Colon Cancer and Pregnancy

Abstract

As the incidence of colorectal cancer (CRC) in the younger population increases and women start their childbearing journey at later ages, CRC in pregnancy will become an increasingly relevant and decreasingly rare occurrence. Unfortunately, there is a dearth of data on this subject given its historical rarity. CRC is often diagnosed at a late stage in pregnancy because of the conflation of symptoms of pregnancy with symptoms of CRC. A major branch point for the diagnosis and treatment of CRC in pregnancy is whether it is diagnosed early or late in pregnancy. The workup for cancer is similar for pregnant and nonpregnant populations and includes endoscopy and staging computed tomography. Treatment is dependent on the stage of cancer and term of pregnancy. This review summarizes the current evidence for diagnosis, workup, and treatment of CRC during pregnancy and explores issues of fertility after a diagnosis of CRC.

The incidence of colorectal cancer (CRC) is increasing in young people both in the United States and internationally and is the third leading cause of cancer death among adults 50 years of age and younger. ¹ Changes in contraception, infertility treatment, and female employment have driven up maternal age worldwide. ² Centers for Disease Control and Prevention (CDC) data suggest that nearly 20% of all pregnancies now occur in women aged 35 years and older. ³ The incidence of any cancer in pregnancy is around 0.001%, ⁴ with CRC occurring in around 0.002% of pregnancies. ⁵ Though these numbers are low overall, this topic is becoming more relevant as CRC affects younger populations and women give birth at older ages. ⁶ This narrative review seeks to summarize the most current and robust evidence regarding CRC and pregnancy.

Presentation and Diagnosis

Current screening guidelines for CRC recommend starting screening at the age of 45 years in the average-risk population. ⁷ The majority of women who are diagnosed with CRC around the time of pregnancy have not undergone screening colonoscopy. CRC in pregnant women is generally discovered due to symptoms and presents at a later stage. Many cases in the literature describe presentations with metastatic disease. ^{4 8 9 10} These presentations can be extremely challenging for physicians because the symptoms of CRC often mimic those of pregnancy itself, such as nausea and vomiting, constipation and changes in stool caliber, weakness and fatigue, abdominal pain, and iron-deficiency anemia ( Table 1 ). ^{11 12 13 14} Furthermore, the typical weight loss that patients may experience due to cancer may be masked by the weight gain of pregnancy. Without hard and late signs of perforation, characterized by sepsis and peritonitis, even symptoms of obstruction can mimic the pain of pregnancy or early labor. ^{15 16} Women who are not severely symptomatic during pregnancy are more likely to be diagnosed after delivery. ⁹

Table 1. Commonly confused signs, symptoms, and laboratory results between pregnancy and colorectal cancer.

Signs, symptoms, laboratory results	Normal pregnant patient	Pregnant patient with colorectal cancer
Weight loss	Weight gain, but women can experience weight loss in first trimester	Pregnancy can obscure weight loss secondary to cancer, primarily in second and third trimesters
Rectal bleeding	Common in pregnancy secondary to high incidence of hemorrhoids	Often attributed to hemorrhoids, delaying further workup
Nausea and vomiting	Common in pregnancy, particularly during first trimester	Often attributed to pregnancy, delaying workup
Constipation, changes in stool caliber	Common in pregnancy	Often attributed to pregnancy, delaying workup
Abdominal mass	Natural process in pregnancy	Potential palpable masses secondary to colon cancer often missed secondary to changes of pregnancy
Anemia	Physiologic finding in pregnancy	Anemia of pregnancy masks blood loss from cancer
Weakness and fatigue	Common symptom in pregnancy	Pregnancy masks the weakness and fatigue from cancer

Source: Adapted from Cappell ¹¹ with permission from Elsevier).

Risk Factors

Any cancer occurring in a young person should prompt obtaining a detailed family history and genetic workup for syndromes such as hereditary non-polyposis CRC (Lynch syndrome), familial adenomatous polyposis, Gardner syndrome, Peutz-Jeghers syndrome, and inflammatory bowel disease. ¹⁷ The majority of CRC diagnosed during pregnancy is felt to be sporadic, though genetic testing was not performed on many of the patients described in the literature. ^{11 17} Obesity, hyperlipidemia, alcohol, prolonged sitting, metabolic syndrome, and poor diet have all been implicated in the increased incidence of sporadic colon cancers in younger populations. ^{6 18 19}

Workup

Endoscopic evaluation is the gold standard for the diagnosis of colon cancer; however, there are many risks associated with endoscopy for pregnant women and the fetus, including complications with anesthesia such as hypoxia and hypotension, exposure to teratogenic drugs, and premature birth risk. ²⁰ Furthermore, there are no robust data on the safety of bowel preparation agents during pregnancy. If the potential benefit exceeds the risks, expert opinion suggests that colonoscopy is generally safe and should be performed during pregnancy. ^{20 21} The American Society of Gastrointestinal Endoscopy (ASGE) released guidelines for best practices in endoscopy in pregnant women which are included in Table 2 . ²² Importantly, these best practices include ensuring a strong indication for the procedure and waiting until the second trimester if possible. ^{11 23}

Table 2. ASGE principles guiding endoscopy in pregnancy.

1. Always have a strong indication, particularly in high-risk pregnancies

2. Defer endoscopy to second trimester whenever possible

3. Use lowest effective dose of sedative medications

4. Wherever possible, use category A or B drugs

5. Minimize procedure time

6. Position pregnant patients in left pelvic tilt or left lateral position to avoid vena cava or aortic compression

7. Presence of fetal heart sounds should be confirmed before sedation is begun and after the endoscopic procedure

8. Obstetric support should be available in the event of a pregnancy-related complication

9. Endoscopy is contraindicated in obstetric complications such as placental abruption, imminent delivery, ruptured membranes, or eclampsia

Computed tomography (CT) of the chest, abdomen, and pelvis is the standard diagnostic modality for staging colon cancer. ²⁴ Though dogma previously dictated that CT was not safe during pregnancy, experts now agree that the dose of radiation for diagnostic imaging is low enough that the risk of harm to the fetus is low. ²⁵ CT is considered safest during the second and third trimesters. Though intravenous contrast crosses the blood–placental barrier, there is no evidence that it causes harm to the fetus. ²⁶ The American College of Obstetrics and Gynecology recommends proceeding with necessary imaging regardless of pregnancy. ²⁴ Adjuncts such as ultrasound and non-contrast MRI, if needed, are considered very low risk for the pregnant population.

Evaluation of laboratory values is essential to the workup of any disease. For colon cancer workup, a complete blood count is important to evaluate for anemia. CEA levels are routinely used for the monitoring of CRC in nonpregnant patients, and may be useful for monitoring cancer progression and recurrence in pregnant patients. However, levels can be elevated during pregnancy, reducing their utility as a screening tool. ²⁷

Cancer Location

Up to 85% of CRC diagnosed during pregnancy is located below the peritoneal reflection. ^{12 28} The majority of these rectal tumors are diagnosed at stage 3 or higher. It is likely that rectal cancer is more commonly discovered during pregnancy than colon cancer because the patients are more symptomatic. Also, rectal tumors are more likely to be identified on DRE, proctoscopy, or sigmoidoscopy, interventions that are lower risk to pregnant women compared with a full colonoscopy. ²⁸ Many colon cancers could theoretically go unnoticed during a pregnancy and thus are underdiagnosed, treated, and studied. ¹⁴

Cancer Biology

Cancer biology is incompletely understood in nonpregnant populations, and even less well understood in pregnant women or younger people without genetic disorders. Estrogen receptors on colon tumors may play a role in the pathogenesis of pregnancy-related colon cancer, as colonic mucosa differentially expresses androgen receptors in male and female patients. ²⁹ During pregnancy, women produce increased levels of estrogen, progesterone, and prolactin which, along with the increased growth factors that accompany the pregnant state, may accelerate the progression of tumor cells. ¹⁷ There is also an older but rigorously examined study which suggests that prostaglandins may be implicated in every stage of pregnancy as well as the formation of colon tumors. ³⁰ However, the connection between pregnancy and CRC remains poorly understood. More research is needed to determine whether the gestational state accelerates the progression of CRC. Certainly, there is mounting evidence that early-onset CRC is biologically different, and often more aggressive than the cancer that affects older populations. ³¹

Management

Great consideration must be given to the complex social–emotional milieu of cancer patients in general, but particularly in the case of pregnant women and their families. A multidisciplinary approach is essential both to treating the cancer and to the complicated environment of treating both the mother and the fetus. Respect should be given to the moral and religious views of the patient. ³² This review adapts the helpful algorithm set forth by Walsh and Fazio to organize treatment by location of tumor, stage of pregnancy, and stage of cancer ( Figs. 1 and 2 ). ³²

Fig. 1.

Colon cancer in pregnancy treatment algorithm. (Adapted from Walsh and Fazio, ³² with permission from Elsevier).

Fig. 2.

Rectal cancer in pregnancy treatment algorithm. (Adapted from Walsh and Fazio, ³² with permission from Elsevier).

Colorectal Cancer Diagnosed before Fetal Viability

Once CRC has been diagnosed early in pregnancy, treatment depends on the specifics of the disease and pathology. Generally, if a CRC diagnosis is made in the first 20 weeks of pregnancy, the fetus has not yet reached viability, but treatment delay can harm the mother and the fetus. Thus, the overarching recommendation is to offer termination of the pregnancy and to treat the mother expediently and definitively with the same protocols as one would follow for a nongravid patient. ^{27 33 34 35 36 37}

In specific cases, the mother may decline pregnancy termination or treatment may be appropriate despite early gestational age. ³² There are case reports illustrating successful treatment, with considerably little harm to the fetus. In one report, a 31-year-old previously healthy woman at 14 weeks of gestation presented with constipation, rectal bleeding, and weight loss for 6 months. She was found to have an 8-cm rectal mass, which was staged as cT3N2M0. She wished to continue her pregnancy, and so started on neoadjuvant FOLFOXIRI to decrease tumor bulk, for 8 cycles up to 30 weeks of gestation. Follow-up MRIs showed stable disease. She was induced at 32 weeks given the concern for oligohydramnios, delivered without complications, and the child was born with mild hypertonicity and feeding difficulties, but without genetic abnormalities and was healthy at 6 months of follow-up. There was no follow-up data for the mother. ³⁵

Surgery

The data on surgery for CRC during pregnancy are mixed. While there are limited data on that topic, general surgery (for any reason) in the first trimester does not appear to worsen fetal outcomes and is not associated with major birth defects. ³⁸ Many suggest that surgery should be performed whenever indicated. ^{12 32 34 38 39} Whenever possible, surgical treatment should be performed with the same standards, margins, and lymph node harvest as in non-pregnant patients. Others suggest that if the cancer is diagnosed after 20 weeks of gestation, surgery should be delayed until after delivery to minimize risk to the fetus. ^{27 37 40} In particular, surgery should be avoided late in pregnancy, unless it is performed postpartum, because of compromised surgical exposure and increased risk of technical complications. ³² In this case, it is safer for both mother and fetus to deliver earlier to facilitate surgical resection. A cesarean section can be considered upfront if the patient will require surgery directly after delivery. Early stage cancers with benign features can be successfully removed endoscopically. ⁴¹ Emergency surgery for obstructing colon or rectal cancer should be performed to save the life of the mother.

There are serious medical–legal and ethical considerations when considering whether to prioritize the safety of the fetus or the mother, which may become even more complicated as courts around the United States move to litigate on issues of fertility and abortion. A multidisciplinary approach should be used, in conjunction with the preferences of the mother and family, to determine whether surgical management is appropriate.

Chemotherapy

Pregnant women are not included in most clinical trials, and as such granular data on the safety of chemotherapeutic agents during pregnancy does not exist. A majority of chemotherapy agents are listed as category C and category D by the U.S. Food and Drug Administration (FDA), which suggests that there is potential or studied adverse effects on the fetus. However, neither of these categories preclude administration during pregnancy. While the first trimester is the most concerning time to receive chemotherapy as it puts the fetus at risk for congenital malformations, chemotherapy during the second and third trimesters still carries risks of low birth weight, premature delivery, and functional deficits. ⁴² Stopping chemotherapy 3 weeks before the expected delivery or after 35 weeks of gestational age is recommended given the increased risk of peripartum complications with an immunosuppressed mother. Data on breast feeding and chemotherapy administration are scarce and breastfeeding while undergoing chemotherapy should be avoided if possible.

Radiotherapy

Radiation of the pelvis is a mainstay of treatment for rectal cancer and is contraindicated during pregnancy with concerns of sexual dysfunction, fetal growth restriction, and spontaneous abortion. ²⁷ Furthermore, radiation can devastate ovarian tissue and compromise the chance of future fertility.

Maternal Prognosis

In small case series and case reports, it appears that the prognosis for babies is better than for the mother. ⁸ Babies who undergo chemotherapy in utero tend to have reasonably good short-term outcomes, but mothers often succumb to their disease within a few years of delivery.

Data on maternal outcomes are lacking given the rarity of CRC during pregnancy. A retrospective analysis of 42 patients with a median follow-up of 47 months for the majority of patients showed poor overall survival for mothers. Of these patients, 93% had stage III or IV disease. For the patients with metastatic disease, median overall survival was 17 months. For surgically unresectable disease, progression-free survival was only 5 months on first-line therapy. ⁴³ In another study of 27 cases of CRC in pregnancy, 73% of mothers presented with advanced disease. Stage-specific 1 year survival rates were 35.2, 84.8, 91.2, and 98.3% for stages IV, III, II, and I, respectively. ⁴⁴ In a recent series of eight patients, all but two were alive at 36 months of follow-up. ¹² Taken together, these data suggest that, as expected, prognosis is dependent on stage, severity of disease, and treatment.

Fetal Prognosis

In the aforementioned cases, fetal prognosis was promising overall. One patient was born with a limb abnormality, otherwise the most common fetal abnormalities were hypothyroidism and small size. However, these cases were not followed out past the defined study period; so, long-term outcomes of these children are unknown. ^{12 43 44} The outcomes for the relatively small number of infants who received intrauterine chemotherapy are good, though the majority of studies do not follow up children past a few months. ^{33 43} There have been no documented cases of spread of cancer to the fetus, though the placenta should be thoroughly examined at delivery for evidence of metastasis. ^{40 45}

Pregnancy after Colorectal Cancer

An increasingly relevant topic in CRC management as women give birth older and CRC incidence affects younger people is how to manage pregnancy after treatment for CRC. A recent nationwide registry-based study from Sweden matched 149 women with a history of CRC who became pregnant with 1,015 parous controls. History of CRC was associated with multiple adverse pregnancy-related outcomes, such as preeclampsia, induction of labor, and emergency cesarean section. It was also associated with adverse neonatal outcomes including medically indicated preterm and very preterm birth. ³

More research is needed on the causes of these negative peripartum and reproductive outcomes in CRC survivors. In addition, issues of reproduction and fertility preservation in CRC patients and survivors will become increasingly relevant in the upcoming years. A recent study showed that over half of young patients with rectal cancer did not receive fertility counseling, and only 20% underwent sperm banking, egg harvesting, or cryopreservation prior to cancer treatment. ⁴⁶ Young women who require radiation who would like to pursue pregnancy in the future should be referred to an oncofertility center to discuss ovarian transposition and cryopreservation. ⁴⁷ Multidisciplinary care of young CRC patients should include this important counseling.

Conclusion

This narrative review shares the most current data on pregnancy and CRC and considers new fields of focus, such as issues of oncofertility in CRC survivors. Because women are giving birth older and CRC incidence is increasing in younger populations, this topic will become more relevant in the coming decades. It is important to take abdominal symptoms seriously during pregnancy, especially if they include rectal bleeding, as symptoms can be missed when attributed to normal pregnancy. Management of CRC during pregnancy is based on the stage of cancer and term of pregnancy. As colorectal surgeons witness a rise in CRC in young people, they should integrate this information into their current management of CRC patients and pregnant patients to better serve this population.