Medication use during pregnancy and the risk of gastroschisis: a systematic review and meta-analysis of observational studies

Gastroschisis is a rare congenital anomaly of the abdominal wall where part of the large intestine, small intestine and rarely other abdominal organs protrude through the right side in the ventral abdomen. This anomaly does not involve the umbilical cord, and the bowel herniation is not covered by a membrane [1, 2]. Gastroschisis is mainly an isolated congenital anomaly [3].

Gastroschisis is a severe congenital anomaly with a high impact on affected individuals and their families regarding the quality of life and healthcare service needs, representing a public health issue [4‐6]. Identifying potential risk factors for gastroschisis is a public health priority aimed at developing preventive actions to reduce this congenital anomaly's prevalence and health burden.

Clinical and embryological studies demonstrated that the wall defect, results from either an amniotic rupture or a separation of the amnio-ectodermal junction at the pars flaccida, with the midgut prolapse into the amniotic cavity. The rupture occurs at the right side of the umbilical cord, during the normal physiologic herniation. Moreover, through the observation of embryonic development events has been estimated that gastroschisis occurs between 56 and 77 days post conception. [1, 2, 7].

The aetiology of gastroschisis is still unclear, most likely multifactorial, caused by the interaction of genes and environmental risk factors.

Several studies reported an increasing prevalence rate worldwide over the past decades, most of them with a higher prevalence among young women aged less than 20 years [8‐12]. While epidemiological studies have consistently evidenced the strong association between gastroschisis and young maternal age, the aetiologic role of environmental factors is still under investigation [13‐15].

Three previous literature reviews collected observational studies assessing the possible associations between non-genetic risk factors (e.g., lifestyle, socio-demographic, maternal illness, medication use) and gastroschisis with widely divergent results [16‐18].

For medication exposure during pregnancy, the observational studies suggested an increased risk of gastroschisis among pregnant women who have used aspirin, ibuprofen, and decongestants. At the same time, inconsistent results were found for anti-histamines, antibiotics and oral contraceptives [16‐18].

A systematic review with meta-analysis by Kozer et al. (2002) on maternal aspirin use during pregnancy and congenital anomalies showed that the exposure to aspirin during the first trimester was associated with a significant increased risk of gastroschisis [19]. A recent meta-analysis showed that maternal smoking, illicit drug use, and alcohol consumption during early pregnancy are associated with an increased risk of gastroschisis in offspring [20].

The present study aimed to qualitatively and quantitatively synthesize the available epidemiological evidence to investigate the association between medication use during pregnancy and gastroschisis.

We conducted meta-analyses of 18 studies from 28 countries, including 751,954 pregnancies spanning 25 years. These meta-analyses suggested that users in the first trimester of pregnancy of over the counter medications (OTC) such as aspirin, ibuprofen, pseudoephedrine and phenylpropanolamine, and oral contraceptives, were associated with an increased risk of gastroschisis in offspring from 1.4 to 1.6 times greater than no users, at the 95% confidence.

Conversely, for paracetamol gestational use, no significant association was observed.

To the best of our knowledge, this is the first systematic review and meta-analysis that provides an overview of the available epidemiological studies examining the association between gestational medication use and the risk of gastroschisis.

These findings are according to the previous meta-analysis by Kozer et al. [19] focused on aspirin use only, that included 5 studies published until 2000, and showed a significant increased risk of gastroschisis for aspirin users during the first trimester.

Several studies have shown that medications use during pregnancy has a teratogenic effect on humans and suggested that oxidative stress is one of the main teratogenic mechanism involved in a wide spectrum of congenital anomalies, foetal growth retardation and in severe cases of in-utero death [84]. In particular, human evidence has consistently showed that the presence of oxidative stress biomarkers may lead to inflammation or might affect the placenta during the early stage of organogenesis demonstrated the relationship between unbalanced oxidative level and the occurrence of adverse pregnancy outcomes [85].

These findings are consistent with Bargy and Beaudoin [2] and Beaudoin [7] embryo researches which showed that the pathogenetic mechanism of gastroschisis could be due to teratogenic agents and that the rapture of the amnion predominantly occurs at 8 weeks.

Other epidemiological findings showed that infections acquired during the first trimester of pregnancy, are associated with gastroschisis, likely through immune and inflammatory pathway [86‐89].

However, since these OTC medications are used for common illnesses, such as maternal fever and upper respiratory infection, questions have been raised about interactions between medications and potential confounding by an underlying illness.

Paracetamol is one of the most widely used OTC analgesic and antipyretic medications. Our findings are consistently with the review of Wang et al. 2017. Several in vivo and in vitro studies showed that paracetamol is safe when used at therapeutic dose and only a paracetamol overdose can cause oxidative stress [90].

The relationship between oestrogen and oxidative stress activation was proposed by Lubinsky et al. [91]. Several studies suggested an increased oxidative stress in combined oestrogens and progestin users [92‐99] with very high hormone levels were detected among healthy young women [98, 99].

However, these findings indicate that the physicians should closely manage medications therapy during pregnancy to optimize the therapeutic regimens at the individual level [100].

Subgroups analysis shows a specific population-related effect as gestational use of aspirin and oral contraceptives report a significant increase in the risk of gastroschisis only in North America. These geographic variations may reflect country-specific maternal lifestyle habits as well as specific sociodemographic characteristics [20]. Furthermore, the results of subgroups analysis indicate that for aspirin and decongestants, the increases are significant only during first-trimester exposure, the critical period for gastroschisis development [7]. For ibuprofen, the exposure during the periconceptional time determines a significant increase, while, for oral contraceptives, the increase was observed both in periconceptional and first-trimester exposure time. Additionally, for all individual medications, only those studies with fully adjustment variables report significant increases in risk. Still, for contraceptives, it was also observed when the study was adjusted for maternal age only. It is important to note that the highest pooled RR for aspirin is reported by only 2 studies adjusted for maternal age and lifestyle risk factors associated with an increased risk for gastroschisis, as observed in a previous study [20].

Regarding the type of control, the subgroup analysis for oral contraceptives shows significant increases when cases are compared to healthy newborns. For the two individual decongestants, the increase is significant when malformed and both healthy and malformed newborns are considered as controls. However, an under or an overestimation of the exposure among the mothers of healthy or unhealthy newborns cannot be ruled out.

Publication bias may have affected aspirin and decongestants' findings, resulting in an overestimation of the statistical significance of the results. However, the trim-and-filled procedure was imputed at few potentially unpublished studies (2 for aspirin; 3 for decongestants), providing a correct RR that confirmed the presence of association. Moreover, as multiple comparisons were carried out, an overestimation of statistical results cannot be excluded.

Our study has several strengths. These meta-analyses included many large, multicenter, population-based studies that allow ample statistical power. In most of the studies, gastroschisis cases were ascertained by rigorous birth defect surveillance methods, including live births, stillbirths and terminations of pregnancy, which reduce potential misclassification due to incomplete ascertainment. Additionally, most of all included studies were adjusted for several confounders reducing biased for residual confounders. Moreover, sensitivity analysis suggested that our results were not influenced by heterogeneity across the studies.

However, several limitations also must be considered. First, included case–control studies may be affected by selection and recall bias. Second, since OTC medications do not required a medical prescription, is very difficult to obtain accurate data on pregnancy exposure due to the absence of pharmacy documentation or medical records. Therefore, when studies relied on self-reported and retrospective exposure assessment, the results might be affected by exposure misclassification and recall bias, particularly for medications like individual non-steroidal anti-inflammatory drugs (NSAIDS), usually used for short-term treatments of common illnesses. Third, these observational studies did not evaluate the dose and/or the frequency of medication use, as well as their combined use and, thereby, their possible interactions. Fourth, despite most studies adjusted for several potential confounders, we acknowledge that the residual confounding by unmeasured factors remains possible. Nevertheless, adjusting for potential confounders, including interactions between medications, is necessary. Moreover, some studies have a small sample size. Consequently, the power to detect an association is low. Finally, our review was limited to English language publications, even if non-English language articles are not all available on PubMed, Scopus and EMBASE databases.

Meta-analysis results suggested that OTC medications such as aspirin, ibuprofen, pseudoephedrine, phenylpropanolamine, as well as oral contraceptives during the first trimester of pregnancy are associated with a moderate but significantly increased risk of gastroschisis. However, these associations are significant only in particular subgroups defined by geographic location, adjustment variables and type of control. Due to the absence of the dosage and frequency of medication use, care should be taken when drawing general conclusions. Moreover, in pharmacoepidemiology research, the distinction between the statistical significance and the clinical meaning must always be considered. Further studies, with large sample size and well-planned methodology, including a dose–response effect, are warranted to verify these findings and to assess individual medication safety to help clinicians decide on their prescription during early pregnancy.