The role of autoimmunity in women with type 1 diabetes and adverse pregnancy outcome: A missing link.

The incidence of pregnancy complications in women with type 1 Diabetes Mellitus (T1D) is greater than in healthy pregnant women. This has mostly been attributed to hyperglycemia. However, despite the implementation of stricter guidelines regarding glycemic control, pregnancy complications remain more common in women with T1D. This may suggest that other etiological factors are involved. We suggest that the immune response may play a role, since the immune response has to adapt during pregnancy in order to facilitate implantation, placental and fetal development, and aberrant immunological adaptations to pregnancy are involved in various pregnancy complications. Since T1D is an autoimmune disorder, the question rises whether the immune response of women with T1D is able to adapt properly during pregnancy. Here we review the current proof and views on the role of aberrant immunological adaptations in pregnancy complications and whether such aberrant adaptations could be involved in the pregnancy complications of T1D patients.

Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis.

OBJECTIVE: Hypertensive disorders affect 3-10% of pregnancies. Delayed delivery carries maternal risks, while early delivery increases fetal risk, so appropriate timing is important. The aim of this study was to compare immediate delivery with expectant management for prevention of adverse maternal and neonatal outcomes in women with hypertensive disease in pregnancy. METHODS: CENTRAL, PubMed, MEDLINE and ClinicalTrials.gov were searched for randomized controlled trials comparing immediate delivery to expectant management in women presenting with gestational hypertension or pre-eclampsia without severe features from 34 weeks of gestation. The primary neonatal outcome was respiratory distress syndrome (RDS) and the primary maternal outcome was a composite of HELLP syndrome and eclampsia. The PRISMA-IPD guideline was followed and a two-stage meta-analysis approach was used. Relative risks (RR) and numbers needed to treat or harm (NNT/NNH) with 95% CI were calculated to evaluate the effect of the intervention. RESULTS: Main outcomes were available for 1724 eligible women. Compared with expectant management, immediate delivery reduced the composite risk of HELLP syndrome and eclampsia in all women (0.8% vs 2.8%; RR, 0.33 (95% CI, 0.15-0.73); I2  = 0%; NNT, 51 (95% CI, 31.1-139.3)) as well as in the pre-eclampsia subgroup (1.1% vs 3.5%; RR, 0.39 (95% CI, 0.15-0.98); I2  = 0%). Immediate delivery increased RDS risk (3.4% vs 1.6%; RR, 1.94 (95% CI 1.05-3.6); I2  = 24%; NNH, 58 (95% CI, 31.1-363.1)), but depended upon gestational age. Immediate delivery in the 35th week of gestation increased RDS risk (5.1% vs 0.6%; RR, 5.5 (95% CI, 1.0-29.6); I2  = 0%), but immediate delivery in the 36th week did not (1.5% vs 0.4%; RR, 3.4 (95% CI, 0.4-30.3); I2 not applicable). CONCLUSION: In women with hypertension in pregnancy, immediate delivery reduces the risk of maternal complications, whilst the effect on the neonate depends on gestational age. Specifically, women with a-priori higher risk of progression to HELLP, such as those already presenting with pre-eclampsia instead of gestational hypertension, were shown to benefit from earlier delivery. © 2019 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.

Blood pressure patterns in women with gestational hypertension or mild preeclampsia at term.

OBJECTIVE: Gestational hypertension (GH) and mild preeclampsia (PE) represent the most common medical complications of pregnancy, with the majority of cases developing at or near term. There is little knowledge of the course of blood pressure over time in these women. We explored the pattern of systolic and diastolic blood pressure over time in women with GH or mild PE at term participating in the HYPITAT trial, and we attempted to identify clinical factors influencing these blood pressure patterns and the impact of severe hypertension on clinical management. STUDY DESIGN: We used data from the HYPITAT trial, that included women with a singleton pregnancy with a fetus in cephalic position between 36 and 41 weeks of gestation with the diagnosis of GH or mild PE. Blood pressure measurements were performed from randomization or admission until delivery or discharge from the hospital. We included the highest blood pressure of each day. We evaluated systolic and diastolic blood pressure change over time, as well as the influence of clinical characteristics and laboratory findings on the course of blood pressure. We used univariate and multivariate regression analysis with a backward stepwise algorithm for the selection of variables. The model with the best fit (lowest AIC) was selected as the final model. We also compared mode of delivery for women with and without severe hypertension. RESULTS: We studied 1076 women who had 4188 blood pressure measurements done. The systolic blood pressure showed a significant non-linear increase over time and for the diastolic blood pressure the pattern was also non-linear. In the multivariable model of systolic blood pressure change over time, nulliparity, ethnicity, systolic blood pressure (at baseline), BMI and LDH at randomization influenced the course of blood pressure. In the diastolic blood pressure model ALT and the baseline diastolic blood pressure had a significant influence. When we explored the association between blood pressure and mode of delivery, it appeared that development of severe hypertension was a risk factor for Caesarean section. CONCLUSION: The blood pressure in patients with GH or PE at term showed a non-linear increase with time, which was aggravated by clinical characteristics. Development of severe hypertension was a risk factor for Caesarean section, which may explain the elevated Caesarean section rates in the expectant monitoring group in the HYPITAT trial.

An economic analysis of immediate delivery and expectant monitoring in women with hypertensive disorders of pregnancy, between 34 and 37 weeks of gestation (HYPITAT-II).

OBJECTIVE: To assess the economic consequences of immediate delivery compared with expectant monitoring in women with preterm non-severe hypertensive disorders of pregnancy. DESIGN: A cost-effectiveness analysis alongside a randomised controlled trial (HYPITAT-II). SETTING: Obstetric departments of seven academic hospitals and 44 non-academic hospitals in the Netherlands. POPULATION: Women diagnosed with non-severe hypertensive disorders of pregnancy between 340/7 and 370/7  weeks of gestation, randomly allocated to either immediate delivery or expectant monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a healthcare perspective until final maternal and neonatal discharge. MAIN OUTCOME MEASURES: Health outcomes were expressed as the prevalence of respiratory distress syndrome, defined as the need for supplemental oxygen for >24 hours combined with radiographic findings typical for respiratory distress syndrome. Costs were estimated from a healthcare perspective until maternal and neonatal discharge. RESULTS: The average costs of immediate delivery (n = 352) were €10 245 versus €9563 for expectant monitoring (n = 351), with an average difference of €682 (95% confidence interval, 95% CI -€618 to €2126). This 7% difference predominantly originated from the neonatal admissions, which were €5672 in the immediate delivery arm and €3929 in the expectant monitoring arm. CONCLUSION: In women with mild hypertensive disorders between 340/7 and 370/7  weeks of gestation, immediate delivery is more costly than expectant monitoring as a result of differences in neonatal admissions. These findings support expectant monitoring, as the clinical outcomes of the trial demonstrated that expectant monitoring reduced respiratory distress syndrome for a slightly increased risk of maternal complications. TWEETABLE ABSTRACT: Expectant management in preterm hypertensive disorders is less costly compared with immediate delivery.

Risk stratification for healthcare planning in women with gestational diabetes mellitus.

BACKGROUND: To identify relevant factors predicting the need for insulin therapy in women with gestational diabetes mellitus (GDM) and secondly to determine a potential 'low- risk' diet-treated group who are likely to have good pregnancy outcomes. METHODS: A retrospective analysis between 2011-2014. Multivariable backward stepwise logistic regression was used to identify the predictors of the need for insulin therapy. To identify a 'low-risk' diet-treated group, the group was stratified according to pregnancy complications. Diet-treated women with indications for induction in secondary care were excluded. RESULTS: A total of 820 GDM women were included, 360 (44%) women required additional insulin therapy. The factors predicting the need for insulin therapy were: previous GDM, family history of diabetes, a previous infant weighing ≥ 4500 gram, Middle-East/North-African descent, multiparity, pre-gestational BMI ≥ 30 kg/m2, and an increased fasting glucose level ≥ 5.5 mmol/l (OR 6.03;CI 3.56-10.22) and two-hour glucose level ≥ 9.4 mmol/l after a 75-gram oral glucose tolerance test at GDM diagnosis. In total 125 (54%) women treated with diet only had pregnancy complications. Primiparity and higher weight gain during pregnancy were the best predictors for complications (predictive probability 0.586 and 0.603). CONCLUSION: In this GDM population we found various relevant factors predicting the need for insulin therapy. A fasting glucose level ≥ 5.5 mmol/l at GDM diagnosis was by far the strongest predictor. Women with GDM who had good glycaemic control on diet only with a higher parity and less weight gain had a lower risk for pregnancy complications.

Caesarean section rates and adverse neonatal outcomes after induction of labour versus expectant management in women with an unripe cervix: a secondary analysis of the HYPITAT and DIGITAT trials.

OBJECTIVE: To evaluate caesarean section and adverse neonatal outcome rates after induction of labour or expectant management in women with an unripe cervix at or near term. DESIGN: Secondary analysis of data from two randomised clinical trials. SETTING: Data were collected in two nationwide Dutch trials. POPULATION: Women with hypertensive disease (HYPITAT trial) or suspected fetal growth restriction (DIGITAT trial) and a Bishop score ≤6. METHODS: Comparison of outcomes after induction of labour and expectant management. MAIN OUTCOME MEASURES: Rates of caesarean section and adverse neonatal outcome, defined as 5-minute Apgar score ≤6 and/or arterial umbilical cord pH <7.05 and/or neonatal intensive care unit admission and/or seizures and/or perinatal death. RESULTS: Of 1172 included women with an unripe cervix, 572 had induction of labour and 600 had expectant management. We found no significant difference in the overall caesarean rate (difference -1.1%, 95% CI -5.4 to 3.2). Induction of labour did not increase caesarean rates in women with Bishop scores from 3 to 6 (difference -2.7%, 95% CI -7.6 to 2.2) or adverse neonatal outcome rates (difference -1.5%, 95% CI -4.3 to 1.3). However, there was a significant difference in the rates of arterial umbilical cord pH <7.05 favouring induction (difference -3.2%, 95% CI -5.6 to -0.9). The number needed to treat to prevent one case of umbilical arterial pH <7.05 was 32. CONCLUSIONS: We found no evidence that induction of labour increases the caesarean rate or compromises neonatal outcome as compared with expectant management. Concerns over increased risk of failed induction in women with a Bishop score from 3 to 6 seem unwarranted. TWEETABLE ABSTRACT: Induction of labour at low Bishop scores does not increase caesarean section rate or poor neonatal outcome.

Relationship between general movements in neonates who were growth restricted in utero and prenatal Doppler flow patterns.

OBJECTIVE: To investigate whether Doppler pulsatility indices (PIs) of the fetal circulation in cases of fetal growth restriction (FGR) are associated with the general movements (GMs) of the neonate after birth. METHODS: This was a prospective observational cohort study including pregnancies with FGR diagnosed between June 2012 and September 2014. A diagnosis of FGR was based on an abdominal circumference or estimated fetal weight < 10th percentile (in conjuction with abnormal Doppler) or declining fetal growth of at least 30 percentiles with respect to previous size measurements. Doppler parameters of the umbilical artery (UA), fetal middle cerebral artery (MCA) and ductus venosus (DV) were measured maximally 1 week prior to delivery. Cerebroplacental ratio (CPR) was calculated as MCA-PI divided by UA-PI. We assessed the quality of neonatal GMs 7 days after birth, around the due date if cases were born preterm, and at 3 months post-term. We performed a detailed analysis of the motor repertoire by calculating a motor optimality score (MOS). RESULTS: Forty-eight FGR cases were included with a median gestational age at delivery of 35 (range, 26-40) weeks. UA-PI, MCA-PI and CPR correlated strongly (ρ, -0.374 to 0.472; P < 0.01) with the MOS on day 7 after birth, but DV-PI did not. Doppler PI measurements did not correlate with MOS at 3 months post-term. CONCLUSION: Fetal arterial Doppler measurements are associated with the quality of neonatal GMs 1 week after birth, but this association is no longer evident at 3 months post-term. Brain sparing in particular is associated strongly with GMs of an abnormal quality. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Prediction of neonatal outcome in women with gestational hypertension or mild preeclampsia after 36 weeks of gestation.

BACKGROUND: There is little knowledge about neonatal complications in GH and PE and induction at term, we aim to assess whether they can be predicted from clinical data. METHODS: We used data of the HYPITAT trial and evaluated whether adverse neonatal outcome (Apgar score < 7, pH < 7.05, NICU admission) could be predicted from clinical data. Logistic regression, ROC analysis and calibration were used to identify predictors and evaluate the predictive capacity in an antepartum and intrapartum model. RESULTS: We included 1153 pregnancies, of whom 76 (6.6%) had adverse neonatal outcome. Parity (primipara OR 2.75), BMI (OR 1.06), proteinuria (dipstick +++ OR 2.5), uric acid (OR 1.4) and creatinine (OR 1.02) were independent antepartum predictors; In the intrapartum model, meconium stained amniotic fluid (OR 2.2), temperature (OR 1.8), duration of first stage of labour (OR 1.15), proteinuria (dipstick +++ OR 2.7), creatinine (OR 1.02) and uric acid (OR 1.5) were predictors of adverse neonatal outcome. Both models showed good discrimination (AUC 0.75 and 0.78), but calibration was limited (Hosmer-Lemeshow p = 0.41, and p = 0.20). CONCLUSIONS: In women with GH or PE at term, it is difficult to predict neonatal complications, possibly since they are rare in the term pregnancy. However, the identified individual predictors may guide physicians to anticipate requirements for neonatal care.

Impact of introduction of mid-trimester scan on pregnancy outcome of open spina bifida in The Netherlands.

OBJECTIVE: To examine the impact of introduction of the mid-trimester scan on pregnancy outcome in cases of open spina bifida in two regions of The Netherlands. METHODS: This was a retrospective cohort study of 190 cases of open spina bifida diagnosed pre- or postnatally, with an estimated date of delivery between 2003 and 2011. RESULTS: With implementation of the mid-trimester scan the percentage of cases of open spina bifida detected before the 24(th) week of pregnancy increased from 43% to 88%. The rise in prenatal detection rate was associated with a significant increase in the number of terminated pregnancies and a decrease in the rate of perinatal loss; the percentage of children born alive did not change significantly. In the subgroup that underwent a scan between 18 and 24 weeks of pregnancy, cranial signs were present in 94.4% of cases. CONCLUSION: Introduction of the mid-trimester scan has led to an increase in early identification of pregnancies complicated by open spina bifida. Pregnancies previously destined to end in perinatal loss are now terminated whilst pregnancies with a relatively good prognosis are frequently continued; the number of children with open spina bifida who are born alive has not changed significantly. Our study confirms that prenatal diagnosis is usually triggered by visualization of a lemon-shaped skull or a banana-shaped cerebellum.

Randomized controlled trials of maternal-fetal surgery: a challenge to clinical equipoise.

This article focuses on maternal-fetal surgery (MFS) and on the concept of clinical equipoise that is a widely accepted requirement for conducting randomized controlled trials (RCT). There are at least three reasons why equipoise is unsuitable for MFS. First, the concept is based on a misconception about the nature of clinical research and the status of research subjects. Second, given that it is not clear who the research subject/s in MFS is/are, if clinical equipoise is to be used as a criterion to test the ethical appropriateness of RCT, its meaning should be unambiguous. Third, because of the multidisciplinary character of MFS, it is not clear who should be in equipoise. As a result, we lack an adequate criterion for the ethical review of MFS protocols. In our account, which is based on Chervenak and McCullough's seminal work in the field of obstetric ethics, equipoise is abandoned. and RCT involving MFS can be ethically initiated when a multidisciplinary ethics review board (ERB), having an evidence-based assessment of the risks involved, is convinced that the value of answering the research hypothesis, for the sake of the health interests of future pregnant women carrying fetuses with certain congenital birth defects, justifies the actual risks research participants might suffer within a set limit of low/manageable.

[The need for uncertainty in clinical research. Equipoise]. / De noodzaak van onzekerheid in klinisch onderzoek. Equipoise.

When a randomized controlled trial (RCT) that has potentially therapeutic benefits for research subjects is conducted, the line between treatment and research is often difficult to draw. However, in order to protect the well-being and rights of prospective research subjects and to ensure that they are not subjected to harmful and pointless research, the distinction between normal care and scientific research must be thoroughly explained. There has to be clear-cut 'equipoise', i.e. uncertainty in physician, patient and investigator regarding the outcome of the study. Strong patient preference for the experimental arm of an RCT does not entail a right to have access to it, as by definition it represents an option of unproven safety or efficacy (equipoise). Only in a therapeutic context do patients have the right to receive the best available care and a right to discuss their treatment preferences with their physicians. A careful informed consent procedure that clarifies the differences between research and therapy, and that emphasizes the experimental nature of trial arms, should be in place prior to randomization.

Perceptions of women, nurses, midwives and doctors about the use of video during birth to improve quality of care: focus group discussions.

The use of video during birth for quality of care was discussed in focus groups with women, nurses, midwives and doctors. Qualitative analysis revealed three categories of importance. First, goals and benefits: improving quality of care, teaching, research and legal issues are important potential applications. Second, limitations: concerns for privacy, fear of feedback and use of video in case of adverse events. Third, rules and regulations: goals and scope of the use of video need to be clearly described, access to video needs to be secured, and time until destruction needs to be specified. Video capture of birth is considered useful and seems acceptable if specific conditions are met.

Posttraumatic stress disorder following preeclampsia and PPROM: a prospective study with 15 months follow-up.

OBJECTIVE: A prospective longitudinal evaluation of the prevalence of and risk factors for posttraumatic stress disorder (PTSD) in women with preeclampsia (PE) or preterm premature rupture of membranes (PPROM) compared to uncomplicated pregnancies. METHODS: Participating women completed PTSD and depression questionnaires during pregnancy, 6 weeks, and 15 months postpartum. Data regarding psychiatric history and indices of obstetric care were collected from patient charts. RESULTS: We included 57 PE, 53 PPROM, and 65 healthy pregnant women, of whom 137 also participated in the 15-month follow-up (PE 70%, PPROM 48%, and controls 95%; P < .001). At 6 weeks postpartum, the prevalence of PTSD, but not depression, following childbirth was significantly higher in patients than in controls (14% vs 3%; P = .023). A history of depression, depressive symptoms during pregnancy, and infant death were significantly associated with symptoms of postpartum PTSD. The maternal condition seems to be of less decisive value, as there was no difference between the prevalence of PTSD after PE and PPROM (11% vs 17%; P = .324). At 15 months postpartum, 11% of women with PE had PTSD, some of which did not have PTSD 6 weeks postpartum. The low response rate in the PPROM group at 15 months postpartum does not allow for definite conclusions. CONCLUSION: Pregnancies complicated by PE or PPROM are associated with PTSD in a substantial number of women. Especially women with proven vulnerability for psychological problems are at risk of developing PTSD postpartum, as are women whose children died in the perinatal period.

An economic analysis of induction of labour and expectant monitoring in women with gestational hypertension or pre-eclampsia at term (HYPITAT trial).

OBJECTIVE: To assess the economic consequences of labour induction compared with expectant monitoring in women with gestational hypertension or pre-eclampsia at term. DESIGN: An economic analysis alongside the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT). SETTING: Obstetric departments of six university and 32 teaching and district hospitals in the Netherlands. POPULATION: Women diagnosed with gestational hypertension or pre-eclampsia between 36(+0) and 41(+0) weeks of gestation, randomly allocated to either induction of labour or expectant monitoring. METHODS: A trial-based cost-effectiveness analysis was performed from a societal perspective during a 1-year time horizon. MAIN OUTCOME MEASURES: One-year costs were estimated and health outcomes were expressed as the prevalence of poor maternal outcome defined as either maternal complications or progression to severe disease. RESULTS: The average costs of induction of labour (n = 377) were €7077 versus €7908 for expectant monitoring (n = 379), with an average difference of -€831 (95% CI -€1561 to -€144). This 11% difference predominantly originated from the antepartum period: per woman costs were €1259 for induction versus €2700 for expectant monitoring. During delivery, more costs were generated following induction (€2190) compared with expectant monitoring (€1210). No substantial differences were found in the postpartum, follow-up and for non-medical costs. CONCLUSION: In women with gestational hypertension or mild pre-eclampsia at term, induction of labour is less costly than expectant monitoring because of differences in resource use in the antepartum period. As the trial already demonstrated that induction of labour results in less progression to severe disease without resulting in a higher caesarean section rate, both clinical and economic consequences are in favour of induction of labour in these women. TRIAL REGISTRATION: The trial has been registered in the clinical trial register as ISRCTN08132825.

Delayed intrauterine repair of an experimental spina bifida with a collagen biomatrix.

BACKGROUND/PURPOSE: The aim of the study was to evaluate whether a collagen biomatrix is useful for delayed intrauterine coverage of a surgically created spina bifida in a fetal lamb. METHODS: In 20 fetal lambs, surgery was performed at 72 or 79 days' gestation. In 15 lambs a spina bifida was created surgically. In 8 lambs it was covered with a collagen biomatrix 2 weeks later and in 7 lambs it was left uncovered. Five lambs served as sham operated controls. Neurological examination was performed at 1 week of age and afterwards the lambs were sacrificed for further histological evaluation. RESULTS: None of the 5 surviving lambs with the defect covered showed loss of spinal function and the architecture of the spinal cord was preserved in 4 of the 5 lambs. In the uncovered group, 1 of the 4 surviving lambs had loss of spinal function, 5 lambs were available for histological evaluation and 4 of them showed disturbance of the architecture of the spinal cord. CONCLUSIONS: Collagen biomatrices can be used for intrauterine coverage of an experimental spina bifida and can preserve the architecture of the spinal cord. Neurological outcome is not different between fetuses with their spinal cord covered and fetuses with uncovered cords.

Histological evaluation of acute covering of an experimental neural tube defect with biomatrices in fetal sheep.

OBJECTIVE: The aim of the study was to determine the histological effect on the neural tissue of in utero covering of an experimental neural tube defect in fetal lambs, with the use of two different biomatrices. MATERIALS AND METHODS: In 23 fetal sheep, surgery was performed at 79 days' gestation. In 19 of these, a neural tube defect was created, while 4 fetuses served as sham-operated controls. In 7 of the 19 operated fetuses the defect was left uncovered. In the remaining 12 animals the defect was covered either with a collagen biomatrix (4 animals), skin (3 animals), or small intestinal submucosa biomatrix (5 animals). The lambs were sacrificed at 1 week of age and histological examination was performed. RESULTS: All lambs with an uncovered neural tube defect showed histological damage of the spinal cord. In lambs in which the neural tube defect was covered, one half showed a normal architecture of the spinal cord while minor histological damage was present in the other half. Between the three groups in which the defect was covered, the histological outcome was comparable. CONCLUSIONS: Acute covering of an experimental neural tube defect in fetal lambs prevents severe histological damage to the spinal cord independent of the two biomatrices used in this study.

In utero repair of an experimental neural tube defect in a chronic sheep model using biomatrices.

OBJECTIVE: Persistent exposure of the unprotected spinal cord to amniotic fluid and the uterine wall can lead to progressive damage of neural tissue in case of a myelomeningocele (two-hit hypothesis). The aim of this study was to evaluate whether in utero repair of an experimental neural tube defect in a fetal lamb could protect neural tissue from secondary injury and save neurologic functions after birth. METHODS: In 19 fetal lambs, a neural tube defect was created at 79 days' gestation. In 12 lambs the defect was covered either with a novel, molecular defined collagen-based biocompatible and biodegradable matrix (UMC) or with a small intestinal submucosa (SIS) biomatrix (Cook) or by closing the skin over the defect. RESULTS: All lambs with the defect covered showed no or minor neurologic morbidity in contrast to the lambs with the defect uncovered in which major neurologic morbidity was seen. CONCLUSIONS: These results demonstrate that long-term exposure of the open spinal cord to the intrauterine environment can lead to damage of neural tissue and, consequently loss of neurologic functions and that coverage of the defect can lead to a better neurologic outcome. Furthermore, we could show that a UMC biomatrix and an SIS biomatrix are useful for in utero coverage of a surgically created neural tube defect in our model.

Different pharmacokinetics of tramadol in mothers treated for labour pain and in their neonates.

OBJECTIVE: The aim of the present study was to investigate the pharmacokinetic profile of tramadol hydrochloride in neonates, born from mothers who underwent analgesia with tramadol for the relief of labour pain. METHODS: Intramuscular tramadol (100--250 mg) was administered to 22 mothers giving birth who requested pain relief. At the time of birth (1.5--6.0 h after last tramadol dose), maternal and umbilical blood samples were taken. Another venous blood sample was drawn from each neonate, and at the same time from its mother, at 1, 2, 3, 6 or 12 h post-partum, providing the data for a population pharmacokinetic evaluation of tramadol and its metabolite M1. Routine APGAR scores and a standard neurological and adaptive capacity test were considered for evaluation of the effect of tramadol on the neonates. RESULTS: Serum tramadol concentrations at the time of birth (t(0)) were 243+/-102 ng/ml (mean+/-SD, umbilical vein), 258+/-103 ng/ml (umbilical artery) and 250+/-113 ng/ml (maternal vein). Serum M1 concentrations were 52+/-27 ng/ml (umbilical vein), 47+/-24 ng/ml (umbilical artery) and 56+/-21 ng/ml (maternal vein). The two-compartment type elimination profiles during the first 12 h post-partum for neonates (and mothers, respectively) were characterised by terminal t(1/2) (tramadol)=7.0 (7.2) h and t(1/2) (metabolite M1)=85.0 (5.5) h. CONCLUSION: The intramuscular application of tramadol in birth-giving mothers almost freely reaches the neonate, confirming a high degree of placental permeability. The neonates already possess the complete hepatic capacity for the metabolism of tramadol into its active metabolite. However, the renal elimination of the active tramadol metabolite M1 is delayed, in line with the slow maturation process of renal function in neonates. Despite this difference in pharmacokinetics between neonates and adults, the intramuscular application of tramadol at the recommended dosage range during delivery appears to effective in the relief of labour pain.