Effects of meloxicam and caffeine co-administration on sow farrowing, colostrum quality and piglet performance in smallholder systems

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Meloxicam reduces fever and pain linked to mastitis-metritis, while caffeine enhances neonatal vitality and growth. This study evaluated their combined administration before farrowing, focusing on pain-related behaviours, colostrum quality, and piglet growth. A total of 150 piglets from smallholder systems were assigned to three treatments (NaCl, meloxicam, or meloxicam with caffeine). Results showed higher colostrum IgG in sows treated with both substances, and piglets from meloxicam and meloxicam + caffeine groups were significantly heavier at weaning. However, more pain behaviours and stillbirths were noted in the combined group, suggesting possible adverse effects on sow comfort. Further research with larger samples is needed to balance productivity gains and animal welfare outcomes. Farrowing sow Stillborn Weaned piglets Methylxanthines NSAID Introduction Genetic selection has increased litter size in swine production, but this has not been accompanied by improvements in piglet weight or farrowing outcomes. Larger litters, while potentially more profitable, often exacerbate farrowing complications and limit maternal care (Sánchez-Salcedo and Yáñez-Pizaña, 2022 ). The health of reproductive females is crucial, as pain and inflammation during farrowing can prolong labor, impair sow recovery, and compromise piglet vitality. Non-steroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, administered to sows around parturition have been shown to reduce pain-related behaviors, enhance piglet growth, and increase immunoglobulin concentrations, critical for piglets due to their agammaglobulinemic condition (Kuller et al., 2021 ; Mainau et al., 2012 ; Mainau et al., 2016 ; Navarro et al., 2021 ). However, the adoption of pain management remains limited due to costs, farming traditions, drug handling, and restrictions in food-producing animals (Ison and Rutherford, 2014 ). Consequently, preweaning mortality remains high, with 10–20% of live-born piglets dying, mainly within the first 72 hours, due to low vitality, low birth weight, stillbirth, and litter size effects (Koketsu et al., 2021 ; Tucker et al., 2021 ). Losses are especially critical for smallholders. Intrapartum asphyxia is a common cause of neonatal mortality in domestic mammals. Caffeine, a methylxanthine, can mitigate this problem due to its ability to cross the placenta and appear in colostrum and milk (Sánchez-Salcedo et al., 2019 a; Superchi et al., 2013 ). After oral intake, it is rapidly absorbed, reaching peak plasma levels within 9.5 h and remaining effective for up to 24 h, which benefits piglets born at different intervals within a litter (Dearlove et al., 2018 ; Mazzoni et al., 2015). Prophylactic subcutaneous caffeine administration to sows (210 mg/day before farrowing) has been shown to improve piglet vitality, respiratory function, and weaning weight in those with high vitality scores (Sánchez-Salcedo et al., 2019 b), while higher doses appear to enhance thermoregulation and adaptation across entire litters (Dearlove et al., 2018 ; Superchi et al., 2013 ). In humans, caffeine is also used as an adjuvant to NSAIDs for acute pain, yet evidence of such combined use in sows is lacking. Therefore, this study aimed to evaluate a protocol combining caffeine and meloxicam on pain-related behaviors during farrowing, colostral IgG concentrations (via on-farm testing), and progeny performance during lactation and weaning. Material and methods The experimental procedure was carried out in a smallholder pig system in the municipality of Acayucan in the central zone of the state of Veracruz, Mexico. A total of 150 piglets from 15 multiparous sows divided into three groups of 5 sows each [Control (NaCl 0.9%), Meloxicam (Melocam, Biofarmex, México) and Meloxicam (Melocam, Biofarmex, México) with Caffeine (Loeffler, México)] were used. All sows were of hybrid genetics (Yorkshire-Landrace: 189.53 ± 4.53 kg and 2.66 ± 0.12 births) and were housed during gestation and farrowing in individual crates at 27.8 ± 0.46 ºC with a standard diet being fed and water being provided ad libitum . All farrowings was induced following routine farm management and cross fostering was not allowed during lactation. The Bioethics Committee of the Academic Program in Agricultural and Livestock Development of Universidad Veracruzana approved the experimental protocol for the study (MDA-BIO-001), and all procedures were performed in accordance with established national guidelines. Experimental procedures Farrowing process and colostrum samples One day before the expected farrowing date (day 114), all sows received 1 ml of cloprostenol (0.075 mg; InducelActive, Virbac, México) intramuscularly at 09:00 h to induce farrowing 24 h later. On day 115, before the onset of farrowing (between 05:00 and 06:00 h), sows were administered two subcutaneous injections (5 ml each) according to experimental group, to simulate an identical procedure across treatments: G1 (Control): NaCl 0.9%; G2 (Meloxicam): 0.4 mg/kg meloxicam + NaCl 0.9%; G3 (Meloxicam + Caffeine): 0.5 g caffeine + 0.4 mg/kg meloxicam. At the end of farrowing, its duration, number of live-born piglets, and stillbirths were recorded. All piglets were weighed immediately after birth and returned to their pen with the sow. Colostrum samples were manually collected from all teats (upper and lower rows), pooled, and analyzed fresh using a Brix refractometer (Atago 3810 Pal-1, China), calibrated with distilled water prior to each set of analyses. A drop of colostrum was placed on the prism, and Brix percentage was recorded as described by Balzani et al. ( 2016 ). Colostrum sampling was repeated 24 h later in all sows. Piglet weights were subsequently recorded on days 7, 14, and 21 of lactation. Neonatal vitality and preweaning mortality Neonatal vitality was evaluated at the litter level 24 h postpartum by a single trained observer using the four-point scoring system described by Schodl et al. ( 2019 ). This system categorizes litters according to the number of piglets showing reduced vitality (weakness, lethargy, pallor, low activity, and insufficient suckling): (1) more than four piglets affected; (2) three to four piglets affected; (3) one to two piglets affected; and (4) no piglets affected. Preweaning mortality was calculated at the end of lactation (21 days postpartum) as the number of piglets that died before weaning divided by the number of live births, multiplied by 100. Pain scale Sow behavior during farrowing was recorded with closed-circuit television (CCTV) cameras mounted above each farrowing pen. Digital video recordings were stored for later analysis using a combination of focal and scan sampling. Following the methodology of Ison et al. ( 2016 ), sows were continuously observed from 2 min before to 2 min after the expulsion of each piglet, from the first to the last piglet born. Frequencies of the recorded behaviors were calculated for the entire farrowing period. The ethogram of observed behaviors is shown in Table 1 . Table 1 Ethogram of behaviors observed during the study. Behavior Description Back leg forward In a lateral lying position, the back leg is pulled forward and/or in towards the body. Back arch In a lateral decubitus position, one or both pairs of legs are tensed and are pulled away from the body and/or brought in towards the center, forming an arch in the back. Tail flick Tail is moved rapidly up and down. Paw In a lateral lying position, the front leg is scraped in a pawing motion Statistical analysis We used one-way analysis of variance (ANOVA) to analyze the effects of treatments on parturition variables, weight gain, and pain-suggestive behaviours, while two-way ANOVA was used for the concentration of immunoglobulins in colostrum followed by Duncan post hoc test. Values ​​of p ≤ 0.05 were considered statistically significant. Results are expressed as mean ± SEM. The data analysis was generated using SAS software, Copyright © 2023, SAS Institute Inc. Results Farrowing process, colostrum evaluation and lactational productive performance The analysis showed that no experimental treatment altered litter characteristics in terms of the number of piglets born alive, stillborn and weaned, as well as the duration of farrowing and the expulsion interval between piglets (Table 2 ). Table 2 Piglet and farrowing process characteristics of the sows involved in this study. Means ± SEM are shown. Variable G1 G2 G3 P -value Farrowing duration (min) 212.5 ± 34.4 326.1 ± 52.8 331.2 ± 166.7 0.66 Birth interval (min) 19.6 ± 2.9 33.6 ± 6.5 26.6 ± 6.1 0.21 Liveborn 10.6 ± 0.6 10.0 ± 0.5 9.4 ± 1.2 0.62 Stillborn 1.8 ± 1.2 0.6 ± 0.4 3.4 ± 1.7 0.30 Litter size 13.0 ± 1.4 10.6 ± 0.6 12.8 ± 2.2 0.51 Weaned piglets 9.0 ± 1.1 8.8 ± 0.5 8.6 ± 1.2 0.96 G1 = Control; G2 = Meloxicam (0.4 mg/kg); G3 = Meloxicam + Caffeine (0.5 g of caffeine and 0.4 mg/kg of meloxicam). Colostrum from all sows in both groups was collected within the first 6 h and at 24 h postpartum by hand milking. ANOVA results showed a significant increase in Brix percentage at the time of first sampling for G3 sows (26.6%) compared to G1 and G2 (24% and 22.6%, respectively). The Duncan post hoc test revealed that meloxicam treatment with caffeine resulted in higher colostral immunoglobulin concentration (F 2,12 = 3.41, P < 0.05) than the other treatments while at 24 h postpartum all immunoglobulin concentrations in milk were reduced (F 2,12 = 0.63, p = 0.50). Regarding litter characteristics, all neonatal piglets showed a similar birth weight distribution among the three groups (G1: 1.42 ± 0.25 kg; G2: 1.37 ± 0.32 kg and G3: 1.41 ± 0.23 kg; F 2,145 = 0.56, P = 0.57). On the contrary, during weaning, a significant increase (F 2,134 = 4.45, P < 0.01) in weight was observed in both experimental groups (G2: 5.49 ± 1.19 kg and G3: 5.49 ± 0.72 kg) compared to the control litters (4.80 ± 1.69 kg). Neonatal vitality and preweaning mortality Although the piglets born in G3 showed a better neonatal performance with respect to the variables analyzed in the four-point vitality scale (G1: 3.4 ± 0.24; G2: 3.4 ± 0.24 and G3: 3.6 ± 0.24), the ANOVA results showed that the totality of the litters achieved similar scores among themselves (F 2,12 = 0.22, P = 0.80). On the other hand, during lactation, piglet survival was increased by both experimental treatments compared to control piglets (G1: 7 deaths; G2: 6 deaths and G3: 3 deaths), since the pre-weaning mortality rate was reduced by the administration of meloxicam alone (12%) or in conjunction with caffeine (6.3%), while for untreated piglets the mortality rate was 13.20% at 21 days postpartum. Pain scale Table 3 shows the analysis of the frequencies of occurrence of the behaviours suggestive of pain evaluated during parturition, in which no significant differences were observed according to the treatments [Back leg forward (F2,9 = 2.55, P = 0.13); Back arch (F2,9 = 1.83, P = 0.21); Tail flick (F2,9 = 0.02, P = 0.98) and Paw (F2,9 = 1.12, P = 0.36)]. Table 3 Behaviors suggestive of pain observed during the labor process. Means ± SEM are shown. Behavior G1 G2 G3 P- value Back leg forward 43.5 ± 13.9 30 ± 9.6 65.7 ± 9.7 0.13 Back arch 50 ± 10.8 29.5 ± 5.3 48.7 ± 8.2 0.21 Tail flick 39.2 ± 7.0 38 ± 2.5 40.5 ± 13.2 0.98 Paw 30.7 ± 7.4 23 ± 11.3 46.2 ± 13.7 0.36 G1 = Control; G2 = Meloxicam (0.4 mg/kg); G3 = Meloxicam + Caffeine (0.5 g of caffeine and 0.4 mg/kg of meloxicam). Discussion Smallholder systems are typically characterized by low technification and small herd sizes. Nevertheless, our results on farrowing outcomes (number of piglets born alive, stillborn, and total litter size) were comparable to those reported in large-scale studies where meloxicam was administered prior to farrowing with hormonal induction (Mainau et al., 2016 ; Navarro et al., 2021 ), confirming the safety of this NSAID for these variables. By contrast, the combination of meloxicam with caffeine, while not affecting these parameters significantly, was associated with an increase in stillbirths and consequently fewer live-born piglets. This effect may reflect the synergistic inhibition of prostaglandin synthesis by caffeine (peripheral analgesic activity) and meloxicam (selective COX-2 inhibitor) (Syrova et al., 2020 ). A similar outcome was reported by van Wettere et al. ( 2018 ), where caffeine combined with progesterone increased neonatal mortality, likely through inhibition of uterine contractility, thereby prolonging farrowing. In our study, farrowing duration and birth intervals tended to be longer in the meloxicam (G2) and meloxicam + caffeine (G3) groups compared with controls, consistent with this mechanism. However, values remained within the range described for hormonally induced farrowing in Yorkshire–Landrace sows (Nam et al., 2022 ), and below the durations considered prolonged in hyperprolific sows (Farmer and Edwards, 2022 ). Still, extended expulsion time increases fetal risk, which may partly explain the rise in stillbirths. Colostrum, rich in proteins, immunoglobulins (Igs), and bioactive compounds, is critical for neonatal survival (Inoue and Tsukahara, 2021 ; Amatucci et al., 2022 ). Using Brix refractometry as an on-farm proxy for IgG concentration (Balzani et al., 2016 ), we found that colostrum from G3 sows was classified as adequate (25–29% Brix; ~50.7 ± 2.1 mg/ml IgG) compared with borderline values in G1 and G2 (20–24% Brix; ~43.8 ± 2.3 mg/ml IgG) (Hasan et al., 2016 ). This suggests a synergistic effect of meloxicam and caffeine. Meloxicam likely contributed by reducing inflammation and pain, favoring both IgG transfer and maternal care (Mainau et al., 2016 ; Navarro et al., 2021 ), while caffeine may have enhanced mammary epithelial activity, as previously shown in rodents and sows (Li and Hacker, 1994). Our findings also align with earlier studies showing positive effects of meloxicam on piglet growth (Mainau et al., 2012 ; Mainau et al., 2016 ; Navarro et al., 2021 ; Arnaud et al., 2023 ). Similarly, subcutaneous caffeine given late in gestation increased piglet vigor and colostrum intake, improving growth as reported in piglets (Sánchez-Salcedo et al., 2019 b) and lambs (Murdock et al., 2021 ). In this study, we observed significant increases in weaning weights (~ 690 g) in both G2 and G3 compared with G1, likely due to enhanced milk production, maternal behavior, and piglet vigor. Although all litters scored high for vitality (> 3; Schodl et al., 2019 ), preweaning mortality decreased by 50% in the G3 group but only marginally in G2. This reduction is notable given that stillbirth and crushing remain the primary causes of mortality (Farmer and Edwards, 2022 ). The improved passive immunity transfer and litter vigor in G3 likely prevented cascading losses associated with poor vitality. Behavioral observations further highlight the dual effects of treatment. Meloxicam tended to reduce pain-related behaviors compared with controls, consistent with previous reports where its administration reduced discomfort and improved recovery (Mainau et al., 2012 ; Plush et al., 2021 ). However, combining meloxicam with caffeine appeared to increase behaviors suggestive of discomfort, possibly reflecting caffeine-induced restlessness, as reported in rodents (Kayir and Uzbay, 2004 ; Solinas et al., 2005 ) and sows (Edwards, 2002 ; Janczak et al., 2003 ; Superchi et al., 2016 ). This raises concerns about potential interference with maternal performance and parturition. Overall, this small-scale study suggests that co-administration of meloxicam and caffeine can improve piglet survival, growth, and colostrum quality, but may simultaneously increase stillbirths and pain-related behaviors, potentially compromising sow welfare. The timing and dosing of these interventions appear critical. Further research in larger populations and under commercial conditions is needed to determine whether the benefits outweigh the risks. Declarations Acknowledgements We thank the farm “Porcícola San Judas” for the facilities granted for the realization of this project. All co-authors except Francisco Acevedo-Herrera are members of the National System of Researchers of SECIHTI in México. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing interest The authors declare no conflict of interest. Author contributions F. Acevedo-Herrera, A. Yáñez-Pizaña, and J.A. Sánchez-Salcedo contributed to conceptualization, methodology, field investigation, project administration, and writing—original draft. D. Vazquez-Luna and D.A. Lara-Rodríguez carried out formal analysis and contributed to writing—review and editing. All authors reviewed and approved the final manuscript. Data availability The datasets generated during the current study are available from the corresponding author on reasonable request. References Amatucci L, Luise D, Correa F, Bosi P, Trevisi P (2022) Importance of breed, parity and sow colostrum components on litter performance and health. Anim. 12, 1230. https://doi.org/10.3390/ani12101230 Arnaud EA, Gardiner GE, Halpin KM, Ribas C, O’ Doherty JV, Sweeney T, Lawlor PG (2023) Postpartum meloxicam administration to sows but not split-suckling increases piglet growth and reduces clinical incidence of disease in suckling piglets. J. Anim. Sci. 101. https://doi.org/10.1093/jas/skad275 Balzani A, Cordell HJ, Edwards SA (2016) Evaluation of an on-farm method to assess colostrum IgG content in sows. Anim. 10, 643–648. https://doi.org/10.1017/S1751731115002451 Dearlove BA, Kind KL, Gatford KL, Van Wettere WHEJ (2018) Oral caffeine administered during late gestation increases gestation length and piglet temperature in naturally farrowing sows. Anim. Reprod. Sci. 198, 160–166. https://doi.org/10.1016/j.anireprosci.2018.09.015 Edwards SA (2002) Perinatal mortality in the pig: environmental or physiological solutions? Livest. Prod. Sci. 78, 3–12. https://doi.org/10.1016/S0301-6226(02)00180-X Farmer C, Edwards SA (2022) Review: Improving the performance of neonatal piglets. Anim. 16, 100350. https://doi.org/10.1016/j.animal.2021.100350 Fosse TK, Toutain PL, Spadavecchia C, Haga HA, Horsberg TE, Ranheim B (2011) Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling. J. Vet. Pharmacol. Ther. 34:338–49. https://doi.org/10.1111/j.1365-2885.2010.01236.x Hasan SMK, Junnikkala S, Valros A, Peltoniemi O, Oliviero C (2016) Validation of Brix refractometer to estimate colostrum immunoglobulin G content and composition in the sow. Anim. 10, 1728–1733. https://doi.org/10.1017/S1751731116000896 Heuß EM, Pröll-Cornelissen MJ, Neuhoff C, Tholen E, Große-Brinkhaus C (2019) Invited review: Piglet survival: benefits of the immunocompetence. Anim. 13, 2114–2124. https://doi.org/10.1017/S1751731119000430 Inoue R, Tsukahara T (2021) Composition and physiological functions of the porcine colostrum. Anim. Sci. J. 92, e13618. https://doi.org/10.1111/asj.13618 Ison SH, Jarvis S, Hall SA, Ashworth CJ, Rutherford KMD (2018) Periparturient behaviour and physiology: Further insight into the farrowing process for primiparous and multiparous sows. Front. Vet. Sci. 5, 122. https://doi.org/10.3389/fvets.2018.00122 Ison SH, Jarvis S, Rutherford KMD (2016) The identification of potential behavioural indicators of pain in periparturient sows. Res. Vet. Sci. 109, 114–120. https://doi.org/10.1016/j.rvsc.2016.10.002 Ison SH, Rutherford KMD (2014) Attitudes of farmers and veterinarians towards pain and the use of pain relief in pigs. Vet. J. 202, 622–627. https://doi.org/10.1016/j.tvjl.2014.10.003 Janczak AM, Pedersen LJ, Rydhmer L, Bakken M (2003) Relation between early fear and anxiety-related behaviour and maternal ability in sows. Appl. Anim. Behav. Sci. 82, 121–135. https://doi.org/10.1016/S0168-1591(03)00055-8 Kayir H, Uzbay IT (2004) Evidence for the role of nitric oxide in caffeine-induced locomotor activity in mice. Psychopharmacol. 172, 11–15. https://doi.org/10.1007/s00213-003-1625-5 Koketsu Y, Iida R, Piñeiro C (2021) A 10-year trend in piglet pre-weaning mortality in breeding herds associated with sow herd size and number of piglets born alive. Porc. Health. Manag. 7, 4. https://doi.org/10.1186/s40813-020-00182-y Kuller W, Sietsma S, Hendriksen S, Sperling D (2021) Use of paracetamol in sows around farrowing: effect on health and condition of the sow, piglet mortality, piglet weight and piglet weight gain. Porc. Health. Manag. 7, 46. https://doi.org/10.1186/s40813-021-00224-z Li S, Hacker RR (1995) The effect of caffeine on mammary gland development and milk yield in primiparous sows. J. Anim. Sci. 73, 534–540. https://doi.org/10.2527/1995.732534x Mainau E, Ruiz-de-la-Torre JL, Dalmau A, Salleras JM, Manteca X (2012) Effects of meloxicam (Metacam®) on post-farrowing sow behaviour and piglet performance. Anim. 6, 494–501. https://doi.org/10.1017/S1751731111001790 Mainau E, Temple D, Manteca X (2016) Experimental study on the effect of oral meloxicam administration in sows on pre-weaning mortality and growth and immunoglobulin G transfer to piglets. Prev. Vet. Med. 126, 48–53. https://doi.org/10.1016/j.prevetmed.2016.01.032 Mazzoni E, Sabbioni A, Bertini S, Menozzi A, Piancastelli C, Catelli E, Zanardelli P, Zambini EM, Salieri R, Superchi P (2012) Estudio preliminary de la utilizacion de la cafeina en las cerdas en el momento del parto. Suis. 90, 32-35. Murdock NJ, Weaver AC, Kelly JM, Kleemann DO, Van Wettere WHEJ, Swinbourne AM (2021) Supplementing pregnant Merino ewes with caffeine to improve neonatal lamb thermoregulation and viability. Anim. Reprod. Sci. 226, 106715. https://doi.org/10.1016/j.anireprosci.2021.106715 Nam NH, Dao BTA, Sukon P (2022) Effects of farrowing induction using cloprostenol on sow farrowing characteristics. Vet. World. 1535–1540. https://doi.org/10.14202/vetworld.2022.1535-1540 Navarro E, Mainau E, De Miguel R, Temple D, Salas M, Manteca X (2021) Oral Meloxicam Administration in Sows at Farrowing and Its Effects on Piglet Immunity Transfer and Growth. Front. Vet. Sci. 8, 574250. https://doi.org/10.3389/fvets.2021.574250 Navarro E, Mainau E, Manteca X (2020) Development of a Facial Expression Scale Using Farrowing as a Model of Pain in Sows. Anim. 10, 2113. https://doi.org/10.3390/ani10112113 Nowland TL, van Wettere WHEJ, Plush KJ (2019) Allowing sows to farrow unconfined has positive implications for sow and piglet welfare. Appl. Anim. Behav. Sci. 104872 https://doi.org/10.1016/j.applanim.2019.104872 Ochroch EA, Mardini IA, Gottschalk A (2003) What is the role of NSAIDs in pre-emptive analgesia? Drugs. 63:2709–2723. https://doi.org/10.2165/00003495-200363240-00002 Plush KJ, McKenny LA, Nowland TL, van Wettere WHEJ (2021) The effect of hessian and straw as nesting material on sow behaviour and piglet survival and growth to weaning. Anim. 15, 100273. https://doi.org/10.1016/j.animal.2021.100273 Sanchez-Salcedo J, Bonilla-Jaime H, González-Lozano M, Hernandez-Arteaga S, Greenwell-Beare V, Vega-Manriquez X, Gonzalez-Hernandez M, Orozco-Gregorio H (2019) Therapeutics of neonatal asphyxia in production animals: a review. Vet. Med. 64, 191–203. https://doi.org/10.17221/86/2018-VETMED Sánchez-Salcedo JA, Orozco-Gregorio H, González-Lozano M, Roldán-Santiago P, González-Hernández M, Ballesteros-Rodea G, Bonilla-Jaime H (2019) Caffeine administered to pregnant sows improves piglet vitality, gas exchange and body weight gain. Anim. Reprod. Sci. 208, 106120. https://doi.org/10.1016/j.anireprosci.2019.106120 Sánchez-Salcedo JA, Yáñez-Pizaña A (2022) Effects of free farrowing system on the productive performance and welfare of sows and piglets. J. Appl. Anim. Welf. Sci. 1–11. https://doi.org/10.1080/10888705.2021.2008935 Schodl K, Revermann R, Winckler C, Fuerst-Waltl B, Leeb C, Willam A, Knapp P, Pfeiffer C (2019) Assessment of Piglet Vitality by Farmers—Validation of A Scoring Scheme and Estimation of Associated Genetic Parameters. Anim. 9, 317. https://doi.org/10.3390/ani9060317 Solinas M, Ferré S, Antoniou K, Quarta D, Justinova Z, Hockemeyer J, Pappas LA, Segal PN, Wertheim C, Müller CE, Goldberg SR (2005) Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats. Psychopharmacology. 179, 576–586. https://doi.org/10.1007/s00213-004-2081-6 Superchi P, Mazzoni C, Zanardelli P, Piancastelli C, Zambini EM, Beretti V, Sabbioni A (2013) Effects of oral caffeine administration to sows with induced parturition on hypoxia in piglets. Livest. Sci. 157, 372–377. https://doi.org/10.1016/j.livsci.2013.08.003 Superchi P, Saleri R, Farina E, Cavalli V, Riccardi E, Sabbioni A (2016) Effects of oral administration of caffeine on some physiological parameters and maternal behaviour of sows at farrowing. Res. Vet. Sci. 105, 121–123. https://doi.org/10.1016/j.rvsc.2016.01.023 Syrova A, Lukyanova L, Kozub S, Zavada O, Levashova O, Shaposhnik V (2020) Investigation of the Peripheral Analgesic Activity of Oxicams and Their Combinations with Caffeine. Turk. J. Pharm. Sci. 17, 408–411. https://doi.org/10.4274/tjps.galenos.2019.92063 Tucker BS, Craig JR, Morrison RS, Smits RJ, Kirkwood RN (2021) Piglet Viability: A Review of Identification and Pre-Weaning Management Strategies. Anim. 11, 2902. https://doi.org/10.3390/ani11102902 Van Wettere WHEJ, Toplis P, Miller HM (2018) Effect of oral progesterone and caffeine at the end of gestation on farrowing duration and piglet growth and survival. Anim. 12, 1638–1641. https://doi.org/10.1017/S175173111700310X Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7593618","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":521688062,"identity":"88e5a1b0-825b-459f-8e80-3b59dd7dfe52","order_by":0,"name":"Francisco Acevedo-Herrera","email":"","orcid":"","institution":"Universidad Veracruzana","correspondingAuthor":false,"prefix":"","firstName":"Francisco","middleName":"","lastName":"Acevedo-Herrera","suffix":""},{"id":521688063,"identity":"e1464664-e13f-4324-b62f-7e5a71369ca5","order_by":1,"name":"Ariadna Yáñez-Pizaña","email":"","orcid":"","institution":"Universidad Autónoma Metropolitana - Xochimilco: Universidad Autonoma Metropolitana - Xochimilco","correspondingAuthor":false,"prefix":"","firstName":"Ariadna","middleName":"","lastName":"Yáñez-Pizaña","suffix":""},{"id":521688064,"identity":"9b9f4173-768e-40dc-9af9-ab1eefe5f14b","order_by":2,"name":"Dinora Vazquez-Luna","email":"","orcid":"","institution":"Universidad Veracruzana","correspondingAuthor":false,"prefix":"","firstName":"Dinora","middleName":"","lastName":"Vazquez-Luna","suffix":""},{"id":521688065,"identity":"d5889a25-8518-49ed-8fcb-6ebe0dd9ff2f","order_by":3,"name":"Daniel A. 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Larger litters, while potentially more profitable, often exacerbate farrowing complications and limit maternal care (S\u0026aacute;nchez-Salcedo and Y\u0026aacute;\u0026ntilde;ez-Piza\u0026ntilde;a, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2022\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe health of reproductive females is crucial, as pain and inflammation during farrowing can prolong labor, impair sow recovery, and compromise piglet vitality. Non-steroidal anti-inflammatory drugs (NSAIDs), such as meloxicam, administered to sows around parturition have been shown to reduce pain-related behaviors, enhance piglet growth, and increase immunoglobulin concentrations, critical for piglets due to their agammaglobulinemic condition (Kuller et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Mainau et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Mainau et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Navarro et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). However, the adoption of pain management remains limited due to costs, farming traditions, drug handling, and restrictions in food-producing animals (Ison and Rutherford, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Consequently, preweaning mortality remains high, with 10\u0026ndash;20% of live-born piglets dying, mainly within the first 72 hours, due to low vitality, low birth weight, stillbirth, and litter size effects (Koketsu et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Tucker et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Losses are especially critical for smallholders.\u003c/p\u003e\u003cp\u003eIntrapartum asphyxia is a common cause of neonatal mortality in domestic mammals. Caffeine, a methylxanthine, can mitigate this problem due to its ability to cross the placenta and appear in colostrum and milk (S\u0026aacute;nchez-Salcedo et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2019\u003c/span\u003ea; Superchi et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). After oral intake, it is rapidly absorbed, reaching peak plasma levels within 9.5 h and remaining effective for up to 24 h, which benefits piglets born at different intervals within a litter (Dearlove et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Mazzoni et al., 2015). Prophylactic subcutaneous caffeine administration to sows (210 mg/day before farrowing) has been shown to improve piglet vitality, respiratory function, and weaning weight in those with high vitality scores (S\u0026aacute;nchez-Salcedo et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2019\u003c/span\u003eb), while higher doses appear to enhance thermoregulation and adaptation across entire litters (Dearlove et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Superchi et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2013\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIn humans, caffeine is also used as an adjuvant to NSAIDs for acute pain, yet evidence of such combined use in sows is lacking. Therefore, this study aimed to evaluate a protocol combining caffeine and meloxicam on pain-related behaviors during farrowing, colostral IgG concentrations (via on-farm testing), and progeny performance during lactation and weaning.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003eThe experimental procedure was carried out in a smallholder pig system in the municipality of Acayucan in the central zone of the state of Veracruz, Mexico. A total of 150 piglets from 15 multiparous sows divided into three groups of 5 sows each [Control (NaCl 0.9%), Meloxicam (Melocam, Biofarmex, M\u0026eacute;xico) and Meloxicam (Melocam, Biofarmex, M\u0026eacute;xico) with Caffeine (Loeffler, M\u0026eacute;xico)] were used. All sows were of hybrid genetics (Yorkshire-Landrace: 189.53\u0026thinsp;\u0026plusmn;\u0026thinsp;4.53 kg and 2.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.12 births) and were housed during gestation and farrowing in individual crates at 27.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.46 \u0026ordm;C with a standard diet being fed and water being provided \u003cem\u003ead libitum\u003c/em\u003e. All farrowings was induced following routine farm management and cross fostering was not allowed during lactation.\u003c/p\u003e\u003cp\u003e The Bioethics Committee of the Academic Program in Agricultural and Livestock Development of Universidad Veracruzana approved the experimental protocol for the study (MDA-BIO-001), and all procedures were performed in accordance with established national guidelines.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eExperimental procedures\u003c/h2\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003ch2\u003eFarrowing process and colostrum samples\u003c/h2\u003e\u003cp\u003eOne day before the expected farrowing date (day 114), all sows received 1 ml of cloprostenol (0.075 mg; InducelActive, Virbac, M\u0026eacute;xico) intramuscularly at 09:00 h to induce farrowing 24 h later. On day 115, before the onset of farrowing (between 05:00 and 06:00 h), sows were administered two subcutaneous injections (5 ml each) according to experimental group, to simulate an identical procedure across treatments: G1 (Control): NaCl 0.9%; G2 (Meloxicam): 0.4 mg/kg meloxicam\u0026thinsp;+\u0026thinsp;NaCl 0.9%; G3 (Meloxicam\u0026thinsp;+\u0026thinsp;Caffeine): 0.5 g caffeine\u0026thinsp;+\u0026thinsp;0.4 mg/kg meloxicam.\u003c/p\u003e\u003cp\u003eAt the end of farrowing, its duration, number of live-born piglets, and stillbirths were recorded. All piglets were weighed immediately after birth and returned to their pen with the sow. Colostrum samples were manually collected from all teats (upper and lower rows), pooled, and analyzed fresh using a Brix refractometer (Atago 3810 Pal-1, China), calibrated with distilled water prior to each set of analyses. A drop of colostrum was placed on the prism, and Brix percentage was recorded as described by Balzani et al. (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Colostrum sampling was repeated 24 h later in all sows. Piglet weights were subsequently recorded on days 7, 14, and 21 of lactation.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\n\u003ch3\u003eNeonatal vitality and preweaning mortality\u003c/h3\u003e\n\u003cp\u003eNeonatal vitality was evaluated at the litter level 24 h postpartum by a single trained observer using the four-point scoring system described by Schodl et al. (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). This system categorizes litters according to the number of piglets showing reduced vitality (weakness, lethargy, pallor, low activity, and insufficient suckling): (1) more than four piglets affected; (2) three to four piglets affected; (3) one to two piglets affected; and (4) no piglets affected. Preweaning mortality was calculated at the end of lactation (21 days postpartum) as the number of piglets that died before weaning divided by the number of live births, multiplied by 100.\u003c/p\u003e\n\u003ch3\u003ePain scale\u003c/h3\u003e\n\u003cp\u003eSow behavior during farrowing was recorded with closed-circuit television (CCTV) cameras mounted above each farrowing pen. Digital video recordings were stored for later analysis using a combination of focal and scan sampling. Following the methodology of Ison et al. (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), sows were continuously observed from 2 min before to 2 min after the expulsion of each piglet, from the first to the last piglet born. Frequencies of the recorded behaviors were calculated for the entire farrowing period. The ethogram of observed behaviors is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eEthogram of behaviors observed during the study.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBehavior\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDescription\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBack leg forward\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIn a lateral lying position, the back leg is pulled forward and/or in towards the body.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBack arch\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIn a lateral decubitus position, one or both pairs of legs are tensed and are pulled away from the body and/or brought in towards the center, forming an arch in the back.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTail flick\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTail is moved rapidly up and down.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaw\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIn a lateral lying position, the front leg is scraped in a pawing motion\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eWe used one-way analysis of variance (ANOVA) to analyze the effects of treatments on parturition variables, weight gain, and pain-suggestive behaviours, while two-way ANOVA was used for the concentration of immunoglobulins in colostrum followed by Duncan post hoc test. Values ​​of p\u0026thinsp;\u0026le;\u0026thinsp;0.05 were considered statistically significant. Results are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM. The data analysis was generated using SAS software, Copyright \u0026copy; 2023, SAS Institute Inc.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eFarrowing process, colostrum evaluation and lactational productive performance\u003c/h2\u003e\u003cp\u003eThe analysis showed that no experimental treatment altered litter characteristics in terms of the number of piglets born alive, stillborn and weaned, as well as the duration of farrowing and the expulsion interval between piglets (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePiglet and farrowing process characteristics of the sows involved in this study. Means\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM are shown.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eFarrowing duration (min)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e212.5\u0026thinsp;\u0026plusmn;\u0026thinsp;34.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e326.1\u0026thinsp;\u0026plusmn;\u0026thinsp;52.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e331.2\u0026thinsp;\u0026plusmn;\u0026thinsp;166.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.66\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBirth interval (min)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e33.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e26.6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLiveborn\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e10.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e9.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.62\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eStillborn\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e1.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.30\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eLitter size\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e13.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e10.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e12.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eWeaned piglets\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e9.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e8.8\u0026thinsp;\u0026plusmn;\u0026thinsp;0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.96\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eG1\u0026thinsp;=\u0026thinsp;Control; G2\u0026thinsp;=\u0026thinsp;Meloxicam (0.4 mg/kg); G3\u0026thinsp;=\u0026thinsp;Meloxicam\u0026thinsp;+\u0026thinsp;Caffeine (0.5 g of caffeine and 0.4 mg/kg of meloxicam).\u003c/p\u003e\u003cp\u003eColostrum from all sows in both groups was collected within the first 6 h and at 24 h postpartum by hand milking. ANOVA results showed a significant increase in Brix percentage at the time of first sampling for G3 sows (26.6%) compared to G1 and G2 (24% and 22.6%, respectively). The Duncan \u003cem\u003epost hoc\u003c/em\u003e test revealed that meloxicam treatment with caffeine resulted in higher colostral immunoglobulin concentration (F\u003csub\u003e2,12\u003c/sub\u003e= 3.41, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) than the other treatments while at 24 h postpartum all immunoglobulin concentrations in milk were reduced (F\u003csub\u003e2,12\u003c/sub\u003e= 0.63, p\u0026thinsp;=\u0026thinsp;0.50). Regarding litter characteristics, all neonatal piglets showed a similar birth weight distribution among the three groups (G1: 1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.25 kg; G2: 1.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.32 kg and G3: 1.41\u0026thinsp;\u0026plusmn;\u0026thinsp;0.23 kg; F\u003csub\u003e2,145\u003c/sub\u003e= 0.56, P\u0026thinsp;=\u0026thinsp;0.57). On the contrary, during weaning, a significant increase (F\u003csub\u003e2,134\u003c/sub\u003e= 4.45, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in weight was observed in both experimental groups (G2: 5.49\u0026thinsp;\u0026plusmn;\u0026thinsp;1.19 kg and G3: 5.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72 kg) compared to the control litters (4.80\u0026thinsp;\u0026plusmn;\u0026thinsp;1.69 kg).\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eNeonatal vitality and preweaning mortality\u003c/h3\u003e\n\u003cp\u003eAlthough the piglets born in G3 showed a better neonatal performance with respect to the variables analyzed in the four-point vitality scale (G1: 3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24; G2: 3.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24 and G3: 3.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.24), the ANOVA results showed that the totality of the litters achieved similar scores among themselves (F\u003csub\u003e2,12\u003c/sub\u003e= 0.22, P\u0026thinsp;=\u0026thinsp;0.80). On the other hand, during lactation, piglet survival was increased by both experimental treatments compared to control piglets (G1: 7 deaths; G2: 6 deaths and G3: 3 deaths), since the pre-weaning mortality rate was reduced by the administration of meloxicam alone (12%) or in conjunction with caffeine (6.3%), while for untreated piglets the mortality rate was 13.20% at 21 days postpartum.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003ePain scale\u003c/h2\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the analysis of the frequencies of occurrence of the behaviours suggestive of pain evaluated during parturition, in which no significant differences were observed according to the treatments [Back leg forward (F2,9\u0026thinsp;=\u0026thinsp;2.55, P\u0026thinsp;=\u0026thinsp;0.13); Back arch (F2,9\u0026thinsp;=\u0026thinsp;1.83, P\u0026thinsp;=\u0026thinsp;0.21); Tail flick (F2,9\u0026thinsp;=\u0026thinsp;0.02, P\u0026thinsp;=\u0026thinsp;0.98) and Paw (F2,9\u0026thinsp;=\u0026thinsp;1.12, P\u0026thinsp;=\u0026thinsp;0.36)].\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eBehaviors suggestive of pain observed during the labor process. Means\u0026thinsp;\u0026plusmn;\u0026thinsp;SEM are shown.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBehavior\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eG1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eG2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eG3\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP-\u003c/em\u003evalue\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBack leg forward\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e43.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e30\u0026thinsp;\u0026plusmn;\u0026thinsp;9.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e65.7\u0026thinsp;\u0026plusmn;\u0026thinsp;9.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBack arch\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e50\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e29.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e48.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTail flick\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e39.2\u0026thinsp;\u0026plusmn;\u0026thinsp;7.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e38\u0026thinsp;\u0026plusmn;\u0026thinsp;2.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e40.5\u0026thinsp;\u0026plusmn;\u0026thinsp;13.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.98\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePaw\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e30.7\u0026thinsp;\u0026plusmn;\u0026thinsp;7.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e23\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e46.2\u0026thinsp;\u0026plusmn;\u0026thinsp;13.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eG1\u0026thinsp;=\u0026thinsp;Control; G2\u0026thinsp;=\u0026thinsp;Meloxicam (0.4 mg/kg); G3\u0026thinsp;=\u0026thinsp;Meloxicam\u0026thinsp;+\u0026thinsp;Caffeine (0.5 g of caffeine and 0.4 mg/kg of meloxicam).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eSmallholder systems are typically characterized by low technification and small herd sizes. Nevertheless, our results on farrowing outcomes (number of piglets born alive, stillborn, and total litter size) were comparable to those reported in large-scale studies where meloxicam was administered prior to farrowing with hormonal induction (Mainau et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Navarro et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), confirming the safety of this NSAID for these variables. By contrast, the combination of meloxicam with caffeine, while not affecting these parameters significantly, was associated with an increase in stillbirths and consequently fewer live-born piglets. This effect may reflect the synergistic inhibition of prostaglandin synthesis by caffeine (peripheral analgesic activity) and meloxicam (selective COX-2 inhibitor) (Syrova et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). A similar outcome was reported by van Wettere et al. (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2018\u003c/span\u003e), where caffeine combined with progesterone increased neonatal mortality, likely through inhibition of uterine contractility, thereby prolonging farrowing. In our study, farrowing duration and birth intervals tended to be longer in the meloxicam (G2) and meloxicam\u0026thinsp;+\u0026thinsp;caffeine (G3) groups compared with controls, consistent with this mechanism. However, values remained within the range described for hormonally induced farrowing in Yorkshire\u0026ndash;Landrace sows (Nam et al., \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2022\u003c/span\u003e), and below the durations considered prolonged in hyperprolific sows (Farmer and Edwards, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Still, extended expulsion time increases fetal risk, which may partly explain the rise in stillbirths.\u003c/p\u003e\u003cp\u003eColostrum, rich in proteins, immunoglobulins (Igs), and bioactive compounds, is critical for neonatal survival (Inoue and Tsukahara, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Amatucci et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Using Brix refractometry as an on-farm proxy for IgG concentration (Balzani et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2016\u003c/span\u003e), we found that colostrum from G3 sows was classified as adequate (25\u0026ndash;29% Brix; ~50.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1 mg/ml IgG) compared with borderline values in G1 and G2 (20\u0026ndash;24% Brix; ~43.8\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3 mg/ml IgG) (Hasan et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). This suggests a synergistic effect of meloxicam and caffeine. Meloxicam likely contributed by reducing inflammation and pain, favoring both IgG transfer and maternal care (Mainau et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Navarro et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e), while caffeine may have enhanced mammary epithelial activity, as previously shown in rodents and sows (Li and Hacker, 1994).\u003c/p\u003e\u003cp\u003eOur findings also align with earlier studies showing positive effects of meloxicam on piglet growth (Mainau et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Mainau et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2016\u003c/span\u003e; Navarro et al., \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e; Arnaud et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Similarly, subcutaneous caffeine given late in gestation increased piglet vigor and colostrum intake, improving growth as reported in piglets (S\u0026aacute;nchez-Salcedo et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2019\u003c/span\u003eb) and lambs (Murdock et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In this study, we observed significant increases in weaning weights (~\u0026thinsp;690 g) in both G2 and G3 compared with G1, likely due to enhanced milk production, maternal behavior, and piglet vigor.\u003c/p\u003e\u003cp\u003eAlthough all litters scored high for vitality (\u0026gt;\u0026thinsp;3; Schodl et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e), preweaning mortality decreased by 50% in the G3 group but only marginally in G2. This reduction is notable given that stillbirth and crushing remain the primary causes of mortality (Farmer and Edwards, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). The improved passive immunity transfer and litter vigor in G3 likely prevented cascading losses associated with poor vitality.\u003c/p\u003e\u003cp\u003eBehavioral observations further highlight the dual effects of treatment. Meloxicam tended to reduce pain-related behaviors compared with controls, consistent with previous reports where its administration reduced discomfort and improved recovery (Mainau et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Plush et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). However, combining meloxicam with caffeine appeared to increase behaviors suggestive of discomfort, possibly reflecting caffeine-induced restlessness, as reported in rodents (Kayir and Uzbay, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2004\u003c/span\u003e; Solinas et al., \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e2005\u003c/span\u003e) and sows (Edwards, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2002\u003c/span\u003e; Janczak et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2003\u003c/span\u003e; Superchi et al., \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). This raises concerns about potential interference with maternal performance and parturition.\u003c/p\u003e\u003cp\u003eOverall, this small-scale study suggests that co-administration of meloxicam and caffeine can improve piglet survival, growth, and colostrum quality, but may simultaneously increase stillbirths and pain-related behaviors, potentially compromising sow welfare. The timing and dosing of these interventions appear critical. Further research in larger populations and under commercial conditions is needed to determine whether the benefits outweigh the risks.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the farm \u0026ldquo;Porc\u0026iacute;cola San Judas\u0026rdquo; for the facilities granted for the realization of this project. All co-authors except Francisco Acevedo-Herrera are members of the National System of Researchers of SECIHTI in M\u0026eacute;xico.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eF. Acevedo-Herrera, A. Y\u0026aacute;\u0026ntilde;ez-Piza\u0026ntilde;a, and J.A. S\u0026aacute;nchez-Salcedo contributed to conceptualization, methodology, field investigation, project administration, and writing\u0026mdash;original draft. D. Vazquez-Luna and D.A. Lara-Rodr\u0026iacute;guez carried out formal analysis and contributed to writing\u0026mdash;review and editing. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAmatucci L, Luise D, Correa F, Bosi P, Trevisi P (2022) Importance of breed, parity and sow colostrum components on litter performance and health. Anim. 12, 1230. https://doi.org/10.3390/ani12101230\u003c/li\u003e\n\u003cli\u003eArnaud EA, Gardiner GE, Halpin KM, Ribas C, O\u0026rsquo; Doherty JV, Sweeney T, Lawlor PG (2023) Postpartum meloxicam administration to sows but not split-suckling increases piglet growth and reduces clinical incidence of disease in suckling piglets. J. Anim. Sci. 101. https://doi.org/10.1093/jas/skad275\u003c/li\u003e\n\u003cli\u003eBalzani A, Cordell HJ, Edwards SA (2016) Evaluation of an on-farm method to assess colostrum IgG content in sows. Anim. 10, 643\u0026ndash;648. https://doi.org/10.1017/S1751731115002451\u003c/li\u003e\n\u003cli\u003eDearlove BA, Kind KL, Gatford KL, Van Wettere WHEJ (2018) Oral caffeine administered during late gestation increases gestation length and piglet temperature in naturally farrowing sows. Anim. Reprod. Sci. 198, 160\u0026ndash;166. https://doi.org/10.1016/j.anireprosci.2018.09.015\u003c/li\u003e\n\u003cli\u003eEdwards SA (2002) Perinatal mortality in the pig: environmental or physiological solutions? Livest. Prod. Sci. 78, 3\u0026ndash;12. https://doi.org/10.1016/S0301-6226(02)00180-X\u003c/li\u003e\n\u003cli\u003eFarmer C, Edwards SA (2022) Review: Improving the performance of neonatal piglets. Anim. 16, 100350. https://doi.org/10.1016/j.animal.2021.100350\u003c/li\u003e\n\u003cli\u003eFosse TK, Toutain PL, Spadavecchia C, Haga HA, Horsberg TE, Ranheim B (2011) Ketoprofen in piglets: enantioselective pharmacokinetics, pharmacodynamics and PK/PD modelling. J. Vet. Pharmacol. Ther. 34:338\u0026ndash;49. https://doi.org/10.1111/j.1365-2885.2010.01236.x \u003c/li\u003e\n\u003cli\u003eHasan SMK, Junnikkala S, Valros A, Peltoniemi O, Oliviero C (2016) Validation of Brix refractometer to estimate colostrum immunoglobulin G content and composition in the sow. Anim. 10, 1728\u0026ndash;1733. https://doi.org/10.1017/S1751731116000896\u003c/li\u003e\n\u003cli\u003eHeu\u0026szlig; EM, Pr\u0026ouml;ll-Cornelissen MJ, Neuhoff C, Tholen E, Gro\u0026szlig;e-Brinkhaus C (2019) Invited review: Piglet survival: benefits of the immunocompetence. Anim. 13, 2114\u0026ndash;2124. https://doi.org/10.1017/S1751731119000430\u003c/li\u003e\n\u003cli\u003eInoue R, Tsukahara T (2021) Composition and physiological functions of the porcine colostrum. Anim. Sci. J. 92, e13618. https://doi.org/10.1111/asj.13618\u003c/li\u003e\n\u003cli\u003eIson SH, Jarvis S, Hall SA, Ashworth CJ, Rutherford KMD (2018) Periparturient behaviour and physiology: Further insight into the farrowing process for primiparous and multiparous sows. Front. Vet. Sci. 5, 122. https://doi.org/10.3389/fvets.2018.00122\u003c/li\u003e\n\u003cli\u003eIson SH, Jarvis S, Rutherford KMD (2016) The identification of potential behavioural indicators of pain in periparturient sows. Res. Vet. Sci. 109, 114\u0026ndash;120. https://doi.org/10.1016/j.rvsc.2016.10.002\u003c/li\u003e\n\u003cli\u003eIson SH, Rutherford KMD (2014) Attitudes of farmers and veterinarians towards pain and the use of pain relief in pigs. Vet. J. 202, 622\u0026ndash;627. https://doi.org/10.1016/j.tvjl.2014.10.003\u003c/li\u003e\n\u003cli\u003eJanczak AM, Pedersen LJ, Rydhmer L, Bakken M (2003) Relation between early fear and anxiety-related behaviour and maternal ability in sows. Appl. Anim. Behav. Sci. 82, 121\u0026ndash;135. https://doi.org/10.1016/S0168-1591(03)00055-8\u003c/li\u003e\n\u003cli\u003eKayir H, Uzbay IT (2004) Evidence for the role of nitric oxide in caffeine-induced locomotor activity in mice. Psychopharmacol. 172, 11\u0026ndash;15. https://doi.org/10.1007/s00213-003-1625-5\u003c/li\u003e\n\u003cli\u003eKoketsu Y, Iida R, Pi\u0026ntilde;eiro C (2021) A 10-year trend in piglet pre-weaning mortality in breeding herds associated with sow herd size and number of piglets born alive. Porc. Health. Manag. 7, 4. https://doi.org/10.1186/s40813-020-00182-y\u003c/li\u003e\n\u003cli\u003eKuller W, Sietsma S, Hendriksen S, Sperling D (2021) Use of paracetamol in sows around farrowing: effect on health and condition of the sow, piglet mortality, piglet weight and piglet weight gain. Porc. Health. Manag. 7, 46. https://doi.org/10.1186/s40813-021-00224-z\u003c/li\u003e\n\u003cli\u003eLi S, Hacker RR (1995) The effect of caffeine on mammary gland development and milk yield in primiparous sows. J. Anim. Sci. 73, 534\u0026ndash;540. https://doi.org/10.2527/1995.732534x\u003c/li\u003e\n\u003cli\u003eMainau E, Ruiz-de-la-Torre JL, Dalmau A, Salleras JM, Manteca X (2012) Effects of meloxicam (Metacam\u0026reg;) on post-farrowing sow behaviour and piglet performance. Anim. 6, 494\u0026ndash;501. https://doi.org/10.1017/S1751731111001790\u003c/li\u003e\n\u003cli\u003eMainau E, Temple D, Manteca X (2016) Experimental study on the effect of oral meloxicam administration in sows on pre-weaning mortality and growth and immunoglobulin G transfer to piglets. Prev. Vet. Med. 126, 48\u0026ndash;53. https://doi.org/10.1016/j.prevetmed.2016.01.032\u003c/li\u003e\n\u003cli\u003eMazzoni E, Sabbioni A, Bertini S, Menozzi A, Piancastelli C, Catelli E, Zanardelli P, Zambini EM, Salieri R, Superchi P (2012) Estudio preliminary de la utilizacion de la cafeina en las cerdas en el momento del parto. Suis. 90, 32-35.\u003c/li\u003e\n\u003cli\u003eMurdock NJ, Weaver AC, Kelly JM, Kleemann DO, Van Wettere WHEJ, Swinbourne AM (2021) Supplementing pregnant Merino ewes with caffeine to improve neonatal lamb thermoregulation and viability. Anim. Reprod. Sci. 226, 106715. https://doi.org/10.1016/j.anireprosci.2021.106715\u003c/li\u003e\n\u003cli\u003eNam NH, Dao BTA, Sukon P (2022) Effects of farrowing induction using cloprostenol on sow farrowing characteristics. Vet. World. 1535\u0026ndash;1540. https://doi.org/10.14202/vetworld.2022.1535-1540\u003c/li\u003e\n\u003cli\u003eNavarro E, Mainau E, De Miguel R, Temple D, Salas M, Manteca X (2021) Oral Meloxicam Administration in Sows at Farrowing and Its Effects on Piglet Immunity Transfer and Growth. Front. Vet. Sci. 8, 574250. https://doi.org/10.3389/fvets.2021.574250\u003c/li\u003e\n\u003cli\u003eNavarro E, Mainau E, Manteca X (2020) Development of a Facial Expression Scale Using Farrowing as a Model of Pain in Sows. Anim. 10, 2113. https://doi.org/10.3390/ani10112113\u003c/li\u003e\n\u003cli\u003eNowland TL, van Wettere WHEJ, Plush KJ (2019) Allowing sows to farrow unconfined has positive implications for sow and piglet welfare. Appl. Anim. Behav. Sci. 104872 https://doi.org/10.1016/j.applanim.2019.104872\u003c/li\u003e\n\u003cli\u003eOchroch EA, Mardini IA, Gottschalk A (2003) What is the role of NSAIDs in pre-emptive analgesia? Drugs. 63:2709\u0026ndash;2723. https://doi.org/10.2165/00003495-200363240-00002\u003c/li\u003e\n\u003cli\u003ePlush KJ, McKenny LA, Nowland TL, van Wettere WHEJ (2021) The effect of hessian and straw as nesting material on sow behaviour and piglet survival and growth to weaning. Anim. 15, 100273. https://doi.org/10.1016/j.animal.2021.100273\u003c/li\u003e\n\u003cli\u003eSanchez-Salcedo J, Bonilla-Jaime H, Gonz\u0026aacute;lez-Lozano M, Hernandez-Arteaga S, Greenwell-Beare V, Vega-Manriquez X, Gonzalez-Hernandez M, Orozco-Gregorio H (2019) Therapeutics of neonatal asphyxia in production animals: a review. Vet. Med. 64, 191\u0026ndash;203. https://doi.org/10.17221/86/2018-VETMED\u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Salcedo JA, Orozco-Gregorio H, Gonz\u0026aacute;lez-Lozano M, Rold\u0026aacute;n-Santiago P, Gonz\u0026aacute;lez-Hern\u0026aacute;ndez M, Ballesteros-Rodea G, Bonilla-Jaime H (2019) Caffeine administered to pregnant sows improves piglet vitality, gas exchange and body weight gain. Anim. Reprod. Sci. 208, 106120. https://doi.org/10.1016/j.anireprosci.2019.106120\u003c/li\u003e\n\u003cli\u003eS\u0026aacute;nchez-Salcedo JA, Y\u0026aacute;\u0026ntilde;ez-Piza\u0026ntilde;a A (2022) Effects of free farrowing system on the productive performance and welfare of sows and piglets. J. Appl. Anim. Welf. Sci. 1\u0026ndash;11. https://doi.org/10.1080/10888705.2021.2008935\u003c/li\u003e\n\u003cli\u003eSchodl K, Revermann R, Winckler C, Fuerst-Waltl B, Leeb C, Willam A, Knapp P, Pfeiffer C (2019) Assessment of Piglet Vitality by Farmers\u0026mdash;Validation of A Scoring Scheme and Estimation of Associated Genetic Parameters. Anim. 9, 317. https://doi.org/10.3390/ani9060317\u003c/li\u003e\n\u003cli\u003eSolinas M, Ferr\u0026eacute; S, Antoniou K, Quarta D, Justinova Z, Hockemeyer J, Pappas LA, Segal PN, Wertheim C, M\u0026uuml;ller CE, Goldberg SR (2005) Involvement of adenosine A1 receptors in the discriminative-stimulus effects of caffeine in rats. Psychopharmacology. 179, 576\u0026ndash;586. https://doi.org/10.1007/s00213-004-2081-6\u003c/li\u003e\n\u003cli\u003eSuperchi P, Mazzoni C, Zanardelli P, Piancastelli C, Zambini EM, Beretti V, Sabbioni A (2013) Effects of oral caffeine administration to sows with induced parturition on hypoxia in piglets. Livest. Sci. 157, 372\u0026ndash;377. https://doi.org/10.1016/j.livsci.2013.08.003\u003c/li\u003e\n\u003cli\u003eSuperchi P, Saleri R, Farina E, Cavalli V, Riccardi E, Sabbioni A (2016) Effects of oral administration of caffeine on some physiological parameters and maternal behaviour of sows at farrowing. Res. Vet. Sci. 105, 121\u0026ndash;123. https://doi.org/10.1016/j.rvsc.2016.01.023\u003c/li\u003e\n\u003cli\u003eSyrova A, Lukyanova L, Kozub S, Zavada O, Levashova O, Shaposhnik V (2020) Investigation of the Peripheral Analgesic Activity of Oxicams and Their Combinations with Caffeine. Turk. J. Pharm. Sci. 17, 408\u0026ndash;411. https://doi.org/10.4274/tjps.galenos.2019.92063\u003c/li\u003e\n\u003cli\u003eTucker BS, Craig JR, Morrison RS, Smits RJ, Kirkwood RN (2021) Piglet Viability: A Review of Identification and Pre-Weaning Management Strategies. Anim. 11, 2902. https://doi.org/10.3390/ani11102902\u003c/li\u003e\n\u003cli\u003eVan Wettere WHEJ, Toplis P, Miller HM (2018) Effect of oral progesterone and caffeine at the end of gestation on farrowing duration and piglet growth and survival. Anim. 12, 1638\u0026ndash;1641. https://doi.org/10.1017/S175173111700310X\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Farrowing sow, Stillborn, Weaned piglets, Methylxanthines, NSAID","lastPublishedDoi":"10.21203/rs.3.rs-7593618/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7593618/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIn swine production, non-steroidal anti-inflammatory drugs (NSAIDs) such as meloxicam and stimulants like caffeine have been investigated for their effects on productivity at farrowing. Meloxicam reduces fever and pain linked to mastitis-metritis, while caffeine enhances neonatal vitality and growth. This study evaluated their combined administration before farrowing, focusing on pain-related behaviours, colostrum quality, and piglet growth. A total of 150 piglets from smallholder systems were assigned to three treatments (NaCl, meloxicam, or meloxicam with caffeine). Results showed higher colostrum IgG in sows treated with both substances, and piglets from meloxicam and meloxicam\u0026thinsp;+\u0026thinsp;caffeine groups were significantly heavier at weaning. However, more pain behaviours and stillbirths were noted in the combined group, suggesting possible adverse effects on sow comfort. Further research with larger samples is needed to balance productivity gains and animal welfare outcomes.\u003c/p\u003e","manuscriptTitle":"Effects of meloxicam and caffeine co-administration on sow farrowing, colostrum quality and piglet performance in smallholder systems","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-09 13:32:49","doi":"10.21203/rs.3.rs-7593618/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2b83f3a9-c46e-45af-8720-e6e89b443659","owner":[],"postedDate":"October 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-05T17:18:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-09 13:32:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7593618","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7593618","identity":"rs-7593618","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}