Unexpected drug residuals in human milk in Ankara, capital of Turkey

Various pharmaceuticals are given to livestock, fish farms, and beekeeping in order to treat infections, ensure efficiency and growth of products [1]. However, metabolites of veterinary medicinal products given in inappropriate time, dosage and indications, can persist in animals’ muscle, organs and products, and then contaminate people who consume these animals’ products [2]. Remarkably, many drugs’ residuals were reported in food products derived from animal husbandry in different parts of the world [1, 3‐9]. The residuals pose a risk of developing some adverse effects including hypersensitivity reaction, antimicrobial resistance, disruption of normal intestinal flora, bone marrow depression and carcinogenicity [10‐12]. Therefore, food safety is now universally recognised as a public health priority [13]. These public health concerns are extremely important for mother-foetus pairs during the gestational and lactational periods. Screening all the nutrients consumed by mothers is impossible. However, breast milk can be used for evaluation of the mother-infant environment. Given the possibility of transfer to infants via milk, pharmaceuticals including antibiotics and nonsteroidal anti-inflammatory drugs (NSAID) are carefully prescribed by doctors to mothers during lactation with prescription of doctors [14‐16]. Similarly, we predicted that a small amount of drugs might also pass into the breast milk of mothers who consumed contaminated foods [17]. There is only one study about detectable drug residues in the breastmilk of mothers without any history of usage of residual antibiotics in Eskişehir, Turkey [18]. This study supports our hypothesis. However, the status of Ankara, the capital of Turkey, is not known.

Although there are many studies on the effects of exposure to drug residues on human health [19, 20], there is no study in the literature about the impact of drug residuals on maternal anthropometric change after delivery, postpartum depression (PPD) and infant crying and sleeping characteristics. The prevalence of PPD varies from country to country and its incidence varies from 0 to 60% [21]. The prevalence of PPD ranged from 21.2 to 25.0% in Turkey [22]. PPD adversely affects infant mental health [23, 24]. Potential risk factors of PPD include low self-esteem, low social support, low socioeconomic status, stressful life, poor marital relationship, unplanned pregnancy, complications during pregnancy, and prenatal depression [25‐27]. However, the pathogenesis of PPD is not fully known [28]. On the other hand, the heptachlor epoxide levels in breast milk samples were found to be positively correlated with Postpartum Bonding Questionnaire, Mother-to-Infant Bonding Scale and indexes of Brief Symptom Inventory indicating some maternal psychopathologies and bonding problems while causing no change in PPD [29]. It is not yet known whether maternal environmental pollutants including pharmaceuticals have an impact on the occurance of PPD.

Sleeping and crying problems among infants were common in the first 3 months postpartum, but the cause could not be elucidated [30]. Maternal drug use can be considered to lead to breast problems and premature discontinuation of breastfeeding and to change the sleeping and crying patterns of infants [10]. Therefore, it can be hypothesised that exposure to veterinarian drugs could affect maternal psychopathologies, breastfeeding success and the well-being of infants.

The primary purpose of the study was to investigate the presence in breastmilk of any residues of drugs that the mother did not take. At the same time it was aimed to investigate the effect of drug residues in breast milk on PPD, breastfeeding success and sleep and crying characteristic of infants.

This descriptive study was done in mother-infant pairs who applied for child health follow-up in Hacettepe University İhsan Doğramacı Children’s Hospital between August 2017 and March 2018. Mothers who were breastfeeding their infants and agreed to participate to the study were included. Twin babies and non-breastfed babies were not taken into the study. Any mothers who had taken antibiotics or NSAID for the last 10 days were not included into the study.

This study protocol was examined by Hacettepe University Medical Faculty Non-Interventional Clinical Research Ethics Committee and was approved on August 24, 2017 with the report numbered GO 17/687. Mothers who participated in the study signed voluntary consent form.

The study was performed on 90 mothers who were still breastfeeding their babies between 18 and 93 days postpartum.

In our study, although it was not used by the mothers themselves, nearly all mother’s milk samples contained some residuals from medicines used in the area of livestock ​​fattening. Only a minority of mothers milk (n = 4) had no drug residues. This is the second article showing the residues of veterinary drugs in human milk [18].

Remnants of NSAID were found in the milk of 27 of 90 mothers included in our study in Ankara, all containing tolfenamic acid. Tolfenamic acid is for the management of both acute and chronic pain in animals and indicated a long half-life in sheep [35]. Previous studies didn’t detect any remnants of tolfenamic acid in 83 studied human milk samples in Eskişehir [18]. However, one or two of samples contained chlormadione, metamizole and meloxicam in both the Ankara and Eskişehir studies.

Most of the drug residues in our study in Ankara were found to be quinolone and beta-lactam antibiotics in our study in Ankara. The Eskişehir study revealed 85.5% of breast milk with beta-lactam residues, however, a lower detection rate for quinolone residues (14.5%) [18]. Of the human’s milk in our study, 31.1% aminoglycoside residues and 3.3% polymyxin residues were found and no residues in the assays of tetracycline, polypeptide and growth promotor drugs were detected in our study. The Eskişehir study revealed 4.8% polymyxin, and only 2.4% aminoglycoside (tobramycin) [18]. This might be explained by different contamination of consumed foods in different cities. A minority of samples had amphenicol, sulphonamide and corticosteroid residues in both cities.

To explicate veterinary drug residues in human milk, we must examine studies in animal products. Honey samples from 22 different regions of Turkey such as Muş, Bingöl, Şemdinli, Yüksekova and Marmaris-Muğla were investigated and although the use in beekeeping was not legal, tetracycline, streptomycin and sulfonamide group antibiotics were detected in 15% of the samples [36, 37]. One study analysed 240 pasteurized and raw milk samples sold in an Ankara market and detected oxytetracycline, penicillin G and neomycin in one milk sample above the maximum residual levels (MRL) allowed [38]. However, another study in Ankara in 2018 revealed 52.5% of milk samples had beta-lactam antibiotic residues above the detection limit (0.1 μg/kg) and 8.75% above 3 μg/kg [39]. However, in another study conducted in Ankara in 2010, 127 chicken meat and 104 beef samples from three different regions were selected randomly and quinolone group antibiotic residues were detected in 45.7% of chicken meat samples and 57.7% of beef meat samples [7]. This may explain the detection of quinolone and beta-lactam in human milk in our study. Residues of veterinary medicinal products are a global problem [40]. In some African countries veterinary drug residues can be as high as 94% in foods of animal origin. In 10 provinces of China, 0.5, 47.2 and 20.1% of 199 raw milk samples were reported to be positive for beta-lactams, quinolones and sulfonamides, respectively at the detectable level [41]. A study from Nepal detected 81% samples positive for amoxicillin, 41% for sulfadimethoxine, 27% for penicillin G, and 12% for ampicillin in 140 fresh milk [6]. These reports can be explained by unnecessary use of antibiotics, ignorance of the prescribed drug use and the recommended pre-slaughter time by the people who practice fattening during the last decade [7, 42].

In our study, no significant relationship was found between the presence of drug residues in mothers’ milk and PPD. In addition, antibiotic and NSAID residues found in breast milk did not have any influence on crying and sleep problems. However, in cases with NSAID residues, neonatal jaundice and breastfeeding problems were detected slightly higher (p = 0.071 and p = 0.073) which was not found to be statistically significant. NSAIDs are consumed widely during the early lactational period [17]. On the other hand, it is known that NSAIDs have a risk for renal injury, constriction of the ductus arteriosus, necrotizing enterocolitis and intracranial haemorrhage when used in the third trimester of gestation [11]. Therefore, further detailed studies in lactating mothers with pharmaceutical intake are necessary to clarify this hypothesis.

It is observed that the presence of NSAID residues has an impact on postnatal maternal weight regulation and may slow down the return of the mother to pre-pregnancy weight. In addition, in the present study, maternal self-use of antibiotics was shown to have a similar effect on maternal postpartum weight change. There has been no study evaluating the influence of analgesic drug usage on the mother’s BMI. However, recent studies showed the association of antibiotic use with obesity in childhood period [43, 44]. Rogawski et al. reported that antibiotic use in the first 6 months of life was associated with increased weight, especially among children with two or more exposures to macrolides, metronidazole, and cephalosporins [43]. Similarly, Block et al. found that antibiotic use at < 24 months of age was associated with a slightly higher body weight at 5 years of age [44]. The changes in anthropometric parameters are explained by the influence of antibiotics on the diversity and composition of the gut microbiota, which can persist long after the treatment and can modify metabolism and energy harvest of the diet [45‐47]. Similarly, antibiotics including tetracyclines, macrolides, avoparcin and penicillins have been commonly used in livestock to promote growth and increase weight gain [48]. We detected no influence of antibiotic residues on infant’s antropometric evaluations. This might be due to the small amount of residues in breast milk. However, a cause-effect relationship could not be established between drug residues and the health parameters of the mother and child with a single assessment in our study. Because of infant and maternal health concern, more extensive studies are needed to illuminate this outcome. Nonetheless, this predicted impact should be particularly emphasised and unnecessary drug use should be prevented.

The majority of the mothers included in the study had drug residues in their breast milk. These results show that mothers are exposed to drugs in an unexpected manner through foods and what’s more, some of these drugs detected in breast milk are prohibited in humans. In our study, the impact of residues in the mother’s milk on baby sleep and crying problems, breastfeeding problems and PPD were not found to be significant. However, drug residues were found to influence the regulation of the anthropometric parameters of the mother.

Preventing unnecessary drug exposure in mother-baby pairs is extremely important for healthy generations. Therefore, veterinary medicinal products must be used in appropriate indications; obedience to appropriate waiting time must be monitored.