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Official websites use. Share sensitive information only on official, secure websites. Cancer is an important cause of childhood mortality, yet the etiology is largely unknown. A combination of pre- and postnatal factors is thought to be implicated, including maternal medication use. We aimed to provide: 1 a systematic review of peer-reviewed publications on associations between maternal medication use and childhood cancer, with a focus on study design and methodology; and 2 suggestions for how to increase transparency, limit potential biases, and improve comparability in studies on maternal medication use and childhood cancer. Altogether, studies were identified. The reviewed studies were heterogeneous in study design, exposure, and outcome classification. The most frequently investigated medication groups were sex hormones 46 studies, excluding fertility medications , and antiinfectives 37 studies. Suggestions for strengthening future pharmacoepidemiologic studies on maternal medication use and childhood cancer relate to choice of cancer classification system, exposure windows, and methods for identification of, and control for, potential confounders. Keywords: cancer, child, delayed effects, medications, pharmacoepidemiology, prenatal exposure. The worldwide incidence of childhood cancer is estimated at per million person-years and is increasing 1 — 3. The etiology of childhood cancer is largely unknown but thought to be explained by both pre- and postnatal factors 4 — 6. The increasing incidence of childhood cancer could point to environmental risk factors that have changed over time 2 — 4. The only fully established transplacental chemical carcinogen is diethylstilbestrol 7. The research on diethylstilbestrol sparked an interest in the investigation of maternal medication use and risk of childhood cancers 8. In recent years, some studies 9 — 12 , but not all 13 , 14 , pointed to an association between maternal medication use and childhood cancer. A review of the literature before illustrated the heterogeneity in the literature, in particular with regard to the applied cancer classification 8. Suggestions for methods have been provided for pharmacoepidemiologic studies of medication-cancer associations in adults 15 , but to our knowledge, guidance has not been provided for maternal medication—childhood cancer associations. Therefore, we aimed to provide: 1 a review of peer-reviewed publications on associations between maternal medication use and childhood cancer, with a focus on study design and methodology; and 2 suggestions on how to increase transparency, limit potential biases, and improve comparability in studies on maternal medication use and childhood cancer. Exposure windows: What timing of maternal medication use was investigated during pregnancy only, including periods before pregnancy, or during breastfeeding? Reference lists of relevant reviews and included studies were screened to ensure complete coverage of the published literature. However, this search proved too narrow, as more studies were identified from reference lists than from the search itself. References were imported into the reference management program Endnote 16 , where duplicates were removed. The remaining references were imported to Rayyan QCRI 17 , a platform for management of systematic review data. Title and abstract screening, as well as full text screening were performed independently by 2 reviewers S. Any disagreement was solved by a discussion among all authors. Studies were considered eligible for inclusion if they fulfilled the following criteria for participants, exposures, comparators, outcomes, and study design: Participants were required to be children, defined as individuals under the age of 20 years. The exposure was restricted to maternal prepregnancy or pregnancy use of prescription or over-the-counter medication, as identified in prescription data or from self-reported data. Comparators were children born to mothers who did not use the specified medications. This included children born to healthy mothers population comparators , children born to mothers with illnesses but not receiving treatment disease comparators , and children born to mothers who used specified medications other than the medication of interest for the study active comparators. The outcome was childhood cancer. Studies that used children with other types of cancer as controls were excluded. Randomized controlled trials, cohort studies, and case-control studies were eligible for inclusion. Papers that were not original studies e. No restrictions were applied as to study date or setting, but for resource reasons, the search was limited to peer-reviewed publications in English, French, or one of the Scandinavian languages. Data was extracted by S. Instead, all eligible studies were assessed according to the prespecified questions mentioned above, and studies were discussed in the author group to identify suggestions for future research. Data was grouped by medication exposure according to indication for use. Given the study aims, no synthesis of study findings was planned. We performed 2 sensitivity analyses post hoc to assess the robustness of the findings. The first was restricted to the most recent studies, published between and , as methodological developments over the years might have had an impact on the quality of the included studies. The second was a restriction to studies where childhood cancer was the main outcome, given that analyses of main and secondary outcomes might differ systematically. The literature search yielded 10, studies. After removal of duplicate records, 6, studies were left for title and abstract screening. Of these, were relevant for full-text assessment, and 78 were eligible for inclusion 7 , 9 — 14 , 20 — An additional 34 studies were identified from reference lists of included studies and relevant reviews 91 — Flowchart for selection of studies relating to the associations between maternal medication use and childhood cancer, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Data was extracted from studies performed between and Studies originated from Europe 50 studies , North America 48 studies , Asia 6 studies , South America 4 studies , and Australia 2 studies. In addition, there were 2 transcontinental studies Table 1. In one country, the design was case-cohort, and in the other, case-control. If main exposure or outcome were not stated, all exposures and outcomes were considered equal, and the study could end up in more than one category. In the remaining papers, the most commonly reported classification system was the ICD. The most commonly reported main diagnostic groups were leukemias 25 studies and central nervous system tumors 14 studies. The most commonly investigated subgroups of childhood cancer were acute lymphoblastic leukemias 26 studies , acute myeloid leukemias 15 studies , and neuroblastomas 14 studies. The most frequently investigated medication groups were sex hormones 46 studies, excluding fertility medications , antiinfectives 37 studies , and fertility medications 30 studies Web Table 2. In 9 studies, there were either no cases, or no exposed cases or controls, for the main analysis. Some studies used more than 1 type of comparator. An example of a statistical method used in these studies is the Mantel-Haenszel method for stratified analysis 44 , 54 , The most frequently included intermediate factors were gestational age at birth 11 studies and birth weight 10 studies. The remaining studies used other age ranges, either determined by the peak incidence of the type of cancer investigated e. The second sensitivity analysis excluded 7 studies that did not have childhood cancer as their main outcome. Of included studies, 34 were identified from reference lists. Half of these investigated fertility medications, whereas the other half did not have any pattern of common characteristics. This could indicate that the search terms included in the literature search were not exhaustive for fertility medications. Because it takes some time from when a study is published to when it can be cited, we might have incomplete coverage of the literature from late and early In addition, we had to exclude 5 studies due to language restrictions. For these studies, we have not been able to assess eligibility in a full-text reading, and thus we do not know whether they fulfilled the inclusion criteria for the present review. Authors for whom English is not their first language are more likely to publish studies with negative findings in local, non-English-language journals It is not known whether methods or reporting differ systematically between studies published in English and studies published in local journals. In brief, this is because cancer is a heterogeneous disease, and no known carcinogens increase the risk of every type of cancer This also applies to childhood cancer, arguing for investigations of specific types of cancer when possible. Although limited sample sizes can render a detailed outcome classification impracticable, it should be noted that the grouping of outcomes might in fact reduce study precision. This seemingly counterintuitive claim stems from the fact that investigating several cancer types in one group will introduce heterogeneity leading to increased variance and therefore wider confidence intervals However, for new and rarely used treatments e. Yet, even if the risk estimate for overall cancer is not increased, this does not rule out the possibility that the studied medication increases the risk of a specific type of cancer. Therefore, results indicating null associations from studies using any cancer as the outcome should be reported and interpreted with caution. On the other hand, if studies using imprecise outcomes do identify a signal, this could warrant further investigation. To prioritize among multiple signals for further investigation, it can be useful to employ methods such as empirical Bayes shrinkage, which adjusts observed estimates of association for random variation and is thought to reduce the number of false positive findings In studies with only a few exposed cases, it might be beneficial to apply a lesson learned from teratology , and report on any patterns of specific cancer types, even if statistical analysis is feasible only for a combination of all cancers. It was the presence of a specific type of cancer that first suggested the transplacental carcinogenicity of diethylstilbestrol 7 , just as the specific patterns of syndromes or malformations flagged the potential teratogenicity of thalidomide and valproic acid For studies that have the statistical power to report risk estimates for specific types of childhood cancer, the next question is what classification scheme to use. To facilitate pooling of data in meta-analyses, a standardization of the outcome classification would be helpful 8. The need for standardization led to the development of the ICCC in Childhood cancers differ from cancers in adults by being embryonal in type and arising in organ systems that do not map onto the traditional sites that are used in classification of adult cancers Therefore, ICCC is based primarily on the type and behavior of the cancer cells, with some site-based groupings to facilitate comparisons with ICD. In addition, the most common childhood cancers have individual codes The International Classification of Diseases for Oncology, while not adapted specifically to childhood cancers, is still preferable to the ICD, because it takes morphology into account. From a pharmacological point of view, it is plausible that morphologically similar cancers will react to medication exposures in a similar fashion, whereas cancers of the same site might not Hence, researchers should consider using the ICCC classification system when possible. The International Classification of Diseases for Oncology, recommended for use in cancer registries, could be an alternative in situations where mapping to the ICCC is not feasible. Both preclinical findings e. If, for instance, the hypothesis is that hormonal disruption from exposure to oral contraceptives plays a causal role in the development of childhood nonlymphoid leukemias 9 , it might be insufficient to study oral contraceptives as a group. Most oral contraceptives contain an estrogen analog and progestin, whereas others contain progestin only. Further, analyses by dose or duration of exposure are helpful when feasible, given that there might be threshold levels for effect Once the exposure has been defined, the relevant exposure window should be chosen. As opposed to teratology, where the relevant exposure window for most malformations is the first trimester , relevant exposure window s for childhood cancers are largely unknown. One proposed relevant exposure window is immediately after fertilization, when the epigenome is thought to be highly sensitive to environmental factors In the present review, different approaches were seen across studies, mainly ranging from a year before conception until the end of pregnancy. One study considered maternal exposure when the mother was a fetus Seeing that the ovaries and egg cells for future offspring are formed in fetal life , it is possible that medications taken throughout the life course could affect the egg cells. In studies where the exposure window extends beyond the prenatal period, the outcome can happen during the exposure window, thus potentially introducing immortal time bias Immortal time bias can be avoided, for example, by moving the start of follow-up or case ascertainment to the end of the exposure window The use of study design diagrams, as advocated by Schneeweiss et al. In Web Figure 1, we provide an example of a study design diagram. Because the relevant exposure window is uncertain, it could be beneficial to investigate several exposure definitions within one study i. Another argument for the use of several different exposure definitions is specific to registry- or claims-based studies. In these studies, exposure in a given time window, such as the first trimester, is not driven solely by prescriptions filled in the time window. Prescriptions filled immediately before the time window might also contribute, if the dispensed medications covered part of the time window Regardless of the data source, authors should consider the risk of exposure misclassification. With prospective exposure ascertainment, the misclassification is often but not always nondifferential, whereas this cannot be assumed for retrospective maternal recall Probabilistic sensitivity analysis is a useful tool to assess the potential impact of misclassification Most studies in the present review addressed potential confounding through matching, adjustment, or both. Some, mainly newer, studies adjusted for potential intermediate factors such as gestational age and birth weight. In the best case scenario, adjusting for intermediate factors can preclude an estimation of the total effect of the exposure However, it might introduce collider-stratification bias from unmeasured variables associated with both the intermediate factor and the outcome Use of directed acyclic graphs could help ensure that adjustments are not made for intermediate factors In Web Figure 2, we present an example of a directed acyclic graph. In many studies, the limited sample size can pose additional challenges for confounder adjustment. To avoid overfitting the models, serial change-in-estimate approaches for variable selection or confounder summary scores can be used Propensity score methods may be used if the exposure is more prevalent than the disease, because propensity scores are constructed from regression models with exposure as the dependent variable and covariates as independent variables Another method to estimate confounding in etiological epidemiology is by introducing a negative control , A negative exposure control that has been suggested in perinatal pharmacoepidemiology is maternal medication use before pregnancy However, as stated above, it cannot be ruled out that maternal prepregnancy exposure can affect the risk of childhood cancers, and so other negative controls should probably be preferred. Maternal medication use after birth can be used as a negative control in noncommunicable diseases, especially if maternal medication use is assessed when the breastfeeding has ceased. Paternal medication use while the mother is pregnant has been proposed to assess confounding by unmeasured genetic factors, or other unknown factors associated with medication use If the main concern is confounding by the underlying maternal illness, the choice of disease or active comparators could be considered. A majority of the studies in the present review used population comparators. This is a good choice in situations where the indication for medication use is not thought to influence cancer risk e. However, if the underlying maternal disease has been linked to an increased risk of childhood cancer e. Here a disease comparator could instead be used, comparing illness treated with medications to the same illness managed without medication. An active comparator i. Sibling comparators are useful primarily if the main source of confounding is thought to be inherited genetic risk Provided that life-course maternal exposure to medications can affect risk of childhood cancers, carryover effects between siblings should be considered Compared with the choice of epidemiologic methods, the choice of statistical methods is less important. That is because childhood cancer, in particular specific types of cancer, occurs so rarely that estimates of rate ratios and risk ratios will be virtually identical Studying associations between maternal medication use and childhood cancer is methodologically challenging. This systematic literature review showed that such studies are largely heterogeneous in their study design, exposure, and outcome classification. To improve the transparency, limit potential biases, and improve comparability of future studies, we propose 3 points of consideration bridging the fields of prenatal pharmacoepidemiology and cancer epidemiology. The points include: 1 investigating specific types of childhood cancer according to the ICCC classification when possible, or as a minimum stating the classification system used; 2 carefully considering relevant exposure windows, including whether several exposure windows should be investigated; and 3 using appropriate methods for identification of potential covariates i. Hemmingsen, Susanne K. This section collects any data citations, data availability statements, or supplementary materials included in this article. As a library, NLM provides access to scientific literature. Am J Epidemiol. Anne Broe Find articles by Anne Broe. Anton Pottegaard Find articles by Anton Pottegaard. Marie Hargreave Find articles by Marie Hargreave. Hedvig Nordeng Find articles by Hedvig Nordeng. Open in a new tab. Study Characteristic No. Click here for additional data file. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Study design a. Exposure ascertainment b. Comparator group c.

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