BACKGROUND: Improved Pregnancy Outcomes via Early Detection (IMPROvED) is a multi-centre, European phase IIa clinical study. The primary aim of IMPROvED is to enable the assessment and refinement of innovative prototype preeclampsia risk assessment tests based on emerging biomarker technologies. Here we describe IMPROvED's profile and invite researchers to collaborate.

METHODS: A total of 4,038 low-risk nulliparous singleton pregnancies were recruited from maternity units in Ireland (N=1,501), United Kingdom (N=1,108), The Netherlands (N=810), and Sweden (N=619) between November 2013 to August 2017. Participants were interviewed by a research midwife at ~11 weeks (optional visit), ~15 weeks, ~20 weeks, ~34 weeks' gestation (optional visit), and postpartum (within 72-hours following delivery).

FINDINGS TO DATE: Clinical data included information on maternal sociodemographic, medical history, and lifestyle factors collected at ~15 weeks' gestation, and maternal measurements, collected at each study visit. Biobank samples included blood, urine, and hair collected at each study visit throughout pregnancy in all units plus umbilical cord/blood samples collected at birth in Ireland and Sweden. A total of 74.0% (N=2,922) had an uncomplicated pregnancy, 3.1% (N=122) developed preeclampsia, 3.6% (N=143) had a spontaneous preterm birth, and 10.5% (N=416) had a small for gestational age baby. We evaluated a panel of metabolite biomarkers and a panel of protein biomarkers at 15 weeks and 20 weeks' gestation for preeclampsia risk assessment. Their translation into tests with clinical application, as conducted by commercial entities, was hampered by technical issues and changes in test requirements. Work on the panel of proteins was abandoned, while work on the use of metabolite biomarkers for preeclampsia risk assessment is ongoing.

FUTURE PLANS: In accordance with the original goals of the IMPROvED study, the data and biobank are now available for international collaboration to conduct high quality research into the cause and prevention of adverse pregnancy outcomes.

PURPOSE: Our purpose was to identify human ovarian extracellular matrix (ECM) components that would support in vitro culture of human ovarian tissue and be compatible with possible future clinical applications. We characterized ovarian expression of laminins and selected three laminin tripeptides for culture experiments to be compared with Matrigel, an undefined and animal-based mixture of ECM components.

METHODS: Expression of the 12 laminin genes was determined on transcript and protein levels using cortical tissue samples (n = 6), commercial ovary RNA (n = 1), follicular fluid granulosa cells (n = 20), and single-cell RNA-sequencing data. Laminin 221 (LN221), LN521, LN511, and their mixture were chosen for a 7-day culture experiment along with Matrigel using tissue from 17 patients. At the end of the culture, follicles were evaluated by scoring and counting from serial tissue sections, apoptosis measured using in situ TUNEL assay, proliferation by Ki67 staining, and endocrine function by quantifying steroids in culture media using UPLC-MS/MS.

RESULTS: Approximately half of the cells in ovarian cortex expressed at least one laminin gene. The overall most expressed laminin α-chains were LAMA2 and LAMA5, β-chains LAMB1 and LAMB2, and γ-chain LAMC1. In culture experiments, LN221 enhanced follicular survival compared with Matrigel (p < 0.001), whereas tissue cultured on LN521 had higher proportion of secondary follicles (p < 0.001). LN511 and mixture of laminins did not support the cultures leading to lower follicle densities and higher apoptosis. All cultures produced steroids and contained proliferating cells.

CONCLUSIONS: LN221 and LN521 show promise in providing xeno-free growth substrates for human ovarian tissue cultures, which may help in further development of folliculogenesis in vitro for clinical practices. The system could also be used for identification of adverse effects of chemicals in ovaries.

Background and aims

The present randomized open label parallel group study was conducted to evaluate if an oral oxycodone (OXY) regimen can be at least equally effective and as safe for postoperative analgesia after caesarean section (CS) as a standard of care program using nurse-administered intravenous morphine (IVM), followed by oral codeine.

Methods

Eighty women (40 + 40) were scheduled for elective CS under spinal anaesthesia. All patients received postoperative multimodal analgesic therapy, including ibuprofen and paracetamol. The OXY group got standardized extended release and short acting oral treatment (and in a few cases intravenous OXY) as needed and the other group received current standard of care, IVM as needed for 24 h, followed by codeine. Opioid treatment lasted maximum five days. Outcome measures were pain intensity (numerical rating scale, NRS), opioid requirements, duration of administering opioids and safety for mother and newborn. All opioids in the study were expressed in OXY equivalents, using a conversion table. As the bioavailability of each opioid has a certain extent of interindividual bioavailability this conversion represents an approximation. The possible influence of opioids on the newborns was evaluated by the Neurological Adaptive Capacity Score at birth and at 24 and 48 h.

Results

During the first 24 h, there were no differences between treatments in opioid requirements or mean pain intensity at rest but pain intensity when asking for rescue medication was lower in the OXY than in the IVM group (mean ± SD; 5.41 ± 6.42 vs. 6.42 ± 1.61; p = 0.027). Provoked pain (uterus palpation) during the first 6 h was also less in the OXY group (3.26 ± 2.13 vs. 4.60 ± 2.10; p = 0.007). During the 25–48 h period postoperatively, patients on OXY reported significantly lower pain intensity at rest (2.9 ± 1.9 vs. 3.8 ± 1.8; p = 0.039) and consumed less opioids (OXY equivalents; mg) (31.5 ± 9.6 vs. 38.2 ± 38.2; p = 0.001) than those on IVM/codeine. The total amount of opioids 0–5 days postoperatively was significantly lower in the OXY than in the IVM/codeine group (108.7 ± 37.6 vs. 138.2 ± 45.1; p = 0.002). Duration of administering opioids was significantly shorter in the OXY group. Time to first spontaneous bowel movement was shorter in the OXY group compared with the IVM/codeine group. No serious adverse events were recorded in the mothers but the total number of common opioid adverse effects was higher among women on IVM/codeine than among those receiving OXY (15 vs. 3; p = 0.007). No adverse outcomes in the newborns related to treatment were observed in either group.

Conclusions

In a multimodal protocol for postoperative analgesia after CS better pain control and lower opioid intake was observed in patients receiving oral OXY as compared to those on IVM/codeine. No safety risks for mother and child were identified with either protocol.

Implications

Our findings support the view that use of oral OXY is a simple, effective and time saving treatment for postoperative pain after CS.

Background

Postoperative pain treatment in women undergoing cesarean section (CS) needs to be effective to enable fast and smooth recovery without adverse outcomes and to improve breastfeeding and bonding between mother and child. It is also important that pain treatment should have minimal impact on the newborn.

The overall aim

The overall aim of this thesis was to investigate how to improve pain management in women undergoing cesarean section.

Specific aims were:

* To investigate if a single injection of bupivacaine with adrenaline close to the fascia could decrease opiate consumption and pain in patients undergoing CS in spinal anesthesia and whether the same treatment influences the need for opiates in women operated in general anesthesia (paper 1 and 3).

* To study the overall incidence and risk factors for persistent pain after CS and to characterize the persistent pain, regarding intensity, body location and impact on daily life (paper 2).

* To clarify whether oral oxycodone (OXY) can provide equal/better and safe postoperative pain relief after CS compared to intravenous morphine followed by oral codeine (IVM) (paper 4).

* To study pharmacokinetic aspects of postoperative OXY treatment of mothers after CS and to investigate possible drug exposure through breast milk, including the effects on the newborn (paper 5).

Methods and results:

Study I: Two hundred and sixty women undergoing CS were randomized to receive injection ofeither 40 ml bupivacaine (2.5 mg/ml) with adrenaline (5 μg/ml) (n=130) or 40 ml saline solution (0.9%) (n=130), close to the fascia before closure of the wound. Morphine consumption, pain assessment by Numerical Rating Scale (NRS) and time to mobilization were recorded. Morphine requirements were significantly less for up to 12 h postoperatively and mean and maximum pain intensity lower during the first 6 h in the group receiving local anesthesia (p ≤0.05).

Study II: A prospective follow up study of the women participating in study I. A questionnaire consisting of the Brief Pain Inventory (BPI) was posted to all women at 3, 6 and 12 months after surgery. Women rated pain intensity as well as interference with factors related to general function and quality of life. Women reported pain in one or more locations, in the CS surgical site as well as in other parts of the body. At 3 months 40% had pain and at 6 and 12 months 27% and 21%, still had pain. CS on maternal request i.e. psychological indication as well as a first CS were significant (p ≤0.05) risk factors for persistent pain at 3 months. Severe postoperative pain in the immediate postoperative period (0-48 h) or undergoing a first CS were significant independent risk factors for the development of persistent pain up to 6 months after CS. Parameters related to quality of life such as sleeping difficulties were significantly impaired in women with persistent pain.

Study III: A retrospective study (2008-2014) was conducted at the Karolinska University Hospital, Huddinge where medical records of women who underwent CS in general anesthesia were reviewed. After applying exclusion criteria 250 medical records remained. Information 3 about women receiving local anesthesia in the surgical wound, 20 or 40 ml bupivacaine/adrenaline (36 and 42 women in each group), were collected and data from women receiving no local treatment were identified and served as controls (n=172). A significantly lower morphine consumption during the 6 first postoperative hours was seen in patients receiving 40 ml local anesthetics when compared with controls (p ≤0.05) but no difference was seen for the 20 ml group or between treatment groups.

Study IV: Eighty women scheduled for elective CS were recruited and randomized to receive extended release tablets and short acting OXY (n=40) or IVM (n=40). All patients received a multimodal therapy with ibuprofen and paracetamol and the opiates were administered as needed. Outcome measures were safety parameters for mother and child, opioid requirements, pain intensity by NRS, time to mobilization and time consumption to administer drugs. To evaluate safety for the newborns Apgar scores, acid base status in the umbilical cord, weight development and the Neurological Adaptive Capacity Score were used. A significantly lower postoperative pain intensity measured by NRS was observed 0-6 hours and 25-48 hours in the OXY group (p ≤0.05). Opioid consumption was significantly less in the OXY than in the IVM group 0-5 days postoperatively. Total time to administer analgesics was significantly shorter in the OXY group. There was a significant difference in common opiate related adverse effects between the two groups (3 women in the OXY group compared to 15 in the IVM/codeine group). No negative effects in the newborns related to opioid treatment were observed in either of the two groups.

Study V: The material was obtained in study IV. Maternal blood and breastmilk were sampled at 24 and 48 hours and neonatal blood was collected at 48 hours postpartum. All samples were analyzed for OXY and the metabolites noroxycodone, oxymorphone and noroxymorphone. Detectable plasma levels of OXY and its metabolites were found in all women and even if there were small quantities of breastmilk detectable levels were found also here. In most cases there were low or non-detectable levels of OXY in the plasma of the neonates.

Conclusions: A single injection of bupivacaine with adrenaline in the surgical wound decreases the need for rescue morphine postoperatively and was demonstrated to be a safe and effective pain management in women undergoing CS both in spinal and general anesthesia. Standardized postoperative treatment with oral OXY after CS was shown to be time effective and to give a better pain control, with lower opioid intake than a protocol using IVM/codeine, both as components of a multimodal analgesic regime. Our clinical data and the pharmacokinetic analyses support the view that OXY treatment is safe for mothers and neonates. As severe postoperative pain is a risk factor for long term pain the initial pain relief is crucial and we found that experiences related to quality of life were significantly impaired in women with persistent pain. We suggest that our findings can be of clinical importance, not least in women who have their CS performed in general anesthesia.

OBJECTIVES: To investigate the overall incidence and risk factors for persistent pain and its interference with daily life after cesarean section.

DESIGN: Prospective long-term follow-up study.

SETTING: Karolinska University Hospital, Stockholm, Sweden.

POPULATION: 260 healthy women who underwent elective cesarean section.

METHODS: Information on demographics, medical history, postoperative pain and analgesic requirements was collected. A questionnaire consisting of the Brief Pain Inventory was posted at 3, 6 and 12 months after surgery. Women rated pain intensity as well as interference with factors related to general function and quality of life.

MAIN OUTCOME MEASURES: The overall incidence and risk factors for persistent postoperative pain at three time points. Persistent pain was considered a secondary outcome.

RESULTS: At 3, 6 and 12 months 40%, 27% and 22% of patients, respectively, reported pain in one or more locations, in the surgical site as well as in other areas. A psychological indication, as well as a first cesarean section, increased the risk for pain at 3 months. Severe postoperative pain in the immediate postoperative period or undergoing a first cesarean section were significant independent risk factors for the development of persistent pain up to 6 months after cesarean section. Parameters related to quality of life were significantly impaired in women with persistent pain.

CONCLUSION: Several factors, including severe postoperative pain, were shown to influence the risk for persistent pain after cesarean section. Long-term pain markedly affected women's wellbeing. This article is protected by copyright. All rights reserved.