Delaying the decision to have children contributes to the proportion of couples who are involuntarily childless. Demographic ¹ and clinical studies² have shown that women experience optimal fertility before the age of 30 to 31 years. After the age of 31, the probability of conception declines rapidly, but this can be partly compensated for by continued insemination for additional cycles. In addition, the probability of an adverse pregnancy outcome starts to increase at about the same age.²

Thereafter, fertility gradually decreases, with acceleration toward the age of 40 years. In women, fertility remains relatively stable until 30 years of age, generally producing more than 400 pregnancies per 1000 exposed women per year; it then begins to decrease substantially.³ By 45 years of age, the fertility rate is only 100 pregnancies per 1000 exposed women.⁴ Already at the age of 40 to 41 years, half of women will have completely lost their capacity for reproduction. It is generally accepted that reproductive aging is in fact ovarian aging and is related to the decreasing quantity and quality of the pool of follicles preserved in the ovaries.⁵

In order to achieve a normal conception, the following are needed:³

• Production of viable sperm with respect to motility, morphology, count, and DNA integrity

• Transport of sperm through the male genital tract and deposition in the female genital tract, usually near the cervix of the uterus during sexual intercourse

• Normal oocyte production (ovulation) by the ovaries

• Transport of sperm and the oocyte within the female genital tract to the site of fertilization in one fallopian tube

• Penetration of sperm into the oocyte, fertilization, development of a preembryo, and its transport to and implantation in the uterus

The reader is directed to Chapter 180, Infertility, Male, for specific information for the male partner. Additionally, Chapter 180 covers the definitions of infertility—primary, secondary, and unexplained.

Fecundity is defined as the couple’s chance of conception in a single menstrual cycle. The normal monthly success rate for couples trying to conceive naturally at age 25 is 25%. This figure decreases with increasing age, particularly after 35 years of age for women. It was once believed that a woman’s age was the only major contributing factor; however, it is now known that male fertility declines with age concurrent with abnormalities evident in semen parameters.

The probability of a couple’s fecundity is calculated to determine the monthly chance a couple has of conceiving a child. It factors in a number of variables and considerations for both the male and female partners. In diagnosing the cause of infertility, it is important to consider all variables as pieces of a couple’s reproductive and fertility health. The clinical presentation may suggest either blatant fertility impediments (e.g., genetic abnormality) or each partner may have minor health concerns that, when combined, constitute major impediments to a successful fertility outcome (Table 179-1).

TABLE 179-1 Causes of Female Infertility

Ovulation disorders (40%)	Aging
	Diminished ovarian reserve
	Endocrine disorder (e.g., hypothalamic amenorrhea, hyperprolactinemia, thyroid disease, adrenal disease)
	Polycystic ovary syndrome
	Premature ovarian failure
	Tobacco use
Tubal factors (30%)	Obstruction (e.g., history of pelvic inflammatory disease, tubal surgery)
Endometriosis (15%)
Other (approximately 10%)
Uterine/cervical factors (>3%)	Congenital uterine anomaly
	Fibroids
	Endometrial polyps
	Poor-quality/quantity cervical mucus (caused by smoking, infection); mucous hostility (sperm antibodies)
	Uterine synechiae or adhesions (Asherman’s syndrome)

Data from Jose-Miller, A., Boyden, JW, Frey, KA. Infertility. Am Fam Physician 2007;75:849-858.

Integrative Infertility Treatment

Assisted Reproductive Technologies and Naturopathy

The statistics suggest that 4.6% of U.S. infants born in 2005 (95% uncertainty range: 2.8% to 7.1%) resulted from ovulation treatments not involving assisted reproductive technologies (ARTs). National ART Surveillance System data indicate that ART treatments currently account for 1.2% of total U.S. live births, 16% of U.S. twins, and 38% of U.S. triplets or higher-order (quadruplets or more) live-born infants.⁷ Therefore, the prudent naturopath must be aware of potential interactions and consider each treatment protocol accordingly. It is advisable for clinicians to recommend the following approach to their patients for safe, integrated treatment:

• Prior to an in vitro fertilization (IVF) cycle, a 3- to 4-month preconception program for both partners should be encouraged to ensure appropriate nutritional status and detoxification to optimize successful outcome.

• Any causative or contributing factors that may hinder the success of an IVF cycle should be investigated and eliminated thoroughly.

• Any preexisting health conditions during the preconception window of three to four months must be addressed and treated.

• During an IVF cycle, it is crucial to enable optimal communication between the naturopath and fertility specialist to prevent any interactions. Dietary and lifestyle recommendations should be encouraged; however, nutritional and/or herbal medicine prescriptions must consider potential negative interactions with IVF medications. As such, all prescriptions must be individualized.

• Once IVF has concluded and a successful outcome has been attained, treatment can be modified to support the pregnancy, focusing on miscarriage prevention in the first trimester and then adjusting as the pregnancy continues.

Optimizing Natural Fertility

Natural conception is clearly the ideal scenario for any couple. It is therefore necessary to assess a few key variables including ovulation detection and the timing and frequency of intercourse. Before infertility is diagnosed, current recommendations are to encourage couples to attempt conception for a minimum of 12 months of unprotected appropriately timed intercourse. The time period is reduced in couples where the female is older than 35 years. In these couples, diagnosis of infertility is achieved after 6 months.

A couple’s fertility is generally highest in the first few months of unprotected sex and declines gradually thereafter. If no conception occurs within the first 3 months, monthly fecundity decreases substantially among those who continue their efforts to conceive.⁸ Therefore, couples who are likely to conceive naturally are likely to do so in a few short cycles. In cases where conception takes longer, other impediments may be present. These may be physical or genetic factors, which may require assistance from ART. However, the cause may simply be a compounding health variable such as a blatant nutritional deficiency. Appropriate investigations, as discussed later on in this chapter, will elucidate the approach required.

Couples should be encouraged to attempt conception during the fertile window. A recently ovulated egg will survive for only a few hours (maximum of 24 hours); however, sperm can survive for up to 5 to 6 days in the presence of fertile-quality cervical fluid. The fertile window is best defined as the 6-day interval ending on the day of ovulation.⁹ As estrogen increases in the female in the lead up to ovulation, she produces fertile-quality cervical fluid, which protects the sperm from the acidic pH of the vagina, provides a medium in which it can travel, and provides nutritional sustenance for it to survive on its journey.

A widely held misconception is that frequent ejaculations decrease male fertility. A retrospective study analyzed 9489 men with normal semen quality, sperm concentrations, and motility and found that profiles remained normal even with daily ejaculation.¹⁰ Of more importance is the finding that males with abnormalities such as oligozoospermia, lowered sperm count, and poor motility concerns may be improved with more frequent (daily) ejaculation.¹⁰

In supporting patients with natural conception, ovulation detection is a key component. Box 179-1 includes the main methods available and highlights their most appropriate application.

BOX 179-1 Ovulation Detection

Fertility charting incorporates consideration of basal body temperature (waking temperature) and changes in both cervical fluid and cervical position.

Waking temperature is a hindsight measurement that confirms ovulation occurrence. It is only able to assist in predicting ovulation once a woman is aware of her cyclic changes. It is used to confirm the luteal shift to progesterone and is beneficial for assessing the lengths of the follicular and luteal phases. It is also used to assess progesterone stability in the luteal phase to support implantation and pregnancy; it can also confirm anovulatory cycles. Progesterone causes the endometrium to support the implantation of a fertilized ovum. It also causes temperature to rise perceptibly, typically 0.4° F/0.2°C. Temperature is best taken immediately on waking after a minimum of 6 hours of unbroken sleep via oral assessment.

Fertile-quality cervical fluid is produced 3 to 5 days prior to ovulation in response to increasing estrogen levels prior to the LH surge. Sperm can theoretically survive for 5 to 6 days in the presence of fertile-quality cervical fluid. The role of cervical fluid is multifaceted; it buffers the pH of the vagina to provide a hospitable environment for sperm survival; provides a medium for sperm to swim in on their journey through the female’s reproductive system; provides nutritional supplementation for sperm survival; and acts as a lubricant to increase sexual pleasure and increase frequency of intercourse, thus providing more opportunities for conception. Assessment should be conducted from the vagina (inserting a finger into the vaginal opening and extracting fluid for assessment) rather than relying on toilet paper or underwear changes.

Cervical position assessment is the most controversial of self-assessments, with reproductive specialists often discrediting its value. This is because the position of the cervix is affected by numerous variables, including the timing of bowel movements. The cervical tissue is responsive to fluctuations in estrogen and produces physical and tangible changes when ovulation is approaching. Signs of fertility include a softening, opening of the cervical os, increased wetness from cervical fluid, and a lengthening of the vaginal canal as the cervix shortens away from the vaginal opening. Signs of infertility include a closed os, hardening, shortening, and dryness.

Urine–based ovulation testing detects the LH surge that occurs prior to ovulation, typically occurring 24 to 36 hours before ovulation. Testing can produce false positives and is inadvisable in women with PCOS or other, similar conditions due to LH increases in these populations. Additionally, because sperm require an optimal 2 days’ travel time, detection of the LH surge can often be too late to optimize conception. It is therefore advisable to make sure that all variables are synchronistic rather than isolated. Additionally, there are some women whose LH surge is shorter (12 hours or less). This can occur in those with hyperprolactinemia and other conditions that interfere with FSH/LH secretion from the anterior pituitary. In these individuals it is advisable to encourage LH testing twice a day (i.e., morning and night), as they can often “miss” the surge.

Saliva assessment testing and tools base their justification on the premise that with increasing estrogen fluctuations, changes in cervical fluid are synchronistic with other fluid media including saliva. Fertility potential is detected by the presence of a “ferning” pattern in the saliva (viewed by microscopy) suggestive of a synchronicity in cervical fluid changes that enable sperm travel. This method is inappropriate for older patients owing to natural estrogen reductions and is also not optimal for hypothyroid patients because of the relationship between estrogen and thyroid function. Additionally, caution with patients experiencing estrogen displacement, such as those with fibroids and/or endometriosis, is advisable.

Diagnostic Considerations

Female Reproductive Assessment

A thorough assessment of the female patient is crucial to accurately determine her general and fertility health. Some of these assessments may require referral to a fertility specialist, gynecologist, or endocrinologist; however, thorough questioning should be conducted by the naturopath to elucidate a full history and assess causative or contributing factors (Table 179-2). All fertility patients should be screened with the queries in Table 179-3, and stage 1 investigations should be conducted with all fertility patients (Table 179-4).

TABLE 179-2 Fertility Enquiry

ASSESSMENT	ELABORATION AND EXPLANATION
Age	What are the ages of the couple?
Fertility history	How long have they been trying to conceive, and have they ever conceived previously (together/separately)? Do they have any idea why they have not been able to conceive?
Sexual history	Potential sexually transmitted disease exposure, symptoms of genital inflammation (e.g., vaginal discharge, dysuria, abdominal pain, fever)
Medical history	Genetic disorders, endocrine disorders, history of pelvic inflammatory disease
Medication history	Hormone therapy, contraceptive pills, psychotropics, NSAIDs
Surgical history	Such as previous reproductive or genitourinary surgery
Contraception	When it was ceased and the likely speed of its reversibility
Fertile times	Whether the couple engage in regular intercourse during fertile times
Lifestyle factors	Diet, exercise, alcohol, smoking cessation, recreational drug use, caffeine, environmental toxin screen
Prior paternity	Previous fertility
Psychosexual issues	Interference with conception
Pubertal development	Poor progression can suggest underlying reproductive issue; initial query regarding age of menarche and secondary sexual characteristics to eliminate Turner’s syndrome and the like
Physical examination	Breast formation
	Galactorrhea
	Genitalia (e.g., patency, development, masses, tenderness, discharge)
	Signs of hyperandrogenism (e.g., hirsutism, acne, clitoromegaly)
	Body-mass index and waist:hip ratio to assess weight impact

Modified from Hechtman, L, 2011, Clinical naturopathic medicine. Sydney, Australia: Elsevier; 2011.

TABLE 179-3 Stage 1 Investigations

ASSESSMENT	TIMING IN CYCLE	JUSTIFICATION
Follicle stimulating hormone (FSH)	Day 3	Stimulates follicle development. High levels can indicate menopause or declining fertility; query primary ovarian failure. Useful to assess ratio comparative to LH to ensure that hormone status is optimal. Eliminates primary ovarian failure.
Luteinizing hormone (LH)	Day 3 or preovulation (day 13)	Triggers ovulation when surges, excessive levels may indicate PCOS. Useful to assess ratio comparative with FSH to ensure hormone status is optimal.
17-OH Progesterone (P4) (17-hydroxyprogesterone)	Day 21 (7 days postovulation)	Evaluates adequacy of progesterone, confirms ovulation. Eliminates luteal phase defect.
Prolactin (PRL)	Any day	Inhibits ovarian production of estrogen, inhibitory role with progesterone if high, stimulates production of breast milk.
Estradiol (E2)	Day 3	Stimulates egg maturation and endometrial maturation for implantation; responsible for fertile quality cervical fluid.
Testosterone (TT), Free Androgen Index (FAI), androstendione	Any day	Eliminate Polycystic Ovary Syndrome (PCOS) or testosterone dominance.
Specific Hormone Binding Globulin (SHBG)	Any day	Evaluates if concentration of SHBG is affecting the amount of testosterone available to body tissues
Transvaginal ultrasound	Day 7	Evaluates follicle maturation, ovulation, endometrial thickness, and character. General assessment of pelvic organs for diagnosing abnormalities of the uterus and ovaries. Assesses thickness and appearance of endometrium to be followed. Enables antral follicle count.
β-hCG	Any day	Eliminate pregnancy or tumor.
Anti-Mullerian hormone (AMH)	Any day	Assesses ovarian reserve (best when combined with antral follicle count through ultrasound).
General Health Screen
CBC, UEC, LFT, iron studies, TSH and urinary iodine (24-hour or morning spot) Serum zinc and copper (including ratio); ceruloplasmin red cell folate, serum vitamin B₁₂, homocysteine, 25[OH]D, Fasting glucose, cholesterol profile, celiac screen, Pap smear	NA	General health assessments to eliminate other abnormalities.
General Pre-pregnancy Screen
Blood group and agglutinins, infectious disease screening, rubella immunity	NA	General pre-pregnancy assessments.
Cervical Swab and Urinalysis
Bacterial culture, screen for sexually transmitted infections	NA	Assess for infective pathogen compromising fertility. General urinalysis to eliminate underlying infection or abnormality. Urogenital infections have been found to play a part in the genesis of miscarriage ¹¹ and infertility¹³; however, patients may be unaware of their presence owing to the asymptomatic nature of many infections. Screening for a range of genitourinary infections is necessary in preconception care to detect possible infection and thus barriers to conception. The most common and essential infections that require screening include: Primary genitourinary tract infections: Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Neisseria gonorrhea Secondary genitourinary tract infections: Gardnerella vaginalis, Group B Streptococcus, Beta-hemolytic Streptococcus, Staphylococcus aureus, Staphylococcus millerii.
Other Fertility Assessments
Waking temperature, cervical fluid assessment, cervical position assessment, ovulation testing (urine), ovulation testing (saliva)	Various	Assessment and interpretation of self-directed assessments (if used). See Box 179-1 for further discussion.
Other Considerations
Salivary hormone screen, including reproductive and adrenal	NA	Salivary screen provides an advantage over blood levels in yielding significantly greater accuracy for interpretation of findings. The adrenal hormone profile determines adrenal function and may help to determine the presence or extent of acute and/or chronic mental and/or physical stress. Prolonged stress has been shown to have suppressive effects on the fertility of both the male and female. Of importance, it is likely to have a profound impact on gonadotropin release (FSH, LH).
Nutrient and toxic element screening	NA	Assessment of toxic elements including aluminium, arsenic, cadmium, lead, and mercury is crucial so that these can be eliminated as causative or contributing factors. It is widely accepted that excessive exposure to heavy metals has detrimental effects on fertility¹⁴ and must therefore be assessed and remedied during the preconception period.
Environmental screen	NA	Other environmental assessments including those that check for porphyrins, PCBs, chlorinated pesticides, volatile solvents, phthalates, parabens, and other toxins. These should additionally be considered owing to their deranging effects on reproductive function, endocrinology, gamete development, and thus embryologic potential.

Modified from Hechtman, L, 2011, Clinical naturopathic medicine. Sydney, Australia: Elsevier; 2011.

TABLE 179-4 Stage 2 Investigations

ASSESSMENT	TIMING IN CYCLE	JUSTIFICATION
Thyroid antibodies and reverse T₃	NA	Indicated if thyroid function appears compromised, ovulation potential is reduced, or patient appears to have implantation issues
Sperm antibodies (serum)	NA	Determines whether antibodies are present against the partner’s sperm. If blood results are positive, cervical mucus sperm antibodies may be required.
Laparoscopy, hysteroscopy, and salpingoscopy	Before ovulation	Inspection of uterotubal junctions. Diagnosis and treatment of pelvic diseases (endometriosis) or adhesions. Hysteroscopy complements hysterosalpingography (HSG) in revealing pathology that disturbs the shape of the endometrial cavity, especially intrauterine adhesions, submucosal fibroids, and endometrial polyps. These can be diagnosed with HSG, but hysteroscopy is required to locate the pathology accurately and treat it accordingly.
HSG ± selective salpingogram (if indicated)	Day 7	Vaginal examination and injection of radiographic fluid into the uterus and fallopian tubes on x-ray. Determines if fallopian tubes are clear and uterine cavity is normal.
Clomid challenge test	Day 3, FSH and estradiol Day 10, FSH	Determines ovarian reserve and if pregnancy can occur before assisted reproductive techniques are implemented.
Curettage or endometrial biopsy	Day 26 (just before menses are expected)	Reveals the tissue structure of the endometrium. Estimates normal ovulation owing to timing. Not advised regularly because of risk of scarring.
Other	NA	If all results show no abnormality or if the patient is more than 38 years old, the clinician is advised to consider a number of miscarriage assessments to improve outcome, because a number of these assessments are associated with implantation failure as well as miscarriage (see Table 179-5)

Modified from Hechtman, L, 2011, Clinical naturopathic medicine. Sydney, Australia: Elsevier; 2011.

Complications

Miscarriage

The comprehensive coverage of the topic of miscarriage is beyond the scope of this chapter. Because the incidence is as high as one in four pregnancies,¹⁶ the prudent naturopath should be informed about the background, useful assessments, and treatment approaches to miscarriage as part of the holistic approach to female fertility.

Implantation of the developing embryo into the receptive endometrium is a critical and key event in the establishment of early pregnancy. The unique process of cell adhesion of the trophoblast to the endometrium at the time of implantation and its subsequent invasion into the maternal tissue is dynamically balanced through the expression of specific cell adhesion molecules and endocrine, paracrine, and autocrine signals. The process can be viewed as a series of distinct events, many of which are similar to those of an inflammatory reaction and are greatly influenced by the factors present in the uterine microenvironment, including hormones, growth factors, and inflammatory and proinflammatory cytokines.¹⁷ The secretion of a number of factors achieves modulation of the immunologic response of the trophoblast. Cytokines produced at the fetal-maternal interface play a key role in regulating maternal tolerance to the fetus and successful pregnancy.

Although approximately 25% of all recognized pregnancies result in miscarriage, less than 5% of women will experience two consecutive miscarriages and only 1% experience three or more.¹⁶ Recurrent pregnancy loss is a disease distinct from infertility, defined by two or more failed pregnancies.¹⁸ When the cause is unknown, each pregnancy loss merits careful review to determine whether specific evaluation may be appropriate. Although the general consensus is to evaluate after three or more losses, it is more in keeping with the naturopathic paradigm to review all patients even after the first and more comprehensively after the second or subsequent miscarriage.

The risk of miscarriage is highest immediately after implantation. It is thought that around 50% of all fertilized eggs do not survive, coming away with a normal (or slightly late) period. This is often referred to as an “unnoticed miscarriage” because it is usually not formally acknowledged by the woman, who is never aware of her pregnancy.

In summarizing the possible clinical scenarios, it is useful to group them into three distinct categories:

1. For a healthy, viable pregnancy to initiate and continue successfully, a number of biochemical, anatomic, and molecular events must occur in a systematic and timely manner. Any deviation can disrupt the process and abort the pregnancy.

2. Overlapping clinical continuum of presentation can conflict with or complicate the fertility presentation. Each clinical presentation has the potential to present as infertility (occult implantation failure), subclinical or clinical miscarriage in the first trimester, a fetal loss in the mid-trimester before viability, a premature birth, or as a birth defect presenting at or after term. Each presentation is unique and must be considered holistically and individually.

3. The number of similarities between previous miscarriages (if any) can enable the clinician to ascertain the most definitive scenario and develop and adjust treatment accordingly.

4. As seen in Table 179-5, various conditions can be associated causally or coincidentally with miscarriage.

TABLE 179-5 Miscarriage Screen

Key
General medical or naturopathic referral
Reproductive endocrinology and infertility subspecialist
Research interest in recurrent miscarriage

ASSESSMENT	JUSTIFICATION	INTERPRETATION
On presentation: at any time in the ovarian (menstrual) cycle
General health screen including CBC, LFT, UEC, fasting glucose, blood group, and agglutinins	General medical checkup	Various; assess for compounding factors.
Red cell folate, serum vitamin B₁₂	Unsuspected folate deficiency; if low, test fasting serum homocysteine.	Folate supplementation in vitamin B₁₂ deficiency masks pernicious anemia and the risk of subacute spinal cord degeneration. RBC and serum are not definitive assessment tools for these nutrients. Additional assessments may be warranted.
Fasting homocysteine	Elevations can correlate with vitamins B₉ and B₁₂ findings, presence (or absence) of MTHFR polymorphism and coagulation or vascular abnormalities	Treat as indicated with high doses of vitamins B₆, B₉, and B₁₂. Correlate findings with vitamins B₉ and B₁₂ and MTHFR status.
Thyroid function tests (TFTs)	Although mild hypothyroidism is strongly associated with anovulation, even mild hyperthyroidism is strongly associated with miscarriage	It is important to keep all aspects of a TFT well within normal limits: avoid even slightly excessive thyroid replacement in cases of hypothyroidism.
Antithyroglobulin Abs (TG Abs), Thyroid Peroxidase Abs (TPO Abs), TSH receptor Abs	The presence of thyroid antibodies can occur with a normal TFT (especially TPO Abs) and is strongly correlated with a first trimester miscarriage	Miscarriage is increased in the presence of any of the thyroid Abs directly correlating with immune modulation requirements of gestation (i.e., implantation and throughout the first trimester at individual increments).
Fasting plasma glucose	Assess for preclinical diabetes, If raised, assess insulin and HbA1c (± GTT) and assess for PCOS factors	Miscarriage is increased in overt diabetes and PCOS.
Serum testosterone, free androgen index, SHBG, +/− androstendione.	Screen for PCOS. If results are positive, confirm with day 7 ultrasound.	Miscarriage is more likely to occur due to disordered follicular development and oocyte function.
Serum gliadin antibodies (IgG, IgA), serum IgA levels and antibodies to tissue transglutaminase or endomysial antibodies. If the patient is already on a low-gluten or gluten-free diet, referral for celiac gene screen is advisable. Note that it is only 95% accurate and a negative reading is not conclusive.	Asymptomatic celiac disease an occasional (though not unequivocal) cause of unexplained infertility or repeated miscarriage. Underdiagnosed in young adult women (population prevalence 1:250 and satisfies WHO criteria for population screening ²⁰)	Confirmation is via small bowel biopsy needed for diagnosis, however, this will require consumption of gluten for three months. Objective clinical opinion is required to warrant this necessity in the fertility context. Note that missing celiac disease in a woman with otherwise unexplained reproductive dysfunction might prove embarrassing when, later, it manifests more classically. Classic presentation may include marked anemia and/or general nutritional deficiencies
Pregnancy infection screen (rubella, Hep B, Hep C+, HIV, toxoplasmosis, CMV, EBV)	Each infection can correlate with miscarriage eventualities (dependent on each infection and timing in pregnancy)	As indicated with each assessment.
Serum copper, serum zinc, and ceruloplasmin	Wilson’s disease, a rare copper storage disorder, can present in young women with repeated miscarriage before other symptoms and signs develop (liver disease, Kayser-Fleischer rings, cerebral dysfunction).²¹ Screen for high copper and ceruloplasmin levels; confirm with elevated 24-hour urinary copper excretion (and then liver biopsy). In assessing zinc status, a 1:1 zinc:copper ratio should be observed. Zinc supplementation can then be calculated on an as-required basis.	Population prevalence is ~1:30,000 (in any ethnic group); ATP7B mutant gene carrier frequency is ~1:90; more than 100 mutations are known and affected people are usually compound heterozygotes. Possible mechanism: raised copper levels in uterine secretions compromising mitochondrial function in the conceptus. Additionally, raised copper levels are antagonistic to zinc absorption and will warrant supplementation. Depending on copper reading, treatment with copper-binding agents may be required and has been shown to reverse pregnancy losses.
Prolactin and βHCG	Assess impact of these hormonal levels on pregnancy sustenance and achievement	Address as indicated; typically, hormonal modulation is required to ensure that hormone levels are optimal for each stage of pregnancy (and preconceptually).
Karyotype, peripheral blood (both partners)	Assess for balanced chromosomal translocation in either partner. If an imbalance is detected, couples are prone not only to conceive embryos with unbalanced translocations: their unstable meiotic spindles also make otherwise unremarkable aneuploidies more common.	Referral for genetic counseling to estimate unbalanced chromosomal segregation patterns and initiate PGD if required.
Hysterosalpingogram	To assess tubal patency and fallopian tube structure	Address as relevant
Antinuclear antibody, anticardiolipin antibody (IgM, IgG), lupus inhibitor/anticoagulant, Immunoglobulin A (IgA)	Screening for the antiphospholipid syndrome, either secondary to SLE or, more commonly but often less aggressively, primary	Lab testing for anticardiolipin antibody is not well standardized and interpretations of isolated elevations are difficult. SLE requires referral to immunologist or rheumatologist. Treatment of definite cases is treated through allopathic means with low-molecular-weight heparin, vaginal progesterone (immunosuppressive locally), corticosteroids, and occasionally plasmapheresis. Naturopathic means include immune modulation, blood coagulation normalization, and dietary modification to support appropriate immune and hematologic systems.
CA-125	Presence does not automatically confirm cancer; however, it can correlate with cancerous conditions, endometriosis, or proliferative disorders	In instances of endometriosis can indicate increased development, poor management, or contributing factors to miscarriage
Anti-TjA antibody (anti-PP1Pk hemolysin)	Rare but well described²²	Plasmapheresis and immunoglobulin replacement during pregnancy can enable term delivery²³
Thrombophilia screen	Protein S, protein C, activated protein C (APC) resistance, Anti-thrombin III	Protein S deficiency: second trimester miscarriage increase x 7.4. Protein C deficiency: less convincing APC resistance: first trimester x 2.1, second trimester x 3.317.
Thrombophilia PCR testing (DNA assessments)	Test for Factor V Leiden, prothrombin G20210A, MTHFR C677T and A1298C	Meta-analysis ²⁴ reports the following increased risks of miscarriage with homozygosity: Factor V Leiden: first trimester x 2.1, second trimester x 3.3. Prothrombin G20210: first trimester x 2.3, second trimester x 2.3. MTHFR alleles (increase miscarriage risk with elevated homocysteine): x 4.3 (if controlled with adequate folate may actually protect against miscarriage and intrauterine growth retardation). The naturopathic model also acknowledges the impact of MTHFR on folate metabolism and its subsequent effects on ensuring that DNA replication within each cell (including the cells of the fetus) is consistent. Additionally, folate is responsible for a number of other roles in the body. Therefore, an MTHFR abnormality can correlate with a number of other health concerns regardless of homocysteine status.
Anti Mullerian Hormone (AMH)	Reduced levels may indicate failing ovarian reserve. Increased levels can indicate PCOS.	Interpretation is controversial, however, in instances of reduced AMH, refer to fertility specialist and possibly concurrent ART.
Day 2 of the menstrual cycle
Serum FSH, LH, estradiol (E2) NB: ovulation tracking over 2 cycles is advisable (E2, LH, and P4)	Reduced oocyte numbers: serum FSH > 11 U/L PCOS: suspected when LH:FSH (U/L) > 2:1. In either case, E2 > 200 pmol/L = more severe. Correlate any findings with a day 7 ultrasound.	Low oocyte numbers: risk of early menopause; IVF may be indicated if also infertile. PCOS: requires additional treatment changes, incidence correlates highly with increased miscarriage risk.
Day 7 of the menstrual cycle (or estimated 1 week prior to ovulation)
Transvaginal ultrasound
Uterine assessment	Normal endometrium is > 5 mm thick and echolucent (thick echogenic endometrium means hyperplasia or polyp; if it is thin, consider endometritis). Assess for fibroid or diagnose other uterine abnormalities.	Treat specific to finding (i.e., thin endometrium will require progesterone support; thick endometrium will respond to uterine tonics, such as herbal medicines) and antioxidant regulation. For fibroid-specific treatment, see Chapter 212.
Ovarian assessment	Follicles present in the ovary indicate the typical number of eggs achievable: many peripheral follicles indicate PCOS; few follicles can indicate premenopause (or oopause).	If PCOS, low follicle numbers or endometriotic cyst, specialist management is indicated, possibly including IVF.
Vaginal and cervical swabs and culture (cervical swabs are often indicated for the most accurate interpretation)	Vaginosis, either Gardneralla vaginalis or other organismal overgrowth, with loss of Lactobacillus. Primary genitourinary infections: Chlamydia trachomatis, Ureaplasma urealyticum, Mycoplasma hominis, Neisseria gonorrhoeae Secondary genitourinary infections: Gardnerella vaginalis, group B Streptococcus, beta-hemolytic Streptococcus, Staphylococcus aureus, Staphylococcus millerii	Urogenital infections have been found to play a part in the genesis of miscarriage ^26,¹² and infertility¹³; however, patients may be unaware of their presence due to the asymptomatic nature of many infections. Midtrimester (and later) pregnancy losses can occur after internal cervical os becomes covered by growing sac, at 13 weeks. Vaginal flora modulation is required. Herbal douches, probiotic supplementation, and in some instances, antibiotic treatment.
7 days post ovulation (typically days 21-28)
Serum progesterone (P4)	Screen for ovulation confirmation	If <35 nmol/L, consider further investigation confirming ovulation. Support progesterone cascades as required.
12 days postovulation (premenstrual phase)
Premenstrual endometrial biopsy for dating	Check integrated action of almost 2 weeks of progesterone on decidualizing the endometrium; confirm progesterone falling to low level and negative ßhCG day before test. Extremely time-critical investigation: usefulness lost if performed in midluteal phase.	Often deficient stromal decidualization in disorders of ovulation (adjust treatment as indicated if present). A deficiency can also indicate endometrial atrophy (which can be untreatable) or, rarely, a molecular defect: in these two cases, gestational surrogacy may be the only treatment option. Best screen for rare molecular bases for decidualization failure causing implantation failure.
Premenstrual endometrial biopsy for lymphocyte (T-cell) subsets on immunocytochemistry [with adjunct T-cell subsets in blood]	Specialist labs can look for relative abundance of peripheral NK cells (CD57+) versus normal uterine (CD56+) NK cells in relation to T cell numbers²⁵	If unfavorable, consider vaginal progesterone during early pregnancy. Relevance of findings is conflictual. Naturopathic treatment measures adapt to module the immune response in relevant instances.

Key: CBC (complete blood count), CMV (Cytomegalovirus), GTT (Glucose Tolerance Test), IVF (In Vitro Fertilization), MTHFR (Methylene Tetra Hydro Folate Reductase), PCOS (Polycystic Ovary Syndrome), PGD (Pre Genetic Diagnosis), RBC (Red Blood Cell), RM (Recurrent Miscarriage), SHBG (Sex Hormone Binding Globulin), SLE (Systemic Lupus Erythematosus), TPO (Thyroid Peroxidase Antibodies), WHO (World Health Organisation).

Data from Jansen R., Gee A. Testing for miscarriage. O&G Magazine 2008: 10(2):48-52.

TABLE 179-6 Summary of Nutrient Considerations to Promote Fertility

Vitamin A^a	3000-5000 IU/day
Vitamin B₁ (thiamine)	50-100 mg/day
Vitamin B₂ (riboflavin)	50 mg/day
Vitamin B₃ (niacin)	50-200 mg/day
Vitamin B₅ (pantothenic acid)	50-200 mg/day
Vitamin B₆ (pyridoxine)	50-250 mg/day
Vitamin B₉ (folic acid)	800-5000 mcg (dependent on MTHFR status and homocysteine levels)
Vitamin B₁₂ (cyanocobalamin)	800-5000 mcg (reflecting vitamin B₉ with a 1:1 ratio where possible)
Vitamin C	1000-4000 mg/day in divided doses
Vitamin D3^b	1000-5000 IU/day (decrease to 1,000 IU/d in summer and 2,000 IU/d in winter when repleted)
Vitamin E (mixed tocopherols and tocotrienols)	500-1000 IU/day
Vitamin K^c	2-75 mg/day
Beta carotene	10-30 mg/day
Coenzyme Q10	100-300 mg/day in divided doses
Calcium	1000-1500 mg/day
Chromium^d	100-1000 mcg/day
Copper^e	2-4 mg/day
Iodine^f	200-400 mcg/day (decrease to 200 mcg/day when repleted)
Iron^g	10-100 mg/day
Magnesium	500-1000 mg/day
Selenium	150-300 mcg/day
Zinc	40-80 mg/day (decrease to 25 mg/day when repleted)
Total omega-3 essential fatty acids	1000-5000 mg/day
Docosahexaenoic acid (DHA)	400-700 mg/day
Eicosapentaenoic acid (EPA)	800-1000 mg/day
Total omega-6 essential fatty acids	1000-2000 mg/day
Evening primrose oil	1000-1500 mg/day
L-Arginine	3000-10,000 mg/day
L-Carnitine	1000-4000 mg/day
Probiotics (mixed strains)	25-50 × 10⁹/day