Enhancing Pregnancy Outcomes in Cattle Reproduction: Role of Anti-inflammatory Drugs in AI and Embryo Transfer

Assisted reproductive technologies such as artificial insemination (AI) and embryo transfer (ET) have significantly advanced veterinary reproductive medicine. Despite improvements in cryopreservation techniques, recipient cow management, and technical expertise, pregnancy outcomes have not consistently improved across ET programs ¹. As a result, researchers have focused on pharmacological strategies to improve reproductive success, particularly by modulating prostaglandin pathways using anti-inflammatory drugs¹. 

Importance of Prostaglandin Inhibition in Reproduction 

Prostaglandins, particularly prostaglandin F2α (PGF2α), play a critical role in luteolysis and reproductive cycle regulation. PGF2α is synthesized from arachidonic acid via cyclooxygenase (COX) enzymes and prostaglandin synthase pathways¹. Excessive PGF2α release following ET can cause premature luteal regression, reduced progesterone levels, and embryonic loss. Nonsteroidal anti-inflammatory drugs (NSAIDs) help counter this process by inhibiting COX enzymes and reducing PGF2α synthesis, thereby supporting corpus luteum function and improving embryonic survival¹. 

Flunixin Meglumine — The Most Widely Studied NSAID in Bovine Reproduction 

Flunixin meglumine (FM) is one of the most extensively studied NSAIDs in cattle reproductive management. 

Mechanism of Action 

FM inhibits the conversion of arachidonic acid into prostaglandins, thereby reducing uncontrolled PG release and preventing embryo loss associated with progesterone deficiency¹. Studies in ACTH-treated beef cows demonstrated that FM administration significantly reduced serum prostaglandin F metabolite (PGFM) concentrations¹. 

Pregnancy Rate Outcomes 

Research findings regarding FM effects on pregnancy outcomes are variable and depend on environmental and physiological factors. 

FM administered 15 minutes before ET in camels helped maintain PGFM levels below 100 pg/mL, whereas control animals showed levels up to 180 pg/mL¹. Some studies reported improved pregnancy rates of 65% compared to 60% in untreated controls¹. In heat-stressed cows, FM increased pregnancy rate to 60% compared to 30% in control animals¹. 

However, several large-scale studies did not demonstrate significant improvement¹: 

• 61.3% vs 58.5% pregnancy rate in FM versus control groups (n = 492). 

• 60.2% vs 58.4% pregnancy rate in larger population studies (n = 975). 

These findings suggest that FM may not universally improve pregnancy outcomes but may be beneficial in selected cases such as poor-quality embryo transfer, difficult cervical passage during ET procedures, and stress-exposed animals. 

Stress and Temperament Effects 

Excitable animals often have elevated cortisol and substance-P levels, which can stimulate PGF2α release and suppress progesterone secretion. FM treatment has been shown to reduce stress-related hormonal changes and support pregnancy maintenance in temperament-sensitive animals^1,2. Pregnancy rates were higher in calm animals compared to excitable animals, demonstrating the role of stress physiology in reproductive success. 

Other NSAIDs in Reproductive Management 

Carprofen 

Carprofen is a long-acting NSAID with a plasma half-life of approximately 30–40 hours in cattle¹. 

Clinical findings include: 

• No significant effects on progesterone concentration or embryo mortality¹. 

• Improved conception rates in long-term infertile cows (>120 days in milk), showing pregnancy rates of 42.26% compared to 25.26% in controls¹. 

• Greater benefits observed in animals with poor body condition scores³. 

However, treatment timing is critical. Administration during key reproductive windows sometimes failed to show benefit. 

Meloxicam 

Meloxicam is a COX-2–preferential inhibitor with a relatively long half-life and is sometimes used as an alternative to FM. 

Positive outcomes include: 

• Pregnancy rate improvement to 72.1% compared to 45.2% in Nelore heifers¹. 

• Higher success rates in animals with difficult cervical passage, reaching 90.48% pregnancy rates¹. 

However, delayed administration can negatively affect fertility: 

• Meloxicam given on Day 15 after insemination reduced pregnancy rates from 52% to 24.3%¹. 

Other NSAIDs 

Low-dose aspirin improved pregnancy rates in cows (40% vs 30%) [23]. Ibuprofen improved pregnancy outcomes in embryo recipient heifers. Tolfenamic acid improved pregnancy maintenance and offspring survival in experimental ET models¹. 

Role of Steroids in Reproductive Management 

Glucocorticoids influence prostaglandin synthesis, implantation physiology, and fetal development. However, their clinical application in improving pregnancy rates remains limited [63]. 

Dexamethasone and Embryo Development 

Dexamethasone supplementation improved blastocyst development and cellular proliferation. Combination therapy using dexamethasone and leukemia inhibitory factor reduced PGF2α concentrations and improved pregnancy rates in experimental models⁴. 

Despite these benefits, high-dose glucocorticoids can induce abortion due to immunosuppression and endocrine disruption effects⁴. Overall, steroids are used less frequently than NSAIDs in bovine reproduction. 

Practical Applications in Veterinary Practice 

Anti-inflammatory reproductive modulation is not universally beneficial but can be applied strategically. 

NSAIDs may be helpful in: 

• Stress-exposed animals 

• Poor-quality embryo recipients 

• Animals requiring prolonged cervical manipulation during ET 

• Repeat breeding cows 

NSAIDs may have limited benefit in: 

• High-performing ET programs with already high pregnancy success rates 

• Well-managed herds with optimal reproductive conditions 

Key Clinical Message 

NSAIDs can improve reproductive outcomes by modulating PGF2α synthesis and supporting luteal function. However, their effectiveness depends on physiological, environmental, and technical factors, including embryo quality and timing of drug administration. Flunixin meglumine remains the most extensively documented reproductive NSAID, while newer COX inhibitors such as meloxicam show promising but context-dependent results. 

References  

1. Jaśkowski BM, Opałka A, Gehrke M, Herudzińska M, Czeladko J, Baumgartner W, Jaśkowski JM. A critical overview on prostaglandin inhibitors and their influence on pregnancy results after insemination and embryo transfer in cows. Animals. 2021 Nov 24;11(12):3368. https://www.mdpi.com/2076-2615/11/12/3368  

2. Kasimanickam RK, Hall JB, Estill CT, Kastelic JP, Joseph C, Aziz RA, Nak DE. Flunixin meglumine improves pregnancy rate in embryo recipient beef cows with an excitable temperament. Theriogenology. 2018 Feb 1;107:70-7. https://www.academia.edu/download/98902487/j.theriogenology.2017.10.04320230220-1-dx305a.pdf  

3. Abay M, Pancarci SM, Gungor O, Nak Y, Alparslan AD, Bekyurek T. Effects of carprofen and/or CIDR administration on pregnancies per artificial insemination around pregnancy recognition in lactating dairy cows. Journal of the Hellenic Veterinary Medical Society. 2021;72(3):3101-8. https://ejournals.epublishing.ekt.gr/index.php/jhvms/article/download/28499/22328  
4. Lopes JS, Alcázar-Triviño E, Soriano-Úbeda C, Hamdi M, Cánovas S, Rizos D, Coy P. Reproductive outcomes and endocrine profile in artificially inseminated versus embryo transferred cows. Animals. 2020 Aug 6;10(8):1359. https://www.mdpi.com/2076-2615/10/8/1359