 cases annually. The rates are highest in the South, among African Americans,
and among those in the 20- to 24-year-old age group.
B. Prostitutes, persons who exchange sex for money or drugs, persons with other STIs, and sexual
contacts of persons with active syphilis should be screened.
V. Herpes simplex virus and human papillomavirus
A. An estimated 200,000-500,000 new cases of herpes simplex occur annually in the United States,
and 25-31 million individuals are infected with the virus. New infections are most common in
adolescents and young adults. Routine screening for genital herpes simplex in asymptomatic patients
is not recommended.
B. About 500,000 to 1 million new cases of human papillomavirus infection occur annually, and an
estimated 24 million Americans are infected. About 30% of young, sexually active individuals are
infected. Routine screening is not indicated.
VI. Human immunodeficiency virus
A. More than 513,000 cases of AIDS have been reported in the United States, and more than 62% of
these individuals have died. Women account for 19% of adult and adolescent AIDS cases. Eighty-five
percent of cases in adult women are among those aged 15-44 years old. Thirty-eight percent of
women were exposed through heterosexual contact.
B. Risk factors for HIV should be assessed in all patients by obtaining a sexual history and
information about drug use. Women at high risk of HIV infection should be offered testing. Women at
risk for HIV infection include past or present intravenous drug users; those seeking treatment for an
STI infection; those exchanging sex for drugs or money or whose sexual partners do; those whose
past or present partners were HIV infected, bisexual, or injection drug users; and persons with a
history of transfusion between 1978 and 1985.
VII. Pelvic inflammatory disease
A. About 1 million cases of PID occur in the United States annually. Risk factors for PID include
young age, low socioeconomic status, unmarried status, residence in an urban area, douching, and
smoking. Pelvic inflammatory disease is a polymicrobial infection, but in 65-70% of cases either C
trachomatis, N gonorrhoeae, or both are isolated.
B. N gonorrhoeae is usually a symptomatic infection. PID attributable to C trachomatis frequently
may be asymptomatic or associated with atypical symptoms such as intermenstrual bleeding or
vaginal discharge.
Criteria for Hospitalization of Pelvic Inflammatory Disease

$ The diagnosis is uncertain and surgical emergencies such as appendicitis and ectopic pregnancy
cannot be excluded
$ Pelvic abscess is suspected
$ The patient is pregnant
$ The patient is an adolescent (among adolescents, compliance with therapy is unpredictable)
The patient has human immunodeficiency virus infection
$ Severe illness or nausea and vomiting preclude outpatient management
$ The patient is unable to follow or tolerate an outpatient regimen
$ The patient has failed to respond clinically to oral antimicrobial therapy
$ Clinical follow-up within 72 hours of starting antibiotic treatment cannot be arranged.
'

Assisted Reproductive Technologies

Assisted reproductive technologies consist of procedures pertaining to the handling of oocytes and
embryos outside of the body, with gametes or concepti replaced into the body to establish pregnancy.
The most commonly used procedure is in vitro fertilization (IVF), which involves extraction of
oocytes, fertilization in the laboratory, and transfer of embryos through the cervix into the uterine
cavity.
In Vitro Fertilization–Embryo Transfer
Infertility due to abnormal fallopian tubes or endometriosis, idiopathic infertility, male infertility, and
immunologic infertility all respond well to IVF. Women who have failed to conceive with donor
insemination or ovulation induction are also excellent candidates. Rough guidelines as to when ART
may be considered are after 2 years of unexplained infertility, 1 year after treatment of a particular
defect, or after at least 1 year of donor insemination or ovulation induction. These may be modified,
depending on factors such as age, presence of severe defects, or multiple infertility factors.
Tests
Levels of FSH and estradiol can be used to identify women with abnormal ovarian function and a
reduced prognosis. When the FSH level exceeds 25 mIU/mL on day 3 of menses, successful birth is
rarely achieved with IVF When the day 3 estradiol level exceeds 75 pg/mL, the prognosis
is similarly low, although this finding has less significance in younger patients. Age alone predicts
prognosis, with successful birth occurring in about one third as many women more than 40 years of
age as those less than 40 years of age. Testing for chlamydia should be performed or empirical
treatment should be given because serologic evidence of infection has been associated with a reduced
birth rate and increased fetal loss.
Many programs test the fertilizing capacity of sperm using zona-free hamster eggs. Some males may
fail to fertilize with routine methods of sperm preparation, whereas alternative methods may enhance
sperm penetration. Routine use of sperm enhancement (eg, with Test-Yolk buffer) also may be
considered. Testing for antisperm antibodies is essential if the patient's own serum is to be used in the
culture medium, but it is also helpful to identify very high levels of antisperm antibodies in one or
both partners (as outlined earlier in this section), allowing the use of a higher-than-usual number of
sperm for insemination. The uterine cavity should be assessed with hysterography, transvaginal
ultrasonography, or hysteroscopy to ensure the absence of any significant uterine defects. The
presence of a hydrosalpinx decreases the IVF pregnancy rate by about 50%, with a normal rate
achieved after salpingectomy. It is not clear whether simple tubal interruption is sufficient to
normalize the chance of pregnancy. Because of the adverse effect of a hydrosalpinx on implantation,
any patient undergoing surgery (such as laparoscopy) who has a hydro-salpinx should be offered the
option of salpingectomy. A complete semen analysis should be done close to the time of the cycle of
treatment; all attempts should be made to resolve pyospermia, which can reduce sperm function; and
varicocele should be treated. Finally, a rehearsal of the transfer has been shown to increase the rate of
pregnancy significantly.
Ovarian Stimulation and Monitoring
Most IVF cycles are conducted with ovarian stimulation because the pregnancy rate increases with the
number of embryos transferred. A meta-analysis of randomized trials has shown a twofold odds ratio
for pregnancy with administration of a combination of an GnRH agonist and human menopausal
gonadotropins compared with other stimulation regimens. This method is used by almost all IVF
programs and also reduces cancellations for poor responses and premature LH surges, yields more
extra embryos for cryopreservation, and gives patients and the program more flexibility in scheduling
by varying the duration of ovarian suppression before stimulation. It is also possible to retrieve the
single mature oocyte from the natural menstrual
cycle, although approximately three such cycles are necessary to achieve a cumulative pregnancy rate
comparable to that of one stimulated cycle. However, retrieving the oocyte from the natural menstrual
cycle avoids any risk of stimulation and multiple pregnancy.
Both transvaginal ultrasonography and serum estradiol are used to determine when hCG should be
injected to initiate resumption of meiosis. With the natural cycle, serum or urinary LH levels must be
monitored either to ensure that the LH surge has not begun or to time retrieval according to the onset
of the LH surge. The ultrasonographic appearance and thickness of the endometrium have been found
to be prognostic for successful pregnancy; a sonolucent superficial layer and a thickness of more than
8-9 mm are ideal.
Oocyte Retrieval
The follicle aspiration is scheduled for 34-36 hours after hCG injection. With administration of GnRH
agonist and human menopausal gonadotropin, this can be extended to as late as 38 hours with minimal
risk of ovulation. Prophylactic antibiotics are commonly given. Retrieval is almost always performed
by ultrasound-guided transvaginal aspiration, even if it is necessary to traverse the uterus when an
ovary is adherent to the uterine fundus. In most cases, intravenous sedation is sufficient for analgesia,
making it an outpatient or office-based procedure. Preparation of the vagina with povidone-iodine is a
wise precaution to prevent pelvic infection, but the povidone-iodine must be thoroughly removed
before the procedure.
Insemination
Usually, 50,000-500,000 sperm are added to each oocyte, depending on sperm parameters, after a
period of 2-8 hours of preincubation to allow further oocyte maturation. The oocytes are stripped of
their surrounding cells and examined 12-20 hours after insemination. Visualization of two pronuclei
confirms normal fertilization. Concepti with three or more pronuclei are discarded. Extra embryos are
most commonly cryopreserved at the two-pronuclei stage.
Embryo Culture and Quality Control
A variety of media has been used with success for embryo culture. Electrolyte concentrations are
often adjusted to simulate the levels in a normal human fallopian tube. Serum from the patient,
umbilical cord blood, or designated donors most often have been added to media to provide protein
and growth factors. Some preparations of serum albumin also have been used successfully. Bioassays
have been used for quality control of the media (eg, mouse embryos, human or hamster sperm) to
detect toxicity. Various methods are used to control the culture environment, such as heating blocks, a
layer of oil over the medium, or carbon dioxide and temperature-controlled mobile chambers that
keep temperature, pH, and osmolarity within narrow limits.
Embryo Transfer
Embryos are most often replaced 2 or 3 days after oocyte retrieval. Embryos are graded, and those
chosen for transfer are loaded in a minute volume of medium into a transfer catheter. The catheter tip
is advanced into the uterine fundus, and the embryos are expelled. The catheter is checked for retained
embryos, and the patient rests for a period before returning home.
Luteal-Phase Supplementation
With GnRH agonist and human menopausal gonadotropin cycles, it is necessary to support the luteal
phase with hCG or progesterone. The latter is probably as effective and carries less risk of ovarian
hyperstimulation. Progesterone supplementation is generally continued until 10 days to 2 weeks of
gestation.
Early Pregnancy
Pregnancy is diagnosed by rising levels of hCG. Clinical pregnancy is confirmed by the presence of a
gestational sac. It is inappropriate for a program to count biochemical pregnancies (rising hCG only)
in their "pregnancy" rate. Because about 5% of clinical pregnancies are ectopic, a careful transvaginal
ultrasonogram should be done at 4 and 6 weeks after transfer. Cornual pregnancies can occur and are
easily visualized. Cervical pregnancies also can occur. A tubal pregnancy usually can be detected, but
the patient with an intrauterine pregnancy should be cautioned not to ignore significant pain. The
likelihood of heterotopic pregnancy is increased. If a heterotopic (ectopic and intrauterine) pregnancy
is found, the ectopic gestation usually can be excised laparoscopically without disturbing the
intrauterine gestation. Elevated hCG levels with no sign of an intrauterine sac by 4 weeks from
transfer should raise suspicion of an ectopic pregnancy.
Complications
There has been a very low incidence of pelvic infection after follicle aspiration. This incidence can be
further minimized by using prophylactic antibiotics and preparing the vagina with povidone-iodine.
Ovarian hyperstimulation occurs in about 0.2% of stimulated cycles; it is more common in
anovulatory women. Multiple pregnancy occurs in approximately 33% of pregnancies. It is more
common in programs with higher success rates, in younger women, when more embryos are
transferred, and when the embryos are of superior quality. Tubal pregnancy occurs almost exclusively
in women with tubal disease and has the highest incidence in those who have had tubal surgery.
Cornual pregnancy primarily occurs when the tube was previously removed.
Cryopreserved Embryos
There is no known limit on duration of embryo storage. Women who are successful with the fresh
embryos are likely to be successful with frozen embryos from the same cycle. About two thirds of
embryos survive the freezing process, but results vary with each woman, just as there are some men
with high-quality sperm whose germ cells do not freeze well. The embryos can be transferred during a
natural cycle or a hormonally controlled cycle. It has not yet been confirmed whether the latter yields
superior pregnancy rates.
Pregnancy Outcome
There is a minor trend toward preterm labor in singleton pregnancies. The rate of spontaneous
abortion is slightly increased (from 10% to about 20%). The rate of congenital anomalies has not been
increased. In one report, the rate of abnormalities was lower after embryo freezing.
Micromanipulation of Oocytes and Embryos
Rapid progress in micromanipulation has resulted in dramatic improvements in success rates with
ART. In addition, the development of new techniques to treat specific abnormalities (eg, relative
azoospermia, genetic disorders) has been pioneered. These techniques involve microsurgical
procedures performed on oocytes and embryos before embryo transfer Micromanipulation allows
embryologists to mechanically assist fertilization, enhance embryo implantation, and screen embryos
for specific genetic disorders. By allowing fertilization to occur when it previously did not, this
technique enables couples who were previously not candidates for IVF to achieve pregnancy at rates
equivalent to those of other IVF candidates. It also improves pregnancy rates in selected patients by
enhancing embryonic implantation rates through creation of a hole in the zona pellucida.
Assisted Hatching
The zona pellucida was believed to be a potential hindrance to implantation. Theories suggest that
during the passage through the fallopian tube there is a thinning or shedding, or both, of the zona
pellucida. If this does not occur, morphologically normal embryos do not implant. Uterine embryo
transfer is believed to minimize, but not completely eliminate, the amount of time the embryo is
exposed to the tubal environment. It has been theorized that techniques that weaken the zona might
enhance implantation. Indeed, studies evaluating embryonic implantation after mechanical or
chemical weakening of the zona have demonstrated an improved implantation rate. The most popular
method of assisted hatching is use of an acidified Tyrode solution to create a hole in the zona by
dissolving the glycoprotein matrix. It is applied selectively to embryos that have increased zona
thickness and a higher percentage of fragmentation on day 3 after oocyte retrieval. It has been shown
to be beneficial in older women and in patients with previous IVF failure or higher day 3 basal FSH
levels. It is possibly detrimental in younger patients who have a thin zona pellucida. Partially
fragmented embryos and embryos with a thick zona pellucida are hatched. Not all embryos of a given
patient are hatched because not all are fragmented or have a thick zona pellucida. There have been
some reports of an increased incidence of monozygotic twinning after the assisted hatching technique,
but this requires further evaluation. There have been no reports of detrimental effects on the fetus or
children born from these techniques, but methodical long-term follow-up is lacking.
Microfertilization
Concern about the safety of these techniques exists despite very little evidence of problems among the
thousands of babies whose births have been possible because of them. Genetic studies of resulting
offspring have failed to reveal an increased incidence of abnormalities. However, the concern exists
that males with oligospermia may have a genetic condition and that these techniques serve to
propagate it. Indeed, a high incidence of microdeletions in the Y chromosomes of men requiring ICSI
to conceive has already been reported. It is probable that these men will have sons with a similar
problem. Additionally, men with congenital absence of the vas deferens have been found to carry one
or several of the identified cystic fibrosis gene mutations. The congenital absence of the vas deferens
is probably a milder form of cystic fibrosis caused by some of the more rare mutations identified in
cystic fibrosis patients. Clearly, a risk of transmitting cystic fibrosis to an offspring exists if the
female partner is a carder of the recessive allele. These concerns are an active area of clinical
investigation.
Preimplantation Genetic Diagnosis
The ability to exclude before the initiation of pregnancy those embryos obtained in vitro that have
diagnosed genetic deficiencies offers an attractive means to prevent in-heritable genetic disease. The
benefits include the elimination of the risks associated with chorionic villus sampling or
amniocentesis, as well as the necessity of terminating an established but affected pregnancy.
Removing a single cell from an early eight-cell embryo and rapidly testing it for a specific genetic
disease before embryo transfer does not decrease embryo viability, nor does it affect the offspring.
Multiple investigators have reported success in this area. However, widespread clinical experience is
required before the absolute safety of these techniques can be established.
The field of preimplantation genetic diagnosis is relatively new. The technique involves screening the
embryo for a Y chromosome by using the polymerase chain reaction on DNA obtained from a single
blastomere removed from eight-cell embryos. The sex of the embryo is determined to avoid the
transmission of X-linked disorders, such as hemophilia and Duchenne muscular dystrophy; in these
cases, unaffected female embryos are transferred. This technique was further refined by simultaneous
amplification of both X and Y chromosomal sequences from single blastomeres to improve accuracy
and protect against amplification failure and misdiagnosis.
Efforts to screen for aneuploidy (abnormal number of an individual chromosome) have been made.
These techniques use fluorescent in situ hybridization with chromosome-specific probes, allowing
determination of the number of copies of a particular chromosome and identification of trisomy and
monosomy as well as sex. The ability to screen for aneuploidy has been hampered by the lack of data
regarding mosaicism in the early embryo, but it has generated significant understanding regarding
IVF failure due to aging of oocytes. Much research on IVF failure has centered on the endometrium
as a cause for implantation failure. However, it is now clear that embryo genetics play a significant
role. Approximately 20% of morphologically normal embryos implant and produce a viable offspring.
Approximately 50% of embryos cultured in vitro have arrested development between postretrieval
day 1 and day 2. It is believed that polyploidy accounts for a large percentage of incidents of arrested
development. In addition, implantation failure, which increases with age, has been shown to be
reflected in higher rates of aneuploidy in embryos from older women. These findings shed new light
on the mechanisms for the age-related decline in fertility and support the notion of using donor egg
treatment in older patients failing traditional therapy.
Use of Donor Gametes
The fertilization rate is entirely normal with frozen donor sperm. The pregnancy rate with donated
oocytes is generally 1.5- to 2-fold higher than with routine IVF because donors are generally young or
fertile or both. Both known and anonymous oocyte donors are used. This has allowed women who
have failed multiple IVF attempts, who have abnormal ovarian function (elevated FSH, poor response
to stimulation), or who are advanced in age (even up to age 55) to have an excellent chance of
pregnancy. Other advantages of egg donation are that amniocentesis is not required (provided the
donor is young) and the rate of spontaneous abortion is low.
Choosing an In Vitro Fertilization Program
Success rates are generally reported as clinical pregnancies and deliveries per retrieval. These rates
are available through the American Society for Reproductive Medicine on an annual basis for
individual programs. For 1994, the average delivery rate per retrieval was 21.2%. Rates are separated
for women older than age 39 years and for couples with abnormal sperm count or motility (Table 10).
The women under age 40 and without any male factor are a group that can be compared across
programs. Individual rates vary dramatically, but many programs are consistently achieving more than
30% delivery per retrieval in women younger than age 40. Because the average of 24.5% is decreased
by many inferior and inexperienced centers, a good rule is that a center should achieve an above-
average rate (more than 20%) to warrant the confidence of a referral. At the same time, many factors
can influence these rates. With many programs reporting relatively small numbers of cases, rates will
vary widely based on chance alone. Ideally, rates should be based on at least 100-200 retrievals,
which may require accumulation of more than 1 year's results. Programs that are well known will
accumulate referrals of more difficult cases. As a general rule, one can adjust the rate by adding 5%
for such programs. Programs that transfer more embryos or hold more embryos until cleavage before
a choice is made for transfer will bias upward their fresh-embryo transfer results while compromising
their frozen-embryo results; programs at the other extreme, which freeze all extra embryos at the two-
pronuclei stage without picking the best for fresh transfer, will compromise their fresh-embryo results
and will have more pregnancies from cryopreservation. The former extreme, given that all other
aspects of the programs are similar, will have a higher overall delivery rate, but at the expense of
more multiple pregnancies.
The proper balance between the risks of multiple pregnancy versus the likelihood of achieving
pregnancy is controversial. In some countries, these decisions have been taken out of the programs'
hands because of the risks and high costs of multiple pregnancies, and laws or strict guidelines
limiting transfer to no more than three embryos have been instituted.
Another factor, which is very difficult to assess, is the selection of patients for IVF. As the duration of
infertility increases and routine infertility treatments become more extensive and effective, the
remaining patients going through IVF become more difficult to treat. In all, the best one can do is to
limit referrals to a well-known program with conscientious, well-trained individuals with at least a
20% delivery rate per retrieval and good results with embryo freezing.
Table 10. In vitro fertilization results reported to the American society for reproductive medicine in
1994 by 249 U.S. and Canadian assisted reproductive technologies programs according to age and
whether a male factor was present
Gamete Intrafallopian Transfer
Gamete intrafallopian transfer is the placement of sperm and eggs into the fallopian tube. This transfer
has generally been done by laparoscopy. The average delivery rate per retrieval for GIFT in 1994 was
28.4%, compared with 21.2% for IVF. Because IVF is less invasive, programs with IVF rates close to,
or exceeding, the national average for GIFT are likely to do relatively little GIFT, both by their
recommendation and by patient choice. As more uniformly high success rates are achieved with IVF,
GIFT may play a progressively smaller role in the future. Ga-mete intrafallopian transfer results for
1994 are shown in Table 11.
Women with significantly abnormal fallopian tubes should not have GIFT because in such women the
success rate is no higher than that with IVF and their rate of tubal pregnancy is increased. Couples
with significant male-fac-tor infertility also do less well with GIFT, and fertilization is better
documented with IVF. The rate of tubal pregnancy may be higher with GIFT, although it may be
decreasing as fewer women with tubal disease undergo GIFT (5% ectopic in 1988, 3.2% in 1994).
This rate still exceeds the rate in women with normal fallopian tubes who have IVF.
Gamete intrafallopian transfer has been performed in combination with IVF. In these cases, fewer
oocytes are placed into the fallopian tubes, leaving more for IVF; a transcervical transfer of embryos
is also performed. This allows better documentation of fertilization but somewhat compromises the
objective of the GIFT procedure.
Zygote or Tubal Embryo Transfer
The placement of fertilized oocytes (ZIFT) or cleaving embryos (tubal embryo transfer or TET) into
the fallopian tubes allows fertilization to be confirmed, while taking advantage of the tubal
environment for part of the early development of the embryo. The success rates for these two
procedures should, theoretically, be higher than that of IVF, but the rate was only modestly increased
over IVF in 1994 (29.1% for ZIFT and tubal embryo transfer versus 21.1% for IVF), and two
randomized studies in programs with good IVF success rates failed to find a difference in outcome
with the tubal procedures. Transfer efficiency may be a factor with ZIFT and tubal embryo transfer;
probably, a small transfer volume and accurate placement are critical. Whether the increased cost and
a second surgical procedure are worthwhile depends on each program's individual experience with
these procedures.
Attempts have been made over the last few years to cannulate the tubes transcervically to avoid the
need for laparoscopy and anesthesia to deposit gametes or embryos into the fallopian tubes. This
procedure has met with irregular and generally inferior results compared with standard GIFT or tubal
embryo transfer.
Ovarian Hyperstimulation With Intrauterine Insemination
The initial success achieved with IVF for treatment of tubal-factor infertility prompted broadening of
the indication for this technique to include infertility in which there was no significant anatomic
abnormality of the female reproductive tract. Later, GIFT proved to be a useful treatment for
subfertile couples. It is now apparent that elements common to IVF and GIFT can be used in a
simpler, less expensive but effective treatment termed superovulation with intrauterine insemination.
As with GIFT and IVF one of the most critical features for success of superovulation with intrauterine
insemination is the ability to stimulate the development of multiple ovarian follicles. Intrauterine
insemination during unstimulated cycles is not effective for most cases of subfertility. Further, when
superovulation with intrauterine insemination is used, the serum concentration of estradiol and
number of ovarian follicles correlate with cycle fecundity. Finally, as with ART, early follicular phase
serum FSH levels provide prognostic information regarding the success of superovulation with
intrauterine insemination.
A second feature that superovulation with intrauterine insemination shares with ART is the increased
number of sperm reaching the site of fertilization. Although some controversy remains regarding the
benefit of intrauterine insemination during ovarian stimulation, most of the reports indicate that the
cycle fecundity achieved with superovulation with intrauterine insemination is greater than that
obtained with superovulation alone.
Many providers of superovulation with intrauterine in-semination treatments are beguiled by the
simplicity of this technique and lapse into poor clinical and laboratory practices. Instead, as with
ART, physicians and laboratory directors should strive to maintain high standards of quality for
ovarian ultrasound examinations, serum hormone assays, media preparation, plasticware and
instrument toxicity assays, and insemination techniques.
Indications
Infertile couples who would benefit from treatment with superovulation with intrauterine insemination
have no significant anatomic abnormality of the adnexa or uterus, have ovaries responsive to
gonadotropin stimulation, and can reliably produce an ejaculate providing at least 500,000 motile
sperm after processing for intrauterine insemination. Consequently, superovulation with intrauterine
in-semination should not be recommended to couples with severe, bilateral distortion of the oviducts;
tubal occlusion; severe oligospermia; or ovaries unresponsive to gonadotropin stimulation due to age
of 40 years or more or due to basal elevation of serum FSH concentrations.
In past years, considerable effort and expense were invested to identify etiologic factors associated
with subfertility. Although demonstration of an abnormality is of considerable psychologic comfort to
some patients, specific treatment of these abnormalities has proved to be of little value in improving
pregnancy rates. More recently, the goal of infertility testing has been to define appropriate treatment
pathways, rather than to establish definitively the cause of the couple's subfertility.
Infertility evaluation for couples undergoing superovulation with intrauterine insemination should
include at least two semen analyses and hysterosalpingography or laparoscopy and hysteroscopy.
Additionally, in ovulatory women undergoing intrauterine insemination, a midluteal serum
progesterone assay or endometrial biopsy is required. Older women would benefit from the prognostic
information provided by early follicular serum FSH and estradiol assays. If the estimated number of
motile sperm recovered after processing for intrauterine insemination is less than 500,000 or if the
concentration, motility, and morphology parameters in the semen analysis are all abnormal, the couple
has a poor prognosis for success with superovulation with intrauterine insemination.
If infertility persists despite correction of significant factors and if superovulation with intrauterine
insemination is not contraindicated as defined above, this technique should be offered to subfertile
couples as an alternative to expectant management. Although the cycle fecundity for superovulation
with intrauterine insemination is less than that for ART, the direct costs of ART are much greater than
those of superovulation with intrauterine insemination and in excess of the proportional increase in
cycle fecundity. Due to diminishing cycle fecundity and increasing exposure to exogenous
gonadotropins with multiple cycles, couples should be advised to undertake no more than three to six
cycles of superovulation with intrauterine insemination before moving on to ART for further
treatment. The couples should be reassured that there is no apparent effect on success with ART after
failure to conceive with superovulation with intrauterine insemination.
Ovarian Stimulation
The goal of ovarian stimulation is to achieve high-quality development of multiple follicles. The most
frequently studied ovarian stimulation protocol incorporates exogenous gonadotropins, usually human
menopausal gonadotropins or urofollitropin. Adjuvant therapy with GnRH agonists, so important in
the prevention of suboptimal treatment cycles in ART, is not cost-effective for all women undergoing
superovulation with intrauterine insemination. Adjuvant GnRH agonists should be reserved for those
women who show evidence of premature luteinization, characterized by a rise in progesterone before
hCG administration, in prior cycles. The ovarian response to stimulation, monitored with serial
ultrasound examinations and assays of serum estradiol, is similar in successive cycles. Those women
who develop few follicles with low serum estradiol concentrations have a poor prognosis for success
in that cycle and should have the dosage adjusted upward in subsequent cycles. However,
requirements for extremely high doses of gonadotropins to achieve a good response are unlikely to
result in favorable pregnancy rates.
Semen Preparation and Insemination Techniques
The objectives of semen preparation for intrauterine in-semination are to eliminate the seminal plasma
while concentrating at least 500,000 motile sperm in a volume of less than 0.5 mL. Several
techniques, including serial standard centrifugation, Percoll density gradient centrifugation, and swim-
up preparation, have been developed to achieve these goals and vary in efficiency of motile sperm
recovery and cost. No one technique, however, has been shown to yield better cycle fecundity than the
other techniques.
The transcervical intrauterine placement of a highly concentrated solution of motile sperm is usually
performed 36-40 hours after the injection of hCG. Although the optimal timing of a single intrauterine
insemination has not been defined, the benefit of two inseminations per cycle remains controversial.
Neither is there any clear advantage of intraperitoneal insemination, tubal cannulation, or fallopian
tube sperm perfusion.
Success Rates
Interpretation of reported success rates with superovulation with intrauterine insemination is difficult
due to varying patient selection criteria; the paucity of prospective, randomized trials; poorly chosen
control groups; reporting bias; and the lack of a national registry. In reviewing the analyses of success
for superovulation with intrauterine insemination compared with pregnancy rates in an untreated
group of infertile couples, it is necessary to distinguish between cycle fecundity and cumulative
pregnancy rate, particularly over a long period of observation. There is no disagreement that the cycle
fecundity achieved with several cycles of superovulation with intrauterine insemination is greater than
the monthly fecundity rate in the untreated groups, but it is generally held that the cumulative
pregnancy rate after 3 years of observation is equal in both groups.
Properly designed studies comparing superovulation with intrauterine insemination with ART are
rare. Conclusions regarding the relative merits of each method of treatment have been sought through
meta-analysis of a few prospective, randomized studies and of nonrandomized studies or retrospective
cohort reviews. One such study indicated that the cycle fecundity achieved with one cycle of IVF or
ZIFT was equivalent to that achieved with two cycles of superovulation with intrauterine
insemination. Additionally, the success rate obtained with one cycle of GIFT was the same as that
obtained with three cycles of superovulation with intrauterine insemination.
Complications
The most frequent complication of superovulation with intrauterine insemination is multifetal
gestation, which occurs in 15-40% of clinical pregnancies. High-order multifetal gestation occurs in
5-7% of pregnancies. Attempts to increase the cycle fecundity through aggressive stimulation of
multiple-follicle development yield rates of multifetal gestation comparable to those seen with ART.
Although mildly symptomatic ovarian hyperstimulation syndrome is common in ovulatory women
undergoing superovulation with intrauterine insemination, severe ovarian hyperstimulation syndrome
is rare, occurring in less than 1% of normally ovulatory women. Cases of severe pelvic infection,
including pelvic abscess, have been reported after intrauterine insemination. Due to the low frequency
(<0.5%) of clinical pelvic infections, it is unlikely that any benefit will be demonstrated with
prophylactic antibiotics provided to the woman or added to the insemination medium. Approximately
4-8% of reported clinical pregnancies are ectopic, similar to rates of ectopic pregnancies in couples
receiving ART. Even higher rates (18%) have been noted when women with peritubal and periovarian
adhesions were treated with superovulation with intrauterine insemination.
Ovum Donation
The guidelines for oocyte gamete donation published by the American Society for Reproductive
Medicine in 1993 include premature menopause attributable to ovarian failure, surgical removal of the
ovaries, and gonadal dysgenesis. Other accepted indications include avoiding transmission of a
genetic defect and increasing the chance of establishing a pregnancy in women with poor oocyte
quality due to advanced maternal age, among other factors.
Patient Selection and Preparation of the Donor
The ideal donor should be 34 years of age or younger with proven fertility. The donor should also
have a general medical history taken and a physical examination performed, including gynecologic
examination, cervical cytology, and pelvic ultrasonography, to rule out underlying reproductive
system pathology. Infectious disease screening to rule out Chlamydia trachomatis, gonorrhea,
hepatitis B and hepatitis C, human immunodeficiency virus (HIV) infection, and syphilis is required.
Donors, whether they are anonymous or known, also must undergo a careful psychologic evaluation
and legal counseling to make them fully aware of the legal situation in their jurisdiction. They
essentially abdicate any and all rights over their gametes. Donors may be compensated for their time
and effort but may not be paid for their oocytes. Donors should be informed of the risks of
medications and the oocyte retrieval process, and this discussion should be documented. Medical
preparation of the patient for the procedure should include a standard controlled ovarian
hyperstimulation regimen in preparation for ART; initiation of therapy with a GnRH agonist to
institute pituitary down-regulation, followed by gonadotropin therapy, ultrasonography, and endocrine
monitoring of follicular development is required. Transvaginal ultrasound-guided oocyte aspiration is
performed approximately 34-36 hours after hCG administration.
Patient Selection and Preparation of the Recipient
The recipient and partner should undergo psychologic and legal counseling. Recipients more than 45
years of age require a general physical examination, including stress electrocardiography, chest x-ray,
and general chemistry panel. The gynecologic evaluation of the recipient should include pelvic
ultrasonography, cervical cytology, and an evaluation of the endometrial cavity by either
hysteroscopy or hysterosalpingography.
Preparation of the recipient depends on the choice between a natural cycle replacement of frozen
embryos and a prepared cycle. For the anovulatory recipient, a prepared cycle is mandatory. Natural
cycle replacement is contingent on demonstrating a timely ovulation and an endogenous endometrial
response to indicate a lining of at least 8 mm in thickness at the time of ovulation, as well as follicular
collapse within 36 hours of the patient's verified LH surge. A prepared cycle should include luteal-
phase down-regulation with GnRH agonist therapy (as evidenced by an estradiol level of <40 pg/mL)
before endometrial stimulation with oral or transdermal estrogen replacement regimen in graduated
doses. Progesterone supplementation is added before embryo replacement after an adequate
endometrial response has been documented ultrasonographically. Some investigators perform
endometrial biopsies in a "mock" cycle to ensure adequate endometrial evaluation.
Embryo or Gamete Replacement
Embryo replacement can be performed transcervically or transfimbrially 2 or 3 days after oocyte
insemination. Ga-mete replacement also can be in the form of GIFT. The number of embryos or
gametes replaced should be contingent on the donor's age. Remaining gametes can be fertilized and
embryos can be cryopreserved. Pregnancy rates, which may be as high as 50% per transcervical
replacement, have limited the clinical indications for transfimbrial replacements.
Care of the Donor After Embryo Transfer
Ovarian hyperstimulation syndrome is a potential risk that must not be overlooked. Donors at risk
include those with a maximal estradiol level greater than 2,000 pg/mL with a rapid rate of rise during
controlled hyperstimulation associated with more than 10 aspirated ova. Such patients may benefit
from luteal-phase down-regulation with GnRH agonists. Careful postoperative follow-up is
mandatory during the midluteal phase of the cycle.
Care of the Recipient After Embryo Transfer
The recipient should be maintained on exogenous estrogen and progesterone replacement until
pregnancy is confirmed; this replacement therapy should be continued until placental function is
ensured. Such pregnancies may be considered high risk on the basis of the recipient's age rather than
the mode of conception.
Other Procedures
Peritoneal oocyte and sperm transfer is a procedure in which 1) the oocytes are retrieved and 2) the
oocytes and sperm are placed into the pelvic cavity by ultrasound guidance. Direct intraperitoneal
insemination is a procedure in which sperm are injected directly into the cul-de-sac. Randomized
trials must be performed to prove that these procedures are superior to superovulation with
intrauterine insemination. Even sperm injection directly into the follicle has been reported to be
successful. As with other procedures, this must be directly compared with superovulation with
intrauterine insemination.
Surrogacy
When a woman who desires children has no uterus or cannot carry a child for health reasons, the use
of surrogates raises issues of possible exploitation and the propriety of paying for such services. In
some instances mothers or sisters have volunteered to carry children. Such cases raise fewer problems
in general than when a complete stranger is used. The argument is made that often the surrogate is of
a lower economic class and is being exploited. Surrogates generally have children of their own who
might be seriously troubled by their mother having a child and giving it up. Some prominent cases
reported in the news involved surrogates who refused to surrender the child. Some European countries
have made use of surrogates illegal. In the United States, there are questions about whether contracts
for surrogacy can or should be enforced. For some, a distinction is made between a surrogate who
provides her oocytes as well as her uterus and conceives via artificial insemination and a surrogate
who receives a transferred embryo and has no genetic ties to the pregnancy. §
Recurrent Spontaneous Abortion
 
Spontaneous abortion occurs in 15% of diagnosed pregnancies in women who are 15-44 years of age.
Recurrent spontaneous abortions occur in about 3-4% of these women, defined as the loss of three or
more consecutive pregnancies. Most spontaneous abortions occur because of abnormalities in the
fetus. Almost 70% of first-trimester abortuses, 30% of second-trimester abortuses, and 3% of
stillbirths have abnormal chromosome numbers. Nongenetic causes include anatomic, environmental,
hormonal, immune, and infectious factors.
Recurrence Risk
The risk of pregnancy loss increases from 15-20% in the first pregnancy to 40% after one spontaneous
abortion, but does not increase thereafter. If a woman has at least one liveborn child, the risk of her
first spontaneous abortion is 15%; after one spontaneous abortion, it increases to 30% with no
subsequent increase.
The prevalence of spontaneous abortion increases with increasing maternal age, although not with
gravidity. The risk begins to increase rapidly at age 35 years. The risk of spontaneous abortion at age
40 years is approximately twice that at age 20 years. Although one might suspect
that the reason for this increase is the known rise in aneuploid conception with increasing maternal
age, this does not wholly account for the rapid rise in spontaneous abortion. Indeed, more euploid
pregnancies are lost with increasing maternal age. This fact suggests that other factors, such as
decreased uterine blood supply, chronic infections, or deficient luteal phase, may be involved.
Furthermore, the endometrial lining contains glycoproteins and integrins important in implantation
that may change with age.
Etiology
Genetics
Patients having a karyotypically abnormal abortus are more likely to have another abortus that is
abnormal. Conversely, if the first abortus has a normal karyotype, the subsequent abortuses are likely
to be normal. Although no therapy can be offered to a patient with recurrent abnormal abortuses, at
least she can be advised of the reason for pregnancy failure. Most embryonal abnormalities result
during ca-mete formation or after fertilization. In 2-5% of couples, a chromosomal abnormality exists
in the parents, which will result in abnormal gametes. This is most often a chromosomal translocation.
Translocations, inversions, and deletions may be found in patients experiencing recurrent spontaneous
abortions. The yield is increased if the couple has a history of a child with anomalies or a stillbirth.
Also, parents with siblings who have a history of stillbirths or children with anomalies have a 10%
risk of carrying a chromosomal abnormality. Obstetric and family history is exceedingly important in
caring for the couple with recurrent spontaneous abortions.
Anatomic Anomalies
Müllerian Fusion Defects
Müllerian defects of all types are associated with a higher incidence of pregnancy loss. The septate
uterus, the most common anatomic abnormality, carries a risk of 70% spontaneous abortion in the
first trimester. This is believed to be due to the relatively less vascular nature of the implantation site.
A higher term pregnancy rate has been reported in women who underwent surgical resection of the
uterine septum compared with those left untreated. The surgery carries relatively little morbidity,
particularly when performed hysteroscopically.
Abdominal metroplasty is reserved for a bicornuate uterus and carries the risk of postoperative
adhesion formation. For properly selected patients in whom other causes of repeated abortion have
been excluded, a significant improvement in fetal salvage may be expected.
Intrauterine Synechiae
Intrauterine synechiae (Asherman's syndrome) may cause oligomenorrhea, infertility, or spontaneous
abortion. Adhesions may follow overzealous curettage of the uterus during the postpartum period,
intrauterine surgery (eg, myomectomy), or endometritis. Dense, avascular adhesions may interfere
with implantation or placentation. As many as 90% of patients conceive after hysteroscopic lysis of
the adhesions, with the subsequent spontaneous abortion rates ranging from 6% to 21%. However, no
randomized data exist to confirm the efficacy of
hysteroscopic lysis of adhesions in preventing subsequent spontaneous abortion. Because the
procedure entails little risk in the hands of skilled surgeons, the possible benefits warrant
hysteroscopic lysis in couples experiencing repeated losses.
Leiomyomas
Uterine leiomyomas are usually multiple and may contribute to pregnancy loss, but the
pathophysiology is unknown. Location, rather than size, of the leiomyoma is probably the most
important factor. Submucous leiomyomas may result in fetal loss through several theoretical
mechanisms: 1) endometrial thinning over the surface of the myomas may impair decidualization and
implantation; 2) necrosis within the myomas (red degeneration) from hormonally stimulated growth
exceeding the blood supply may lead to uterine contractions and fetal expulsion; or 3) the myomas
may encroach on the space required by the developing fetus and lead to fetal expulsion in the second
trimester.
Therapeutic efficacy of myomectomy has not been documented in controlled trials, but has been
suggested by surgical cohorts with increased postoperative term pregnancy rates. As in incomplete
müllerian fusion, careful patient selection is important and the increased risk of mechanical infertility
after surgery must be considered.
Endocrine Abnormalities
Thyroid Disease
The theory that thyroid disorders cause spontaneous abortion is now disproved. Although there is no
need to screen asymptomatic patients with spontaneous losses for thyroid disease, irregular menses
and amenorrhea remain indications for testing. Serum tests to diagnose thyroid disorders are
commonly available and thwart the need to treat empirically "subclinical" disease.
Diabetes Mellitus
When inadequately controlled, type 1 diabetes (formerly referred to as insulin-dependent diabetes
mellitus) may increase the risk of spontaneous abortion. However, euglycemic patients with diabetes
mellitus do not have an increased risk of pregnancy loss. Therefore, routine screening for diabetes
mellitus in patients with recurrent spontaneous abortion is not warranted.
Luteal-Phase Defect
The luteal-phase defect is presumably responsible for abnormal development of the endometrium
required for implantation and placentation. The luteal-phase defect results either from a deficient
secretion of progesterone or a poor endometrial response to adequate levels of progesterone.
Endometrial histologic dating lagging at least 2 days behind the actual postovulatory date in two
menstrual cycles is diagnostic of the luteal-phase defect. Due to the pulsatile nature of progesterone
secretion, random serum progesterone levels are inadequate for consistent diagnosis.
Many studies suggest a role for luteal-phase defect in infertility and spontaneous abortion.
Luteal inadequacy seems to be a result of inadequate follicular development that may lead to
fertilization of an oocyte but, ultimately, to spontaneous abortion. Therefore, progesterone
supplementation would appear to be useless; however, clomiphene citrate therapy to improve
follicular development may benefit some patients. Because not all patients will respond to this
therapy, an appropriately timed and dated endometrial biopsy should be performed during the
treatment cycle to document correction of endometrial histology.
That luteal-phase defect is indicative of ovulation disorder is supported by the finding of increased
recurrent miscarriage rates in patients with PCOS compared with normal control subjects.
Furthermore, high serum LH concentrations in the early follicular phase have been found to increase
the risk of spontaneous abortion. Levels of LH greater than 10 ml/mL before cycle day 9 may identify
a subgroup of patients best treated with GnRH analogue suppression and ovulation induction.
Current investigations are focused on the role of surface contact molecules, such as integrins, that may
be important in implantation. Conditions affecting the concentration of these factors in the
endometrium may reflect a novel way of diagnosing what histologically has become known as the
luteal-phase defect.
Infectious Agents
Almost every infectious agent except HIV has been implicated in causing recurrent spontaneous
abortion. However, prospective controlled studies are lacking. The only organism for which
prospective data are available is T-strain mycoplasma (Ureaplasma urealyticum). Women who have
T-strain mycoplasma endometritis have a higher prevalence of spontaneous abortion.
Furthermore, controlled prospective data indicate that doxycycline therapy improves resultant term
pregnancy rates. Women who have positive endometrial cultures for T-strain mycoplasma should be
treated along with their partners with doxycycline. Cultures for other organisms are unnecessary in
patients with repetitive spontaneous abortion.
Immunologic Disorders
Autoimmune Disease
Patients with an autoimmune disease, such as systemic lupus erythematosus, have an increased risk of
spontaneous abortion. These patients seem to form antibodies not only against their own tissue, but
also against placental tissue, which ultimately causes rejection of early pregnancy.
There is no evidence that other autoimmune factors, such as antisperm antibodies, cause spontaneous
abortion; therefore, autoimmune factors need not be considered in evaluation of couples with
recurrent spontaneous abortion.
Antiphospholipid Antibodies
The antiphospholipid antibodies, including lupus anticoagulant and anticardiolipin antibodies, are
aimed at cellular phospholipids, which were identified when testing patients with recurrent
spontaneous abortion suspected of having systemic lupus erythematosus. A prospective longitudinal
study performed by the National Institutes of Health revealed that patients who had high
antiphospholipid titers and a history of spontaneous abortions were more likely to lose their
pregnancies than those with lower titers. Nulligravid women with high titers ($80 IgG phospholipid
units) and multigravid women with moderate titers (16-80 IgG phospholipid units) had a 35% chance
of pregnancy loss. Multigravid women with high titers had an 85% chance of spontaneous abortion
and may require therapy. However, screening patients prospectively during pregnancy reveals a low
yield of positive tests.
A variety of agents, such as aspirin, heparin, and glucocorticoids, have been suggested for treatment
of women with high antiphospholipid antibody titers. However, controlled prospective studies have
not shown consistent effectiveness. Low-dose aspirin (75-80 mg/d) is commonly used to restore the
equilibrium between prostacyclin and thromboxane, which is altered by the presence of antibodies.
Administration of heparin subcutaneously, in addition to the aspirin, has been found effective in a few
studies but not in others. The use of high-dose glucocorticoid steroids combined with low-dose aspirin
has been discouraged due to the high incidence of gestational hypertension and diabetes caused by
steroids. Despite unknown efficacy and minimal side effects, low-dose aspirin therapy may be
recommended for patients with high antiphospholipid titers.
Shared Parental Histocompatibility Antigens
A fetal allograft that contains foreign paternal antigens theoretically should be rejected by the mother.
One theory suggests that the paternal antigens, which are foreign to the mother, invoke protective
blocking antibodies and prevent the normal maternal "immune cells of rejection" from recognizing the
fetus as a foreign organism. These protective antibodies form only when maternal and paternal
histocompatibility antigens are dissimilar; these antibodies account for the formation of protective
maternal antipaternal leukocyte antibodies. If antigenic similarity exists, the antibodies are thought
not to form and, therefore, the fetus is rejected by the mother's immune cells. The major
histocompatibility antigens were the first anti-gens suggested to be involved in this recognition.
However, multiple studies have now shown that parental sharing of human leukocyte antigens does
not increase the risk of spontaneous abortion. Other data suggest that trophoblast lymphocyte cross-
reacting antigens may be the antigen system involved. In addition to parental sharing of human
leukocyte antigens, other circumstantial evidence exists to support that parental histoincompatibility is
beneficial. Only 16.6% of women with multiple abortions have antipaternal cytotoxic antibodies, in
contrast to 64% of multiparous women and 20% of primiparous women. Similarly, 50% of women
with three or more recurrent abortions show no blocking factors, as evidenced by failure to
demonstrate a mixed lymphocyte reaction when their lymphocytes are exposed to their spouse's
lymphocytes.
Passive Immunization
Embryo rejection in animal models depends on activated natural killer cells rather than antigen-
specific lymphocytes. A number of centers have suggested immunizing the mother with paternal
leukocytes to suppress natural killer cells. In one study, immunization with paternal lymphocytes
resulted in an increase in antipaternal leukocyto-toxic antibodies that protect the fetus and improve
pregnancy outcome. However, a meta-analysis of 19 case series and four randomized controlled trials
did not document a significant increase in viable pregnancy rates and recommended against the use of
leukocyte therapy.
Active Immunization
Administration of IgG has been proposed to decrease overall maternal antibody production in an
attempt to reduce fetal rejection. Theoretically, treatment with IgG would decrease antibodies against
the phospholipids and foreign fetal antigen; however, it would also decrease any blocking antibody
that exists and that is protective. The overall effect may be estimated by examining the results of five
European pilot studies of 172 patients: 68-87% of pregnancies in patients treated with IgG carried
their pregnancy to term. However, the pregnancy outcome in the treated group was not different from
that in the patients treated with placebo (5% albumin).
Although some argue that the albumin was immunomodulating, no efficacy data exist to warrant the
expensive immunoglobulin therapy at this time.
Environmental Factors
A variety of environmental factors may result in spontaneous abortion. Many studies involving
spontaneous abortions are difficult to conclude because of the multiple confounding variables that are
difficult to control.
Irradiation and Antineoplastic Agents
X-irradiation and antineoplastic agents are known to be abortifacients. Therapeutic X-rays or
chemotherapeutic drugs are administered during pregnancy only to seriously ill women. In diagnostic
doses, X-rays have not been proven to cause fetal demise, but it would be prudent to perform X-ray
examinations during pregnancy only when absolutely necessary. Even relatively low doses of
antimetabolite drugs (eg, methotrexate) might be considered abortifacients, consistent with successful
use of such agents in management of ectopic gestations and induced abortions.
Cigarette Smoking and Alcohol
Both cigarette smoking and alcohol ingestion are apt to increase the risk of first-trimester spontaneous
abortion. Cigarette smoking increases the risk of euploid pregnancy loss independent of maternal age
and alcohol consumption. A woman smoking one pack of cigarettes a day and having one drink of
alcohol a day has almost a fourfold risk of spontaneous abortion compared with a patient who does
not smoke or drink. It is important to advise patients of these factors without making them feel guilty
about such use in prior pregnancies.
Chemical Exposures
Exposure to various chemicals in the workplace has been shown to be associated with increased risk
of spontaneous abortion. Such chemicals include anesthetic gases, arsenic, aniline, benzene, ethylene
oxide, formaldehyde, and lead. Tetrachloroethylene, a compound frequently found in dry cleaning and
laundry establishments, has been shown to increase the risk of spontaneous abortion more than
threefold. Similarly, nurses mixing chemotherapeutic agents have an almost twofold risk of
spontaneous abortion. Medical residents have no increased risk of spontaneous abortion as compared
with the wives of their male colleagues. Of additional note are studies showing no increased risk for
pregnant laboratory workers, pharmaceutical industry workers, or anesthetists and anesthesiologists.
Other Exposures and Trauma
Exposure to electromagnetic radiation from video display terminals does not increase the risk of
spontaneous abortion. Studies with women working at computers for months before their pregnancy
and continuing throughout pregnancy reveal no decrease in term pregnancy compared with those
women who stopped computer usage.
Women can be reassured that they can safely use hair dyes, watch television, and fly on commercial
airlines (although there may be some restrictions in late pregnancy) during their pregnancy. Although
high-altitude (above 11,000 feet) skiing is ill advised, physically fit and experienced women can
continue to ski during early pregnancy. These questions frequently arise in counseling the patient who
has experienced pregnancy loss and serve to highlight her anxiety.
Women should be counseled to avoid prolonged use of hot tubs and scuba diving during pregnancy.
Women commonly attribute pregnancy losses to trauma, such as a fall or blow to the abdomen.
However, fetuses are well protected from external trauma by intervening maternal structures and
amniotic fluid.
Evaluation of Recurrent Pregnancy Loss
Patients experiencing recurrent pregnancy loss would benefit from a battery of the following tests:
• Karyotype in husband and wife
• Karyotype in any subsequent abortus
• Endometrial biopsy --Histologic dating --U urealyticum culture
• Hysterosalpingography or hysteroscopy
• Fluorescent antinuclear antibodies
• Antiphospholipid antibodies --Lupus anticoagulant --Anticardiolipin antibodies
In general, these tests are performed after three spontaneous abortions or, in women older than 35
years of age, after two spontaneous abortions. Although there is no more likelihood of finding an
abnormal test result after three spontaneous abortions than after one, cost-effectiveness as well as
other practical considerations support this rule. Any test with an abnormal result should be repeated
after treatment has been initiated.
Follow-Up
Perhaps more important than evaluation and treatment in the patient experiencing spontaneous
pregnancy loss is the care for the patient during her next pregnancy. These patients will benefit
emotionally by seeing their physician weekly during the first trimester. Frequent ultrasound ex-
aminations help establish viability and reassure the patient that the pregnancy is continuing.
When ultrasonography shows cardiac activity at 8 weeks of gestation, patients have a 3-5% risk of
spontaneously aborting. This short-term goal of demonstrating cardiac activity at 8 weeks of gestation
enables patients to have a shorter period of anxiety, rather than setting a 9-month goal of a babe in
arms. Another reason to follow the patient frequently in early pregnancy is to rule out the risk of
ectopic pregnancy. Patients who are experiencing repetitive spontaneous abortions have a fourfold
risk of subsequent ectopic pregnancy. After reaching 8 gestational weeks, routine obstetric care may
be initiated.

Human Papilloma Virus

 
HPV is the most common tumor of the vulva. The incubation period varies from weeks to months.
Clinical evaluation
Condyloma acuminata lesions appear as rough, verrucous papillomas on the genitalia. Enlargement
often occurs during pregnancy and sometimes lesions disappear spontaneously.
No practical screening tests for subclinical infection exist. Pap smear diagnosis of HPV does not
correlate well with detection of HPV DNA.
Treatment of genital/perianal warts
Cryosurgery with liquid nitrogen or cryoprobe is more effective than topical therapies. Lesions
should be frozen until a 2 mm margin of freeze appears, then allowed to thaw, then refrozen. Repeat
freeze several times.
Podophyllin 25% in of benzoin may be applied and washed off 4 hours later. Two or 3 applications, 1
week apart, may be needed. Podophyllin should not be used on the vagina or cervix; it is
contraindicated in pregnancy.
Trichloracetic acid (80%). Apply to lesion with a cotton-tip applicator, then observe for 5-10
minutes; 2 or 3 applications may be needed, 1 week apart. Burning is common. TCA can be used on
the cervix, vaginal sidewalls, and external warts; it can be used during pregnancy.
Podofilox 0.5% (Condylox) solution for self-treatment: Apply twice daily for 3 days followed by 4
days of no therapy. This cycle may be repeated as necessary for a total of 4 cycles; not for use on
vagina or cervix; contraindicated in pregnancy.
Surgical excision and electrocoagulationor laser may be used.
Large, bulky or extensive lesions
General anesthesia and wire loop cautery is effective.
Topical 5-fluorouracil cream in a 1-2% concentration is effective in the treatment of vaginal
condylomata; it is contraindicated in pregnancy.
Recurrence rates are high (25% within 3 months). No therapy has been proven to eradicate HPV.
Partner referral
Examination is not required.
Annual Pap smears are recommended for partners, independent of wart history.
The use of condoms may reduce transmission to partners.

 VULVODYNIA -- New Advances in Management

Vulvodynia is defined as symptoms of chronic vulval soreness, burning, or pain, as opposed to
pruritus or itching. Currently, vulvodynia applies to this set of symptoms, whatever their origin; it is
often nonetheless applied only to those cases in which the cause is not so obvious.
VULVODYNIA RELATED TO INFECTION AND DERMATOSES
This form of vulvodynia stems from erosion of the surfaces and is common in such conditions as
fissured lichen sclerosus, erosive lichen planus, herpes simplex, or severe Candida infection. It can be
confirmed or excluded by history and examination. The symptoms usually subside when the
underlying condition is treated. Occasionally symptoms persist, and the patient is then best considered
as having dysesthetic vulvodynia, which is discussed later.
Cyclical vulvitis holds an uncertain place in classification, mainly because in itself it is not well
defined, but it is best noted here. It concerns patients who have cyclical symptoms and may respond to
prolonged anti- Candida treatment; signs are usually indefinite and the microbiological findings are
variable. Vaginal hypersensitivity to Candida has been postulated, but not demonstrated.
VULVODYNIA WITHOUT EVIDENCE OF AN ACTIVE DERMATOSIS OR INFECTION
Such patients fall into two main groups although we shall see there is some overlap. Their
presentation and management will be described, and the developing views on etiology, which largely
endorse the current clinical approach, is discussed.
Dysesthetic Vulvodynia  
Dysesthetic vulvodynia is largely found among postmenopausal women. The symptoms are constant
and unprovoked; therefore, if the woman is sexually active, she does not complain of dyspareunia.
The pain or burning may affect the perianal and perineal region and the inner thighs, as well as the
vulva. One investigator, using MRI, found sacral meningeal cysts in 10 out of 17 patients, and 9 of the
10 were pain-free 6 months after appropriate surgery. However, others, using the same technique,
found no such lesions in their 17 patients, and such investigation is not indicated as a routine measure.
Some patients are depressed, whether primarily or as a result of the pain, and a few may even be at
risk of suicide; many suffer great limitation of activity. Not infrequently there is a history of other
chronic pain such as glossodynia. Formal assessment of these patients as a group has yielded
somewhat discrepant results. There is no abnormality on examination and no tenderness on touch or
pressure.
Mildly affected patients are helped by 5% lignocaine ointment and those more severely affected are
improved by oral amitriptyline, in lower dosages than those used to treat depression. It is important to
explain to the patient that the drug is not being given as an antidepressant as such, and a useful word
to employ is neuralgia, citing some common example such as pain after herpes zoster. This older age
group does not tolerate large dosages well, but a starting dosage of 10 mg at night, increasing by 10
mg weekly up to a maximum daily dosage of 70 mg to 100 mg, is usually safe and effective. When
symptoms have been controlled at a given level the dosage can slowly be reduced; several months of
treatment may be needed. If the response is unsatisfactory, alternative drugs such as doxepin or
carbamazepine may be used.
Vulval Vestibulitis
In this second main group the patients are young, often frustrated after fruitless consultations, and
sometimes concerned by other problems such as irritable bowel syndrome or back pain. The
symptoms often have an acute onset after some trigger such as surgery, childbirth, or an infection. The
patients complain of pain on attempted vaginal entry, that is, with intercourse or using tampons, and
demonstrate acute tenderness in the vestibule on pressure with a cotton-wool tip, together with
variable erythema. The tenderness is usually maximal near the site of Bartholin's gland orifices;
occasionally there is tenderness in the anterior vestibule, and there may be urinary symptoms
diagnosed as interstitial cystitis. It has been shown that many asymptomatic women have some
erythema and tenderness on pressure, but the acute nature of the pain in the vestibulitis patients is
readily recognizable.
The histology shows nonspecific inflammatory changes, but it has now been shown that such changes
occur also in normal vestibular tissue.  It is now accepted that the human papillomavirus is not
involved; nor are the minor vestibular glands (the orifices of which are often to be seen in the
vestibule) now thought to be relevant.
Management begins with a careful explanation to the patient, and an assurance that the condition is
well recognized. Simple measures such as a soap substitute, for example aqueous cream with 5%
lignocaine ointment, and perhaps hydroxyzine as a mild anxiolytic at night, are instituted. For those
with a short history and a stable personality this may suffice. Some patients have pelvic floor
hypertonia and can be helped by biofeedback. Low-oxalate diets have been advocated but with little
evidence of benefit. Psychosexual problems, whether primary or secondary, are common although
often initially denied; and the help of a trained counsellor, who may be a doctor, nurse, or clinical
psychologist, is on occasion called for. In severe cases, it is worth introducing amitriptyline.
Sometimes, particularly when the history is long and the patient's psychological state very disturbed,
the pain begins to occur independently of intercourse, and becomes constant; she should then be
regarded as having dysaesthetic vulvodynia and treated accordingly.
Surgical treatment, in the form of vestibulectomy, vestibuloplasty, and perineoplasty, has its
advocates, but follow-up results are limited, and it is hard to justify on rational grounds. Surgical
treatment should be used, if at all, only in those who have failed to respond to other measures. The
surgical procedure should be very fully explained to achieve the best outcome. Of the usual
techniques, it seems that perineoplasty gives the best results, but recently, good results have been
claimed from a small skinning dissection under local anesthesia. 
DISCUSSION
The recognition of some overlap between dysesthetic vulvodynia and vulval vestibulitis, in that in the
latter, the pain may be helped by amitriptyline and in some cases may change into a constant,
unprovoked affair, has gradually led to the concept that both may be pain syndromes. This view well
explains the absence of an infective cause, the essentially normal histology and the onset in relation to
a trigger factor in vestibulitis, and the similarity of dysesthetic vulvodynia to such conditions as
glossodynia and facial neuralgia.
The two conditions may be satisfactorily categorized as complex regional pain syndromes, akin for
example to reflex sympathetic dystrophy. Pain in these syndromes persists in the absence of tissue
injury. This pain is initiated by mediators following perhaps some minor lesion; "inappropriate"
impulses in nonmyelinated pain fibers then reach the dorsal horn neurons. Thence fibers transmit
impulses to the thalamus, parietal lobe, and other areas of the brain, and a complex interaction is set.
There is `cross-talk' between mediators of somatic and sympathetic pain. Both dorsal horn and central
neurons may become sensitized. Unpleasant sensations are perpetuated; light touch for example in
myelinated fibers being interpreted as pain (allodynia), and there is hyperesthesia, where pain is
increased and prolonged. According to the gate theory of pain, impulses traveling more quickly in
myelinated fibers can block sensation of pain; hence, the use of transcutaneous electrical stimulation
devices and descending impulses can also favorably modify pain sensations. The transmitters are
various neuropeptides, for instance substance P, endorphins, serotonin (5-hydroxytryptamine), and
other catecholamines. Amitriptyline blocks synaptic uptake of serotonin and noradrenaline; doxepin
also has some antihistaminic effect; however, drugs acting on serotonin alone are less helpful. Topical
capsaicin acts on substance P and blocks pain afferents, but unfortunately is too painful to use in
clinical practice.
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