Table 3 Maternal synthetic oxytocin administration: maternal plasma oxytocin levels

 Fuchs et. al. (1991)

Oxytocin secretion and human parturition: pulse frequency and duration increase during spontaneous labor in women

18 women

Experimental study of bolus SOT in late pregnancy

Dose regimen:

Single IV bolus of 2, 4, 8 or 16 mU

Total dose:

2, 4, 8 or 16 mU

Sampling regimen:

Baseline and at 1, 2, 3, 4, 5 and 10 min

Results:

(Estimated from Fig. 5)

Range, pg/mL (μU/mL)

Basal (late pregnancy)

0.5–0.7 pg/mL (0.3–0.4 μU/mL)

With SOT infusion

0.8–1.7 pg/mL (0.5–1.0) peak

Important findings:

Dose-dependent rise at 1–2 min at doses 4 mU or higher

Decline to approx. Basal over 10 min

Assay: RIA

Comments:

Levels similar to spontaneous pre-labour pulses, as measured in this study

Other reported data:

Contraction pattern and oxytocin levels

Number of contractions following the bolus correlated with mean oxytocin peak levels

 Amico et. al. (1984)

Studies of oxytocin in plasma of women during hypocontractile labor

11 women

Labour augmentation with SOT

Dose regimen:

IV infusion

1 mU/min increased by 1 mU/min every 40 min until ‘adequate contractility’ up to 4 mU/min

Maximum dose:

Mean 3.4 ± 0.7 mU/min

Range 1–8 mU/min

Sampling regimen:

Baseline and every 20 min until 60–100 min after final infusion rate increase

Results:

(Estimated from Fig. 4)

Mean ± SEM, pg/mL (μU/mL)

Basal (in labour)

1.7 ± 0.52 pg/mL (1.0 ± 0.31) μU/ml)

With SOT infusion

2.7 ± 0.5 (1.6 ± 0.3) at 1 mU/min

3.8 ± 0.7 (2.3 ± 0.4) at 2 mU/min

4.8 ± 1.1 (2.9 ± 0.7) at 3 mU/min

6.3 ± 1.5 (3.8 ± 0.9) at 4 mU/min

Important findings:

Steady-state oxytocin levels reached 40 min after SOT dose

Linear dose-dependent rise (r² = 0.99)

Assay: RIA

RIA assay giving very low basal levels

Comments:

Doubling infusion rate approx doubled oxytocin levels

Other reported data:

Oxytocin metabolic clearance rate (MCR)

11–32.5 (mean 17.3) mL/kg/min

SOT administered to 4 men at 125 mU/min

1.3 pg/mL (0.76 μU/mL) basal

188 (112.5) at 60 min

Linear dose-dependent rise

Steady state oxytocin levels at 30 min

Oxytocin MCR 25–34 (mean 17.6) mL/kg/min

SOT half-life: 12.3–17.4 min

Data from this study also published in Seitchik et al. (1984)

 Amico et. al. (1986)

The plasma of pregnant women contains a novel oxytocin-vasotocin-like peptide.

4 women

Labour augmentation with SOT

Dose regimen:

IV infusion

1 mU/min increased 1 mU/min every 40 minutes

Maximum dose:

4 mU/min

Sampling regimen:

Baseline, every 20 min until 60 min after increase to maximum dose

Results:

(Estimated from Fig. 1)

Assay Ab-1

Range, pg/mL (μU/mL)

13–25 pg/mL (8–15 μU/mL) basal (in labour)

12–28 (7–17) with SOT infusion

Assay Ab-2

Mean pg/mL (μU/mL)

< 0.8 pg/mL (< 0.5) basal (in labour)

3.0 (1.8) at 1 mU/min

4.7 (2.8) at 2 mU/min

6.7 (4.0) at 3 mU/min

8.4 (5.0) at 4 mU/min

Important findings:

Assay Ab-1: No significant rise with infusion

Assay Ab-2: Linear dose-dependent rise (p < 0.01)

Assay:

Analysed by 2 different RIA assays:

Pitt Ab-1 antiserum

Pitt Ab-2 antiserum

Comments:

Low-dose SOT regimen

No rise with Ab-1 assay due to high basal levels vs. clear rise seen with Ab-2 assay

Doubling infusion rate approx doubled oxytocin levels (Ab-2 assay)

Other reported data:

Basal oxytocin in 16 pregnant women at > 36wks (pg/mL ± SE (μU/mL))

Assay Ab-1: 12.9 ± 1.5 (7.7 ± 0.9)

Assay Ab-2: 1.5.0 ± 0.3 (0.9 ± 0.2)

 Fuchs et. al. (1983)

Oxytocin and the initiation of human parturition. III. Plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2α in spontaneous and oxytocin-induced labor at term

15 women

Labour induction with SOT

17 women

Spontaneous labour, no SOT infusion

Dose regimen:

IV infusion

1-2 mU/min increased every 15 min

Maximum dose:

Range 1–16 mU/min

Sampling regimen:

Baseline and just before each increase in infusion rate

Results:

Mean ± SEM, pg/mL

With SOT infusion

17.4 ± 4.8 pg/mL pre-induction

21.1 ± 6.4 at 1–3 mU/min

49.1 ± 10.9 at 4–6 mU/min

58.8 ± 9.9 at 7–9 mU/min

110 ± 22.7 at 10–16 mU/min

Important findings:

Linear dose-dependent rise (p < 0.001)

No SOT

15.4 ± 8.7 late pregnancy

19.9 ± 3.1 at < 2 cm

47.2 ± 7.6 at < 4 cm

46.3 ± 7.8 at 4-6 cm

43.0 ± 6.6 at 7-9 cm

45.8 ± 13.6 at 10 cm

45.4 ± 3.9 mean 1st stage

Assay: RIA

Comments:

Doubling infusion rate approx doubled oxytocin levels

Oxytocin levels below 10 mU/min are within range of levels in women with no SOT

 Furuya et. al. (1988)

[Fundamental studies on the measurement of plasma concentration of oxytocin during perinatal period]

5 women

Labour induction with SOT

Dose regimen:

IV infusion

12 mU/min (20 ng/min) increased up to maximum 32 mU/min (53 ng/min)

Maximum dose:

Range 24-32 mU/min (40–53 ng/min)

Sampling regimen:

Baseline and with each increase

Results:

(Estimated from Fig. 7)

Mean ± variation, pg/mL

Infusion rate mU/min (ng/min)

Basal (pre-labour)

2 pg/mL

With SOT infusion

8 ± 5 at 12 mU/min (20 ng/min)

17 ± 5 at 16 mU/min (26)

19 ± 8 at 20 mU/min (33)

38 ± 14 at 24 mU/min (40)

55 ± 6 at 32 mU/min (53)

Important findings:

Fig. 7 shows approx. Linear dose-response curve, although no statistics provided

Assay: RIA

Comments:

No control group

Dose intervals not stated

Variation statistic not stated

Doubling infusion rate approx tripled oxytocin levels

Data at highest infusion rate based on 3 samples

Other reported data:

Oxytocin with breastfeeding (n = 1, estimated from Fig. 8)

2.5 basal

14.3 peak at 20 min

Peak levels similar to SOT infusion at 16 mU/min

 Perry et. al. (1996)

The pharmacokinetics of oxytocin as they apply to labor induction

10 women

Labour induction with SOT

Dose regimen:

6 mU/min, increasing by 6 mU/min every 40 min to max 42 mU/min

Maximum dose:

Mean maximum dose: 22.8 ± 3.6 mU/min

Sampling regimen:

Baseline (in labour) and at intrauterine pressures of; 100–150, 150–200 and > 200 Montevideo units

All samples taken > 40 min after change of SOT infusion rate

Results:

Mean ± SEM, pg/mL

Basal (pre-labour)

21.2 ± 0.9 pg/mL

With SOT infusion

26.4 ± 1.3 at maximum uterine pressure

Important findings:

Oxytocin levels correlated with SOT infusion rate (p < 0.001) but not uterine pressure. (Data not provided)

Assay: RIA

Comments:

Small increment in oxytocin levels with quite high SOT infusion rates suggests insensitive assay

Other reported data:

Oxytocin MCR

MCR independent of oxytocin levels (p = 0.71)

 Seitchik et. al. (1984)

Oxytocin augmentation of dysfunctional labor. IV. Oxytocin pharmacokinetics

See Amico et al. (1984)

See Amico et al. (1984)

See Amico et al. (1984)

Data from this study also published in Amico et al. (1984)

 Thornton et. al. (1990)

Effect of human pregnancy on metabolic clearance rate of oxytocin

10 women

Labour induction with SOT

10 women Administered SOT at 8–10 weeks postpartum

(see below)

Dose regimen (lLabour):

IV infusion

10.7 mU/min (17.9ng/min) increased after 30 min to 21 mU/min (35.7 ng/min)

Maximum dose:

21 mU/min (35.1 mg/min)

  ( Postpartum:

see below)- italics please

Sampling regimen:

6 samples over 60 sec at baseline and 30 min, then 30 min after each infusion rate increase

Results:

Mean ± SEM, pg/mL

Infusion rate mU/min (ng/min)

With SOT infusion

1.5 ± 0.3 pg/mL basal (pre-labour)

5.0 ± 0.5 at 10.7 mU/min (17.9 ng/min)

8.0 ± 0.9 at 21 mU/min (35.7)

Important findings:

These oxytocin levels were similar to those in postpartum women who were administered significantly lower SOT doses (see below), suggesting greater metabolism of SOT in pregnancy

Assay: RIA

Comments:

Doubling infusion rate approx doubled oxytocin levels

Other reported data:

Oxytocin MCR

MCR independent of concentration and higher in pregnancy vs postpartum (p < 0.001).

Plasma oxytocinase activity

High oxytocinase activity in pregnancy (2.1 ± 0.02 IU/mL), very low postpartum (< 0.1 IU/mL)

 Arai T. (1980)

The significance of plasma oxytocin in pregnancy and at parturition

Publication in Japanese

Data obtained from full article translated into English

14 women

Labour induction with SOT

16 women

Spontaneous labour, no SOT infusion or other interventions

Dose regimen:

IV infusion

Stated as 15 μU/min (=0.015 mU/min, extremely low dose More likely 15 mU/min)

Total dose, duration:

Not stated

Sampling regimen:

Before labour During 2nd stage labour

Results:

Mean ± SD, pg/mL (μU/mL)

Basal (40 wks gestation)

69.3 ± 17.7 (41.6 ± 10.6) (n = 8)

With SOT infusion

120.1 ± 42.8 (71.9 ± 25.6) in labour

No SOT

77.0 ± 28.2 (46.1 ± 16.9) in labour

Important findings:

Mean levels in labour significantly higher with SOT vs no SOT (p < 0.01)

Assay: RIA

Comments:

Oxytocin levels in labour with SOT approx double vs in labour without SOT

Other reported data:

Oxytocin patterns in a single contraction cycle

Reported below

Oxytocin levels following prostaglandin induction, pre-labour and in-labour caesarean, and caesarean following SOT treatment in labour (This data to be reviewed in subsequent systematic review^a)

 De Tina et.al (2019) Oxytocin and Oxytocinase in the Obese and Nonobese Parturients during Induction and Augmentation of Labor

50 women

(25 obese & 25 non-obese)

Labour induction with SOT

Dose regimen:

IV infusion

Maximum dose:

20 mU/min

Total Dose:

(mean ± SD)

Nonobese women

3.4 ± 1.6 IU

Duration:

Nonobese women,

397 ± 159 min

Sampling regimen:

Baseline and 20 min after maximum infusion rate

Results:

Non-obese women with complete data (n = 18)

Median (IQR), pg/mL

Basal (pre-labour)

351 pg/mL(56, 790)

With SOT infusion

463 (15, 791)

Important findings:

No increase following SOT infusion

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

Similar data in obese group, which was analysed separately in this study

Low SOT dose (generally insufficient to increase plasma oxytocin)

Small oxytocin rise may reflect labour-related release

Other reported data:

Oxytocin and oxytocinase levels in obese vs. non-obese women

Oxytocin levels or total SOT dose not significantly different in obese vs non-obese women

Lower initial oxytocinase levels in obese vs non-obese (p = 0.03)

 Husslein et. al. (1983b)

Oxytocin and the initiation of human parturition. IV. Plasma concentrations of oxytocin and 13,14-dihydro-15-keto-prostaglandin F2 alpha during induction of labor by artificial rupture of the membranes

6 Women

Labour induction with ROM and later required SOT

16 women

Labour induction with ROM, no SOT

Dose regimen:

IV infusion 5 mU/min

Started 4–15 hr. after ROM when required

Maximum dose:

Not stated

Sampling regimen:

Before ROM, at 15 min and 2 hr., then 2–3 hourly

Results:

Mean ± SEM, pg/mL

With SOT infusion (after ROM)

38.3 ± 10.7 pg/mL basal (pre-induction)

59.9 ± 15.4 at 5 hr (3/6 with SOT)

53.0 ± 24.3 at 8 hr (2/3 with SOT)

63.1 ± 9.2 mean all samples

No SOT

33.6 ± 7.7 basal (pre-induction)

40.6 ± 11 at 5 hr

32.9 ± 8.1 at 8 hr

Important findings:

Oxytocin levels significantly increased after vs before SOT infusion

Assay: RIA

Comments:

Oxytocin levels in labour with SOT approx double vs in labour without SOT

Other reported data:

Plasma PGFM (PG metabolite) following SOT infusion:

PGFM increased in 6/6 women with successful induction

Oxytocin levels following ROM (This data to be reviewed in subsequent systematic review^a)

 Otsuki et al. (1983)

Feto-maternal plasma oxytocin levels in normal and anencephalic pregnancies.

5 women Labour induction with SOT

6 women

Spontaneous labour, no induction or SOT

Dose regimen:

Not stated

Maximum dose:

Not stated

Sampling regimen:

Baseline, early labour and 2nd stage

Results:

Mean ± SEM, pg/mL

(reported in μU/mL)

Basal (pre-induction)

20.7 ± 2.8 pg/mL (12.4 ± 1.7 μU/mL)

With SOT infusion

40.7 ± 8.7 (24.4 ± 5.2) early labour

63.1 ± 12.9 (37.8 ± 7.7) 2nd stage

No SOT

21.0 ± 3.0 (12.6 ± 1.8) early labour

29.4 ± 6.0 (17.6 ± 3.6) 2nd stage

Important findings:

SOT significantly higher vs no SOT at 1st (p < 0.05) and 2nd (p < 0.01) stages

Assay: RIA

Comments:

Oxytocin levels in labour with SOT approx double vs. in labour without SOT

Other reported data:

Maternal oxytocin levels in 4 women with anencephalic babies induced with SOT at 32–34 wk

22.4 ± 13.4 pg/mL 2nd stage

Other reported data:

Newborn UA and UV oxytocin levels with maternal SOT exposure

(See Table 4)

 Padayachi et. al. (1988)

Serial oxytocin levels in amniotic fluid and maternal plasma during normal and induced labour

8 women

Labour induction with SOT and amniotomy

(women allocated alternately with PG induction)

13 women

Spontaneous labour, no SOT

Dose regimen:

IV infusion at 2 mU/min increased every 30 min

Maximum dose:

32 mU/min

Sampling regimen:

Collected over 4 min every hr.

Results:

Mean ± SEM, pg/mL (μU/mL)

With SOT infusion

5.9 ± 1.0 pg/mL at < 4 cm

(3.55 ± 0.62 μU/mL)

10.1 ± 1.3 (6.07 ± 0.78) at 8–10 cm

No SOT

6.8 ± 0.65 (4.05 ± 0.39) at < 4 cm

9.2 ± 1.15 (5.48 ± 0.69) at 8–10 cm

Important findings:

Significant rise during labour with SOT (p < 0.02)

Assay: RIA

Comments:

RIA giving very low levels in all groups

Slow sampling may average out any peaks of oxytocin

 Pochard & Lutz-Bucher (1986)

Vasopressin and oxytocin levels in human neonates. Relationships with the evolution of labour and beta-endorphins

6 women

Labour induction with ‘oxytocic drugs’

21 women

No oxytocic drugs

10 women

No oxytocic drugs

Fetal distress in labour

Dose regimen:

Not stated

Maximum dose:

Not stated

Sampling regimen:

Before expulsive phase

Results:

(Estimated from Fig. 1)

Mean, pg/mL

Oxytocic drugs

3 pg/mL

No oxytocic drugs

2–3

Fetal distress

4

Important findings:

No statistically significant differences between any groups.

Assay: RIA

Comments:

Oxytocic drugs presumed to be SOT

Other reported data: Newborn UA and UV oxytocin with maternal SOT exposure (See Table 4)

Maternal plasma and newborn UA and UV AVP (vasopressin) levels

No difference between any groups

Maternal plasma and newborn UA and UV oxytocin levels with pre-labour caesarean

(This data to be reviewed in subsequent systematic review^a)

 Risberg et. al. (2015)

Water balance during parturition and early puerperium: A prospective open trial

12 women

Spontaneous labour, augmentation with SOT for ‘dystocia’(9/12 epidural, 5/12 postpartum SOT)

30 women

Spontaneous labour

No IV fluids or other medication (14/30 postpartum SOT)

9 women

Spontaneous labour

IV fluids only (7/9 epidural, 6/9 postpartum SOT)

Women who required SOT were randomised to continuous (n = 6) or pulsatile (n = 5) infusions

Dose regimen:

10 IU/L (10 mU/mL) by continuous (n = 6) or pulsatile (n = 5) infusion:

Continuous infusion

15 mL/hr. (2.5 mU/min) increased until adequate contractions (3–5/10 min)

Duration: 72–480 min

Maximum dose: 120 mL/hr. (20 mU/min)

Total dose: 2.5 ± 1.1 IU total

Pulsatile infusion 1.8 mL/hr. (0.3 mU/min) increased until adequate contractions

Duration: 20–240 min

Total dose: 0.4 ± 0.5 IU

Postpartum dose:

25 of these women also received 10–30 IU SOT bolus

Sampling regimen:

Arrival, early 1st stage, early 2nd stage, just after birth and 9, 15, 27 hr. postpartum

Results:

Mean ± SD, pmol/L equivalent to pg/mL

With SOT infusion

(Includes continuous and pulsatile infusion regimens)

31.3 ± 3.0 at arrival

29.4 ± 3.8 early 1st stage

29.5 ± 2.8 early 2nd stage

32.7 ± 3.3 just after birth

26.3 ± 2.5 9 hr. postpartum

28.8 ± 2.4 15 hr. postpartum

27.3 ± 3.6 27 hr. postpartum

No SOT or IV fluids

32.4 ± 3.8 at arrival

20.7 ± 2.7 early 1st stage

29.3 ± 2.9 early 2nd stage

41.5 ± 8.3 just after birth

26.7 ± 1.2 9 hr. postpartum

28.0 ± 1.1 15 hr. postpartum

27.5 ± 1.3 27 hr. postpartum

Important findings:

Oxytocin concentrations not significantly different with vs without SOT or before vs after parturition

Assay: ELISA with previous extraction

ELISA gives higher levels than RIA with different effect patterns

Comments:

Very low SOT dosage, especially with pulsatile dosage

Multiple sub-groups and co-interventions make interpretation difficult

High mean oxytocin just after birth in No SOT group may relate to mother-newborn SSC initiated soon after birth

Other reported data:

Pulsatile vs continuous SOT infusion

Significantly lower total SOT dose (p < 0.05), no difference in labour progress

SOT vs. controls

SOT-exposed had lower plasma osmolarity at arrival (p < 0.05) and lower sodium (p < 0.01) in late labour

AVP vs. controls

AVP levels not significantly different between groups

 Seitchik et. al. (1985) Oxytocin augmentation of dysfunctional labor. V. An alternative oxytocin regimen

10 women

Labour augmentation with SOT

Dose regimen:

IV infusion

5 mU/min increased by timed or arithmetic protocol until adequate uterine response

Maximum dose:

Range 2.3–5.7 mU/min

Sampling regimen:

Baseline (2 samples 5 min apart), at adequate uterine response, and every 15 min (up to 4 samples) after maintenance dose reached

Results:

Mean ± SD, pg/mL (μU/mL)

Basal (in labour)

1.4 ± 0.20 pg/mL (0.83 ± 0.1 μU/mL)

With SOT infusion

2.6 ± 0.3 (1.6 ± 0.2) at adequate uterine response

3.0 ± 0.5 (1.8 ± 0.3) at 45 mins

2.8 ± 0.6 (1.7 ± 0.3) at 60 mins

Important findings:

Oxytocin levels approx doubled from basal at the infusion rate that gave adequate uterine response

Assay: RIA

Comments:

Oxytocin levels not analysed in relation to SOT infusion rate

Other reported data:

Time required to achieve steady-state blood oxytocin levels

40 min after dose increase

 Thornton et. al. (1992)

Plasma oxytocin during the first and second stages of spontaneous human labour

5 women

Spontaneous labour, augmentation with SOT

7 women

Spontaneous labour, no SOT

Dose regimen:

4 mU/min increased every 15 min until adequate uterine activity

Total dose:

Not stated

Sampling regimen:

Every minute for 15 min in early labour (baseline) and in late 1st stage

From onset 2nd stage pushing until birth

Results:

Mean ± SD, pmol/L equivalent to pg/mL

U: undetectable

With SOT infusion

U-4.6 pg/mL early labour

U-10.0 late 1st stage

No SOT

U-6.2 early labour

U-4.8 late 1st stage

Important findings:

Significant oxytocin rise following SOT infusion

No significant oxytocin rise in 6/8 controls

“Large increase” in oxytocin in 2nd stage in 2/8 women e.g. 27 pmol/L

Assay: RIA

Assay detection limit 1.4 pmol/L

Comments:

Many samples with undetectable levels

No increase during labour despite frequent sampling suggests insensitive assay

Oxytocin levels in labour with SOT approx double vs in labour without SOT

 Arai T. (1980)

The significance of plasma oxytocin in pregnancy and at parturition

Publication in Japanese

Data obtained from full article translated into English

14 women

Labour induction with SOT

16 women

Spontaneous labour, no SOT infusion or other interventions

Dose regimen:

IV infusion

Stated as 15 μU/min (=0.015 mU/min, extremely low dose More likely 15 mU/min)

Total dose, duration:

Not stated

Sampling regimen:

Sampled 4 times during a single contraction cycle in both 1st and 2nd stages

Results:

Mean ± SD, pg/mL (μU/mL)

Basal (40 weeks gestation)

69.3 ± 17.7 pg/mL (32.9 ± 10.6 μU/mL)

Oxytocin levels in a single contraction cycle

Sampled between, early, at peak and late in contractions:

With SOT infusion:

Stage 1 (2 samples)

107.9 ± 25.9 (64.6 ± 15.5) between contractions

98.2 ± 33.7 (58.5 ± 20.2) peak

Stage 2:

97.2 ± 44.8 (58.2 ± 26.8) between

74.6 ± 1.2 (44.7 ± 0.7) early

102.2 ± 37.7 (61.2 ± 22.6) peak

64.1 ± 8.7 (38.4 ± 5.2) late

Important findings:

Levels significantly lower between vs. during contraction (Stage 1)

No SOT:

Stage 1

83.5 ± 17.5 (50.0 ± 10.5) between

70.0 ± 31.9 (41.9 ± 19.1) early

42.9 ± 15.4 (25.7 ± 9.2) peak

55.9 ± 28.4(33.5 ± 17.0) late

Stage 2:

85.2 ± 16.4 (51.0 ± 9.8) between

70.0 ± 16.4 (41.9 ± 9.8) early

72.0 ± 29.1 (43.1 ± 17.4) peak

65.0 ± 30.7 (38.9 ± 18.4) late

Important findings:

Levels significantly lower at peak of contraction vs other times (Stage 1 only, p < 0.02)

Assay: RIA

Comments:

Differing patterns, with lowest oxytocin levels between contractions with SOT vs lowest at contraction peak with no SOT

Other reported data:

Oxytocin levels following prostaglandin induction, pre-labour and in-labour caesarean, and caesarean following SOT treatment in labour (This data to be reviewed in subsequent systematic review^a)

 Dawood et. al. (1980)

Plasma oxytocin levels and disappearance rate after buccal Pitocin

9 women

Labour induction or augmentation with SOT

Dose regimen:

Buccal administration

400 IU every 20 min

Total dose:

400–2200 IU

Sampling regimen:

Baseline, at 20–30 min, then hourly

Results:

Range, pg/mL

Basal (before SOT)

1.5–107 pg/mL

With SOT buccal

6.8–181 peak

Important findings:

Very variable rise

Levels not related to dose

Assay: RIA

Comments:

Buccal SOT is no longer used clinically

Other reported data:

Male subjects (3) given buccal SOT 200–400 IU every 20 min

Mean levels 24–32 at 400 IU

Still elevated above basal 45 min after administration

 Ende et.al. (2019) Association of Interindividual Variation in Plasma Oxytocin With Postcesarean Incisional Pain

18 women

Pre-labour caesarean with postpartum IV SOT (all women)

Dose regimen:

(Titrated to effect)

Intra-operative dose:

3–35 IU (mean 14.1 ± 8.6 SD)

Post-operative dose:

9–31.5 IU (mean 15.5 ± 4.8 SD)

Duration: not stated

Total dose:

19–48.5 (mean 29.5 ± 9.4 SD)

Sampling regimen:

I hr. before, then 1 and 24 hr post-caesarean

Results:

Mean ± SD pg/mL (ng/mL)

Mean (all women)

335 ± 452 pg/mL

Range

(Estimated from Fig. A)

1–1200 pre-caesarean

(0.001–1.2 ng/mL)

30–1200 (0.03–1.2) 1 hr post-caesarean

4–1100 (0.004–1.1) 24 hr post-caesarean

Important findings:

Very high interindividual variability

Significantly lower oxytocin at 1 and 24 hr. post- vs pre-caesarean (p = 0.001)

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

Oxytocin data difficult to interpret

Assay did not detect oxytocin rise at 1 hr. despite high intra- and post-operative SOT dose

Other reported data:

Pain score at 24 hr

Significantly lower in women with higher oxytocin levels at 1 and 24 hr. post-caesarean (p = 0.047, p = 0.008 respectively)

 Fuchs et. al. (1982)

The origin of circulating 13,14-dihydro-15-keto-prostaglandin F2 alpha during delivery

10 women Postpartum SOT IV infusion

10 women Postpartum IV infusion without SOT

Dose regimen:

In labour: Some women also received SOT IV infusion 1–8 mU/min, stopped average 50 min before birth

Postpartum: 100–150 mU/min starting immediately after birth for 2 hr., infusion rate reduced over time

Total postpartum dose:

12–18 IU

Sampling regimen:

Full dilatation, then 5 min, 30 min and 2 hr. postpartum

Results:

Mean ± SD, pg/mL

Basal

18.0 ± 3.2 pg/mL pre-labour

With SOT infusion

50.1 ± 9.7 2nd stage

93.4 ± 20.6 5 min postpartum

275 ± 46.5 30 min postpartum

127 ± 22.6 2 hr. postpartum

No SOT

50.1 ± 10.7 2nd stage

41.1 ± 11.0 5 min postpartum

29.1 ± 9.7 30 min postpartum

29.4 ± 6.8 2 hr. postpartum

Important findings:

Postpartum oxytocin significantly higher with vs without SOT at 30 min and 2 hr. (both p < 0.001)

Assay: RIA

Comments:

Skin-to-skin contact not recorded

Other reported data:

PG levels postpartum

Significantly higher PG levels at 2 hr. postpartum following postpartum SOT vs no postpartum SOT

Data from this study also published in Husslein et al. (1982)

 Gibbens, D et.al

(1972)

The circulating level of oxytocin following intravenous and intramuscular administration of Syntometrine

10 W

SOT IM

14 W

SOT IV

2 W SOT by subcutaneous injection (SC)

Dose regimen:

Single injection at birth of baby’s anterior shoulder

Total dose:

5 IU (combined with ergometrine 500 mcg)

Sampling regimen:

Basal then at varying intervals up to 120 mins:

Frequent intervals 0–240 sec after IV (n = 4)

Results:

(Estimated from Fig. 1)

Mean, pg/mL

Basal:

Undetactable in all

Intramuscular:

10 at 15 sec

20 at 30 sec

40 at 1 min

50 at 3 min

45 at 6 min

43 at 12 min

18 at 18 min

18 at 30 min

0 at 60 min

Intravenous:

35 at 15 sec

330 at 30 sec

550 at 1 min

280 at 3 min

100 at 6 min

70 at 12 min

40 at 18 min

20 at 30 min

0 at 60 min

Important findings: Following IM, much lower peak levels vs. IV, with a more sustained elevation

Oxytocin assay: RIA

Max sensitivity reported as 1.5 pg/mL

No oxytocinase inhibitor was added, suggesting that some degradation may have occurred

Comments: Low basal levels suggests that actual peak levels may be higher than reported

Other reported data:

IM oxytocin levels Oxytocin first detected at 45 sec (average), still detectable at 60 min in 3/10

IV oxytocin levels Initial rapid fall (initial half-life 3 min) followed by slower disappearance

IV levels at 20–220 sec (Fig. 2, n = 2) show peaks around 400–700 pg/mL at 40–80 sec with marked variability and decline to < 100 pg/mL at 220 sec

SC oxytocin levels Levels undetectable (n = 1) and very low (39 pg/mL at 30 mins, n = 1)

 Husslein P et.al. (1983a)

[Oxytocin- and prostaglandin plasma concentrations before and after spontaneous labor: evidence of involvement of prostaglandins in the mechanism of placental separation].

Publication in German

See Fuchs et.al (1982)

See Fuchs et.al (1982)

See Fuchs et.al (1982)

Data from this study also published in Fuchs et.al (1982)

 Thornton et. al. (1988)

Plasma oxytocin during third stage of labour: comparison of natural and active management

25 women

Postpartum SOT IM

15 women

No postpartum SOT

Dose regimen:

Single IM injection of at birth of baby’s anterior shoulder

Total dose:

5 IU (combined with ergometrine 500 mcg)

Sampling regimen:

Every 30 sec for 15 min from crowning of the head

Results:

Mean ± SD, pmol/l equivalent to pg/mL

With SOT IM postpartum

3.1 ± 2.0 pg/mL before anterior shoulder

15.9 ± 2.7 after birth

Mean peak level 30.5 ± 2.5

No SOT

In 9/15 women:

2.4 ± 3.1 before anterior shoulder

2.2 ± 2.2 after birth

In 6/15 women:

3.2 ± 2.0 before anterior shoulder

6.4 ± 2.0 after birth

Mean peak level 11.6 ± 1.5

Important findings:

Significant rise following SOT (p < 0.001)

In 6/15 with no SOT, significant rise (p < 0.01) with “remarkably similar” pattern to SOT

Assay: RIA

 Thornton et. al. (1990)

Effect of human pregnancy on metabolic clearance rate of oxytocin

10 women Administered SOT at 8–10 weeks postpartum

(experimental)

(SOT also administered in labour- see above)

Dose regimen:

IV infusion 4.3 ng/min (2.6 mU/min) increased after 30 min to 8.5 ng/min (5.1 mU/min)

Maximum dose:

8.5 ng/min (5.1 mU/min)

Sampling regimen:

6 samples over 60 sec at baseline and 30 min, then 30 min after infusion rate increase

Results:

Mean ± SEM

Infusions, mU/min (ng/min)

Basal

1.7 ± 0.5 pg/mL

With SOT infusion

5.2 ± 0.4 pg/mL at 2.6 mU/min (4.3 ng/min)

8.0 ± 0.3 at 5.0 mU/min (8.5)

Important findings:

Oxytocin levels postpartum similar to labouring women who were administered significantly higher SOT doses (see above), suggesting greater metabolism of oxytocin in labour

Assay: RIA

Comments:

Doubling infusion rate approx doubled oxytocin levels, similar to dose-response elevations seen in labouring women in this study

Other reported data:

Oxytocin metabolic clearance rate (MCR)

MCR independent of concentration and higher in pregnancy vs postpartum (p < 0.001)

Plasma oxytocinase activity

High in pregnancy (2.1 ± 0.02 IU/mL), very low postpartum (< 0.1 IU/mL)

 Velandia (2012)

Parent-Infant Skin-to-Skin Contact Studies

34 women

Pre-labour caesarean

Randomised to 25 min newborn SSC with mother or with father

Control groups: the parent without SSC

All groups Initial 5 min SSC with mother and were returned to mother after 30 min

Dose regimen:

All women received 5 IU SOT IV after birth

19 women also received 50 IU SOT IV infusion over 90–158 min (316–555 mU/min)

Sampling regimen:

Basal (before surgery)

At birth then every 5 min for 45 min, then every 15 min up to 120 min

Results:

(Estimated from Figs. 13, 14, 15)

Mean, pM equivalent to pg/mL

SOT infusion & SSC (n = 7)

35 pg/mL basal

49 at 10 min

64 at 20 min

49 at 30 min

30 at 40 min

32 at 60 min

53 at 75 min

No SOT infusion & SSC (n = 8)

22 basal

26 at 10 min

31 at 20 min

32 at 30 min

29 at 40 min

24 at 60 min

23 at 75 min

SOT infusion, no SSC (n = 12)

26 basal

37 at 10 min

37 at 20 min

32 at 30 min

33 at 40 min

31 at 60 min

50 at 75 min

No SOT infusion, no SSC (n = 7)

29 basal

32 at 10 min

42 at 20 min

32 at 30 min

31 at 40 min

31 at 60 min

32 at 75 min

Important findings:

Rise from basal was significant at 20 and 75 min for women with SOT and SSC (p < 0.001) but not for other groups

Assay: RIA

Other reported data:

Oxytocin levels postpartum

All groups of mothers and fathers with or without SSC had non-significant oxytocin rise over first 60 min, then levels decreased to basal

SSC vs no SSC

Fathers: no difference in oxytocin with SSC vs no SSC

Newborns: Earlier first breastfeed when SSC with mother vs father (p = 0.018)

Girls cried more in SSC with mother vs father (p = 0.004)

Maternal personality profile at 2 days in relation to SOT and SSC

Greatest personality changes on Karolinska Scale of Personality (vs. normative) in women with both SOT and SSC

 Yamaguchi et. al. (2011)

Serum oxytocin concentrations in elective caesarean delivery: A randomized comparison of three infusion regimens

30 women

Pre-labour caesarean

Randomised to 3 postpartum SOT IV regimens

Dose regimen:

IV infusion started post-op (just after newborn cord clamped)

Randomised to:

a. 10 IU over 30 min (330 mU/min)

b. 10 IU over 3 min (3330 mU/min)

c. 80 IU over 30 min (2670 mU/min)

Total dose:

10 or 80 IU

Sampling regimen:

Basal (pre-infusion) 5, 30 and 60 min after initiation of SOT infusion

Results:

Mean ± SD pg/mL (reported in ng/mL)

a. 10 IU over 30 min (330 mU/min)

60 ± 20 pg/mL (0.06 ± 0.02) basal

710 ± 270 (0.71 ± 0.270) at 5 min

1170 ± 370 (1.17 ± 0.37) at 30 min

650 ± 260 (0.65 ± 0.26) at 60 min

b. 10 IU over 3 min (3330 mU/min)

40 ± 20 (0.04 ± 0.02) basal

1970 ± 650 (1.97 ± 0.65) at 5 min

410 ± 210 (0.41 ± 0.21) at 30 min

360 ± 260 (0.36 ± 0.26) at 60 min

c. 80 IU over 30 min (2670 mU/min

70 ± 40 (0.07 ± 0.04) basal

3650 ± 740 (3.65 ± 0.74) at 5 min

6190 ± 1190(6.19 ± 1.19) at 30 min

80 ± 250 (0.08 ± 0.25) at 60 min

Important findings:

8-fold higher dose (80 IU vs 10 IU) gives 5-fold higher levels at 5 and 30 min

Assay: ELISA with extraction

ELISA gives higher levels than RIA with different effect patterns

Other reported data:

Uterine tone:

Adequate in all groups, no additional uterotonic drugs required

Cardiovascular:

No significant changes in blood pressure or heart rate in any group, despite very high SOT dose

 Yuksel et. al. (2016)

Immediate breastfeeding and skin-to-skin contact during cesarean section decreases maternal oxidative stress, a prospective randomized case-controlled study

90 women

Pre-labour caesarean

Randomised to immediate vs. delayed (1 hour) newborn SSC

Dose regimen:

5 IU bolus after newborn cord clamped then 20 IU/hour infusion

Sampling regimen:

Basal (before surgery)

15 mins post-surgery

Results:

Mean (range), pg/mL

Delayed SSC

363.3 (187–645) pg/mL at 15 mins

Immediate SSC

670.0 (435–890) at 15 mins

Important findings:

Oxytocin levels significantly higher with immediate vs delayed SSC (p = 0.003)

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

All women received SOT

Other reported data:

Postoperative serum oxidative stress markers:

Oxidative stress markers more favourable with immediate vs delayed SSC (p < 0.001), and positively correlated with oxytocin levels (p < 0.001)

SSC and pain markers:

Women with immediate vs delayed SSC had non-significantly lower pain scores and lower analgesia requirements

 Handlin et. al. (2009)

Effects of sucking and skin-to-skin contact on maternal ACTH and cortisol levels during the second day postpartum-influence of epidural analgesia and oxytocin in the perinatal period

See Jonas (2009)

See Jonas (2009)

See Jonas (2009)

(Data from this study also published in Jonas et al. 2009)

 Jonas et. al. (2009)

Effects of intrapartum oxytocin administration and epidural analgesia on the concentration of plasma oxytocin and prolactin, in response to suckling during the second day postpartum

Intrapartum:

8 women

Labour augmentation with SOT

14 women

Labour augmentation with SOT plus epidural analgesia

20 women

Spontaneous labour, no SOT or other interventions

All women primiparous

Dose regimens:

SOT IV infusion:

Total dose:

Median 0.8 IU (1.35 μg)

IQR 0.3–1.6 IU (0.53–2.73 μg)

SOT IV infusion with epidural (SOT/EDA):

Total dose: Median 0.9 IU (1.43 μg)

IQR 0.4–1.8 IU (0.74–3.06 μg)

Sampling regimen:

During breastfeeding at 24–48 hr. postpartum with skin-to-skin contact (SSC)

Baseline sample at first latch then 15 samples at 30 sec intervals over first 7.5 min and then 10, 20, 30, and 60 min

Results:

A median of all samples for each woman was calculated, which were combined into group medians

Median (IQR), pg/mL

SOT/No EDA

156.3 pg/mL (102.0–376.2) basal

176.6 (161.2–193.3) at 1.5 min

171.3 (134.3–234.1) median all samples

SOT/EDA

96.2 (82.6–123.0) baseline

121.4 (110.4–132.0) at 1.5 min

106.8 (96.7–157.1) median all samples

No interventions

131.6 (97.1–227.2) basal

190.6 (121.0–234.6) at 1.5 min

144.1 (93.2–224.8) median all samples

Important findings:

Median all samples SOT/EDA significantly lower vs other groups (p = 0.033–0.005) with depressed profile, both basal and peak levels

Higher SOT IV dose (in SOT IV and SOT/EDA groups) correlated with significantly lower median oxytocin (p = 0.019), mainly due to lower levels in SOT/EDA, see Fig. 3

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

The combination of SOT and epidural gave rise to a unique depressed oxytocin effect pattern

Other reported data:

Oxytocin levels during breastfeeding at 2 days following labour epidural analgesia (This data to be reviewed in subsequent systematic review^a)

Blood pressure and personality changes in relation to SOT and other interventions (Data published elsewhere)

Data from this study also published in Handlin et al. (2009)

Postpartum:

13 women

Postpartum SOT IM, no SOT in labour

20 women

Spontaneous labour, no SOT or other interventions in labour or postpartum

All women primiparous

Dose regimens:

SOT postpartum IM injection: 10 IU (8.3 μg)^b

Sampling regimen:

During breastfeeding at 24–48 hr. postpartum with SSC

Baseline at first latch then 15 samples at 30 sec intervals over first 7.5 min and at 10, 20, 30 and 60 min

Results:

Median (interquartile range), pg/mL

With SOT IM postpartum

159.3 pg/mL(100.1–219.6) basal

173.0 (122.1–205.8) at 1.5 min

158.2 (119–187.2) median all samples

No SOT

131.6 (97.1–227.2) basal

190.6 (121.0–234.6) at 1.5 min

144.1 (93.2–224.8) median all samples

Important findings:

Median levels in SOT IM group not significantly different to No SOT group, with similar pattern of oxytocin release in response to breastfeeding

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Other reported data:

Oxytocin levels during breastfeeding at 2 days following labour epidural analgesia (This data to be reviewed in subsequent systematic review^a)

Blood pressure and personality changes in relation to SOT and epidurals (Data published elsewhere)

 Takahashi et. al. (2021)

Epidural Analgesia With or Without Oxytocin, but Not Oxytocin Alone, Administered During Birth Disturbs Infant Pre-feeding and Sucking Behaviors and Maternal Oxytocin Levels in Connection With a Breastfeed Two Days Later

[updated search 2022 Rev1]

Intrapartum: 5 women

Labour augmentation with SOT

10 women

Labour augmentation with SOT plus EDA

13 women

Spontaneous labour, no SOT or other interventions

All women primiparous

Dose regimens:

SOT IV infusion:

Total doses:

Median 1.1 IU (1.86 μg)

IQR 0.7–3.0 IU (1.145–5.046 μg)

SOT IV infusion with epidural (SOT + EDA):

Total dose:

Median 2.5 IU (4.16 μg)

IQR 0.89–3.78 IU (1.487–6.308 μg)

Sampling regimen:

(see Jonas above)

Results:

Group means±SE, pg/mL

(Estimated from Fig. 2)

Mean: mean of OT levels from 0 to 60 min

Variance: mean of OT variance between 0 and 7.5 mins

SOT/No EDA

190 ± 80 mean

830 ± 200 variance

SOT + EDA

110 ± 30 mean

820 ± 100 variance

No interventions

160 ± 55 mean

780 ± 130 variance

Important findings:

No significant difference in mean OT levels or variance in SOT group vs controls.

Lowest mean OT in SOT + EDA group (p < 0.005 vs SOT, p < 0.005 vs controls)

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

Variance reflects pulsatility of oxytocin release

Other reported data:

Breastfeeding behaviour, IBFAT score:

Shorter duration of rooting in: SOT vs controls (p < 0.05); SOT + EDA vs controls (p < 0.0001) and SOT vs SOT + EDA (p < 0.0001)

Oxytocin levels during breastfeeding at 2 days following labour epidural analgesia (This data to be reviewed in subsequent systematic review^a)

Blood pressure, and personality changes in relation to SOT and other interventions (Data published elsewhere)

Data from this study also published in Jonas et al. (2009) and Handlin et al. (2009)

Postpartum:

8 women

Postpartum SOT IM (no SOT in labour)

13 women

Spontaneous labour, no SOT or other interventions in labour or postpartum

All women primiparous

Dose regimens:

SOT postpartum IM injection: 10 IU

Sampling regimen:

(see Jonas above)

Results:

Group means±SE, pg/mL

(Estimated from Fig. 2)

Mean: mean of OT levels from 0 to 60 min

Variance: mean of OT variance between 0 and 7.5 mins

SOT IM postpartum

165 ± 50 mean

870 ± 200 variance

No SOT (Controls)

160 ± 55 mean

780 ± 260 variance

Important findings:

No significant difference in mean OT levels or variance in SOT IM group vs. controls.

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

Variance reflects pulsatility of oxytocin release

Other reported data:

Breastfeeding behaviour, IBFAT score:

Shorter duration of rooting in SOT IM vs controls (p < 0.0001)

Oxytocin levels during breastfeeding at 2 days following labour epidural analgesia (This data to be reviewed in subsequent systematic review^a)

Blood pressure, cortisol levels and personality changes in relation to SOT and other interventions (Data published elsewhere)

Data from this study also published in Jonas et al. (2009) and Handlin et al. (2009)

 Erickson et.al. (2020)

Oxytocin, Vasopressin and Prolactin in New Breastfeeding Mothers: Relationship to Clinical Characteristics and Infant Weight Loss

46 women

Spontaneous labour

With (11) and without (35) SOT augmentation in labour, birth

18/46 also received epidural analgesia

33/46 women also received postpartum SOT

Dose regimen:

Not stated

Total or maximum dose:

Intrapartum

Max infusion rate: 20 mU/min

Max duration: 12 hours

Total intrapartum dose: mean 1.3 IU (SD 1.3)

Postpartum

Dose not stated

Total SOT (intra and postpartum) Mean 8.9 IU (SD 8.3)

Sampling regimen:

4–5 days postpartum (n = 35)

Blood sampled at breastfeeding commencement and 20 min later (n = 32 with > = 1 successful samples)

Results:

(Oxytocin levels not given for women with SOT vs no SOT)

Mean ± SD (all women)

Basal

1641.5 ± 121.7 pg/mL baseline

20 mins breastfeeding 1713.6 ± 127.2

Important findings:

Significantly higher basal levels in women with higher SOT dose in labour (p = 0.03)

Assay: ELISA

ELISA gives higher levels than RIA with different effect patterns

Comments:

Mixture of intra- and post-partum exposures

Data used for correlations not provided

Other reported data: Oxytocin in relation to birth and breastfeeding

Significant increase in mean oxytocin (all women) at 20 min breastfeeding (p < 0.001)

Higher basal oxytocin correlated with shorter labour (p = 0.003)

AVP and prolactin during breastfeeding

Women administered SOT in labour had increase in AVP levels from basal to 20 min breastfeeding, whereas women without SOT had reduced AVP (p = 0.03)

 Gu V. et.al. (2016)

Intrapartum Synthetic Oxytocin and Its Effects on Maternal Well-Being at 2 Months Postpartum

Data includes several study populations, including two groups of women (stated as n = 287) who appear to be included in Prevost (2014)

386 women

With and without SOT in labour, birth, postpartum

29/386 without SOT exposure included in combined analysis

Dose regimen:

Intrapartum

2 mU/min increasing by 2 mU/min to maximum 20 mU/min

Postpartum

Intramuscular injection, stated as “standard dose 100 μg converted to 50 IU”

Total or maximum dose:

Mean 36.61 IU (SD 24.36) including postpartum dosage

Sampling regimen:

Single blood sample at home visit at 2 months postpartum (n = 318)

Results:

(Oxytocin levels not given for women with SOT vs no SOT)

Mean ± SD (all women)

281.02 ± 233.66 pg/mL

Important findings:

SOT total dose significantly predicted oxytocin levels at 2 months (p < 0.001) and accounted for 2.2% of the variance (data not provided)

Women who were exclusively breastfeeding at 2 months postpartum had received significantly less SOT vs non-exclusively breastfeeding women (p < 0.001, data not provided)

Assay: ELISA, not extracted

ELISA gives higher levels than RIA with different effect patterns

Comments:

Study design combines

several populations

Numbers of women included and sampled appear contradictory

Reported intramuscular postpartum dose is very high (50 IU) in comparison to other included studies and to standard clinical practice (5-10 IU)

Total dose is very high in comparison to other included studies

Other reported data:

SOT and mental health Higher SOT dose associated with greater (self-reported) depressive, anxious, and somatization symptoms (p < 0.05), and accounted for 4.7% of variance in depression symptoms

 Prevost et.al. (2014)

Oxytocin in pregnancy and the postpartum: relations to labor and its management.

This study population appears to be also included in Gu (2016)

272 women

Some women had SOT for induction or augmentation (numbers not stated)

Dose regimen:

Not stated

Total or maximum dose:

(Calculated from data in Table 2)

Total dose 0.58–3.02 IU

Overall mean total dose: 1.4 IU

Sampling regimen:

Single blood sample at home visit at 2 months postpartum

Results:

(Oxytocin levels not given for women with SOT vs no SOT)

Mean ± SD, pg/mL

All women

286.3 ± 272.7

Important findings:

SOT total dose positively associated with oxytocin levels (data and significance not provided)

Each extra IU SOT in labour increased oxytocin levels by 15.6 pg/mL (95% CIs: 5.7, 25.5)

Assay: ELISA, not extracted

ELISA gives higher levels than RIA with different effect patterns

Comments:

Very high individual variability

Study design combines two different populations

Low doses unlikely to significantly raise oxytocin levels in labour

No tests of significance given

Other reported data:

Oxytocin variability:

Oxytocin (all samples, including during pregnancy) varied 70-fold between individuals (32.3–2297.6 pg/mL)

Oxytocin and breastfeeding:

Higher oxytocin levels (basal) in non-breastfeeding vs. breastfeeding women

Oxytocin in pregnancy:

Levels fell from early to late pregnancy in 73 women (27%)