Preinvasive disease

Neither the disease nor the pregnancy affect each other.

Invasive disease

Vaginal bleeding is the most common symptom regardless of pregnancy. During pregnancy, however, the bleeding may be mistaken for threatened miscarriage or antepartum haemorrhage. Failure to inspect the cervix, and being only interested in the viability of the pregnancy by an ultrasound scan, can delay the diagnosis considerably, leading to major management problems. There is no evidence to suggest that the pregnancy worsens the outcome of the disease. These women have similar survival rates, stage for stage, as non-pregnant women.

Preinvasive disease

The diagnosis of cervical intraepithelial neoplasia (CIN) on a Pap smear must lead to a proper visual examination of the cervix under good light. If no obvious lesion is seen, a colposcopy should be carried out by someone who is experienced in the procedure. The ectropion that accompanies pregnancies makes identification of the transformation zone easier. If no invasive lesion is suspected, the woman may be observed without biopsy, and a re-examination carried out 6 weeks postpartum. Although cervical biopsy is safe in pregnancy, the bleeding that occurs after the procedure may be more than in the non-pregnant state. This may lead to unnecessary anxiety for both the woman and the clinician. Therefore, many experts recommend biopsy only if an invasive lesion is suspected. If biopsy is indicated, a careful, colposcopically directed punch biopsy of the most abnormal area is carried out. If the biopsy confirms only CIN, regardless of the grade, the woman may be followed, without treatment, until she delivers and is reassessed in the puerperium.

If the biopsy shows microinvasive disease, a cone biopsy is indicated to exclude invasive disease. Cone biopsy should be avoided in the first trimester as it is associated with an abortion rate of about 33%. It is important to bear in mind the increased risk of profuse haemorrhage with excisional procedures carried out in pregnancy.

Invasive disease

With invasive cervical cancer in pregnancy, fertility preservation is only possible in the early stages, namely, stages IA and IB1. Cervical cancer is staged clinically, which relies on clinical examination. In pregnant women with cervical cancer, especially if the pregnancy is in the second trimester and beyond, clinical examination can be difficult. In non-pregnant women, anatomic imaging modalities like computed tomography scan, magnetic resonance imaging and positron emission tomography imaging are used to establish more accurately the tumour size, parametrial spread and nodal involvement. Although the findings do not change the clinical stage, they can affect management. During pregnancy, computed tomography scans should be avoided owing to radiation hazard. Magnetic resonance imaging, which does not use ionising radiation, is safe, but only needs to be used if the disease is thought to be more advanced than clinical impression. As the effects of radio-isotopes used in positron emission tomography scans on the fetus are unknown, it is best to avoid these in pregnancy.

The main challenge in management is the timing of the intervention. No randomised-controlled trials have been conducted on the effect of delay on the outcome of the cancer. Information presented is based mainly on observational studies and expert opinion. Generally, if the cancer is diagnosed in the first trimester, the woman is advised to terminate the pregnancy (provided it is religiously acceptable) and definitive surgical treatment carried out afterwards. If the diagnosis is made in the second trimester, the treatment is delayed until the fetus is matured (usually about 34 weeks). The baby is then delivered followed by definitive surgery for the cervical cancer. The question of whether the mode of delivery (vaginal or cesarean section) modifies the survival of women with cervical cancer diagnosed in pregnancy has no definite answer yet. Three groups did not report a difference in survival between vaginal and abdominal delivery, whereas one reported a better outcome with caesarean delivery. The potential for haemorrhage, and the possibility of tumour implantation at episiotomy sites have discouraged many from conducting vaginal delivery.

Stage Ia1 disease (measured invasion of stroma up to 3 mm) is usually diagnosed only after a cone biopsy. If both the ecto and endocervical margins are free, and the woman wishes to continue the pregnancy, it is considered to be adequate treatment. Completion hysterectomy after delivery is not necessary.

In women diagnosed with stages la2 (measured invasion of stroma of 3–5 mm and no wider than 7 mm) and IB1 disease where the tumour size is not larger than 2 cm, and the histology is squamous cell carcinoma, a radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy may be carried out in those wishing to preserve fertility. Although most cases of radical vaginal trachelectomy have been carried out in non-pregnant women (the consensus is that it is a safe procedure from an oncological point of view), few investigators have reported on the procedure in pregnant women. It is usually carried out in the early second trimester (to avoid treating a pathological pregnancy). Others have reported on successful abdominal radical trachelectomy in pregnancy. These procedures can be even more challenging than in non-pregnant women and, currently, should only be offered by surgeons who are experienced with the procedures.

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NACT) given before definitive treatment of cervical cancer can help prolong the pregnancy until lung maturity is reached. No large studies have described the safety of chemotherapeutic agents in pregnancy. Caluwaerts et al. reported that, because the risk of congenital malformations in children exposed to chemotherapy in the first trimester is about 10–20%, neoadjuvant chemotherapy should be withheld till after 13 weeks gestation, when organogenesis is completed. Mir et al. in a systematic analysis of reports, from 1977–2008, on the use of platinum derivatives in pregnancy, found three malformations in 43 pregnancies. These included moderate bilateral ventriculomegaly, hearing impairment and micropthalmos. The causative links between cisplatin, however, and these malformations remained speculative for the confounding factors. More recently, Marnitz et al. reported on the in-vivo analysis of the use of cisplatin in pregnancy. Seven women with cervical cancer received cisplatin NACT during the second trimester. The umbilical cord blood and amniotic fluid levels of cisplatin were measured. These levels were found to be significantly less than that found in the maternal serum. These findings seem to indicate that platinum drugs are probably safe in pregnancy. The use of paclitaxel, as NACT, has been reported in six pregnancies. All had caesarean section between 33 and 35 weeks of gestation. All the fetuses were normal at birth.

In a recent International Consensus Meeting on Gynaecologic Cancers in Pregnancy held in Belgium in 2008, the following guidelines were suggested for fertility preservation in cervical cancer in pregnancy : in stage IA2-IB1 less than 2 cm, a lymphadenectomy should first be carried out. In the absence of nodal metastasis, either a trachelectomy or NACT followed by trachelectomy may be considered. If nodes are positive, standard treatment (radical hysterectomy or chemoradiation) is given. For stage IB1 2–4 cm tumours, again lymphadenectomy is mandatory, but in selected cases this may be carried out after NACT. The potential to preserve the pregnancy and fertility depend on the nodal status and response to NACT. For stage IB2-IIB, fertility-sparing surgery has not been sufficiently evaluated. Neoadjuvant chemotherapy is given until fetal maturity and the baby is delivered by caesarean section. In cases of excellent response to NACT, where the primary tumour shrinks below 4 cm, trachelectomy may be considered in a purely experimental setting. Otherwise, standard treatment is offered.

In more advanced stages, there is no place for fertility-preserving surgery. Definitive treatment, either radical hysterectomy or radiation therapy, depending on the stage, should be offered after the baby is delivered at the appropriate time.

Preinvasive disease

Neither the disease nor the pregnancy affect each other.

Invasive disease

Vaginal bleeding is the most common symptom regardless of pregnancy. During pregnancy, however, the bleeding may be mistaken for threatened miscarriage or antepartum haemorrhage. Failure to inspect the cervix, and being only interested in the viability of the pregnancy by an ultrasound scan, can delay the diagnosis considerably, leading to major management problems. There is no evidence to suggest that the pregnancy worsens the outcome of the disease. These women have similar survival rates, stage for stage, as non-pregnant women.

Preinvasive disease

The diagnosis of cervical intraepithelial neoplasia (CIN) on a Pap smear must lead to a proper visual examination of the cervix under good light. If no obvious lesion is seen, a colposcopy should be carried out by someone who is experienced in the procedure. The ectropion that accompanies pregnancies makes identification of the transformation zone easier. If no invasive lesion is suspected, the woman may be observed without biopsy, and a re-examination carried out 6 weeks postpartum. Although cervical biopsy is safe in pregnancy, the bleeding that occurs after the procedure may be more than in the non-pregnant state. This may lead to unnecessary anxiety for both the woman and the clinician. Therefore, many experts recommend biopsy only if an invasive lesion is suspected. If biopsy is indicated, a careful, colposcopically directed punch biopsy of the most abnormal area is carried out. If the biopsy confirms only CIN, regardless of the grade, the woman may be followed, without treatment, until she delivers and is reassessed in the puerperium.

If the biopsy shows microinvasive disease, a cone biopsy is indicated to exclude invasive disease. Cone biopsy should be avoided in the first trimester as it is associated with an abortion rate of about 33%. It is important to bear in mind the increased risk of profuse haemorrhage with excisional procedures carried out in pregnancy.

Invasive disease

With invasive cervical cancer in pregnancy, fertility preservation is only possible in the early stages, namely, stages IA and IB1. Cervical cancer is staged clinically, which relies on clinical examination. In pregnant women with cervical cancer, especially if the pregnancy is in the second trimester and beyond, clinical examination can be difficult. In non-pregnant women, anatomic imaging modalities like computed tomography scan, magnetic resonance imaging and positron emission tomography imaging are used to establish more accurately the tumour size, parametrial spread and nodal involvement. Although the findings do not change the clinical stage, they can affect management. During pregnancy, computed tomography scans should be avoided owing to radiation hazard. Magnetic resonance imaging, which does not use ionising radiation, is safe, but only needs to be used if the disease is thought to be more advanced than clinical impression. As the effects of radio-isotopes used in positron emission tomography scans on the fetus are unknown, it is best to avoid these in pregnancy.

The main challenge in management is the timing of the intervention. No randomised-controlled trials have been conducted on the effect of delay on the outcome of the cancer. Information presented is based mainly on observational studies and expert opinion. Generally, if the cancer is diagnosed in the first trimester, the woman is advised to terminate the pregnancy (provided it is religiously acceptable) and definitive surgical treatment carried out afterwards. If the diagnosis is made in the second trimester, the treatment is delayed until the fetus is matured (usually about 34 weeks). The baby is then delivered followed by definitive surgery for the cervical cancer. The question of whether the mode of delivery (vaginal or cesarean section) modifies the survival of women with cervical cancer diagnosed in pregnancy has no definite answer yet. Three groups did not report a difference in survival between vaginal and abdominal delivery, whereas one reported a better outcome with caesarean delivery. The potential for haemorrhage, and the possibility of tumour implantation at episiotomy sites have discouraged many from conducting vaginal delivery.

Stage Ia1 disease (measured invasion of stroma up to 3 mm) is usually diagnosed only after a cone biopsy. If both the ecto and endocervical margins are free, and the woman wishes to continue the pregnancy, it is considered to be adequate treatment. Completion hysterectomy after delivery is not necessary.

In women diagnosed with stages la2 (measured invasion of stroma of 3–5 mm and no wider than 7 mm) and IB1 disease where the tumour size is not larger than 2 cm, and the histology is squamous cell carcinoma, a radical vaginal trachelectomy with laparoscopic pelvic lymphadenectomy may be carried out in those wishing to preserve fertility. Although most cases of radical vaginal trachelectomy have been carried out in non-pregnant women (the consensus is that it is a safe procedure from an oncological point of view), few investigators have reported on the procedure in pregnant women. It is usually carried out in the early second trimester (to avoid treating a pathological pregnancy). Others have reported on successful abdominal radical trachelectomy in pregnancy. These procedures can be even more challenging than in non-pregnant women and, currently, should only be offered by surgeons who are experienced with the procedures.

Neoadjuvant chemotherapy

Neoadjuvant chemotherapy (NACT) given before definitive treatment of cervical cancer can help prolong the pregnancy until lung maturity is reached. No large studies have described the safety of chemotherapeutic agents in pregnancy. Caluwaerts et al. reported that, because the risk of congenital malformations in children exposed to chemotherapy in the first trimester is about 10–20%, neoadjuvant chemotherapy should be withheld till after 13 weeks gestation, when organogenesis is completed. Mir et al. in a systematic analysis of reports, from 1977–2008, on the use of platinum derivatives in pregnancy, found three malformations in 43 pregnancies. These included moderate bilateral ventriculomegaly, hearing impairment and micropthalmos. The causative links between cisplatin, however, and these malformations remained speculative for the confounding factors. More recently, Marnitz et al. reported on the in-vivo analysis of the use of cisplatin in pregnancy. Seven women with cervical cancer received cisplatin NACT during the second trimester. The umbilical cord blood and amniotic fluid levels of cisplatin were measured. These levels were found to be significantly less than that found in the maternal serum. These findings seem to indicate that platinum drugs are probably safe in pregnancy. The use of paclitaxel, as NACT, has been reported in six pregnancies. All had caesarean section between 33 and 35 weeks of gestation. All the fetuses were normal at birth.

In a recent International Consensus Meeting on Gynaecologic Cancers in Pregnancy held in Belgium in 2008, the following guidelines were suggested for fertility preservation in cervical cancer in pregnancy : in stage IA2-IB1 less than 2 cm, a lymphadenectomy should first be carried out. In the absence of nodal metastasis, either a trachelectomy or NACT followed by trachelectomy may be considered. If nodes are positive, standard treatment (radical hysterectomy or chemoradiation) is given. For stage IB1 2–4 cm tumours, again lymphadenectomy is mandatory, but in selected cases this may be carried out after NACT. The potential to preserve the pregnancy and fertility depend on the nodal status and response to NACT. For stage IB2-IIB, fertility-sparing surgery has not been sufficiently evaluated. Neoadjuvant chemotherapy is given until fetal maturity and the baby is delivered by caesarean section. In cases of excellent response to NACT, where the primary tumour shrinks below 4 cm, trachelectomy may be considered in a purely experimental setting. Otherwise, standard treatment is offered.

In more advanced stages, there is no place for fertility-preserving surgery. Definitive treatment, either radical hysterectomy or radiation therapy, depending on the stage, should be offered after the baby is delivered at the appropriate time.