Managing Cancer during Pregnancy

8. Supportive Care During Pregnancy

Flora Zagouri  and Ioanna Maniou2

(1)

Department of Clinical Therapeutics, Alexandra Hospital, Athens, Greece

(2)

Department of Gynecology and Obstetrics, Hospital of Yverdon les Bains, Vaud, Yverdon-les-Bains, Switzerland

Flora Zagouri

Email: florazagouri@yahoo.co.uk

The definition of supportive care treatment is the use of agents to counteract the side effects of cancer treatment. It is well known that the most common adverse events of chemotherapy are nausea, vomiting, and hematologic toxicities. An oncologist may prescribe a variety of supportive medications in order to overcome the adverse events of chemotherapy; this is quite challenging and not well established as the main concern is the effect of the drugs on the developing fetus and long-term complications after in utero exposure. The most commonly used agents as supportive care in patients receiving chemotherapy are antiemetics, dexamethasone, bisphosphonates, granulocyte colony-stimulating factor, erythropoietin, antibiotics, etc. Unfortunately, there are limited data regarding supportive treatment in pregnant women receiving chemotherapy. Table 8.1 summarizes the categories of drugs for use during pregnancy, while Table 8.2 summarizes the safety of the most commonly used agents during pregnancy and lactation.

Table 8.1

Categories of drugs for use in pregnancy

FDA pregnancy category

Recommendation

Category A

Controlled studies do not demonstrate a risk to the fetus

Category B

Animal studies have shown adverse effect but human studies show no risk

Category C

Animal studies have shown an adverse effect on the fetus and there are no controlled studies in humans

Category D

There is positive evidence of human fetal risk from investigational studies

Category X

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience. The drug is contraindicated

Table 8.2

Safety of the most commonly used agents during pregnancy and lactation

Agent

Trimester

Lactation

Category (FDA)

 

First

Second

Third

   

Antiemetic

Granisetron

Y

Y

Y

Y

B

Ondansetron

Y

Y

Y

Y

B

Tropisetron

N

N

N

Y

C

Scopolamine

Y

Y

Y

Y

C

Metoclopramide

Y

Y

Y

Y

B

Antidiarrheal

Loperamide (Imodium)

Y

Y

Y

Y

B

Antibiotics

Tetracycline

N

N

N

N

D

Phenicols

         

Broad-spectrum penicillin

Y

Y

Y

Y

B

Beta-lactamase-sensitive penicillins

Y

Y

Y

Y

B

Beta-lactamase-resistant penicillins

Y

Y

Y

Y

B

Beta-lactamase inhibitor (Tazobactam)

Y

Y

Y

Y

B

Cephalosporins

Y

Y

Y

Y

B

Carbapenems (imipeneme/meropeneme)

Y

Y

Y

Y

B/C

Trimethoprim

N

Y

Y

Y

C

Sulfonamides

Y/N

Y

Y

Y

 

Macrolides

Azithromycin

Y

Y

Y

Y

B

Clarithromycin

N

N

N

Y

C

Erythromycin

Y

Y

Y

Y

B

Josamycin

Y/N

Y/N

Y/N

Y

B

Roxithromycin

Y/N

Y/N

Y/N

Y/N

C

Spiramycin

Y

Y

Y

Y

B

Lincosamides (clindamycin/lincomycin)

Y

Y

Y

Y

B

Streptomycin

N

N

N

Y

D

Fluoroquinolone

N

N

N

N

C

Amphotericin B

Y/N

Y/N

Y/N

Y/N

B

Corticosteroids

Betamethasone

Y/N

Y/N

Y/N

Y

B

Dexamethasone

Y/N

Y/N

Y/N

Y

B

Hydrocortisone

Y/N

Y/N

Y/N

Y

B

Methylprednisolone

Y/N

Y/N

Y/N

Y

B

Prednisolone

Y

Y

Y

Y

B

Prednisone

Y

Y

Y

Y

B

G-CSF (filgrastim)

Y

Y

Y

Y

B

Epoetin

Y

Y

Y

Y

B

Y yes, N no, Y/N could be used if highly indicated

5-HT3 Antagonists

This category of agents is often used in conjunction with glucocorticoid steroids such as dexamethasone for the treatment of acute emesis occurring in the first 24 h after chemotherapy administration. There are three major classes of the chemical structures of the first-generation 5-HT3 receptor antagonists: (I) carbazole derivatives (ondansetron), (II) indazoles (granisetron), and (III) indoles (dolasetron) [1]. Palonosetron is a highly selective second-generation 5-HT3 receptor antagonist that has two stereogenic centers and may exist as four stereoisomers. Palonosetron has a longer half-life (40 h) and greater receptor binding affinity versus first-generation 5-HT3RAs [1]. Some studies advocate for intravenously administered 5-HT3 antagonists; others argue for oral administration. The concomitant use of aprepitant, an NK1 receptor antagonist, significantly increases the efficacy of the 5-HT3 antagonist in acute or delayed chemotherapy-induced nausea and vomiting.

Nausea and vomiting are really often symptoms during pregnancy; hence, there are a lot of data published in the literature regarding administration of antiemetics during pregnancy. On the other hand, there are no data regarding chemotherapy-induced vomiting during pregnancy; however, we normally extrapolate the data for pregnant women receiving chemotherapy from pregnant women not receiving chemotherapy.

As far as antiemetics is concerned, Einarson et al. [2] reported that there was no increased risk for a major malformation after exposure to ondansetron comparing with other antiemetics among 176 pregnant women. In line with the aforementioned findings, Anderka et al. [3], using data from the National Birth Defects Prevention Study, reported that there is no increased risk with the use of 5-HT3 antagonists as antiemetics. Of note, metoclopramide is considered the first choice of treatment for nausea and/or vomiting and is also recommended during lactation, whereas ondansetron is more effective in controlling vomiting and may safely be used during pregnancy (Table 8.2).

Corticosteroids During Pregnancy

Corticosteroids are used during pregnancy as supportive treatment mainly for controlling vomiting and nausea. However, systematic, inhaled, and topical use of corticosteroids is frequently used as a treatment of a plethora of diseases. According to the study of Janssen et al. [4], there are two categories of corticosteroids: those that are needed to treat fetal conditions (i.e., immature lungs) such as dexamethasone and betamethasone because they are less metabolized by the placenta and greater doses are available to the fetus and those that are needed to treat maternal conditions such as prednisone which is metabolized by the placenta and only a small percentage of the maternal dose can cross human placenta.

As far as the complications of the use of corticosteroids on the fetus is concerned, there are case reports of women treated with prednisone without any evidence of embryopathy [56]. The increased incidence of low birth weight reported in fetuses exposed to corticosteroids may be linked with the underlying maternal conditions for which the agents were given. Several studies have mentioned a slightly increased risk of oral clefts using systematic corticosteroids but cohort studies have not [78]. Regarding the complications of the use of corticosteroids on pregnant woman, there are the pregnancy-specific complications such as premature rupture of the membranes, exacerbation of gestational diabetes, and hypertension and the nonspecific complications that may occur in nonpregnant patients (such as immunosuppression, avascular necrosis of bone, osteopenia, hypertension, hyperglycemia, etc.) [4]. Hence, it seems that corticosteroids may be given relatively safe during pregnancy (Table 8.2).

During lactation, the breast milk of women taking prednisone can contain small amount of these drugs; however, according to the American Academy of Pediatrics, women who take high doses of glucocorticoids are encouraged to breastfeed. They should wait 4 h after ingesting a dose to resume breastfeeding; this is a strategy that decreases the amount of glucocorticoid in the milk [9].

Granulocyte Colony-Stimulating Factor

The granulocyte colony-stimulating factor (G-CSF) is commonly used in cancer patients receiving myelosuppressive chemotherapy associated with febrile neutropenia in order to decrease the incidence of infection. Although filgrastim has a very high molecular weight, it has the possibility to cross the human placenta at least in the second and third trimester [10]. Medlock et al. [11] reported that maternally administered rhG-CSF crosses the placenta of rats and specifically induces bone marrow and spleen myelopoiesis in the fetus and neonate. The significant myelopoietic effects of rhG-CSF at low concentrations in the fetus suggest an exquisite degree of developmental sensitivity to this cytokine and may provide enhanced defense mechanisms to the neonate [12]. Moreover, it seems that maternal administration of rhG-CSF increases neonatal defenses against a lethal bacterial challenge.

However, data on human beings are limited. According to Calhoun et al. [13], rhG-CSF administration to women before preterm delivery does not appear to have any significant immediate adverse effects on either the mother or the neonate; moreover, it could increase fetal neutrophil production and improve neonatal outcome. In line with the above, Cardonick et al. [14] reported that there is no significant difference in gestational age at birth, congenital abnormalities, birth weight, incidence of long-term medical issues, mean WBC, or neutropenia at birth between the newborns exposed to G-CSF added to chemotherapy and newborns exposed to chemotherapy alone before the delivery.

Concerning breastfeeding, there is no data available. Filgrastim may be excreted in breast milk, but there is no risk to a nursing infant, as filgrastim is a glycoprotein and probably is digested in his stomach [15].

Erythropoietin

Erythropoietin is a glycoprotein hormone that is produced by the interstitial fibroblasts of the kidney and stimulates red blood cell production (erythropoiesis). Recombinant human erythropoietin is often used to treat anemia caused by chemotherapy and by chronic renal failure. Unfortunately, there are no data concerning the treatment of chemotherapy-induced anemia with recombinant human erythropoietin in cancer pregnant patients. However, there are some data concerning the use of recombinant human erythropoietin in women with renal failure [1617]. More specifically, it has been reported that the recombinant human erythropoietin does not cross the placental barrier according to data on pregnant women with renal failure; hence, it seems to be safe for the fetus and the mother [1819]. However, more data on pregnant women with cancer diagnosis are more than warranted in order to draw definitive conclusions.

Antibiotics

It is widely known that there is an increased risk of infection in patients receiving chemotherapy. This is mainly due to neutropenia caused by the toxic effect of chemotherapy on the bone marrow. This complication adds complexity to treatment especially if the patient is a pregnant woman. Antibiotics, such as penicillins (beta-lactamase-sensitive and beta-lactamase-resistant penicillins, beta-lactamase inhibitor), cephalosporins, carbapenems, and the most of macrolides (azithromycin, erythromycin, and spiramycin), are approved by FDA as category B, and their use is recommended during pregnancy. Table 8.2 summarizes the safety of the most commonly used antibiotics [20].

Bisphosphonates During Pregnancy

Bone metastases, commonly seen in many solid tumors, may cause major morbidity including fractures, severe pain, hypercalcemia, and nerve compression [20]. It is widely known that bone-targeted agents, i.e., bisphosphonates, have changed the natural history of patients suffering from bone metastases. The bisphosphonates are analogues of pyrophosphate, and their structure allows them to bind to the bone matrix and promote the skeletal retention [20]. Hence, it is obvious that treatment with bisphosphonates represents a cornerstone in the supportive therapy of cancer patients [21]; however, their data on pregnant women are limited.

Bisphosphonates cross the placenta, and animal studies, done mostly at doses much higher than those commonly used in humans, have shown adverse effects on both the fetus and the mother (protected parturition, maternal mortality, embryolethality, several general underdevelopment, and marked skeletal retardation of the fetuses) [22]. However, human reports regarding women exposed to bisphosphonates before conception or during pregnancy did not demonstrate complications except for low neonatal birth weight and transient hypercalcemia [23].

In line with the above, in a recently published review on 78 pregnant women exposed to bisphosphonates before conception or during pregnancy, no serious secondary effects were noted in the vast majority of mothers and infants [22]; hence, it seems that in cases of absolute or relative indications of bisphosphonates prior to pregnancy, close observation of the mother and the infant, especially during the first 2 weeks of life, is mandatory. Furthermore, no increased risk of major birth defects from intrauterine exposure to bisphosphonates was recorded in a multicenter prospective study including 21 women who used bisphosphonates during or within 12 months before pregnancy [24]. In this study, the indications of bisphosphonate administration were primary osteoporosis, osteoporosis associated with cancer, and osteoporosis secondary to corticosteroid use.

However, given that bisphosphonates remain in mineralized bone for several years and that data on pregnant patients are limited, it should be clearly stated that bisphosphonates should be used on personalized basis and with caution; if used, hypocalcaemia affecting the contractility of the uterus should be avoided.

Conclusion

In conclusion, it seems that physicians should pay special attention apart from the treatment per se to supportive therapy given to prevent or treat adverse events correlated with chemotherapy administration. The optimal supportive treatment of pregnant women with cancer diagnosis is not well established; the main concern is the effect of the agents on the developing fetus and long-term implications in offspring born after in utero exposure. A multidisciplinary approach involving medical oncologists, high-risk obstetric care, pharmacists, and neonatologists is mandatory for the successful management of women with cancer during pregnancy.

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