**3.1. Pathogenesis**

This technique is currently the most used fertilization treatment worldwide and it has deeply increased the chances of successful fertilizations and pregnancies; ICSI technique allows to have the same fertilization and pregnancy rates between CF males and men with no vas

Although most men with CF have significant anatomical abnormalities of the reproductive tract, most CF women have an anatomically normal reproductive tract and may be able to conceive spontaneously, but in literature it is reported that only slightly more than half of them have spontaneous pregnancies. The fertility problems in CF female are multifactorial: the main cause would be the difficult transport of sperm through the female reproductive tract, secondary to thick secretions; but certainly also the underlying medical conditions (especially lung function and nutritional status) have a major impact on fertility in these patients. The improved health and longevity of CF women naturally leads to an increased number of CF

The first reported successful pregnancy in a CF woman was in 1960 [16], and in 1966 13 pregnancies in 10 different patients were reported [17]. These early reports were discouraging. However, with aggressive management of infections and significant improvement in pulmo‐ nary and nutritional interventions, pregnancies today are well tolerated in CF, especially in women with mild to moderate disease [18, 19]. The North American CF Registry reported in

2007 that 3–4% of CF women over 17 years old become pregnant each year [20].

deferens obstructive disease (Figure 6).

118 Cystic Fibrosis in the Light of New Research

**Figure 6.** ICSI technique

**3. Fertility in women with cystic fibrosis**

women who become or desire to become pregnant.

Despite CF has long been associated with female infertility, the underlying causes remain unclear. Actually, we know that the majority of CF women have a normal fertility, but ovulation disturbance may occur in patients with advanced disease [21], also with amenorrhea in the most compromised subjects. Although most girls have normal menstrual cycles, there is a higher incidence of missed or irregular periods and amenorrhea. This is more likely in those with a reduced percentage of body fat and may occur in case of malnutrition or alimen‐ tary disorders.

Fertility problems may be related to lung disease severity, poor weight, and to an unsatisfying control of CF-related diabetes [22]. Historically, the predictors of poor pregnancy outcome for mother and/or fetus were a forced vital capacity (FVC) of less than 50% of the predicted value and poor nutritional status. In the past, an FVC of less than 50% of the predicted value was an absolute contraindication to pregnancy.

For several years, it has been postulated that the thickened cervical mucus present in CF women reproductive tract could lead to fertility disturbance. Normally, when the egg is released from the ovary, cervical and uterine mucus thins and allows easier passage of sperm into the uterus and fertilization. Increased thickness of this mucus in women with CF may theoretically act as a barrier to sperm penetration and could reduce fertility, but nowadays the majority of women with CF can become pregnant without any difficulty.

In 2008, Hodges et al. [23] studied the mouse model of CF, indicating that in CF mice the major cause of decreased fertility is the impaired sperm transport within female reproductive tract. In their experience, excess cervical mucus played a minor role, because instead of a physical barrier, the decreased fertilization seemed to be due to an inadequate fluid production in reproductive system, with a subsequent decrease in sperm number in the oviduct. CFTR could play not only an important role in female reproductive tract fluid control but also in sperm capacitation with its bicarbonate transport.

### **3.2. Impact of pregnancy on CF**

The physiologic changes associated with pregnancy may contribute to increased morbidity and mortality risks for the mother in CF women. Volumetric increase of abdomen with the consequent upward displacement of diaphragm causes a decrease in functional residual volume, and the concomitant increase in resting minute ventilation can lead to a relevant breath disturbance. Also gas exchange has deep alterations in pregnant women, with an increased alveolar–arterial oxygen gradient, especially in supine position [24].

In a recent study [25], it is reported that adjusting for the FEV1 percent predicted, weight, height, and pulmonary exacerbation rate per year, pregnancy is not associated with an increased risk of death. Pregnancy did not appear to be harmful even in a subset of women with diabetes mellitus or with FEV1 less than 40% of predicted. Important predictors of pregnancy outcome for the fetus are the severity of maternal pulmonary impairment and nutritional status; in women with advanced lung disease, preterm delivery is very common.

McMullen et al. [26] in 2006 characterized health outcomes in CF pregnant women, comparing them with a group of never-pregnant CF population: this large observational study showed a nonsignificant difference in terms of FEV1 decline between the two groups (6.8% in pregnant group and 4.7% in never-pregnant, *P*=0.61). Respiratory exacerbations and hospitalizations were increased during pregnancy, as well as the number of outpatient visits and administered therapies.

The risk for congenital anomalies in the fetus is not increased in CF gravidas and breastfeeding is possible without complications.
