Maternal plasma levels of oxytocin during physiological childbirth - a systematic review with implications for uterine contractions and central actions of oxytocin

RESEARCH ARTICLE Open Access Maternal plasma levels of oxytocin during physiological childbirth –a systematic review with implications for uterine contractions and central actions of oxytocin Kerstin Uvnäs-Moberg 1 , Anette Ekström-Bergström 2,3* , Marie Berg 4,5 , Sarah Buckley 6 , Zada Pajalic 7 , Eleni Hadjigeorgiou 8 , Alicja Kotłowska 9 , Luise Lengler 10 , Bogumila Kielbratowska 11 , Fatima Leon-Larios 12 , Claudia Meier Magistretti 13 , Soo Downe 14 , Bengt Lindström 15 and Anna Dencker 4,5 Abstract Background: Oxytocin is a key hormone in childbirth, and synthetic oxytocin is widely administered to induce or speed labour. Due to lack of synthetized knowledge, we conducted a systematic review of maternal plasma levels of oxytocin during physiological childbirth, and in response to infusions of synthetic oxytocin, if reported in the included studies. Methods: An a priori protocol was designed and a systematic search was conducted in PubMed, CINAHL, and PsycINFO in October 2015. Search hits were screened on title and abstract after duplicates were removed (n= 4039), 69 articles were examined in full-text and 20 papers met inclusion criteria. As the articles differed in design and methodology used for analysis of oxytocin levels, a narrative synthesis was created and the material was categorised according to effects. Results: Basal levels of oxytocin increased 3–4-fold during pregnancy. Pulses of oxytocin occurred with increasing frequency, duration, and amplitude, from late pregnancy through labour, reaching a maximum of 3 pulses/10 min towards the end of labour. There was a maximal 3- to 4-fold rise in oxytocin at birth. Oxytocin pulses also occurred in the third stage of labour associated with placental expulsion. Oxytocin peaks during labour did not correlate in time with individual uterine contractions, suggesting additional mechanisms in the control of contractions. Oxytocin levels were also raised in the cerebrospinal fluid during labour, indicating that oxytocin is released into the brain, as well as into the circulation. Oxytocin released into the brain induces beneficial adaptive effects during birth and postpartum. Oxytocin levels following infusion of synthetic oxytocin up to 10 mU/min were similar to oxytocin levels in physiological labour. Oxytocin levels doubled in response to doubling of the rate of infusion of synthetic oxytocin. Conclusions: Plasma oxytocin levels increase gradually during pregnancy, and during the first and second stages of labour, with increasing size and frequency of pulses of oxytocin. A large pulse of oxytocin occurs with birth. Oxytocin in the circulation stimulates uterine contractions and oxytocin released within the brain influences maternal physiology and behaviour during birth. Oxytocin given as an infusion does not cross into the mother’s brain because of the blood brain barrier and does not influence brain function in the same way as oxytocin during normal labour does. Keywords: Oxytocin, Plasma levels, Pregnancy, Physiological labour, Birth, Uterine contractions, Central effects, Neurobiology, Infusion of synthetic oxytocin © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. * Correspondence: anette.ekst[email protected] 2 School of Health and Education, University of Skövde, Skövde, Sweden 3 Department of Health Sciences, University West, Trollhättan, Sweden Full list of author information is available at the end of the article Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 https://doi.org/10.1186/s12884-019-2365-9 Plain English Summary Oxytocin is an important hormone in labour and birth, when it helps the labouring woman’s uterus to contract and birth her baby. We searched for all the studies that measured blood levels of oxytocin in women during normal (physiological) labour and birth. We found that blood oxytocin levels gradually rise in pregnancy and become even higher during labour, when pulses of oxytocin become progressively bigger and more frequent. Oxytocin contracts the uterus and promotes the progress of labour. A large oxytocin pulse occurs with the birth, and pulses continue afterwards, which help the new mother to birth the placenta, prevent bleeding, and warm her chest for skin-to-skin contact with her baby. During labour, oxytocin is released into both the blood and brain, with high oxytocin levels in the brain fluid (cerebrospinal fluid, CSF). Oxytocin has many positive effects in the mother’s brain during labour, and prepares her for motherhood. Oxytocin reduces anxiety, stress and pain in labour and switches on brain pleasure and reward centres, making the new mother relaxed, and happy as she meets her baby for the first time. Several studies measured oxytocin levels when infusion of synthetic oxytocin was used for induction or augmentation of labour. These studies found that low doses of synthetic oxytocin produced similar oxytocin levels as physiological labour whereas high doses gave abnormally high oxytocin levels, in proportion to dosage. Labour induced by synthetic oxytocin differs in some way from normal, physiological labour. It may, especially at high dosages cause more, longer and more painful contractions, when compared to normal labour. Oxytocin given as an infusion does not cross into the mother’s brain because of the blood brain barrier and does not influence brain function in the same way as normal labour does. Background The peptide hormone oxytocin was discovered in 1906 by Sir Henry Dale, who found that a pituitary extract stimulated uterine contractility in cats [1]. The chemical structure of oxytocin was elucidated in the 1950s by Vincent du Vigneaud and oxytocin was synthesized soon after [2]. It is well known that oxytocin plays a pivotal role during human labour and birth. Oxytocin is produced in neurons that originate in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, and is transported to the posterior pituitary. During labour, oxytocin is released in pulses from the pituitary into the circulation to induce uterine contractions [3]. Research interest in oxytocin has increased dramatically in recent years, as oxytocin has been found to have many positive physiological and psychological effects [4]. This is due to the fact that oxytocin is released within the brain. Oxytocinergic nerves originating in the PVN project to many important regulatory areas, where oxytocin is released to act as a neuromodulator, with widespread central effects [5]. For example, oxytocin enhances mood and wellbeing; promotes friendly social interactions; reduces anxiety and pain; and lowers physiological and psychological stress, among other benefits [6]. In addition, it reduces sympathetic nervous system activity (“fight or flight”), and increases parasympathetic nervous system activity (“relaxation and growth” and “calm and connection”)[4]. Given this information on oxytocin, and its established role in maternal behaviours in all mammals [7], it is important to consider the possible effects of oxytocin released in the brain during childbirth. In addition, infusions of synthetic oxytocin are widely used in maternity care to induce or augment labour, and are also recommended to prevent or treat postpartum bleeding [8]. Because of the widespread and increased use of synthetic oxytocin, it is critical to understand the possible impacts on endogenous oxytocin, and on oxytocin-mediated effects in mothers and babies [9,10]. As part of a collaborative European project initiated within the European COST program IS1405, we aim at performing several systematic reviews summarizing existing data on plasma levels and effects of oxytocin in mothers, during and after physiological childbirth, including longer-term effects on breastfeeding, attachment, and mental health, and in women with and without medical interventions. Recent information on the beneficial central effects of oxytocin must be incorporated into the present knowledge about the role of oxytocin during physiological labour. Previous studies that measured oxytocin levels during birth were mainly published in the 1970s to 90s. Most of these older studies are of high quality and provide an accurate assessment of oxytocin levels, and would be difficult to perform today because of technical, practical and ethical reasons. It is of importance to bring back this forgotten but highly relevant knowledge to healthcare professionals of today involved in labour and birth. In addition, there are many misunderstandings regarding the effects of endogenous oxytocin and exogenous synthetic oxytocin during childbirth that could be resolved by access to this knowledge, with benefits for clinical care. The specific aim of this systematic review is to summarize existing data on plasma levels of oxytocin during normal physiological birth. In addition, data from the reviewed studies on plasma levels of oxytocin after infusions of synthetic oxytocin will be included. This will allow comparison between oxytocin levels observed during physiological birth and in birth induced or augmented with synthetic oxytocin. We will also discuss the Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 2 of 17 possible central effects of oxytocin released in the brain during physiological birth. Methods A systematic review was carried out according to the PRISMA statement [11]. An a priori protocol was designed, outlining the aim and procedure for the review. Inclusion criteria were studies presenting blood/plasma oxytocin levels in women having had a normal pregnancy without medical complications, a physiological birth, and who had given birth to a healthy baby at term. Included were peer-reviewed original research studies comprising at least one measure of plasma oxytocin levels in women during a physiological labour, and which were written in either English, French or German as these were the languages available to the review team. Search strategy A comprehensive and systematic search was done in the following databases: PubMed, CINAHL and PsycINFO in October 2015, to identify studies or existing systematic reviews. We also hand-searched the reference lists of all eligible publications for references to other possibly relevant studies. The search string is available in the Additional file 1. A total of 4039 publications were found after removal of duplicates. Assessment of titles and abstracts were divided in six groups of authors (KUM & AEB; AK& BK; MB & LL; EH & CMM; FLL & ZP; AD & SD) and assessed independently by the authors in pairs. The assessment was based on the inclusion criteria, i.e. women without medical complications during pregnancy or labour. In case of disagreement a third reviewer (KUM) was involved. This process ended in exclusion of 3973 papers. The full text of the remaining papers (n= 66) was read by a team of two researchers (KUM and AEB). Three further studies were added from reference lists giving 69 papers which were screened for eligibility. Of these studies 49 were excluded because they did not fulfil the inclusion criteria. This process led to a final number of 20 publications to be included for data extraction. For overview of study selection see the flow diagram in Fig. 1. Data extraction and analysis A combined analysis of all data was not possible because the studies differed substantially as to the type of biochemical analysis used to determine oxytocin levels as to when during labour, as well as to the timing and the frequency of blood sampling (single samples, repeated samples with different time intervals including months, weeks, hours, minutes or seconds). We therefore created a narrative synthesis for each article. From these narrative results, oxytocin levels during labour were extracted and then summarized to allow characterization of oxytocin levels during the different time periods of birth, and also comparison between groups. Some of the included studies also contained information about plasma levels of oxytocin during basal conditions (non-pregnant women) and during pregnancy. These data were included to allow comparison between oxytocin levels in these situations and plasma levels of oxytocin during birth. Information about oxytocin levels in cerebrospinal fluid (CSF) during pregnancy and birth was also included. Data on oxytocin levels following bolus injections or infusions of synthetic oxytocin described in the included studies are also presented. Finally, data on the association between uterine contractions and plasma levels of oxytocin were included. In some studies, oxytocin levels were measured both before and after medical interventions. In all except one of the included studies, radioimmunoassay (RIA) was used to determine oxytocin levels [12]. The levels of oxytocin in the 20 selected papers were presented in different measures/units, e.g. μU/mL, pg/mL or pmol/L (pM). In order to facilitate interpretation of the results, Table 1shows conversion between international units (IU), weight units (g) and molar units (M). All samples were from peripheral veins, except one study that simultaneously also collected blood from the jugular vein. Results As described, 20 articles that measured oxytocin levels during labour and birth met the criteria for inclusion [13–32]. The studies were published between 1965 and 2001. In addition to measurement of oxytocin levels in labour, oxytocin levels were also measured during pregnancy in 10 of the 20 included studies. Some studies also included measures of oxytocin levels in non-pregnant women. Characteristics of the included articles are reported in Table 2. Fig. 1 Flow diagram of study selection Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 3 of 17 All oxytocin levels converted to pg/mL are summarized in Table 3. The results obtained after extraction of data from the individual articles were summarized into categories, which are presented as follows; “Summary of oxytocin levels during labour and birth”(Table 4); “Summary of oxytocin levels during pregnancy and in non-pregnant women” (Table 5)and“Summary of the occurrence of uterine contractions in relation to plasma levels of oxytocin during labour without and with synthetic oxytocin”(Table 6). Four schematic figures were created which describe the change of oxytocin levels over time (Figs. 2,3a, b, and 4). The data used for the figures have been taken from the included studies, as indicated in the text legends of the figures, and have been transformed and simplified for clarity. Figures show oxytocin levels during pregnancy and labour (Fig. 2), the pattern of oxytocin levels during spontaneous labour versus induction of labour with infusion of synthetic oxytocin (Fig. 3a and b), and the very short-lasting character of oxytocin pulses (Fig. 4). Extraction of data from the included articles Data from the included articles has been reported in Tables 1,2,3,4,5,6and Figs. 2,3a, b, and 4,as described above. Coch et al. 1965 [13] Serial blood samples were collected from 18 women during physiological birth. “Oxytocin equivalent activity”was demonstrated in samples collected from both the jugular vein (levels ranged between 300 and 900 μU/mL) and a peripheral vein (levels up to 100 μU/mL). The oxytocin equivalent activity increased as labour progressed and reached maximum levels during the second stage of labour, when oxytocin equivalent activity in the jugular vein was up to 8- to 9-fold higher than that in peripheral plasma. After birth, jugular vein oxytocin equivalent activity decreased to levels in peripheral venous blood. The high levels of oxytocin equivalent activity in the jugular vein relative to those in a peripheral vein indicate that oxytocin is released from a central source (the pituitary) during the second phase of labour. Kumaresan et al. 1974 [14] Multiple blood samples (n= 79) were collected at random intervals from 5 women during active physiological labour and birth. Oxytocin levels in plasma averaged 181 μU/mL (range 35–435 μU/mL) in 79 samples. The variation between samples was enormous, indicative of a pulsatile release of oxytocin. The data obtained in this study could not determine whether oxytocin levels were higher during labour than during pregnancy, perhaps due to the wide between-sample variations. In relation to oxytocin in pregnancy, levels rose from 66 μU/mL to 165 μU/mL between weeks 4 and 40 (n= 280). The main rise was observed between weeks 25 and 40. There was a significant correlation between oxytocin levels and weeks of gestation (p< 0.01). Oxytocin levels were less than 1.0 μU/mL (n= 15) in non-pregnant women. Note that there was a marked difference between oxytocin levels in non-pregnant and pregnant women. Kumaresan et al. 1975 [15] Serial blood samples were collected from 29 women, from physiological labour and birth to 4 days postpartum. Mean oxytocin levels were approximately the same 10 min before and directly after birth: 90 ± 11 μU/mL and 82 ± 12 μU/mL respectively. Oxytocin levels decreased gradually postpartum (day 1–66 ± 8 μU/mL, day 2–50 ± 9 μU/mL, day 3–54 ± 9 μU/mL and day 4, the same as day 3). The fall in oxytocin levels between day 1 and days 2, 3 and 4 was significant (p < 0.01). Lower oxytocin levels postpartum indicates that oxytocin levels were raised during labour. Gibbens et al. 1976 [16] Serial blood samples (8) were collected from 97 women during physiological labour and birth. Oxytocin levels were not detected in all samples, likely due to its pulsatile release. A progressive increase in the number of positive results was apparent throughout the first and second stage of labour, suggesting that oxytocin levels increase during the course of labour. Oxytocin levels, indicating the size of pulses, varied between 2 and 12.5 μU/mL. A decrease in oxytocin levels was seen in the third stage of labour. There was no obvious relationship Table 1 Conversion of oxytocin levels between units Conversion of different size units: 1 Unit (IU) = 1000 milliunits (mU) = 1000,000 microunits (μU) 1 g (g) = 1000 mg (mg) = 1000,000 micrograms (μg) = 1000,000,000 nanograms (ng) = 1000,000,000,000 picograms (pg) 1 Mol/L = 1 Molar (M) = 1000 milliMolar (mM) = 1000,000 microMolar (μM) = 1000,000,000 nanoMolar (nM) = 1000,000,000,000 picoMolar (pM) Conversion of units (U) to weight units: 1 IU = 1.67 μg, 1 μg = 0.60 U 1 mU = 1.67 ng, 1 ng = 0.60 mU 1μU = 1.67 pg, 1 pg = 0.60 μU Conversion of weight/volume of oxytocin to Molarity (molecular weight of oxytocin equal to 1007 g/mol): 1 g/mL = 1 mol/L = 1 M 1 mg/mL = 1 mmol/L = 1 mM 1μg /mL = 1 μmol/L = 1 μM 1 ng/mL = 1 nmol/L = 1 nM 1 pg/mL = 1 pmol/L = 1pM Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 4 of 17 Table 2 Characteristics of included studies First author, year, ref. no. Data collection Methodology Comment Coch 1965 [13] Blood samples from the jugular and a peripheral vein at various stages of labour and postpartum, in 18 women. Bioassay a Bioassay based on milk ejection in rabbits calculating “oxytocin equivalent activity.”Very high levels compared to modern assays using RIA. Kumaresan 1974 [14] Single blood samples between weeks 4 and 40 during pregnancy in 280 women. 79 random samples during active labour in 5 women. Serial samples were obtained before and after oxytocin infusion of 100 mU per min to women with midpregnancy terminations. RIA b OT determinations performed with RIA without prior extraction, explaining why high levels. OT levels were already very high at term, but did not rise further during labour, maybe due to an insensitivity of this assay at high levels of OT. Kumaresan 1975 [15] Single maternal blood samples were collected from 29 women 10 min before birth, just after birth and daily for 4 days postpartum. RIA b OT determinations performed with RIA without prior extraction, giving higher levels. Lack of a significant peak at birth suggests possible insensitivity of the assay at high levels. Gibbens 1976 [16] 8 serial blood samples from 97 women during spontaneous labour (1st stage 33, 2nd stage 14, 3rd 10). Single samples from a further 30 women during the 3rd stage of labour. The serial samples were collected over a period of 4 to 8 min. RIA c Pulsatile release of OT was detected. Very low basal levels of OT may be due to insensitivity of the RIA used, or to a loss of OT during the extraction procedure. Vasicka 1978 [17] Blood samples were collected in a longitudinal study (during pregnancy, onset of labour and birth) in 15 women. Samples at one- to two-week intervals during pregnancy and one minute to one hour intervals throughout labour and birth. RIA b OT determinations performed with RIA without prior extraction, explaining high levels. Dawood 1979 [18] 362 blood samples were collected from normal pregnant women. Serial blood samples of blood were obtained from 10 pregnant women through gestation until labour onset. Serial samples taken at 1 min intervals over a 10 min period in 7 pregnancies and 3 in 1st stage of labour. RIA c OT levels recorded within the range normally observed with established RIA after prior extraction of the samples. Leake 1981 [19] Plasma oxytocin levels in 102 non-pregnant women, 20 women receiving oral contraceptive medications and 59 pregnant women from 15 to 42 w of pregnancy. Repeated samples were collected in 38 healthy women during spontaneous labour. RIA c Very low OT levels. RIA did not pick up differences between pregnant and non-pregnant women; the rise of oxytocin occurring during pregnancy; or the rise of OT observed during labour, suggesting that the RIA used was very insensitive. Significant rise of OT level observed was in connection with birth only. Otsuki 1983 [20] Individual samples from 38 normal pregnant women between the 15th and the 41 st w of pregnancy. Serial samples from 2 women in the mid trimester, from 4 women at term without labour contractions and from 6 women in the 1st stage of normal spontaneous labour, at 10 s intervals over a period of 2–3 min. RIA c Relevant OT levels within the range normally observed with established RIAs. Goodfellow 1983 [21] 20 primigravidae with normal labour, after 37 to 41 weeks of pregnancy. Epidural analgesia was chosen by half of the women. Blood samples at the beginning and end of 2nd phase of labour. RIA c Relevant OT levels within the range normally observed with established RIA. Husslein 1983 [22] 20 women with spontaneous labour. Blood samples were collected just before the 2nd phase of labour, 5 min postpartum, 30 min after expulsion of placenta and 2 h after birth. 7 women received oxytocin drip in a low dosage at the end of the first phase of labour. Directly after birth 10 women received oxytocin drip in a high dosage (100-150mIU/min). RIA c Relevant OT levels giving values within the range normally observed with established RIA. Fuchs 1983 [23] 17 women in early spontaneous labour and 15 women at term who were given oxytocin induction. Five blood samples. In one group at admission to the labour ward and subsequent samples were taken at 1–3h intervals. In another group a blood sample just before infusion of oxytocin was started and thereafter just before the infusion rate was increased. Infusion was begun at the rate of 1–2 mU/min and increased stepwise every 15 min until contractions occurred with about 3 min intervals. RIA c Relevant OT levels within the range of values normally observed with established RIA. Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 5 of 17 Table 2 Characteristics of included studies (Continued) First author, year, ref. no. Data collection Methodology Comment Thereafter the infusion rate was kept constant. 10 of these 17 women contributed a blood sample 1–2w before labour. The control group consisted of 4 pregnant women at term but not in labour. Four serial samples were taken at 2 h intervals from each woman. Amico 1984 [24] Eleven women with “hypocontractile labour”received oxytocin infusion in a dose of 1 mU/min and it was increased by one 1 mU every 40 min until adequate contractions were observed. Blood samples were drawn before start of infusion and at every 20 min, during infusion and for 60 min after the end of infusion. RIA c Very low basal levels of OT maybe due to insensitivity of the RIA used or to loss of OT during the extraction procedure. Takeda 1985 [25] 42 participants were included in the study, 4 healthy males, 15 non-pregnant women, and 23 pregnant women (11 before and 12 in labour). Blood and cerebrospinal fluid (CSF) samples were collected simultaneously from all the participants. RIA c Relevant OT levels within the range of values normally observed with established RIA. Takagi 1985 [26] 36 women were included in the study (7 non pregnant women, 11 pregnant women having an emergency CS and 18 pregnant women having an elective CS. 1 blood and cerebrospinal fluid (CSF) samples were collected simultaneously from all the women RIA c Relevant oxytocin levels within the range of values normally observed with established RIA. De Geest 1985 [27] 10 pregnant women and 15 women during normal labour, 5 of which received EDA. Four blood samples during pregnancy and during the 1st and 2nd stage of labour. Blood samples were also collected from umbilical arterial and venous blood vessels after birth RIA b OT determinations performed with RIA without prior extraction, which explains high OT levels.A rise of OT level observed during pregnancy, but not during labour, suggesting that the RIA used was insensitive at higher levels than those observed during pregnancy. Kuwabara 1987 [28] Repeated blood samples in 6 normal pregnant women and blood samples were taken in 7 normal pregnant women every 2 days for at least 14 days before the onset of labour. Simultaneous blood samples were collected from maternal venous blood, umbilical arterial and venous vessels in 10 normal deliveries, 15 elective caesarean sections, and 5 emergency caesarean sections. Amniotic fluid samples were collected during pregnancy and in elective caesarean sections. Blood samples were also collected from 10 non-pregnant women. RIA c Relevant OT levels within the range of values normally observed with established RIA. Thornton 1988 [29] 25 women having spontaneous labour, of these 10 women received synthetic OT i.m. when the anterior shoulder was delivered. Blood samples were collected every 30th second (for 15 min) after crowning of the head. RIA c Low, but relevant OT levels within the range of values observed with established RIA. Oosterbaan 1989 [30] Maternal venous blood was collected at the time of amniocentesis (n= 17), elective CS (n= 18) and/or immediately after normal birth of the baby (n= 44). Mixed cord blood or blood from the umbilical artery or vein was collected at the time of elective CS or after spontaneous birth of the baby. RIA c Relevant OT levels within the range of values normally observed with established RIA. Fuchs 1991 [31] 50 pregnant women (38 to 42 weeks of gestation) Samples were collected with 1 min intervals for 30 min from the following groups: 1) Women at term who were scheduled for elective CS, with a closed cervix and not in labour (n= 11). 2) Women in the 1st stage of spontaneous labour with < 6 cm cervical dilation (n= 13) 3) Women in the 2nd stage of spontaneous labour with full dilatation of the cervix (n= 8). Five of these women delivered during the 30 min long sampling period and therefore samples were collected also after birth until delivery of the placenta. 4) 18 women who were not in labour were give bolus injections of OT iv, 2, 4, 8 or 16 mU. 8 blood samples before and 30 s, 1, 2, 3, 4, 5 and 10 min after injection (n = 18). RIA d Very low basal levels of OT perhaps due to insensitivity of the RIA used or a loss of OT during the extraction procedure. Frequent sampling of blood, together with low basal levels of OT, allowed recording and quantitative analysis of individual OT pulses. Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 6 of 17 in time between oxytocin levels and the occurrence of uterine contractions. Vasicka et al. 1978 [17] Serial blood samples were collected from 15 women during physiological labour and birth. No surge of oxytocin was observed at the onset of labour, suggesting that other factors than a rise oxytocin may be responsible for initiation of labour. Oxytocin levels varied between 64 and 148 μU/mL during labour. The most extensive release of oxytocin was seen in connection with maximal cervical and vaginal distention in 12 of the 15 women. The substantial rise of oxytocin levels in connection with birth most likely corresponds to the Ferguson reflex. Oxytocin levels were also measured in pregnancy, and increased from 126.9 ± 21.1 μU/mL in gestational week 24 to 153.0 ± 26.6 μU/mL in week 40 (n= 15). While oxytocin levels rose during pregnancy, the relationship between oxytocin levels and gestational age did not reach statistical significance. Two spikes per patient were observed during gestational weeks 24 to 34 and from 36 weeks progressively increasing oxytocin levels were found in three consecutive samples collected with 1 week intervals. Dawood et al. 1979 [18] Serial blood samples were collected every minute, during a 10-min period, from 7 women during pregnancy and physiological labour and birth. The release of oxytocin was episodic with a frequency of 2–3“spurts”(pulses) per 10 min. The levels of oxytocin varied between 0 and 86 pg/mL during labour (n= 3). There was no obvious connection in time between oxytocin levels and uterine contractions. Plasma levels of oxytocin during pregnancy rose from 17.9 ± 2.1 pg/mL (weeks 1–20) to 28.9 ± 4.7 pg/mL (weeks 21–30) and to 32.9 ± 2.9 pg/mL (weeks 31–32) (n= 362). There was a highly significant correlation between the mean maternal plasma oxytocin and the week of gestation (p< 0.005). A marked increase in maternal oxytocin levels to 74.2 ± 14.2 pg/mL was observed at 39 weeks of gestation, compared to the levels at 38 weeks (26.4 ± 4.8 pg/mL). A significant drop in levels from 39 to 40 weeks of gestation was also found. When sampling was performed every minute, 2–3 pulses per 10 min were observed. The amplitude of the pulses was greater during labour than in samples collected during pregnancy according to the same time schedule. Leake et al. 1981 [19] Blood samples were collected from 59 pregnant women, and serially from 50 women at the onset, peak and immediately after, individual contractions, at several times during physiological labour and birth. The oxytocin concentrations were 1.3 ± 0.2 μU/mL (n=6)1.6±0.2μU/mL (n= 14) during the latent and active phases of labour respectively, and 1.1 ± 0.1 μU/mL (n= 19) at the time of initial visualization of the fetal head. During birth of the fetal head, there was a significant 4-fold rise in plasma oxytocin to 4.2 ± 1.1 μU/ mL (n= 11), compared to the levels obtained at the time of initial visualization of the fetal head (p< 0.05). Average oxytocin levels measured during a single uterine contraction during the latent or active phase of physiological birth were 1.5 ± 0;3 μU/mL before, 1.4 ± 0.2 μU/mL at the peak and 2.0 ± 0.3 μU/mL after the contraction. This indicates no immediate correlation in time between plasma oxytocin levels and uterine contractions. Average oxytocin levels in women between 15 and 42 weeks’gestation were 1.3 ± 0.1 μU/mL (n= 59), and in non-pregnant women, 1.4 ± 0.2 μU/mL (n= 102). Plasma oxytocin levels obtained during labour did not differ from the levels obtained during pregnancy or from the levels observed in non-pregnant women, 1.3 ± 0.1 μU/ mL, nor was there any significant difference between oxytocin levels in pregnant and non-pregnant women. Otsuki et al. 1983 [20] Serial blood samples were collected from 2 subjects in the mid trimester, from 4 subjects at term without labour contractions, and from 6 subjects in the first stage of normal, physiological birth. Blood was taken at 10 s intervals over a period of 2–3 min. Table 2 Characteristics of included studies (Continued) First author, year, ref. no. Data collection Methodology Comment Stocche 2001 [32] 30 women included in a randomized open label. Each women was in spontaneous labour at > 5 cm cervix dilatation. Patients received either intrathecal sufentanil 10 microgram or epidural plain bupivacaine 0.25% Serial blood samples were collected before analgesia and 15, 30, 60 and 90 min after the induction of the analgesia. RIA c Low, but relevant OT levels within the range of values observed with established RIA. CS caesarean section, min = minute/s, hrs = hours, w = weeks, EDA = epidural analgesia, OT = oxytocin a Oxytocin like activity was measured by bioassay b Radioimmunoassay performed on unextracted plasma c Radioimmunoassay performed on extracted plasma d Radioimmunoassay performed on extracted plasma. Note that the antibody does not, measure the type of oxytocin released during pregnancy Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 7 of 17 Table 3 Oxytocin levels in blood samples collected during physiological birth in the 20 selected papers. Values from pregnant and non-pregnant women are included. All values are presented in pg/mL, with SD or range in parentheses First author, year Labour and birth (pg/mL) Time for blood sample Pregnancy (pg/mL) Gestational week (w) Non-pregnant (pg/mL) Coch 1965 [13] a 167 Active labour Kumaresan 1974 [14] a 302 (58.3–725.0) Active labour 110 4 w < 1.7 275 40 w Kumaresan 1975 [15] a 150.0 (18.3) 10 min before birth 136.7 (20.0) Immediately after birth Gibbens 1976 [16] a 4.2–20.8 1st –3rd stage Vasicka 1978 [17] a 73.3–273.3 Active labour 211.5 (35.2) 24 w 255.0 (44.3) 40 w Dawood 1979 [18]0–86 1st stage of labour 17.9 (2.1) 1–20 w 28.9 (4.7) 21–30 w 32.9 (2.9) 31–32 w 26.4 (4.8) 38 w 74.2 (14.2) 39 w Leake 1981 [19] a 2.2 (0.3 Latent phase 2.2 (0.2) 15–42 w 2.3 (0.3) 2.7 (0.3) Active labour 1.8 (0.2) Visible head 7.0 (1.8) Delivery of head Otsuki 1983 [20] a 21.0 (63.3–146.7) Active labour 8.3 20 w 20.8 (12.8) 36–41 w Goodfellow 1983 [21] 7.2–46.0; Full dilatation 8.8–85.0 c Crowning of head Husslein 1983 [22] 50.7 (10.7) 29.1 (9.7) Full dilatation 30 min postpartum Fuchs 1983 [23] 45 (3.9) 21.1 (6.4) 49.1 (10.9) 58.8 (9.9) 110 (22.7) 1st stage 1–3 mU/min SOT inf 4–6 mU/min SOT inf 7–9 mU/min SOT inf 10–15 mU/min SOT inf 15.4 (8.7) 17.4 (4.8) 19.9 (3.1) 1–2 weeks before labour Before induction At term Amico 1984 [24] a 1.7 (0.5) Arrest in active labour Takeda 1985 [25] a 32.8 (5.5) Active labour 26.8 (4.8) 7–41 w 8.0 (0.8) Takagi 1985 [26] a 75.3 (32.7) Before emergency CS 11.7 (8.8) De Geest 1985 [27] a 276.7 < 3 cm cx dilatation 78.3 8–12 w 298.3 5–7 cm 128.3 20–24 w 281.7 10 cm 208.3 30–34 w 276.7 2nd stage 226.7 38–42 w Kuwabara 1987 [28] a 51.0 (8.3) Immediately after birth 27–28 6–41 w 6.8 (0.8) 33.3 At term Thornton 1988 [29] b 3.2 (2) Crowning of head 6.4 (2) After delivery of shoulder 11.6 Mean peak after birth Oosterbaan 1989 [30] 65 (9) 12 (9) Immediately after birth During prelabour CS Fuchs 1991 [31] a 1.8 (0.2) 1st stage < 6 cm 1.5 (0.5) At term before elective CS 2.3 (0.6) 2nd and 3rd stage Stoche 2001 [32] 7.4 (2.1) 1st stage 6.6 (3.1) Before analgesia pg/mL picograms per millilitre, mU/min milliunits per minute, SOT inf synthetic oxytocin infusion, CS caesarean section, μU/mL microunits per millilitre, pmol/L picomoles per litre a Oxytocin levels have been converted from μU/mL to pg/mL b Oxytocin levels have been converted from pmol/L (pM) to pg/mL c Corrected from Table 1in Goodfellow 1983 Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 8 of 17 The mean level of oxytocin was 12.6 μU/mL during the first stage of physiological labour, with fluctuations and sometimes spurt releases observed. The size of the spurts in active labour varied between 38 and 88 μU/ mL. No correlation in time was observed between spurts or fluctuations of oxytocin levels and uterine contractions. The mean level of oxytocin was 12.1 μU/mL during uterine contractions and 11.5 μU/mL during relaxation. Plasma levels of oxytocin during pregnancy showed a gradual rise from 5 μU/mL at week 20 to 12.5 ± 7.7 μU/ mL at term (n= 38). There was no difference between the mean level of oxytocin at term (12.5 μU/mL) and during the first stage of physiological labour ((12.6 μU/ mL). Almost no fluctuations of oxytocin levels were observed at mid-pregnancy, whereas substantial fluctuations were seen at term. Compared with labour, the oxytocin fluctuations were not small at term, but the pulse phenomenon was more often detected amongst women who were in labour (3/6), compared to those not in labour (1/4). Goodfellow et al. 1983 [21] Serial blood samples were collected from 10 women at the beginning and at the end of the second stage of physiological birth (crowning of the head). Oxytocin levels at full dilatation were between 7.2 and 46.0 pg/mL and at crowning between 2.3 and 85.0 pg/mL. The rise in oxytocin levels between full dilatation and crowning was significant. Husslein et al. 1983 [22] Blood samples were collected from 20 women in physiological labour and 14 pregnant women at term but not in labour. Of these, 7 women received an infusion with synthetic oxytocin in a low dosage at the end of the first stage of labour, and directly after birth 10 women received an oxytocin infusion in a high dosage (100- 150mIU/min). Plasma oxytocin levels at full cervical dilatation (50.7 ± 10.7 pg/mL) were significantly raised over oxytocin levels at term (18 ± 3.2 pg/mL) and had returned to levels observed at term 30 min postpartum (29.1 ± 9.7 pg/mL). Taken together the data demonstrate a substantial rise of oxytocin levels during birth. Fuchs et al. 1983 [23] Serial blood samples were collected from 17 women in early physiological labour and 15 women at term in Table 4 Summary of oxytocin levels during labour and birth (converted to pg/mL) Oxytocin levels varied significantly between the studies. Very low values around 1.7–3.4 pg/mL were reported by: Leake 1981 [19], Amico 1984 [24], and Fuchs 1991 [31]. Very high levels, around 167–340 pg/mL, were reported by Coch 1965 [13], Kumaresan 1974 [14] and 1975 [15], Vasicka 1978 [17], and De Geest 1985 [27]. These high levels were obtained using bioassay or RIA without previous extraction of the plasma samples, which likely explains the higher-than-expected results. The majority of the articles report the levels as expected, between 17 and 85 pg/mL; Gibbens 1976 [16], Dawood 1979 [18], Otsuki 1983 [20], Goodfellow 1983 [21], Husslein 1983 [22], Fuchs 1983 [23], Takeda 1985 [25], Takagi 1985 [26], Kuwabara 1987 [28], Thornton 1988 [29], Oosterbaan 1989 [30], and Stoche 2001 [32]. Difference in oxytocin levels between pregnancy and labor A rise of oxytocin levels between pregnancy and labor was observed by Dawood 1979 [18], Husslein 1983 [22], Fuchs 1983 [23], and Fuchs 1991 [31]. No rise was observed by Kumaresan 1974 [14] and 1975 [15], and De Geest 1985 [27], which was most likely due to a lack of sensitivity of the assay used. Difference in oxytocin levels over time during labor, or between the 1st and the 2nd stage of labor A rise of oxytocin levels during labor was observed by Coch 1965 [13] and Gibbens 1976 [16]. In addition, Dawood 1979 [18], Otsuki 1983 [20], and Fuchs 1991 [31] found an increasing incidence, frequency, and/or amplitude of oxytocin pulses, from late pregnancy through to the first and second phases of labor. Fuchs 1991 [31] found a maximum pulse frequency of 3 per 10 min in late labor. Rise of oxytocin levels in connection with birth A very pronounced rise of oxytocin levels (sometimes as much as a 4- fold increase) was observed in connection with birth of the baby, compared to levels in pregnancy, early labor, or immediately following PLCS: Vasicka 1978 [17], Leake 1981 [19], Goodfellow 1983 [21], Husslein 1983 [22], Kuwabara 1987 [28], Thornton 1988 [29], Oosterbaan 1989 [30]. Elevation of oxytocin levels in connection with expulsion of the placenta or postpartum In some studies, elevated oxytocin levels were also found during the third stage of labor, likely in connection with expulsion of the placenta (Kumaresan 1975 [15], Husslein 1983 [22], Thornton 1988 [29], Fuchs 1991 [31]) Table 5 Summary of oxytocin levels during pregnancy and in non-pregnant women In the studies by Kumaresan 1974 [14], Vasicka 1978 [17], Dawood 1979 [18], Otsuki 1983 [20], De Geest 1985 [27], and Kuwabara 1987 [28], a rise of oxytocin levels was recorded with advancing pregnancy. These data demonstrate that oxytocin levels increase during pregnancy. Regardless of the basal levels, and the type of technique used for analysis of oxytocin levels, oxytocin levels increased about 2 to 4-fold. Oxytocin levels in non-pregnant women varied between 1.7 and 11.7 pg/mL. Table 6 Summary of the occurrence of uterine contractions in relation to plasma levels of oxytocin during labour without and with synthetic oxytocin Dissociation between oxytocin levels and uterine contractions The time relationship between oxytocin levels and uterine contractions was studied in 4 of the articles. In all of these studies, no association was found between oxytocin peaks and uterine contractions: Gibbens 1976 [16], Dawood 1979 [18], Leake 1981 [19], Otsuki 1983 [20]. Effect of synthetic oxytocin administration on oxytocin levels and uterine contractions Infusions of synthetic oxytocin at a rate of 4–6 mU/minute gave rise to a significant rise in oxytocin levels in women at term without labour, which corresponded to the oxytocin levels seen during physiological labour. At an infusion rate of 10–16 mU/min, oxytocin levels were higher than physiological levels (Fuchs 1983 [23]). Doubling the dose lead to doubled levels (Fuchs 1983 [23]), Amico 1984 [24]), Bolus injections of 4–8 mU of synthetic oxytocin in women at term, without labour gave rise to an increase of oxytocin levels of the same size as observed during physiological oxytocin pulses and was associated with uterine contractions. (Fuchs 1991 [31]). Uvnäs-Moberg et al. BMC Pregnancy and Childbirth (2019) 19:285 Page 9 of 17 is born. Circulating oxytocin promotes uterine contractions. Infusions of synthetic oxytocin at low doses (less than 10 mU/mín) give rise to similar levels of oxytocin as during physiological labour. Oxytocin released into the brain during labour and birth influences neuroendocrine mechanisms and thereby maternal mood, behaviour, and physiology in a positive way. Infusions of synthetic oxytocin do not give rise to the same beneficial effects in the brain as does endogenous oxytocin released during physiological labour and birth, because oxytocin from the circulation does not pass the blood brain barrier. This implies that labour with synthetic oxytocin infusion does not fully replicate the adaptive effects of physiological labour and birth. Additional file Additional file 1 Search strategy, 6 th October 2015. (DOCX 38 kb) Abbreviations ANS: Autonomic Nervous System; CNS: Central Nervous System; COST: European Cooperation in Science and Technology; CSF: Cerebrospinal Fluid; EIA: Enzyme Immunoassay; ELISA: Enzyme-Linked Immunosorbent Assay; L: Liter; mg: Milligram; Min: Minute; mL: Milliliter; mM: Millimolar; mU: Milli-unit; ng: Nanogram; nM: Nanomolar; pg: Picogram; pM: Picomolar; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta- Analyses; PSNS: Parasympathetic Nervous System; PVN: Paraventricular Nuclei; RIA: Radioimmunoassay; SNS: Sympathetic Nervous System; SON: Supraoptic Nuclei; μg: Microgram; μM: Micromolar; μU: Micro-unit Acknowledgements We acknowledge the support from group members of COST action IS1405: Building intrapartum research through health. https://www.cost.eu/actions/ IS1405/#tabs|Name:overview Authors’contributions KUM, MB, EH, BK, AK, LL, FLL, CMM, BL, SD and AD planned the study. EH, LL and ZP conducted the literature search. KUM, MB, AEB, EH, BK, AK, LL, FLL, CMM, ZP and AD screened papers including full text assessment for inclusion. KUM and AEB extracted descriptive data and characteristics of included studies. AEB and AD made the tables, and SB verified data. MB made Fig. 1and AEB, KUM and SB made Figs. 2,3,4. KUM, AEB, SB, MB and AD drafted and revised the manuscript. All authors read and approved the final manuscript. Funding The study was partly funded by EU COST IS1405 birth: Building intrapartum research through health. https://www.cost.eu/actions/IS1405/#tabs|Name: overview Availability of data and materials All information is given in the article and additional files. Ethics approval and consent to participate This is a systematic review of already published primary sources and as such no further ethical approval was required. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Author details 1 University of Agriculture (SLU), Uppsala, Sweden. 2 School of Health and Education, University of Skövde, Skövde, Sweden. 3 Department of Health Sciences, University West, Trollhättan, Sweden. 4 Institute of Health and Care Sciences, University of Gothenburg, Gothenburg, Sweden. 5 Centre for Person-Centred Care, University of Gothenburg, Gothenburg, Sweden. 6 School of Public Health, The University of Queensland, Brisbane, Australia. 7 Faculty of Health Sciences, Oslo and Akershus University College of Applied Sciences, Oslo, Norway. 8 Faculty of Health Sciences, Cyprus, University of Technology, Limassol, Cyprus. 9 Faculty of Health Sciences with Subfaculty of Nursing and Institute of Maritime and Tropical Medicine, Medical University of Gdańsk, Gdańsk, Poland. 10 Midwifery Research and Education Unit, Hannover Medical School, Hannover, Germany. 11 Faculty of Medical Sciences, Medical University of Gdańsk, Gdańsk, Poland. 12 Faculty of Nursing, Physiotherapy and Podiatry, University of Seville, Seville, Spain. 13 Department of Social Work Center for Health Promotion and Social Participation, Lucerne University of Applied Sciences and Arts, Luzern, Switzerland. 14 Research in Childbirth and Health (ReaCH) group, University of Central Lancashire, Preston, UK. 15 Norwegian University of Science and Technology, Trondheim, Norway. 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