Abstract Background The reproductive hormone oxytocin facilitates labour, birth and postpartum adaptations for women and newborns. Synthetic oxytocin is commonly given to induce or augment labour and to decrease postpartum bleeding. Aim To systematically review studies measuring plasma oxytocin levels in women and newborns following maternal administration of synthetic oxytocin during labour, birth and/or postpartum and to consider possible impacts on endogenous oxytocin and related systems. Methods Systematic searches of PubMed, CINAHL, PsycInfo and Scopus databases followed PRISMA guidelines, including all peer-reviewed studies in languages understood by the authors. Thirty-five publications met inclusion criteria, including 1373 women and 148 newborns. Studies varied substantially in design and methodology, so classical meta-analysis was not possible. Therefore, results were categorized, analysed and summarised in text and tables. Results Infusions of synthetic oxytocin increased maternal plasma oxytocin levels dose-dependently; doubling the infusion rate approximately doubled oxytocin levels. Infusions below 10 milliunits per minute (mU/min) did not raise maternal oxytocin above the range observed in physiological labour. At high intrapartum infusion rates (up to 32 mU/min) maternal plasma oxytocin reached 2–3 times physiological levels. Postpartum synthetic oxytocin regimens used comparatively higher doses with shorter duration compared to labour, giving greater but transient maternal oxytocin elevations. Total postpartum dose was comparable to total intrapartum dose following vaginal birth, but post-caesarean dosages were higher. Newborn oxytocin levels were higher in the umbilical artery vs. umbilical vein, and both were higher than maternal plasma levels, implying substantial fetal oxytocin production in labour. Newborn oxytocin levels were not further elevated following maternal intrapartum synthetic oxytocin, suggesting that synthetic oxytocin at clinical doses does not cross from mother to fetus. Conclusions Synthetic oxytocin infusion during labour increased maternal plasma oxytocin levels 2–3-fold at the highest doses and was not associated with neonatal plasma oxytocin elevations. Therefore, direct effects from synthetic oxytocin transfer to maternal brain or fetus are unlikely. However, infusions of synthetic oxytocin in labour change uterine contraction patterns. This may influence uterine blood flow and maternal autonomic nervous system activity, potentially harming the fetus and increasing maternal pain and stress. 

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Maternal and newborn plasma oxytocin levels in response to maternal synthetic oxytocin administration during labour, birth and postpartum – a systematic review with implications for the function of the oxytocinergic system

Simple Summary Caffeine is a stimulant used in humans and animals to improve newborns’ respiratory and neurological responses. The use of caffeine after birth could increase neonate survival. However, due to the immature systems of animals at birth, caffeine use can have different results. This review aims to understand caffeine’s effects on respiratory and neurological systems in neonate animal models (rat and mouse pups, goat kids, lambs, and piglets). Abstract Caffeine is widely used to improve neonatal health in animals with low vitality. Due to its pharmacokinetics and pharmacodynamics, caffeine stimulates the cardiorespiratory system by antagonism of adenosine receptors and alteration in Ca+2 ion channel activity. Moreover, the availability of intracellular Ca+2 also has positive inotropic effects by increasing heart contractibility and by having a possible positive effect on neonate vitality. Nonetheless, since neonatal enzymatic and tissular systems are immature at birth, there is a controversy about whether caffeine is an effective therapy for newborns. This review aims to analyze the basic concepts of caffeine in neonatal animal models (rat and mouse pups, goat kids, lambs, and piglets), and it will discuss the neuroprotective effect and its physiological actions in reducing apnea in newborns.

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Cardiorespiratory and Neuroprotective Effects of Caffeine in Neonate Animal Models

Skin‐to‐skin contact immediately after birth is recognised as an evidence‐based best practice and an acknowledged contributor to improved short‐ and long‐term health outcomes including decreased infant mortality. However, the implementation and definition of skin‐to‐skin contact is inconsistent in both practice and research studies. This project utilised the World Health Organization guideline process to clarify best practice and improve the consistency of application.

Skin‐to‐skin contact after birth: Developing a research and practice guideline

Developing and testing a clinical care bundle incorporating caffeine citrate to manage apnoea of prematurity in a resource-constrained setting: a mixed methods clinical feasibility study protocol

BACKGROUND
Despite its associated benefits which include better long-term pulmonary and neurodevelopmental outcome, the use of caffeine for apnoea of prematurity (AoP) has been limited in low- and middle-income countries (LMIC).


AIM
To better understand current caffeine use, the barriers and facilitators to its use and perceptions and practices in LMIC which have a disproportionately high burden of prematurity.


METHODS
An anonymous online global survey was conducted, targeting healthcare providers working and training in paediatrics and/or neonatology in LMIC.


RESULTS
A total of 181 respondents in 16 LMIC were included in the analysis; most were physicians working in publicly-funded urban tertiary hospitals. Most had received training in the use of caffeine for AoP (77%), reported expertise (70%) and confidence (96%) in its use, and had access to caffeine (65%). Caffeine availability was reported to be the greatest barrier (48%) and the greatest facilitator (37%). Other common barriers included cost (31%), access (7%) and policies or guidelines on caffeine use (7%); other common facilitators included policies or guidelines on caffeine use (11%), access (10%), staff/other providers' acceptance of caffeine as an appropriate treatment (9%) and the availability of staff to administer caffeine (8%). Most (79%) noted that access to caffeine was important, 92% agreed that caffeine improves quality of care, and 95% agreed that caffeine improves patient outcome.


CONCLUSION
Improving availability and access to low-cost caffeine will be key to increasing caffeine use in LMIC.


ABBREVIATIONS
AoP: Apnoea of Prematurity; LMIC: low- and middle-Income countries; REDCap: Research Electronic Data Capture.

A survey of barriers and facilitators to caffeine use for apnoea of prematurity in low- and middle-income countries.

Background Methylxanthine, including caffeine citrate and aminophylline, is the most common pharmacologic treatment for apnea of prematurity. However, due to the lack of high-quality evidence, there are no clear recommendations or guidelines on how to choose between caffeine and aminophylline. Objective This meta-analysis aimed to assess the comparative efficacy and safety of caffeine and aminophylline for apnea of prematurity, and provide reliable evidence for clinical medication in the treatment for apnea of prematurity. Methods PubMed, Scopus, Embase, EBSCO, Web of Science, and Cochrane databases were systematically searched from May 1975 to June 2022. Results Ten studies including a total of 923 preterm infants were evaluated. Our results showed that there was no significant difference in the effective rate of 1-3days between caffeine and aminophylline (OR 1.05, 95%CI: 0.40–2.74, P = 0.914). However, for side effects such as tachycardia (OR 0.22, 95%CI: 0.13–0.37, P<0.001) and feeding intolerance (OR 0.40, 95%CI: 0.23–0.70, P = 0.001), the incidence rate was lower in the caffeine group compared with the aminophylline group. No significant difference was found in hyperglycemia (OR 0.45, 95%CI: 0.19–1.05, P = 0.064). Conclusion This meta-analysis reveals that caffeine citrate and aminophylline have similar therapeutic effectiveness on respiratory function, but caffeine has fewer side effects and should be considered first for treatment.

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Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis

Background Hyperthyroidism affects about 0.2%-2.7% of all pregnancies, and is generally treated with propylthiouracil (PTU). However, previous studies about the effects of propylthiouracil on maternal or foetal are contentious. Objective This meta-analysis was carried out to investigate the safety and efficacy of propylthiouracil during pregnancy. Materials and methods PubMed, EBSCO, Embase, Scopus, Web of Science, Cochrane, CNKI, Wanfang and VIP database were searched from inception until August 31, 2021 for all available randomized controlled trials (RCTs) or cohort studies that evaluated the efficacy of propylthiouracil and its effects on pregnancy outcomes. Odds ratio (OR) and 95% confidence interval (CI) were used for binary variables, weighted mean difference (WMD) and 95% confidence interval (CI) were used for continuous variables. RevMan5.4 and Stata 16.0 were used for performing the meta-analysis. Results The researchers examined data from 13 randomized controlled trials and cohort studies involving 18948 infants. Congenital anomalies were not significantly associated with PTU in the pooled results (OR = 1.03, 95%CI: 0.84–1.25, P = 0.80, I2 = 40.3%). There were no statistically significant differences in neonatal hypothyroidism (OR = 0.55, 95%CI: 0.06–4.92, P = 0.593, I2 = 57.0%) or hepatotoxicity (OR = 0.34, 95%CI: 0.08–1.48, P = 0.151, I2 = 0.0%) exposed to PTU compared to the control group. The serum levels of FT3, FT4, TT3, and TT4 were significantly lower in the propylthiouracil group compared to the control group. Conclusion This meta-analysis confirmed the beneficial effects of propylthiouracil treatment, namely the risks of adverse pregnancy outcomes were not increased, and it also proved PTU’s efficacy in the treatment of pregnant women with hyperthyroidism. The findings supported the use of propylthiouracil during pregnancy with hyperthyroidism in order to improve clinical pregnancy outcomes in patients with thyroid dysfunction.

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Efficacy of propylthiouracil in the treatment of pregnancy with hyperthyroidism and its effect on pregnancy outcomes: A meta-analysis

Abstract Synthetic oxytocin is the current domestic first-line agent of induced labor and labor augmentation, and its potential effects on neonatal neurobehavioral development is currently attracting increased attention. To explore the effect of different doses of synthetic oxytocin on neonatal instinctive breastfeeding behavior and breastfeeding by observing neonatal behaviors during skin-to-skin contact with mothers after delivery. Observations and comparisons of neonatal instinctive behaviors were conducted by using Widström's 9 Stages method. According to the total dosage of oxytocin administered during labor, participants were divided into a low dose group (≤ 2.5 U) of 39 pairs, a medium dose group (&gt; 2.5 U) of 38 pairs, a high dose group (&gt; 7.5 U) of 38 pairs and a control group (no synthetic oxytocin use) of 39 pairs. The occurrence time of newborns' instinctive movements and the duration of each behavior stage for the four groups were also analyzed. The number of exclusive breastfeeding sessions within 3 days after birth and the rate of exclusive breastfeeding at 3 months were collected and compared. There were significant differences among the four groups in the occurrence time of raising head or turning head ( p = 0.004), eating hands ( p = 0.011), moving body ( p = 0.001), locating areola ( p &lt; 0.001), licking nipples ( p = 0.002), containing nipple ( p = 0.001), sucking ( p &lt; 0.001). There were significant differences among the four groups in the duration of activity ( p = 0.004), clawing ( p = 0.001), familiarization ( p = 0.001), and sucking ( p &lt; 0.001). There was also a significant difference in the number of exclusive breastfeeding sessions of 24 h ( p = 0.011), 48 h ( p &lt; 0.001), 72 h ( p = 0.001) after birth among the four groups, but there was no statistical difference in the rate of exclusive breastfeeding at 3 months after birth. The intrapartum administration of synthetic oxytocin was associated with the expression of neonatal instinctive breastfeeding. With increases in drug dose, the effect of breast seeking activity and breast attachment was more significant, and the association of synthetic oxytocin on sucking and breastfeeding was dose-dependent. 

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Yun Zhou

Papers

Comparative efficacy and safety of caffeine citrate and aminophylline in treating apnea of prematurity: A systematic review and meta-analysis

Efficacy of propylthiouracil in the treatment of pregnancy with hyperthyroidism and its effect on pregnancy outcomes: A meta-analysis

Effects of different doses of synthetic oxytocin on neonatal instinctive behaviors and breastfeeding