David Thomas Monks

Summary: Oxytocin is widely used to prevent atonic postpartum haemorrhage after caesarean delivery. Initial treatment failure rates are high and inadequate dosing may contribute. Excessive doses, however, are associated with serious adverse effects. The pharmacokinetic data from this context are sparse and there is a lack of data in the immediate postpartum minutes after an initiating bolus. The pharmacodynamic data from this context are exclusively from dose‐effect studies, with some suggesting that higher doses of oxytocin are required to provide adequate uterine tone in obese compared with non‐obese women. We aimed to perform a pharmacokinetic and pharmacodynamic study that would facilitate more precise weight‐based oxytocin dosing. We measured arterial oxytocin concentration, uterine tone and haemodynamic parameters in 25 women in the first 40 min after exogenous oxytocin administration at elective caesarean delivery. Serum oxytocin concentrations varied considerably between individuals. We constructed a one‐compartment pharmacokinetic model of exogenous oxytocin deposition, after its administration with an initiating bolus and a maintenance infusion, at elective caesarean delivery. Body weight was evaluated as a potential covariate but was not included in the model due to lack of statistically significant reduction in the objective function. We calculated the volume of distribution and clearance (mean [coefficient of variation]) as 156.1 l [18%] and 83 ml.s ⁻¹ [32%] but found no within‐individual correlation between serum oxytocin concentration and uterine tone or haemodynamic parameters. In conclusion, we observed a large variation in serum oxytocin concentrations between individuals receiving similar doses of oxytocin and were unable to establish weight‐based dosing of exogenous oxytocin at caesarean delivery. Our findings suggest that future studies on oxytocin pharmacokinetics would need large sample sizes. In the absence of such data, oxytocin dosing should continue to be guided by uterine tone assessments and adjusted according to a strategy based on the best evidence from dose‐effect studies.

Introduction: Postpartum depression has costly consequences for the mother, baby, and society. Numerous pharmacological and non-pharmacological interventions are available for the prevention and treatment of postpartum depression. To date, no attempt has been made to synthesize the evidence from comparisons of interventions both within and across these categories. Methods: We will perform a systematic review of the literature and perform network meta-analysis of interventions to (a) prevent and (b) treat postpartum depression. This review will include studies of primiparous or multiparous women during pregnancy or within 12 months of delivery of their baby that assess either interventions initiated during pregnancy or within 1 year of childbirth. Comparators will be other eligible interventions or control conditions. The outcome of interests will be related to the antidepressant efficacy of the interventions as well as their acceptability. The published literature will be searched in Ovid MEDLINE 1946-, Embase.com 1947-, Scopus 1823-, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. The search will use a combination of standardized terms and keywords for postpartum depression, a sensitive search filter to limit for randomized controlled trials, and a librarian-created “humans” filter. The search results will be uploaded to the Covidence online systematic review platform (Veritas Health Information Ltd., Victoria, Australia) where two review team members will independently screen articles. We will extract data to include year of publication, language, country, participants (number, demographic data, eligibility criteria, psychiatric symptoms, and co-morbidities), characteristics of the intervention and control conditions, and reported outcomes. Risk of bias for each study will be assessed independently by two review authors using the RoB 2: A revised Cochrane risk of bias tool for randomized trials. Network meta-analysis will be performed using a Bayesian hierarchical model supplemented with a Markov chain Monte Carlo approach. Discussion: Postpartum depression is a devastating disease with long-lasting consequences. Given the numerous available interventions to both prevent and treat postpartum depression and the great number of studies comparing them, it is imperative that clinicians and patients are provided with an assessment of their comparative efficacy and acceptability. Systematic review registration: Prospero registration (CRD42022303247).

Background: Evidence suggests ketamine may prevent postpartum depression (PPD) after cesarean delivery (CD) although intolerability and inconvenience of administration are problematic. We assessed the feasibility of studying ketamine (0.5 mg/kg, via subcutaneous injection or 40-min intravenous infusion) to prevent PPD after CD. Methods: Twenty-three women scheduled for cesarean delivery under neuraxial anesthesia were randomized to one of three groups: subcutaneous ketamine (SC Group, n = 8), intravenous ketamine (IV Group, n = 8) or placebo (n = 7). We measured depression (Edinburgh Postpartum Depression Scale [EPDS]) scores pre-operatively and at 1, 2, 21 and 42 days postoperatively. Anxiety, adverse effects, surgical site pain and analgesic consumption were also assessed. Feasibility was assessed based on acceptability, burden of disease, ability to collect study data and, tolerability of interventions. Results: Baseline characteristics of groups were similar, however, more women in the placebo group had pre-existing anxiety disorder (p = 0.03). 20.7% (25/121) of those approached consented to participate and 34.8% (8/23), of those assessed, screened positive for depression in the postpartum (EPDS > 12). PPD screening data was complete in 78.3% (18/23). No differences were observed for any adverse effect outcomes except for fewer incidences of intraoperative shivering with ketamine (SC: 25%, IV: 0% and Placebo: 85.7%, p = 0.01). No statistically significant difference in positive screening for PPD was observed (SC: 14.3%, IV: 50% and Placebo: 42.9%, p = 0.58). Conclusion: An RCT was judged to be feasible and there was no evidence of intolerability of either route of ketamine administration. Dispensing with the need for intravenous access makes the subcutaneous route a particularly attractive option for use in the postpartum population. Further examination of these interventions to prevent, and possibly treat, postpartum depression is warranted. Trial registration: NCT04227704, January 14^th, 2020.

Summary: Oxytocin is one of the most commonly used medications during labour and delivery. Recent insights from basic neuroscience research suggest that the uterotonic effects of oxytocin may arguably be trivial when compared with its profound effects on higher‐order human behaviour. The purpose of this review is to highlight the potential consequences of manipulating oxytocinergic signalling during the peripartum period and its long‐term impact on the maternal‐infant dyad. We identified four domains where modulation of oxytocinergic signalling might be consequential: postpartum depression; breastfeeding; neurodevelopment; and chronic pain, and performed a literature search to address the impact of peripartum oxytocin administration. We have shown modest, but inconsistent, evidence linking peripartum oxytocin administration with postpartum depression. Breastfeeding success appeared to be negatively correlated with peripartum oxytocin exposure, perhaps secondary to impaired primitive neonatal reflexes and maternal‐infant bonding. The association between perinatal oxytocin exposure and subsequent development of neurodevelopmental disorders such as autism in the offspring was weak, but these studies were limited by the lack of information on the cumulative dose. Finally, we identified substantial evidence for analgesic and anti‐hypersensitivity effects of oxytocin which might partly explain the low incidence of chronic pain after caesarean birth. Although most data presented here are observational, our review points to a compelling need for robust clinical studies to better dissect the impact of peripartum oxytocin administration, and as stewards of its use, increase the precision with which we administer oxytocin to prevent overuse of the drug.

Field experiments were conducted at two locations (Clayton and Jackson Springs, NC) to determine the influence of vegetation-free strip width (VFSW) and irrigation on newly planted peach growth and yield in a low-density orchard with a volunteer weedy ground cover. The experiments included VFSW of 0, 0.6, 1.2, 2.4, 3, or 3.6 m under irrigated or nonirrigated conditions. Seasonal variation in the orchard floor vegetation was observed as different weed species reported in summer and winter. However, this difference was not apparent with respect to VFSF and irrigation. At Jackson Springs, NC, the predicted irrigated VFSW which would produce the same trunk cross-sectional area (TCSA) as the grower standard (3-m nonirrigated) was 1.5, 1.3, and 0.8 m for one-, two-, and three-year-old trees, respectively. The predicted irrigated VFSW which would produce the same yield as the grower standard was 1.16 m. At Clayton, TCSA and fruit yield were not different by irrigation, but did increase linearly with VFSW. At both locations, leaf nitrogen (N) concentration was lower in irrigated trees than nonirrigated trees. Leaf N, leaf area, and SPAD were positively related to VFSW at Jackson Springs. In contrast, leaf N concentration was not different by VFSW at Clayton. However, leaf area and SPAD were positively related to VFSW at Clayton. These results suggest that a 1.5 m VFSW combined with proper irrigation and fertilization will produce tree growth and yield in newly planted orchard with volunteer weedy vegetation similar to the current grower standard in the southeastern USA.