In the present study, we investigated pregnancy outcomes in more than 800 pregnancy-related hospitalizations in women with brain and spine tumors. To date, there are no large population-based studies of obstetric outcomes in patients with CNS neoplasms. Evidence-based guidelines are not available, making it difficult for physicians to counsel patients and to monitor the pregnancy and delivery process. In contrast, guidelines exist for the management of other cancers during pregnancy. Because of the increasing mean age at which US women give birth, cancer during pregnancy is becoming more common. Improving outcomes for breast and cervical cancer and long clinical experience with chemotherapy have informed this discussion for well over a decade.26–30
However, the incidence of CNS tumors is much lower than many other cancers in this age group; a recent population-based assessment estimated the incidence of maternal malignant brain tumors at 3.6 per 1 million live births.4
Several studies have attempted to collect cases of CNS neoplasms and other lesions amenable to neurosurgical intervention during pregnancy. Although most are reports of single cases, there are 2 retrospective series comprising a total of 36 pregnant women with intracranial neoplasms.13,14
Johnson et al found significantly more gliomas in those diagnosed prior to pregnancy and more meningiomas diagnosed during pregnancy. Cohen-Gadol et al published an institutional series including 14 patients with intracranial neoplasms, 9 of whom underwent a neurosurgical procedure while pregnant. No fetal or maternal complications were directly related to these procedures, and all mothers who underwent surgery at or near term subsequently delivered healthy infants.13
Neither study had a large enough sample size to achieve statistical significance.
Given these limitations, a large registry or administrative database, such as the NIS, is probably the only feasible way to conduct an adequately powered study of this clinical question. Because the NIS includes all payers and all types of hospitals, it enables sampling of young, otherwise healthy patients, such as pregnant women, who would not be represented in other US databases, such as the Medicare and VA registries. Our approach allowed us to collect the largest possible number of pregnant women with CNS tumors, an effort that could take years or decades if subjects were recruited prospectively. Our study also addresses the issue of referral bias, which in prior institutional series may have excluded patients presenting in very poor clinical condition. Encompassing a large sample of hospitalized pregnant women in the United States, we demonstrated that patients with CNS neoplasms during pregnancy are far more likely to be cared for at a tertiary referral center. However, we also were able to capture those treated at smaller hospitals. Thus, our estimates for adverse outcomes, whether surgery was performed, are more likely to be realistic national estimates.
We found that serious pregnancy complications, including preterm labor, IUGR, and mortality, were more likely to occur in patients with malignant brain tumors. This may be related to maternal compromise caused by the underlying malignancy. For example, seizures, hydrocephalus, and aspiration pneumonia are common sequelae of malignant brain tumors and can all have deleterious effects on a pregnancy. Although we found a markedly increased risk of in-hospital mortality among pregnant women with malignant brain tumors, the baseline maternal mortality rate in the United States is very low (most recently estimated at 13 deaths per 100,000 live births);31
thus, the absolute risk of mortality is still quite low.
For benign brain tumors, preterm labor was the only complication that occurred at a significantly higher frequency. There are many risk factors for preterm labor, including older age and a greater frequency of chronic comorbid illnesses. However, the difference persisted even when adjusting for these factors. For both cohorts, early planned induction or Caesarean delivery was likely performed in some cases as soon as fetal lung maturity was documented, to commence definitive treatment as soon as possible.
Similar to other adults with brain tumors, pregnant women commonly presented with seizures and hydrocephalus. Moreover, we found an increased frequency of hyperemesis gravidarum in patients with both malignant and benign brain tumors, suggesting that nausea and vomiting may be misattributed to the pregnancy itself in women with elevated intracranial pressure due to CNS pathology. This highlights the importance of a thorough examination for suspicious symptoms during pregnancy.
Hospitalizations of patients with brain tumors differed in several ways from the general population. They were much less likely to deliver while in the hospital, perhaps implying that they delivered their infants during a subsequent hospitalization or that they experienced more antenatal hospitalizations. They were more likely to have a Caesarean delivery, probably because of conservative management of the delivery process.
Both malignant and benign brain tumors were strongly associated with Caesarean delivery even when controlling for potential confounders, probably because of conservative management of the delivery process in these patients. Pregnancies in patients with intracranial lesions may be perceived as higher risk and, therefore, may be managed by Caesarean delivery. For example, some obstetricians discourage pushing during the second stage of delivery, because this can dramatically increase intracranial pressure and theoretically exacerbate cerebral edema or precipitate an intratumoral hemorrhage.1
As mentioned, some patients may undergo an early scheduled Caesarean delivery or labor induction, which confers a higher rate of Caesarean delivery if labor fails to progress. Finally, we must use caution in interpreting an increased OR for an outcome that is common even in the general population experiencing normal pregnancy and delivery (Figure ). However, because our results were fairly consistent between the univariate and multivariate analyses, it seems unlikely that including more or different covariates in the model would have appreciably changed the results.
Trend in US Caesarean delivery rate for brain tumors and the general population, 1988–2009.
In patients with brain tumors who underwent a neurosurgical procedure, adverse outcomes were not more likely to occur, although these patients experienced significantly more Caesarean deliveries, likely as part of a definitive treatment plan. This confirms the findings of smaller observational series, which have not demonstrated increased maternal or fetal risks with neurosurgical procedures. Thus, there seems to be no compelling reason to delay indicated surgery because of concerns that it would pose additional risks to the pregnancy.
Similar to brain tumors, spine tumors were associated with hospitalization not resulting in a delivery and with a higher rate of Caesarean delivery. No significant associations between spine tumors and pregnancy complications were observed, although small sample size warrants caution in interpretation of these findings as negative.
There are limitations to our approach. In any large database, clinical detail is lacking. Of importance, because ICD-9-CM diagnosis codes generally do not include information on histology, low-grade gliomas are classified as malignant brain tumors, even though their natural history and prognosis are very different from those of glioblastomas or CNS metastatic disease. Similarly, pituitary tumors and craniopharyngiomas, although their pathology and clinical behavior are very different, share the same ICD-9-CM code.
Many patients, especially those with asymptomatic, small benign lesions, may be treated entirely in the outpatient setting, with definitive treatment deferred until after delivery.1,7
In addition, patients with long-term controlled CNS neoplastic disease, such as low-grade astrocytoma, may have a relatively uneventful pregnancy and delivery course. Our study of hospitalizations is inherently biased toward the larger and more symptomatic tumors encountered in the inpatient setting, and thus, our estimates may represent an upper limit of risk. In addition, because there is no way to link maternal and neonatal hospitalizations in the NIS, we were unable to obtain information on neonatal outcomes, an area that should be addressed by future research.
We chose to adjust for race and ethnicity in our statistical analysis, because African-American race has been reported as an independent risk factor for adverse pregnancy outcomes, possibly as a result of the higher baseline rate of chronic hypertension and other medical comorbidities in African-Americans.32
However, because not every state reports data on race, approximately 30% of such data are missing. To address this, we created a separate “missing” category and adjusted for it in the statistical analysis.
In the United States, where the proportion of births taking place at home is less than 1%,33
nearly all pregnancies result in at least one hospital admission (for delivery). Therefore, we are confident that we captured a representative sample of women during their pregnancies. However, because the unit of analysis in the NIS is a hospitalization rather than an individual patient, we could not account for multiple admissions related to a single pregnancy. Because the probability of delivery twice during a calendar year is quite low (0.25%),34,35
hospitalizations associated with a definitive delivery likely reflect individual patients, and we feel that these estimates are the most accurate.
In summary, we found an increased frequency of adverse pregnancy outcomes among pregnant women with brain tumors, particularly malignant brain tumors; these risks were not increased for spine tumors. Physicians who care for patients with CNS neoplasms should be aware of the potential for enhanced obstetric risk. Because of the challenges of studying pregnancy outcomes in a rare disease, well-designed prospective studies are needed to address the aforementioned limitations and to provide detailed patient-level information. Our hope is that, by illuminating areas of enhanced risk during pregnancy, we can contribute to the understanding and management of pregnancy in patients with CNS disease. By collecting the largest possible sample of pregnant women with both malignant and benign CNS tumors, we hope to move beyond the individualization of care and expert opinion and lay the groundwork for future research that will help better define obstetric risk in this patient population.