In this study, sociodemographic profiles and independent risk factors that were associated with prenatal exposure to psychoactive substance were identified by the measuring of biomarkers in neonatal matrices. To our knowledge, this is the first study of these characteristics carried out in our country in a NICU.

The prevalence estimates for prenatal substance use vary widely and they have been difficult to establish. The true prevalence of drug use among pregnant women is difficult to ascertain and widely vary across countries [38,39]. Therefore, clinical laboratories through the measurement of biomarkers of exposure to psychoactive substances in biological matrices can play an essential role in assessing the real fetal exposure, allowing for the generation of appropriate policies and interventions.

The top three substances detected, cannabis, EtG, and cocaine, showed a similar pattern to the drug abuse results that were published to Spain by the European Monitoring Centre for Drugs and Drug Addiction in women between aged 15 and 35 years, lending high reliability to the data [40]. As expected, cannabis was the most frequently detected substance. The incidence of prenatal cannabis use detected in this study (8.3%, including cases positives for more than one drug), was in the range of other studies performed using drug testing in meconium samples (2.8 to 10.3%) [21,41,42].

After cannabis, the second detected substance was EtG (4.3% of samples over established cut-off, including cases positives for more than one drug). Moreover, EtG was also detectable, although at levels that were below the established cutoff, in an additional 7.5% of patients. In agreement with previously reported data, our results show the high prevalence of women consuming a non-negligible amount of alcohol during their pregnancies [43].

The third detected substance was cocaine (3.2%, including cases positives for more than one drug). The obtained results were similar to the results reported in meconium samples in other studies, ranging from 1.2 to 5.6 [13,44,45].

Finally, in our study one sample was found positive to opiates and one positive to methadone in one mother in opioid substitution treatment. Ecstasy or amphetamines were not detected. These findings were lower than the results found in other cohorts of Mediterranean area [12,37,46].

The EtG levels found in the positive meconium samples were in the range of previous studies, with concentrations between 71-208 ng/mg [31,47,48]. Meconium samples were considered to be positive for cannabis and cocaine when they were above the detection limit of the assays (5 ng/g for THC-COOH and 50 ng/g for cocaine metabolites), but the levels were not quantified.

When considering the positive cases detected in our study (13.2%) and the annual average of live neonates (8053 infants in the last five years according to data from the Statistics Institute of the Balearic Islands), more than 1000 mothers and babies in Mallorca could test positive every year. However, this number is likely to be higher than the real one, since neonates that are exposed to psychoactive substances are more likely to be admitted to a NICU than those non-exposed. Nevertheless, this does help demonstrate the potential magnitude of this issue in the study area.

Drug use during pregnancy is a risk factor for both maternal and fetal complications. Additionally, children that are exposed to drug use are susceptible to many adverse long-term effects [2,3,4,10,49,50]. Some studies have associated cannabis use during pregnancy with lower birth weights and an increased incidence of tremors, exaggerated startles, and diminished crying in the neonate and longer gestations. In addition, children exposed to cannabis had a lower performance on standardized tests, indicating that long-term behavioral and neurodevelopmental issues may occur in these children [1,50].

With cannabis being touted on the Internet as a safe treatment of nausea during pregnancy, current rates of use of cannabis during pregnancy are a concern. However, there are currently no indications for its use during pregnancy and research is needed before cannabis can be considered for use in hyperemesis gravidarum. Koren et al. suggested that cannabis should be tested in appropriately powered control trials for this severe and protracted maternal condition, addressing both maternal effect and potential adverse fetal effects [51,52]. Pregnant women who are using cannabis in pregnancy should be counseled about the lack of safety data and the possible adverse effects of THC on the developing fetus and referred to their health care provider for alternative treatments that have better pregnancy-specific safety data [40,50].

Alcohol exposure during pregnancy can have many serious consequences for the offspring, including miscarriage, stillbirth, preterm birth, intrauterine growth retardation, teratogenicity, and alcohol-related neurodevelopmental disorders. The fetal alcohol spectrum disorder (FASD) describes the consequences that are associated with prenatal alcohol exposure. The clinical presentation of the disease is inconsistent, some lacking evidence of central nervous system neurodevelopment abnormalities. Typically, for the definite diagnosis of FASD, the confirmation of prenatal ethanol exposure is needed, because some of the characteristics of the disease, in particular, physical, may be absent [22,53,54].

Prenatal cocaine exposure is associated with low birth weight, prematurity, spontaneous abortions, stillbirths, and microcephaly. In addition, maternal hypertension, tachycardia, vasoconstriction, increased uterine contractility, and placenta complications have been described, including placental abruption, and an increased risk of diminished blood flow to the fetus. Exposure to cocaine during childhood can increase the risk for hypertension, ventricular arrhythmia, seizures, and intracranial bleeding. Behavioral problems also present themselves during development to both prenatally and postnatally exposed children. Infants that are exposed in utero are found to have attention deficits with an increased incidence of attention-deficit/hyperactivity disorder and transient central and autonomic nervous system signs and symptoms. Prenatal cocaine exposure is associated to sudden infant death syndrome [54,55,56,57].

Poly-substance use is common among substance users, and this and the acuteness or the chronicity of the use may also modify or exacerbate the individual effects on maternal and fetal health [1]. In our study, poly-substance use was associated significantly with previous abortions; these findings were in accordance with other studies [12,13,37,41,46,58]. As in other studies, SUDs were not associated with a higher frequency of preterm births [12,13,14,37,46].

Moreover, pregnant women who are substance users often have complex social and mental health issues and these women need access to assertive outreach care from specialists in addiction and mental health. There is also the additional risk of transmission of viral infections (hepatitis B, hepatitis C, or HIV).

Taken together, these adverse consequences of substance use to the developing fetus and mother are complex, and efforts should be made to identify and support women who are using substances. It is important that health care providers understand the risk factors and adverse consequences of substance use during pregnancy on maternal and fetal health to provide appropriate advice to substance-using pregnant women [1].

Th obtained data underline the usefulness of meconium testing as an analytical tool for a more accurate identification of neonates exposed in utero to drugs of abuse compared to the identification based only on maternal questionnaire. The toxicological results objectively demonstrated that sociodemographic characteristics, such as maternal age, lack of pregnancy care, being a single mother, or smoking increased the risk of prenatal exposure to toxic substances in the neonate. Our findings are in agreement with the well-known under-reporting of alcohol and drug use by pregnant women [59].

The average age of mothers that were included in our study (32.4 years) was similar to that previously reported in the international literature [37,42,58,60]. Psychoactive substance use was significantly associated with younger age, as reported in other studies [42]. Pregnant cannabis users, as well as her partners, were significantly younger than non-users and cocaine and alcohol users. The pregnant cannabis users were younger than those that were reported in other studies (28.9–30.1 years) [5,13,37], but pregnant cocaine and alcohol users were older [12,13,46,48]. The results showed that mothers under 24 were over three and a half times more likely to use psychoactive substances during pregnancy. Thus, there is a need to target initiatives to prevent prenatal drug exposure, especially cannabis, at younger age groups.

Many studies have documented that substance-using women, particularly cocaine or opiate users, are significantly less likely to obtain pregnancy care, despite accruing greater benefit from it [14,40,52,61,62]. Our regression results showed that mothers with a lack of pregnancy care was over eight times more likely to use psychoactive substances. Moreover, this lack of pregnancy care was significantly associated with the use of cocaine or of more than one psychoactive substance. The low rate of pregnancy care in cocaine and poly-drug users could be explained by: (1) surrounding circumstances and chaotic lifestyles, (2) resource or attitudinal barriers to care, such as fear of police report, or (3) some direct, disruptive effect of the particular substance [2,61].

In contrast, the lack of pregnancy care was not associated with cannabis or alcohol use. Schempf el al. also found cannabis to be not independently related to pregnancy care [61].

The adequate pregnancy care that is associated with alcohol use could be explained by the underestimation of alcohol consumption by the mothers themselves [48], which implies adequate pregnancy care, despite continuing with substance use.

Co-use of tobacco and illicit drugs, particularly cannabis, is relatively high during pregnancy, as reported previously [47,52]. The results indicate that women who smoke cigarettes are more than six and a half times more likely use psychoactive substances during pregnancy. Given the strong association between smoking and other drug use, clinicians should routinely assess for illicit drug use in women who smoke during pregnancy [63]. Smoking tobacco has a significant relationship with cannabis use during pregnancy, but not with cocaine use, as also reported in other studies [5,13,37,42,46]. As in our work, tobacco consumption was declared by the mother and no toxicological analyses were performed.

Our results showed a significantly relation between licit drugs and illicit drug use in pregnant women. Published data on this association are scarce, but prescription drug abuse, especially opiates, benzodiazepines, and stimulants prescribed for attention-deficit/hyperactivity disorder, often co-occurs with other illicit substances or alcohol abuse [61]. Joya et al. [46] founded a correlation between cocaine and antidepressant use. The association between licit and illicit drug represents an increased risk to the mother and the fetus.

Even exposure to drugs of abuse have been associated with lack of education, some studies found no associations with academic level [37,46]. Our data showed that only having a primary level education was more common in cannabis users, both in mothers and fathers alike, in agreement with other studies [64,65]. The association between alcohol consumption and a higher academic level has been described previously [60]. In our study, an association was found between fathers with a bachelor’s degree and a higher frequency of alcohol consumption, although no differences were found in mothers. No clear association was found between academic level and cocaine use.

In a previous study that was performed in Spain, of the mothers who tested positive for psychoactive substance use, 40–60% had custody of their child removed [66]. In our population, child removed frequencies were lower, with a maximum of 25% in cases of polydrug use.

The referral to Social Services of cases of cannabis, cocaine and other psychoactive substance use was very frequent. However, the results of alcohol exposure were not available in the perinatal period and detected cases of alcohol consumption could not be referred to Social Services. These data suggest that social services may need to be involved with a larger proportion of mothers as, there may be mothers with addiction issues needing support, especially related to non-detected alcohol consumption.

Our results confirmed previous data in the literature, with psychoactive substance use during pregnancy being independently associated with low maternal age, a lack of pregnancy care, single mother status, and smoking habits [13,66,67,68,69]. These factors can lead to suspicion of a SUD, and can be used for the purpose of preventive health and policy strategies, especially in cases when the mother’s lack of awareness regarding health care, pregnancy planning, and low economic resources are also evident.

In our study, the potential SUDs in mothers were identified by the neonatologists. This was done due to the lack of attention to pregnancy and detection of psychoactive substance use, which meant that SUDs were not detected during pregnancy. Therefore, these studies reinforce the need to strengthen strategies for identifying such women.

Other risk factors that must be assessed in the preventive health and policy strategies are a history of mental illness [4] and domestic violence, as well as the presence of infectious diseases and employment status of the mother. These factors were outside the scope of the current study.

The limitations of this study first include that biomarkers of tobacco, new synthetic psychoactive drugs, or licit drug use were not analyzed. Mothers are often reluctant to admit having used drugs or they may not even be aware that they had been using a medication, so the measurement of drug concentrations (licit or illicit drugs) provides useful information for immediate infant treatment and subsequent medical follow-up.

Secondly, the results of alcohol exposure were not available in the perinatal period, which made it impossible to use them in early clinical or social health management. Finally, biomarkers analysis in meconium samples only detects psychoactive substance use in the second and third trimesters of pregnancy.