Abstract
Infertility is defined as the inability to conceive naturally after one year of regular unprotected intercourse. Most couples do not have absolute infertility but subfertility with a reduced chance of conception in each cycle due to one or more factors. Subfertility has major clinical and social implications and affects approximately thirteen to fifteen per cent of couples worldwide. In the United Kingdom, one in six to seven couples complain of infertility. Half of these couples will conceive either spontaneously or with relatively simple advice or treatment. However, eight per cent of the population remain subfertile and require more complex treatment with assisted reproductive techniques (ART) [1].
1 Introduction
Infertility is defined as the inability to conceive naturally after one year of regular unprotected intercourse. Most couples do not have absolute infertility but subfertility with a reduced chance of conception in each cycle due to one or more factors. Subfertility has major clinical and social implications and affects approximately thirteen to fifteen per cent of couples worldwide. In the United Kingdom, one in six to seven couples complain of infertility. Half of these couples will conceive either spontaneously or with relatively simple advice or treatment. However, eight per cent of the population remain subfertile and require more complex treatment with assisted reproductive techniques (ART) [1].
The incidence of female subfertility is rising and varies from ten to twenty per cent. On one hand lifestyle changes such as delayed child bearing, increasing weight, alcohol intake and smoking have a negative impact on fertility but on the other hand modern medicine has increased life expectancy for severe illnesses such that women with complex co-morbidities are now surviving to the child-bearing age and requiring help with conception. The causes of female subfertility are ovulation failure, tubal damage, endometriosis, uterine abnormalities, psychosexual disorders or a combination of the above, but equally may be unexplained.
2 Evaluation of the Subfertile Female
2.1 History and Examination
The assessment of infertility requires a detailed history from the patient and her partner. Examination should include measurement of body mass index (BMI), assessment for signs of endocrine disorders and a pelvic examination (Box 4.1).
Box 4.1 History, examination and investigations in women presenting with infertility
History
Age
Duration of infertility
Frequency and any difficulty with intercourse
Menstrual history
Menarche
Menstrual cycle length
Duration of menstrual blood loss
Dysmenorrhea
Oligomenorrhoea or amenorrhoea
Intermenstrual bleeding
Surgical history
Previous abdominal or pelvic surgery
Medical history
Thyroid disease
Chronic illness
Previous chemo or radiotherapy
Obstetric history
Number of previous pregnancies, including miscarriages, ectopic pregnancies and termination of pregnancy
Gynaecological history
Cervical smear history
Previous pelvic infection and STI
Previous contraceptives duration and type
Drug history
Family history
Genetic defects
Birth defects
Medical disorders
Tobacco and marijuana smoking
Alcohol intake
Caffeine intake
Examination
Body Mass Index
Fat and hair distribution
Thyroid nodules or enlargement
Galactorrhea
Signs of androgen excess
Abdominal masses or tenderness
Pelvic examination
Investigations
Early follicular phase LH/FSH
Mid-luteal progesterone
HSG/HyCoSy
Rubella status
Screen for chlamydia
HIV/Hep B/Hep C (prior to ART)
3 The Impact of Lifestyle Factors on Female Fertility
3.1 Age
A woman’s age is one of the most important determinants of her fertility. Up to twenty-five years of age the cumulative conception rate is sixty per cent at six months and eighty-five per cent at one year. By the age of thirty-five years the cumulative conception rate is half of this [2]. The incidence of genetic abnormalities and miscarriage also increases with advancing age. The chance of a live birth after ART also varies with the woman’s age, with the chance of a live birth significantly decreased after thirty-five years of age and less than fifteen per cent above the age of forty years [3].
3.2 Weight
Fecundity has been found to be lower at extremes of BMI in women trying to conceive spontaneously and with assisted conception. Time to pregnancy is increased among obese women compared to women of normal weight and the chance of conception falls with increasing BMI. Being underweight (BMI less than twenty) is also associated with reduced fecundity among nulliparous women.
3.2.1 Obesity
Obesity is now a common problem in women of reproductive age. The relationship between obesity and subfertility is well documented and obesity is known to be associated with anovulation, irregular menstrual cycles, miscarriage and adverse pregnancy outcomes. The mechanisms responsible for these effects are however complex, multifactorial and still not fully understood. Some of the factors that may contribute include insulin resistance, hyperandrogenaemia and changes in leptin, adipokine and steroid concentrations [4].
A number of hypotheses have been developed to explain the effect of obesity on female fertility by studying the outcomes of obese women undergoing ART and animal models of obesity. Obese women undergoing ART are less likely than women of normal weight to achieve a clinical pregnancy due to decreased clinical pregnancy rate, increased early pregnancy loss and reduced live birth rates [5]. Whether obesity affects fertility through poorer oocyte or embryo quality, impairment in embryo implantation or a combination of these factors is unknown.
It is evident that weight loss among overweight and obese women improves fertility. The British Fertility Society recommends that ART should not be recommended in women with a BMI greater than thirty. Even a small weight loss in anovulatory, obese, subfertile women results in improved ovulation, pregnancy rate and pregnancy outcome. However, the effect of weight loss in overweight and obese women with regular menstrual cycles is still unclear. Bariatric surgery may be considered in women with a BMI of forty or higher (or thirty-five and above with sleep apnoea/diabetes/cardiac disease); however, there is limited evidence about its effect on fertility. Data from observational studies suggest it improves menstrual regularity, ovulation and thus fertility [6]. To avoid nutritional deficiencies, pregnancy should be delayed for one to two years following surgery.
3.2.2 Underweight
Being underweight and having extremely low amounts of body fat are associated with ovarian dysfunction and subfertility. The risk increases in women with a BMI less than seventeen by affecting the hypothalamo-pituitary-ovarian axis and causing hypogonadotrophism that leads to a down stream hypogonadism. In general, weight gain restores ovulatory function and consequent fertility.
3.3 Smoking
Female smokers have an increased risk of infertility compared to non-smokers. This is due to reduced ovarian function and reserve and altered hormone levels with higher FSH and lower luteal progesterone. There is also evidence of impaired tubal oocyte pick up and transport of the fertilized embryo within the oviduct [7]. Women trying to conceive should be advised to stop smoking and be referred for smoking cessation counselling.
3.4 Alcohol
High alcohol consumption is associated with sub-fertility. This is thought to be due to hormonal fluctuations leading to increased oestrogen and reduced FSH levels and thus reduced ovulation [8]. Women trying to conceive either naturally or through ART should be advised to limit alcohol intake or not drink alcohol at all.
3.5 Caffeine
Excessive caffeine consumption (greater than five hundred milligrams per day) has been associated with increased time to pregnancy, increased risk of miscarriage and stillbirth. While the exact mechanism by which caffeine affects fertility is unknown, it may be related to caffeine causing reduced oocyte and embryo quality [9]. Women with subfertility should be advised to limit caffeine consumption although the exact safe threshold remains unclear.
3.6 Existing Illnesses
Many pre-existing illness can have an impact on female fertility; common examples include Turner’s syndrome, severe renal, hepatic, respiratory and cardiac disease, diabetes and the effects of cancer treatment. These patients require careful pre-pregnancy counseling and consideration prior to ART.
Both clinical and subclinical hypo and hyperthyroidism are associated with subfertility and recurrent miscarriage. In women with hypothyroidism, maintaining serum TSH levels below 2.5 mU/l pre-conceptually may be associated with improved fertility [10].
4 Investigation and Management of Female Subfertility
4.1 Tubal Factor
The Fallopian tube is the site for fertilization and not only needs to be patent but also function effectively as damage to the tubes can effect sperm transport, oocyte pick up and fertilization and transport of the embryos to the uterus.
Tubal factor infertility is caused by tubal obstruction, endosalpingeal destruction and peri-adenexal adhesions. Pelvic inflammatory disease (PID) secondary to Chlamydia trachomatis is the most common etiology representing greater than fifty per cent of cases. One episode of PID increases the rate of subsequent infertility by eight per cent; two or three episodes increase it further by twenty and forty per cent respectively. Other infective causes of tubal disease are Neisseria gonorrhoeae, Actinomyces isrealli (a rare complication of intrauterine devices) and in the developing world, genital tuberculosis. The other potential causes of tubal disease are complicated appendicitis, endometriosis, previous ectopic pregnancy and congenital abnormalities.
Distal tubal obstruction is the most common site of tubal disease. It is caused by salpingitis secondary to any pelvic inflammatory condition namely infection, endometriosis, appendicitis and abdomino-pelvic surgery. Mid-tubal obstruction is usually iatrogenic from tubal sterilization. Proximal tubal obstruction occurs in only fifteen per cent of women. It can be due to salpingitis isthmica nodosa (nodular thickening of the tunica muscularis of the isthmic portion of the Fallopian tube), mucus plugs, endometriosis, tubal polyps or congenital tubal obstruction.
Before tubal patency is assessed, both semen analysis and assessment of ovulation should occur. Women without co-morbidities should be offered a hysterosalpingography (HSG) or hysterosalpingo-contrast-sonography (HyCoSy) as a screening test for tubal patency. In women with a history of PID, previous ectopic pregnancy or symptoms suggestive of endometriosis, a laparoscopy and dye should be offered. Salpingoscopy and falloposcopy allow direct visualization of the internal tubal mucosa but are not used in routine practice.
The main determinants for the prognosis of pregnancy in women with tubal disease are the severity, the site and the nature of the disease. There are two therapeutic options: tubal surgery or ART. Reconstructive tubal surgery aims to correct damage to the Fallopian tube and restore the normal anatomical relationship between the fimbriae and ovary.
Counselling patients with tubal infertility regarding corrective surgery versus ART is complex and requires a number of considerations [11]. The advantages of tubal surgery are that it involves a single procedure, it is usually minimally invasive, patients may attempt conception every month without further intervention and may conceive more than once. They also avoid the complications of ART. However, the disadvantages are the risks of the procedure, the surgical expertise required and the increased risk of ectopic pregnancy. Several patient factors are important and include maternal age, ovarian reserve, prior fertility and the site and extent of disease.
The advantage of ART is the improved per cycle success rates and reduced invasive surgery. However the disadvantages are the need for frequent hormonal injections, monitoring, risks of multiple pregnancy and ovarian hyperstimulation syndrome. A recent Cochrane review comparing the probability of a livebirth following tubal surgery compared with expectant management or in vitro fertilization (IVF) in the context of tubal infertility (regardless of grade of severity) was inconclusive due to a lack of randomized control trials [12].
4.1.1 Tubal Surgery Prior to ART
Numerous studies have shown that hydrosalpinges have a detrimental effect on IVF success rates thought to be due the direct embyrotoxic effects of the fluid from within the hydrosalpinx. Randomized control trials have shown that laparoscopic salpingectomy in women with hydrosalpinges prior to IVF improves IVF success rates. A recent Cochrane review concluded that laparoscopic salpingectomy or occlusion should be considered for all women with a hydrosalpinx prior to IVF treatment [13]. The couple should be counselled regarding tubal pathology and be given the option of treating the hydrosalpinx. However, the possible effects of surgery on the ipsilateral ovary and the reduced chance of spontaneous conception post treatment should also be considered.
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