Effect of oxytocin administration at different time points during parturition on the farrowing process in sows

ABSTRACT Oxytocin is commonly used to shorten farrowing duration in sows. Therefore, determining the optimal time for this application is necessary. This study investigated the effects of oxytocin administration at different time points during parturition on the stillbirth rate, birth interval and farrowing duration to determine the optimal moment of this application in crated sows. The information on 1914 piglets born after oxytocin administration at different time points was collected. The three studied parameters in different groups were compared. The results showed that the stillbirth rate was minimized when oxytocin was used after the birth of the 5th and before the birth of the 8th piglets. The birth interval was the shortest when the oxytocin was used after the birth of the 5th piglet and before the birth of the 9th piglet. The farrowing duration was the shortest when the oxytocin was used after the birth of the 6th piglet and before the birth of the 8th piglet. In conclusion, if oxytocin is destined to be used during parturition, it should be used after the birth of the 6th piglet and before the birth of the 8th piglet to minimize the stillbirth rate and to shorten birth interval and farrowing duration.


Introduction
An increase in the litter size of the pig during recent decades (Koketsu et al. 2017) results in prolonged farrowing duration (van Dijk et al. 2005;Oliviero et al. 2019;Peltoniemi et al. 2021) and increased stillbirth rate (Borges et al. 2005;Vallet et al. 2010;Vanderhaeghe et al. 2010).Farrowing duration has increased from 130 min in 2004 (van Rens and van der Lende 2004) to 272 min in 2010 (Oliviero et al. 2010) and 396 min in 2017 (Björkman et al. 2017).Parturition is the energyconsuming, stressful process, then the increased farrowing duration may affect sows' health and their maternal ability (Lund et al. 2002;Rutherford et al. 2013).Prolonged parturition also increased retained placentas (Björkman et al. 2017), the amount of vaginal discharge (Grahofer et al. 2021a) and the risk of postparturient metritis (Björkman et al. 2018).Studies also showed that the stillbirth rate in piglets may vary between 5 and 10% (Langendijk and Plush 2019;Nam andSukon 2020a, 2020b) causing considerable reductions in the reproductive performance of the pig.Therefore, these issues raise an ethical concern and economic problem in the pigraising industry (Ward et al. 2020).
For shortening the farrowing duration and reducing stillbirth rate uterotonic drugs, most of the time oxytocin and carbetocin, and sometimes prostaglandin E-2, have been investigated (Bill et al. 2021;Muro et al. 2021;Grahofer et al. 2021b).In a recent systematic review and meta-analysis study, oxytocin and carbetocin have been found to decrease birth interval and farrowing duration while an increase in the stillbirth rate in comparison with the control group (Muro et al. 2021).Unfortunately, most of the published papers dealt with the oxytocin administration at 24h after farrowing induction with a prostaglandin product (Decaluwé et al. 2014;Zaremba 2014;Boonraungrod et al. 2018) or after the birth of the first piglet (Alonso- Spilsbury et al. 2004;Mota-Rojas et al. 2006;Jiarpinitnun et al. 2019).The use of uterotonic drugs at such stages of parturition prevents successful exploration of the effects of these drugs' administration at other stages of parturition on farrowing characteristics.Among a few studies that used uterotonic drugs in the middle process of parturition, Udomchanya et al. (2019) used carbetocin after the birth of the 7th piglet and reported that the treatment shortened farrowing duration but did not reduce the stillbirth rate.Another study investigated the effects of oxytocin administration after the birth of the 1st, 4th and 8th piglets on farrowing characteristics, and found that the use of oxytocin after the birth of the 8th piglet minimized the stillbirth rate but the birth interval and farrowing duration in this group were longer than those in other treatment groups (Mota-Rojas et al. 2007).Therefore, with such available findings, it is challenging to determine the optimal time of application of uterotonic drugs (Muro et al. 2021) at which they can generate the most benefit to both sows and piglets depicted by minimized birth interval, farrowing duration and stillbirth rate.
The present study, therefore, aimed at exploring the effect of oxytocin use at different time points during parturition on farrowing characteristics including farrowing duration, birth interval and stillbirth rate to determine the optimal time of this application.

Animals and housing
This study enrolled mixed parity Landrace x Yorkshire crossbred sows and their piglets from 8 farms located in 5 provinces in the North of Vietnam from February 2019 to January 2021.These farms had a capacity of 200-500 breeding sows.Sows were inseminated with Duroc boars' semen.Sows were vaccinated against classical swine fever, foot and mouth disease, pseudorabies disease, reproductive and respiratory syndrome and parvovirus.Sows were dewormed twice a year.Depending on the gestation stage, sows received 1.8-3.5 kg of industrial pelleted feed.About 3 days before farrowing, the feed offered to the sows was reduced to 1kg per day.Sows received 2 meals per day.On the day of farrowing, sows received no feed.Studied sows received water from a bite nipple system with a flow rate of 2 l/min.
During gestation, sows were allocated in individual gestation crates sized 1.32 m 2 .About a week before farrowing, pregnant sows were moved to farrowing rooms.In the farrowing rooms, sows were allocated into farrowing pens of 3.92 m 2 .The farrowing pens were divided into sows' place (1.32 m 2 ) in the centre and piglets' places at both sides of the sows' place.Both gestation and farrowing crates had a slatted concrete floor.The piglets' place was equipped with a slatted hard plastic floor.The creep area for piglets which was put on one side of the farrowing pens was heated with an infrared lamp.The temperature in the farrowing unit ranged 26-30°C.Sows were monitored for any sign of farrowing including vulval swelling, milk letdown and nest building.All farrowing incidents were spontaneous.

Data collection and definition
Sows were continuously monitored by humans from the birth of the first to the birth of the last piglets.In this study, none of the sows received oxytocin administration before the birth of the first piglets.Only sows that received oxytocin during the foetal expulsion stage (any time after the birth of the first but before the birth of the last piglet) were included in the study.In the case a litter was born without oxytocin assistance, the sow and her piglets were discarded from the present study.As a result, 317 sows were included in this study.These sows gave birth to 4542 piglets.The litter size ranged between 4 and 24.Among born piglets, 1914 piglets were born after the use of oxytocin and were used to study the effect of oxytocin administration at different birth orders on farrowing characteristics.Other 2628 piglets born before the use of oxytocin were included in the descriptive study only.All oxytocin (20IU) injections were administered intramuscularly into the neck of the sows.The use of oxytocin was a routine procedure in the farms and decided by the herd veterinarians.Usually, when a birth interval exceeded 30-45 min, the oxytocin injection was conducted.Manual extraction was sometimes conducted in these farms when there were signs of foetal obstruction in the birth canal.However, it could also be conducted when the birth interval exceeded 30-45 min without any signs of foetal obstruction.Being a subjective and variable practice this obstetric intervention was not recorded in this study despite its potential effects on farrowing performance.
The birth time of all piglets was recorded for calculation of birth interval and farrowing duration.The birth interval was the time interval between the birth of two successive piglets and the farrowing duration was the time interval between the birth of the first and the last piglets.The birth order in which the oxytocin was administered to the sows was recorded.Stillbirth piglets were those born dead without signs of autolysis.Other information in parity number, gestation length, litter size (total born) and individual birth weight was also recorded.

Statistical analysis
All available data were used for descriptive statistics (Table 1).Parity number, gestation length, litter size, farrowing duration and birth interval were shown as mean and standard deviation.Stillbirth was calculated as a percentage.
A Chi-square test and one-way ANOVA tests were used to roughly detect the effect of time of oxytocin administration on stillbirth and birth interval and farrowing duration, respectively (SPSS version 22, IBM SPSS Statistics for Windows, Version 22.0.Armonk, NY: IBM Corp).The detected effect patterns were subsequently used as cut-off values for dividing the time of oxytocin injection into different intervals.Concerning its effect on stillbirth (SB) the use of oxytocin was divided into 3 intervals, i.e. before the birth of the 5th piglet (SB-1), after the birth of the 5th piglet and before the birth of the 8th piglet (SB-2) and after the birth of the 8th piglet (SB-3).Concerning the effect of oxytocin on the birth interval (BI), its use was divided into 3 intervals, i.e. before the birth of the 5th piglet (BI-1), after the birth of the 5th piglet and before the birth of the 9th piglet (BI-2) and after the birth of the 9th piglet (BI-3).To evaluate the effect of oxytocin on farrowing duration (FD), its use was divided into 3 intervals, i.e. before the birth of the 6th piglet (FD-1), after the birth of the 6th piglet and before the birth of the 8th piglet (FD-2) and after the birth of the 8th piglets (FD-3).Subsequently, the effects of oxytocin administration on stillbirth were analyzed with a Generalized Linear Mixed Model (GLMM), and the effects of oxytocin administration on birth interval and farrowing duration were analyzed with the Linear Mixed Effect Model (LMEM).The use of these tests was to deal with the hierarchical characteristics of data where piglets might be born from the same sows and sows might be raised on the same farms.Additionally, Linear Mixed Effect Models were also used to compare the birth weight, litter size, parity number and birth order in different groups.GLMM and LMEM were conducted in RStudio Desktop 1.4.1106.A pvalue <0.05 was set as the significance level in all tests.

Results
Descriptive statistics of investigated sows and piglets are shown in Table 1.The birth interval and farrowing duration were 18.4 ± 36.4 and 232.7 ± 132.8 min, respectively.The total stillbirth rate and stillbirth rate in piglets born before and after oxytocin use were 5.7%, 3.6%, and 8.4%, respectively.The average birth order at which oxytocin injection occurred was 8.1 ± 3.6.
Table 2 shows the stillbirth rates, birth intervals and farrowing durations when oxytocin was used at different birth orders.
The use of oxytocin at different birth orders influenced the stillbirth rate, farrowing duration and birth interval.The administration of oxytocin after the birth of the 5th piglet and before the birth of the 8th piglet minimized the stillbirth rate (P < 0.05).Similarly, the administration of oxytocin after the birth of the 5th piglet and before the birth of the 9th piglet resulted in the shortest birth interval (P < 0.05).Also, the administration of oxytocin after the birth of the 6th piglet and before the birth of the 8th piglet engendered the shortest farrowing duration (P < 0.05) (Table 3).
The litter size of the piglets born within BI-1, BI-2 and BI-3 groups was 13.2 ± 3.7, 13.5 ± 3.1, and 15.5 ± 2.6, respectively (P < 0.05).The birth weights of these piglets were 1.27 ± 0.40, 1.37 ± 0.37, and 1.37 ± 0.36kg, respectively (P < 0.05).Different superscripts in the same category showed a significant difference.SB-1: oxytocin was used before the birth of the 5th piglet; SB-2: oxytocin was used after the birth of the 5th piglet and before the birth of the 8th piglet; SB-3: oxytocin was used after the birth of the 8th piglet.BI-1: oxytocin was used before the birth of the 5th piglet; BI-2: oxytocin was used after the birth of the 5th pirglet and before the birth of the 9th piglet; BI-3: oxytocin was used after the birth of the 9th piglet.FD-1: oxytocin was used before the birth of the 6th piglet; FD-2: oxytocin was used after the birth of the 6th piglet and before the birth of the 8th piglet; FD-3: oxytocin was used after the birth of the 8th piglet.

Discussion
Many studies investigated the effects of oxytocin on the farrowing characteristics of the pig (see review by Muro et al. 2021).However, a few studies aimed at determining the optimal time of oxytocin used to minimize the stillbirth rate and shorten the birth interval and farrowing duration (Mota-Rojas et al. 2007).This study indicated that in case oxytocin was routinely planned to be used during farrowing it should be used after the birth of the 6th piglet and before the birth of the 8th piglet.This indication is partly in line with many previous studies that suggested that uterotonic drugs such as oxytocin and carbetocin should not be administered to sows at an early stage of foetal expulsion (after the birth of the 1st piglet) (Jiarpinitnun et al. 2019;Ward et al. 2019).Also, the suggestion that oxytocin should be used after the birth of the 6th piglet and before the birth of the 8th piglet is novel because previous studies only suggested that oxytocin could be used late in labour (Mota-Rojas et al. 2007) or when the farrowing was prolonged (Udomchanya et al. 2019) without an indication of a specific time.The gap in findings between this study and previous ones may be attributable to the lack of information on the effects of oxytocin/carbetocin administration at various times on stillbirth and other farrowing characteristics in previous studies.The present study also demonstrated an interesting finding that using oxytocin during the suggested time reduced all the evaluated farrowing characteristics including stillbirth, birth interval and farrowing duration.
Many previous studies have shown that stillbirth increased when the birth order increased (Baxter et al. 2008;Baxter et al. 2009;Baxter et al. 2012;Langendijk et al. 2018;Nam andSukon 2020b, 2021a).If those results had been still true in the present study the stillbirth rate of piglets in the SB-1 group would have been lower than that in the SB-2 group.However, since the stillbirth rate in the SB-2 group was lower than that in the SB-1 group, the present finding suggested that the use of oxytocin after the birth of the 5th piglet and before the birth of the 8th piglet had reduced the stillbirth rate in comparison with oxytocin administration at other time points.Also, the indifference in the stillbirth rate between SB-1 and SB-3 groups suggested that oxytocin had altered the stillbirth rate in favour of lowering it in the SB-3 group.It is of note that the birth order of piglets born in the SB-1 group was significantly lower than that in the SB-3 group (9.2 vs. 13.6).This result, therefore, corroborates the finding that oxytocin administration after the birth of the 8th piglets resulted in a lower stillbirth rate in comparison with that in the group used oxytocin after the birth of the 1st piglet and the group used oxytocin after the birth of the 4th piglet (Mota-Rojas et al. 2007).From another standpoint, because stillbirth is associated with birth weight (Canario et al. 2006;Baxter et al. 2009;Nam and Sukon 2021a), one may argue that the lower stillbirth rate in the SB-2 group as compared with that in the SB-1 group may be attributable to the difference in the birth weight of piglets.However, the birth weight could not be the only key to explain this phenomenon, because there was no difference in birth weight between SB-2 and SB-3 groups.To this point, the explanation for the difference in stillbirth rate between SB-2 and SB-3 groups may have to come back to its association with birth order.If it is the case, the difference in the effects of oxytocin administration at different time points may be the explanation for the difference in stillbirth rate between SB-1 and SB2 groups.
The shortest farrowing duration in the FD-2 group is an interesting finding.Litter size is well-known to be positively associated with farrowing duration (Fahmy and Friend 1981;van Dijk et al. 2005;Nam and Sukon 2020a).Therefore, it was assumed that if the effects of oxytocin administration at different time points on farrowing duration had been the same, the farrowing duration in the FD-3 (litter size = 15.3) group would have been longer than that in FD-1 (litter = 13.2) and FD-2 (litter size = 13.4) groups, and that in the FD-1 and FD-2 groups would not have been different.Moreover, the parity number, which was positively associated with farrowing duration (Björkman et al. 2017), in the FD-3 group (parity = 4.9) was also higher than that in FD-1 (parity = 4.3) and FD-2 (parity = 3.8) groups.It is, therefore, suggested that oxytocin administration had indeed produced different effects on farrowing duration when it was used at different time points, and its use after the birth of the 6th piglet and before the birth of the 8th piglets would gain the most beneficial effect on farrowing duration.
On the one hand, the birth interval is positively associated with birth weight (van Dijk et al. 2005).Therefore, the birth interval of piglets in the BI-1 group (birth weight = 1.27kg) was expected to be shorter than that in the BI-2 group (birth weight = 1.37 kg).A similar expectation was also the case of BI-1 and BI-3 (birth weight = 1.37 kg) groups.On the other hand, the birth interval was negatively associated with litter size (Vallet et al. 2010;Nam and Sukon 2021b).Although the litter size in the BI-3 group was larger than that in the BI-2 group (15.7 vs. 13.2), the birth interval in the BI-3 group was longer than that in the BI-2 group.Taken together, the use of oxytocin at different time points during farrowing must have expressed different effects on the birth interval, and the present results indicated that the use of oxytocin after the birth of the 5th piglet and before the birth of the 9th piglet would result in the highest benefit concerning birth interval.
The results of the present study are interesting because the optimal time of oxytocin administration that resulted in minimized stillbirth rate, and shortest farrowing duration and birth interval have been determined.Several indirect findings such as the association between these three parameters with others including birth order, litter size, birth weight and parity number have also been discussed to prove potentially different effects of oxytocin administration at various time points during the farrowing process.However, the mechanism(s) under which oxytocin produced different effects on investigated outcomes are yet to be explored.Oxytocin administration at an early stage of farrowing may cause hyperstimulation to the uterine contraction and result in a higher risk of asphyxia and stillbirth, while its use at the later stage of parturition (after the birth of the 8 th piglet) may result in a mild stimulation to fatigue uteri, shorten the farrowing duration and subsequently lower stillbirth rate (Mota-Rojas et al. 2007).Nevertheless, this mechanism cannot explain why the optimal time towards stillbirth was after the birth of the 5th and before the birth of the 8th piglet.Similarly, how oxytocin shortened the birth interval and farrowing duration when it was used after the birth of the 5-8th and 6-7th piglets, respectively, is in the need of investigation.

Conclusion
The results of the present study indicated that when oxytocin was used at different time points during the farrowing in the pig, it generated different effects on stillbirth, birth interval and farrowing duration.Firstly, the stillbirth rate was minimized when oxytocin was used after the birth of the 5th piglet and before the birth of the 8th piglet.Secondly, the birth interval was the shortest when oxytocin was used after the birth of the 5th piglet and before the birth of the 9th piglet.Finally, the farrowing duration was the shortest when the oxytocin was used after the birth of the 6th piglet and before the birth of the 8th piglet.Collectively, when oxytocin is destined to be used during farrowing it should be administered to sows after the birth of the 6 th piglet and before the birth of the 8th piglet so that it can generate the most beneficial effects on farrowing characteristics of the pig.

Ethical approval
This research was waived from the animal care and use committee of the Vietnam National University of Agriculture because it was an observational study that did not involve sample collection.

Disclosure statement
No potential conflict of interest was reported by the author(s).
Birth order at which oxytocin was used 317 8.1 ± 3.6 SD: Standard deviation; n: number of animals.

Table 3 .
Effect of oxytocin administration at different time points during parturition on stillbirth rate (%), farrowing duration (min) and birth interval (min).