APPENDIX Supplement S3.

Uterotonics and breastfeeding

References are in the bibliography, below
Dopamine agonists
Ergometrine and prostaglandins are dopamine agonists, reducing prolactin secretion (de
Groot et al 1998, England et al 1988) (table 1). Prostaglandins administered per vaginam
are systemically absorbed and metabolites remain in the circulation for several hours
(duration depends on dose), and are transferred to the fetus (Bygdeman 2003). Ergot
alkaloids act on dopamine receptors to suppress prolactin production and lactation. One
drug in this group, bromocriptine, is prescribed to manage galactorrhoea and, occasionally,
to suppress lactation post-partum. Intramuscular methylergonovine, 200 micrograms after
delivery of the placenta, inhibits the normal post-partum rise in serum prolactin (Weiss et
al, 1975). Oral ergometrine, 600 micrograms daily for seven days, reduces serum prolactin
and progressively inhibits lactation with some individual variation (Canales et al, 1976).
Intravenous ergotamine, 500 micrograms, was associated with a statistically non-significant
reduction in serum prolactin concentration 48-72 hours post partum, after suckling (n =
132) (Begley, 1990). In this study, use of intravenous ergometrine for active management
of the third stage of labour gave a statistically significant increase in the number of women
supplementing and ceasing breastfeeding by one and four weeks post-partum, mainly
because lactation was inadequate for the infants needs (Begley, 1990).
Oxytocin
Maternal-infant bonding, initiation of breastfeeding and milk ejection depend on pulsatile
secretion of oxytocin from the posterior pituitary (Nissen et al 1998, Winberg 2005),
together with further synthesis of oxytocin in myoepithelial cells in a local positive
feedback mechanism (Cassoni et al 2006). During stress, including blood loss, prolonged
labour or Caesarean delivery, pulsatile oxytocin secretion is replaced by continuous
secretion, reducing stimulation to the myoepithelial cells (Russell et al 2001, Dewey 2001).
Exogenous oxytocin has the potential to interrupt initiation of lactation by: disruption of
pulsatile secretion and fluctuating concentrations; desensitisation of receptors; and, more
speculatively, infant or maternal behaviour.
Interruption of fluctuations in oxytocin concentrations
Exogenous oxytocin may: augment or mimic the stress response; interupt pulsed oxytocin
secretions and subsequent activity of the myoepithelial cells, necessary for initiation of
lactation (Nissen et al 1996, Russell et al 2001); disrupt oxytocin receptor signalling in
myoepithelial and endothelial cells (Reversi et al 2005); stimulate then deplete oxytocin
secreting neurons (Rossoni et al 2008); disrupt oxytocin balance and changes in neuronal

architecture at the sensitive period of delivery, affecting maternal adaptations (Jonas et al

2008, Leng et al 2008).
Desensitisation
Exogenous oxytocin rapidly desensitizes and down-regulates oxytocin receptors in the
myoepithelium (Leng et al 2005), and brain (Kimura et al 2003), whereas prolonged
exposure is required in myometrium (Plested & Bernal 2001, Robinson et al 2003). This
suggests that administration of relatively high doses of oxytocin could: interfere with the
rapid proliferation of oxytocin receptors on myoepithelial cells that occurs at term (Kimura
et al 1998).
Behaviour
The placenta is not an effective barrier to the passage of drugs, and the blood/brain barrier
is under-developed in the fetus. Permeability may be further increased by cytokines
released during stress associated with hypoxia and labour (Rosenberg 2002). Therefore, the
assumption that oxytocin does not cross the placenta and the fetal blood/brain barrier has
been questioned, and it is speculated that oxytocin administered to mothers may affect
infant behaviour, although support for this emanates mainly from animal studies (Wahl
2004, Uvnas-Moberg et al 1998). The impact of exogenous oxytocin on behaviour (Carter
2003) and breastfeeding has not been thoroughly investigated: there would appear to be
little information regarding possible disruption of pulsatile oxytocin release (Nissen et al
1996), concomitant local peptide release (Uvnas-Moberg & Eriksson 1996), oxytocin release
into the central nervous system (Febo et al 2005), or changes in homeostatic norms (Carter
2003), any of which could influence maternal behaviour. [In the population under
investigation it takes very little for women to revert to the more convenient cultural norms
of formula feeding.]
Clinical studies
Exogenous oxytocin may not mimic the endogenous hormone, for example: intranasal
oxytocin has no impact on milk production [by mothers of preterm babies] (Fewtrell et al
2006); induction of labour by any method, including administration of oxytocin (as
syntocinon) (Out et al 1988, Rajan 1994, Leng et al 1999), is associated with increased
numbers of women abandoning intentions to breastfeed (Ounsted et al 1978); oxytocin
infusion reduces the chances of breastfeeding within 4 hours and increases the chances of
artificial feeding (Wiklund et al 2007). Epidurals reduce release of exogenous oxytocin
(Rahm et al 2002) and most women receiving oxytocin in the first and second stages also
receive epidural analgesia, making it difficult to disentangle the effects of the two drugs
(Wiklund et al 2007). However, we found that the association between intramuscular and
oxytocin and formula feeding was stronger when women receiving epidural and spinal

analgesia were excluded from the analysis, suggesting that oxytocin may exert an
independent effect (table 7).
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