Ethnic group
Disorder
Ashkenazi Jews
Cystic fibrosis
Tay-Sachs disease
Canavan disease
Familial dysautonomia
Non-Hispanic Whites
Cystic fibrosis
African American, Mediterranean, Southeast Asian populations
Sickle cell anemia, thalassemias
Social History
All patients should be asked about diet, exercise, environmental exposures, and substance use. The nutritional status of the patient should be reviewed including determination of adequate consumption of folic acid, calcium, and vitamin D. Folic acid intake is critically important to assess given its known protective impact on certain birth defects. However, up to 30% of women attempting pregnancy who are aware of the benefits of preconception folic acid may not be taking it [16]. The use of herbal preparations, vitamin supplements, or mega-vitamins should also be addressed as they may contain ingredients such as hormones or anti-inflammatory agents that may negatively impact fertility [17]. Exercise habits should also be reviewed since reproductive dysfunction has been reported to have a higher prevalence in athletes than in non-athletes. Specifically, menstrual disturbances, with amenorrhea being the most severe form, is one mechanism that is often reported, particularly in patients with a low BMI. Other mechanisms such as luteal phase defect (dysfunction of the corpus luteum) and abnormal follicular development have also been described in the literature [18, 19]. Environmental exposures at work or in the household should be addressed. For example, second-hand smoke may increase the risk of spontaneous abortion [20] and smoking should be discouraged in both the patient and her partner with a stop date agreed upon. Use of alcohol, tobacco, and recreational drug use should be assessed in both the patient and male partner [21–23]. Furthermore, chronic alcohol consumption and smoking have been shown to have a detrimental effect on male reproductive hormones and sperm quality [24]. Smoking cessation should be discussed within the context of any medical evaluation. Lastly, excessive caffeine use has been associated with both infertility and miscarriage and a recommendation for consumption of less than three cups a day should be made.
Sexual History
Coital frequency and timing should be evaluated in order to maximize the chances of conception, as couples may be engaging in intercourse which is not timed. Generally, intercourse is most likely to result in pregnancy when it occurs in the 3 days leading up to ovulation based on the survival time of sperm in the female reproductive tract [25, 26].
12.3.2 Review of Systems
In addition to the general medical history, a focused review of systems should be performed, targeting hormonal or physiologic abnormalities such as intracranial lesions and thyroid abnormalities which are closely associated with anovulation.
Headaches
Headaches are a common complaint in the outpatient setting and are benign in the majority of cases. However, headaches may reflect medical conditions and/or pituitary lesions which can negatively impact on fertility [27–30]. The features of the patient’s headache should be characterized, specifically whether the pain is resolved with medication, presence of associated symptoms such as visual field disturbances, and if the headaches are new or have changed in character. Additionally, patients should be counseled that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during ovulation or infertility treatment regimens may adversely impact ovulation and subsequent implantation [31, 32].
Visual Changes
Visual impairment is a common presenting feature of space-occupying pituitary lesions such as craniopharyngiomas or macroadenomas [33]. These pituitary lesions, if large enough, can extend out of the sella turcica and compress the optic chiasm. Although uncommon, this most frequently presents as bitemporal hemianopsia, or bilateral loss of the peripheral visual fields, and rarely total blindness due to optic atrophy. These patients typically present in an infertility consultation with abnormalities of their menstrual cycles and/or with galactorrhea.
Constitutional Symptoms and Systemic Diseases
Any significant decline in overall health and functional status or symptoms such as heat or cold intolerance should be investigated as these symptoms may suggest underlying medical conditions such as thyroid disease, diabetes, or cancer, all of which can greatly impact on both fertility and a woman’s plans for conceiving.
Physical Examination
A complete physical examination should be performed at the initial visit with emphasis on the following components.
Body Mass Index
A body mass index (BMI) above or below the normal range has been associated with anovulation, oligo-ovulation, subfertility, and infertility [34]. Patients should be informed about the association between BMI and ovulation and counseled on lifestyle modifications to optimize their BMI . It is important to note that excessive weight negatively impacts fertility independent of ovulatory status. Furthermore, it is well accepted that obesity is associated with multiple high-risk obstetrical conditions which provides an independent incentive to lose weight.
Thyroid
As stated above, thyroid hormone disorders are associated with anovulation and menstrual irregularities. The thyroid gland is located in the anterior neck below the prominence of the thyroid cartilage and should be palpated for thyromegaly or nodules. Abnormalities on physical exam should be further evaluated with laboratory testing and possible imaging.
Breast
The breast examination in the fertility evaluation should focus on symmetry of the breasts and any evidence of galactorrhea as this could be indicative of a pituitary lesion. Galactorrhea is defined as active secretion of breast milk at a physiologically inappropriate time, namely other than during pregnancy or lactation. Secretions are usually white in color and occur bilaterally from hormonal stimulation of multiple ducts. Conversely, pathological discharge usually originates from a single duct and therefore is unilateral. One helpful technique is to have the patient squeeze her breast to attempt to express any discharge. She will likely apply more pressure than the provider and, in a patient who states that she has discharge, this will show what is necessary to generate the milk (i.e., gentle pressure or significant manipulation).
Abdomen
In cases of obesity, the abdomen should be evaluated for distribution of adipose tissue. Central adiposity in addition to other signs of hypercortisolemia could be associated with Cushing’s syndrome (see Skin section below). Additionally, thorough inspection for any scars indicating previous surgery that the patient may have neglected to mention should also be undertaken.
Skin
The skin should be evaluated for findings that can correlate with underlying endocrine pathology: acanthosis nigricans, abdominal striae, and hirsutism. Acanthosis nigricans is defined as hyperpigmented, velvety plaques found most commonly along the base of the neck, axilla, and the inner thighs. The formation of these lesions is thought to be triggered by hyperinsulinemia, a consequence of obesity-induced insulin resistance. Polycystic ovarian syndrome is often associated with insulin resistance. Therefore, the presence of these lesions warrants further investigation.
Abdominal striae are characterized as violaceous striations most frequently noted on the skin of the abdomen and hips [35]. They can be associated with Cushing’s syndrome and therefore would warrant further evaluation for hypercortisolemia.
It is also important to assess the patient’s hair growth pattern to assess for hirsutism. Hirsutism is the overgrowth of facial or body hair on women. Specifically, it can be seen as coarse, dark hair that may appear on the face, chest, lower abdomen, back, upper arms, or upper legs. Hirsutism is caused by hyperandrogenism, most commonly in the setting of polycystic ovarian syndrome when the ovaries produce excessive amounts of androgens. Hirsutism can affect up to 10% of women and its presence should also help direct further laboratory testing [36].
Gynecologic Exam
The gynecologic exam should focus on identifying anatomical abnormalities that can be a result of congenital structural anomalies or organic diseases, both of which can impact fertility. For the purposes of the infertility evaluation, the gynecologic exam should assess for the presence of clitoromegaly and structural abnormalities of the cervix, uterus, and pelvis.
Normally, in the non-erect state, the clitoris is generally 3–4 mm in width, 4–5 mm in length and partially covered by a hood of skin. Clitoromegaly, enlargement of the clitoris, is a consequence of inappropriate androgen exposure and is typically defined as a size greater than 35 mm2 [37]. This finding on physical exam warrants further investigation about ingestion of exogenous androgens, possible in-utero exposure to androgenic substances taken by the patient’s mother or an androgen-producing tumor. Physical signs of androgen excess should be correlated with laboratory testing.
Examination of the cervix should assess for cervical stenosis and structural abnormalities such as transverse ridges, cervical collars, hoods, coxcombs, pseudopolyps, cervical hypoplasia, and agenesis [38]. Cervical stenosis is the cervical abnormality most commonly associated with infertility. It decreases fertility by diminishing the mucus bridge from the vagina to the endocervix that is necessary for sperm transport. The remaining structural abnormalities are less common and can be secondary to idiopathic developmental anomalies or obstetrical trauma and surgical procedures. In utero exposure to diethylstilbestrol (DES), a medication prescribed in the 1940s to 1970s for miscarriage prevention, had been a common cause of cervical malformations. Fortunately, it is rare in younger women but should still remain on the differential for women in their forties with a cervical malformation.
The bimanual examination should assess for cervical motion tenderness as well as structural abnormalities of the uterus and adnexae. Cervical motion tenderness can be elicited by gentle lateral movement of the cervix. This finding can be associated with an active or prior pelvic infection or adhesive disease. The mechanism of this physical exam finding is that the movement of the cervix causes movement of the adnexae as well. Therefore, in the setting of an infection or adhesions around or in the vicinity of the fallopian tubes or ovaries, sliding of the inflamed peritoneum with this test may elicit significant tenderness.
Even without pelvic adhesions, endometriosis can cause cervical motion tenderness when it involves structures attached to the cervix such as the vaginal apex, cardinal ligaments, uterosacral ligaments, and inferior aspect of the broad ligaments. The cervix may be laterally deviated as a result of ipsilateral shortening of a uterosacral ligament which has endometriosis or based on a Müllerian anomaly such as a unicornuate uterus. Nodularity of the uterosacral ligaments can often be felt on bimanual examination if endometriosis is present in that region and may be especially prominent on recto-vaginal exam.
The size and contour of the uterus should also be assessed on the bimanual exam. Notable findings such as enlargement, irregularity, asymmetry, or tenderness all warrant further investigation. Abnormalities associated with decreased fecundity include leiomyomata, adenomyosis, and Müllerian anomalies. The adnexae should also be evaluated on bimanual exam. Any abnormalities on bimanual exam should be further evaluated, typically with imaging such as ultrasound.
Diagnostic Testing
After a thorough medical history and physical examination has been performed, further testing is needed and can be divided into two categories: (1) preconception screening and (2) the infertility evaluation (◘ Table 12.2).
Tests | |
|---|---|
Preconception screening | Current Pap smear when appropriate |
ABO, Rh factor typing | |
Verify immunity with vaccination if indicated | |
Rubella titer | |
Varicella titer | |
Appropriate genetic screening (see ◘ Table 12.1) | |
Sexually transmitted diseases | |
Recommended screening | |
Syphilis screen (VDRL/RPR) | |
Hepatitis B surface antigen (HBsAg) | |
HIV 1 and 2 | |
Hepatitis C antibody (HCA) | |
Gonorrhea (RNA/DNA-based testing) | |
Chlamydia (RNA/DNA-based testing) | |
Infertility testing | Semen analysis |
Hormonal Tests | |
TSH | |
Prolactin | |
Ovulatory function | |
Basal body temperature chart (not routinely recommended) | |
Mid-luteal serum progesterone | |
Urinary LH surge detection | |
Ovarian reserve testing options | |
Day 2 or 3 FSH and Estradiol | |
Clomiphene Citrate Challenge Test (CCCT) | |
Anti-Müllerian Hormone | |
Antral follicle count | |
Imaging study options | |
Transvaginal ultrasonography | |
Sonohysterography | |
Hysterosalpingogram | |
Hysteroscopy, diagnostic or operative as indicated | |
Diagnostic laparoscopy as indicated |
Preconception Screening
Preconception screening consists of tests that should be performed on all women considering pregnancy. This includes a current Pap smear, type and screen, testing for sexually transmitted diseases (STDs), and documentation of immunity to rubella and varicella. Recommended screening for STDs includes syphilis, hepatitis B surface antigen, HIV 1 & 2, hepatitis C antibody, and RNA/DNA-based gonorrhea and chlamydia testing. Patients who are not immune to varicella or rubella should receive the appropriate vaccination at least 1 month prior to conception. Women should also be up-to-date on their tetanus- diphtheria -pertussis vaccine [39]. Furthermore, patients should receive appropriate preconception genetic screening based on their ethnicity, as outlined earlier in this chapter (◘ Table 12.1). When indicated, additional targeted well-women health screenings, such as mammograms, should be performed during this time to maximize health and avoid delays in screening tests.
Infertility Evaluation
The infertility evaluation consists of laboratory testing in addition to those performed for preconception screening. These tests assess: (1) male infertility, (2) ovulatory function, (3) ovarian reserve. Imaging studies such as hysterosalpingography and sonohysterography are also typically performed, and if warranted from the patient’s history or physical exam, hysteroscopy or laparoscopy may be indicated as well.
Male Factor
Semen analysis is the main screening tool for male infertility problems. The seminal fluid is analyzed for volume, viscosity, pH, color, presence of round cells (which may be immature sperm or red and white blood cells), and sperm concentration. In terms of sperm characteristics, motility, forward progression, and morphology are assessed. However, sperm function is not assessed in the semen analysis. Men with persistently abnormal semen analyses should be further evaluated by a reproductive urologist. Of note, semen analysis varies widely in quality between different labs and care should be taken when interpreting results.
Thyroid-Stimulating Hormone (TSH )
Hypothyroidism is a relatively common medical problem in women and can result in ovulatory dysfunction even in the presence of minimal or no symptoms. Fortunately, it is relatively easy to treat. TSH is the screening test of choice for identifying thyroid hormone abnormalities and should be drawn at the initial infertility visit. Hypothyroidism is suggested when TSH is elevated and should be repeated with a measurement of free T4 [40]. When TSH is abnormally low, it can indicate hyperthyroidism and further testing is required. Subclinical hypothyroidism is a special issue in women attempting to conceive and, although controversial, there are recommendations for tighter control of thyroid function during peri-conception and pregnancy compared to other periods in a woman’s life with the goal of a TSH being <2.5 [41].
Prolactin
Like hypothyroidism, hyperprolactinemia is a relatively common problem with many causes. It may lead to oligomenorrhea or amenorrhea, therefore causing infertility. The most common cause for hyperprolactinemia in women is a prolactin-secreting adenoma usually diagnosed with MRI after an elevated prolactin is identified on blood work. It is also important to note that thyrotropin-releasing hormone (TRH) is a potent prolactin stimulating substance and since this is increased along with TSH in hypothyroid states, prolactin levels can be elevated in women with hypothyroidism [42]. For this reason, TSH and prolactin should be drawn together at the initial evaluation to establish the correct diagnosis. Lastly a careful medication history should be taken as various medications can also contribute to an elevated prolactin.
Tests for Ovulation
Ovulatory function can often be deduced from a patient’s menstrual history, specifically women with regular cycles (25–35 day intervals) and symptoms such as breast tenderness, bloating, and dysmenorrhea are likely to have ovulatory cycles. As previously noted, several hormonal abnormalities can commonly cause ovulatory dysfunction in otherwise healthy patients. Therefore, tests such as TSH and prolactin are important to obtain. Other tests such as basal body temperature charts, mid-luteal serum progesterone, and urine luteinizing hormone surge detection can provide additional information about ovulatory function.
Basal Body Temperature Charts
Basal body temperature (BBT) charts are based on progesterone-related increase of core body temperature. During the follicular phase, the BBT can fluctuate between 97.0 and 98.0°F. Progesterone levels >5 ng/mL, achieved after ovulation, raise the hypothalamic set-point for basal temperature by approximately 0.6°F. Due to the variable timing in the rise of temperature following ovulation, the stress associated with taking one’s temperature every morning before getting out of bed, and the significant false-positive and false-negative rates, this modality is uncommonly recommended [43].
Serum Progesterone
Measurement of serum progesterone levels can also be used to document ovulation. Serum progesterone levels remain below 1 ng/mL during most of the follicular phase rising during the late follicular phase to 1–2 ng/mL [44]. After ovulation, progesterone is secreted from the corpus luteum and levels rise steadily until they peak approximately 7–8 days following ovulation. Typically, a serum progesterone level >3 ng/mL provides reliable evidence that ovulation has taken place but does not provide information on when it occurred [45].
There are several methods of measuring serum progesterone. Classically, it can be measured on day 21 with the assumption being that the woman has a 28-day menstrual cycle [46]. However, since normal menstrual cycles fluctuate in length, measurement of serum progesterone on day 21 may not be completely accurate. If a woman is able to estimate how long her menstrual cycles are, then she can simply obtain this test approximately 1 week before her period is due.
Urinary LH Measurements
Of the three tests described in this section, measurement of urinary LH is the only test that can predict ovulation before it occurs, therefore giving patients the ability to time intercourse. These highly accurate over-the-counter tests are designed to change color when urinary LH levels reach those associated with the mid-cycle LH surge, indicating imminent ovulation. Testing should be performed daily starting 3 days before the expected day of ovulation to ensure that ovulation is not missed. Ovulation will generally follow within 12–36 h following a positive surge with the variability reflecting the once daily testing of an ongoing process. If used for timed intercourse or intrauterine insemination (IUI), the day after the first positive test will have the highest success rate [47].
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