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To investigate the effects of the antenatal administration of betamethasone on fetal Doppler and short term fetal heart rate variation (CTG-STV) in early growth restricted (FGR) fetuses. Post hoc analysis of data derived from the TRUFFLE study, a prospective, multicenter, randomized management trial of severe early onset FGR. Repeat Doppler and CTG-STV measurements between the last recording within 48 hours before the first dose of betamethasone (baseline value) and for 10 days after were evaluated. Multilevel analysis was performed to analyze the longitudinal course of the umbilico-cerebral ratio (UC ratio), the ductus venosus pulsatility index (DVPIV) and CTG-STV. We included 115 fetuses. A significant increase from baseline in CTG-STV was found on day + 1 (p = 0.019) but no difference thereafter. The DVPIV was not significantly different from baseline in any of the 10 days following the first dose of betamethasone (p = 0.167). Multilevel analysis revealed that, over 10 days, the time elapsed from antenatal administration of betamethasone was significantly associated with a decrease in CTG-STV (p = 0.045) and an increase in the DVPIV (p = 0.001) and UC ratio (p 0.001). Although steroid administration in early FGR has a minimal effect on increasing CTG-STV one day afterwards, the effects on Doppler parameters were extremely slight with regression coefficients of small magnitude suggesting no clinical significance, and were most likely related to the deterioration with time in FGR. Hence, arterial and venous Doppler assessment of fetal health remains informative following antenatal steroid administration to accelerate fetal lung maturation.ZIEL: Untersuchung des Effekts der antenatalen Gabe von Betamethason auf den fetalen Doppler und die Kurzzeitvariation der fetalen Herzfrequenz (CTG-STV) bei Föten mit früher Wachstumsrestriktion (FGR). Post-hoc-Analyse von Daten der TRUFFLE-Studie, einer prospektiven, multizentrischen, randomisierten Managementstudie bei schwerer, früh einsetzender FGR. Wiederholte Doppler- und CTG-STV-Messungen zwischen der letzten Aufnahme innerhalb von 48 Stunden vor der ersten Betamethason-Dosis (Ausgangswert) und über 10 Tage wurden bewertet. Eine mehrstufige Analyse erfolgte, um den longitudinalen Verlauf der umbilikal-zerebralen Ratio (UC-Ratio), des Pulsatilitätsindex des Ductus venosus (DVPIV) und der CTG-STV zu analysieren. Wir haben 115 Föten eingeschlossen. Ein signifikanter Anstieg der CTG-STV gegenüber dem Ausgangswert wurde am Tag + 1 (p = 0,019) ermittelt, danach gab es keinen Unterschied. Der DVPIV unterschied sich an keinem der 10 Tage nach erster Betamethason-Dosis signifikant vom Ausgangswert (p = 0,167). Eine mehrstufige Analyse ergab, dass die verstrichene Zeit nach der antenatalen Betamethason-Gabe über 10 Tage hinweg signifikant mit der Abnahme der CTG-STV (p = 0,045) und der Zunahme des DVPIV (p = 0,001) und der UC-Ratio (p 0,001) assoziiert war. Obwohl die Steroidverabreichung bei früher FGR eine kleine Auswirkung auf den Anstieg der CTG-STV 1 Tag darauf hatte, waren die Effekte auf die Doppler-Parameter äußerst gering mit Regressionskoeffizienten von geringer Höhe, die nicht auf klinische Signifikanz schließen lassen. Sie stehen höchstwahrscheinlich in Zusammenhang mit der Verschlechterung bei FGR im Laufe der Zeit. Daher bleibt die Beurteilung der arteriellen und venösen Doppler bezüglich des Gesundheitszustandes des Fötus aussagekräftig, nachdem diesem zur Beschleunigung der fetalen Lungenreifung antenatal Steroide verabreicht wurden.

OBJECTIVE: Selective fetal growth restriction (sFGR) occurs in monochorionic twin pregnancies when unequal placental sharing leads to restriction in the growth of just one twin. Management options include laser separation of the fetal circulations, selective reduction or expectant management, but what constitutes the best treatment is not yet known. New trials in this area are urgently needed but, in this rare and complex group, maximizing the relevance and utility of clinical research design and outputs is paramount. A core outcome set ensures standardized outcome collection and reporting in future research. The objective of this study was to develop a core outcome set for studies evaluating treatments for sFGR in monochorionic twins. METHODS: An international steering group of clinicians, researchers and patients with experience of sFGR was established to oversee the process of development of a core outcome set for studies investigating the management of sFGR. Outcomes reported in the literature were identified through a systematic review and informed the design of a three-round Delphi survey. Clinicians, researchers, and patients and family representatives participated in the survey. Outcomes were scored on a Likert scale from 1 (limited importance for making a decision) to 9 (critical for making a decision). Consensus was defined a priori as a Likert score of ≥ 8 in the third round of the Delphi survey. Participants were then invited to take part in an international meeting of stakeholders in which the modified nominal group technique was used to consider the consensus outcomes and agree on a final core outcome set. RESULTS: Ninety-six outcomes were identified from 39 studies in the systematic review. One hundred and three participants from 23 countries completed the first round of the Delphi survey, of whom 88 completed all three rounds. Twenty-nine outcomes met the a priori criteria for consensus and, along with six additional outcomes, were prioritized in a consensus development meeting, using the modified nominal group technique. Twenty-five stakeholders participated in this meeting, including researchers (n = 3), fetal medicine specialists (n = 3), obstetricians (n = 2), neonatologists (n = 3), midwives (n = 4), parents and family members (n = 6), patient group representatives (n = 3), and a sonographer. Eleven core outcomes were agreed upon. These were live birth, gestational age at birth, birth weight, intertwin birth-weight discordance, death of surviving twin after death of cotwin, loss during pregnancy or before final hospital discharge, parental stress, procedure-related adverse maternal outcome, length of neonatal stay in hospital, neurological abnormality on postnatal imaging and childhood disability. CONCLUSIONS: This core outcome set for studies investigating the management of sFGR represents the consensus of a large and diverse group of international collaborators. Use of these outcomes in future trials should help to increase the clinical relevance of research on this condition. Consensus agreement on core outcome definitions and measures is now required. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. ispartof: ULTRASOUND IN OBSTETRICS & GYNECOLOGY vol:55 issue:5 pages:652-660 ispartof: location:England status: published

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)—96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13—were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

PurposeNoninvasive prenatal screening (NIPS) using cell-free DNA in maternal blood is highly sensitive for detecting fetal trisomies 21, 18, and 13. Using a genome-wide approach, other chromosome anomalies can also be detected. We report on the origin, frequency, and clinical significance of these other chromosome aberrations found in pregnancies at risk for trisomy 21, 18, or 13.MethodsWhole-genome shallow massively parallel sequencing was used and all autosomes were analyzed.ResultsIn 78 of 2,527 cases (3.1%) NIPS was indicative of trisomy 21, 18, or 13, and in 41 (1.6%) of other chromosome aberrations. The latter were of fetal (n = 10), placental (n = 22), maternal (n = 1) or unknown (n = 7). One case lacked cytogenetic follow-up. Nine of the 10 fetal cases were associated with an abnormal phenotype. Thirteen of the 22 (59%) placental aberrations were associated with fetal congenital anomalies and/or poor fetal growth (

Background and Objectives: In Caucasians, fetal/neonatal alloimmune thrombocytopenia (FNAIT) is most commonly due to maternal HPA-1a antibodies. HPA-1a typing followed by screening for anti-HPA-1a antibodies in HPA-1bb women may identify first pregnancies at risk. Our goal was to review results from previous published studies to examine whether the maternal antibody level to HPA-1a could be used to identify high-risk pregnancies. Materials and Methods: The studies included were categorized by recruitment strategies: screening of unselected pregnancies or samples analyzed from known or suspected FNAIT patients. Results: Three prospective studies reported results from screening programmes, and 10 retrospective studies focused on suspected cases of FNAIT. In 8 studies samples for antibody measurement, performed by the monoclonal antibody immobilization of platelet antigen (MAIPA) assay, and samples for determining fetal/neonatal platelet count were collected simultaneously. In these 8 studies, the maternal antibody level correlated with the risk of severe thrombocytopenia. The prospective studies reported high negative predictive values (88–95%), which would allow for the use of maternal anti-HPA-1a antibody level as a predictive tool in a screening setting, in order to identify cases at low risk for FNAIT. However, due to low positive predictive values reported in prospective as well as retrospective studies (54–97%), the maternal antibody level is less suited for the final diagnosis and for guiding antenatal treatment. Conclusion: HPA-1a antibody level has the potential to predict the severity of FNAIT. (Less)

Objectives: To explore whether, in early fetal growth restriction (FGR), the longitudinal pattern of fetal heart rate (FHR) short-term variation (STV) can be used to identify imminent fetal distress and whether abnormalities of FHR recordings are associated with 2-year infant outcome. Methods: The original TRUFFLE study assessed whether, in early FGR, delivery based on ductus venosus (DV) Doppler pulsatility index (PI), in combination with safety-net criteria of very low STV on cardiotocography (CTG) and/or recurrent FHR decelerations, could improve 2-year infant survival without neurological impairment in comparison with delivery based on CTG monitoring only. This was a secondary analysis of women who delivered before 32 weeks and had consecutive STV data recorded > 3 days before delivery and known infant outcome at 2 years of age. Women who received corticosteroids within 3 days of delivery were excluded. Individual regression line algorithms of all STV values, except the last one before delivery, were calculated. Life tables and Cox regression analysis were used to calculate the daily risk for low STV or very low STV and/or FHR decelerations (below DV group safety-net criteria) and to assess which parameters were associated with this risk. Furthermore, it was assessed whether STV pattern, last STV value or recurrent FHR decelerations were associated with 2-year infant outcome. Results: One hundred and forty-nine women from the original TRUFFLE study met the inclusion criteria. Using the individual STV regression lines, prediction of a last STV below the cut-off used by the CTG monitoring group had sensitivity of 42% and specificity of 91%. For each day after study inclusion, the median risk for low STV (CTG group cut-off) was 4% (interquartile range (IQR), 2-7%) and for very low STV and/or recurrent FHR decelerations (below DV group safety-net criteria) was 5% (IQR, 4-7%). Measures of STV pattern, fetal Doppler (arterial or venous), birth-weight multiples of the median and gestational age did not usefully improve daily risk prediction. There was no association of STV regression coefficients, a low last STV and/or recurrent FHR decelerations with short- or long-term infant outcomes. Conclusion: The TRUFFLE study showed that a strategy of DV monitoring with safety-net criteria of very low STV and/or recurrent FHR decelerations for delivery indication could increase 2-year infant survival without neurological impairment. This post-hoc analysis demonstrates that, in early FGR, the daily risk of abnormal CTG, as defined by the DV group safety-net criteria, is 5%, and that prediction is not possible. This supports the rationale for CTG monitoring more often than daily in these high-risk fetuses. Low STV and/or recurrent FHR decelerations were not associated with adverse infant outcome and it appears safe to delay intervention until such abnormalities occur, as long as DV-PI is within normal range. Copyright (C) 2016 ISUOG. Published by John Wiley & Sons Ltd.

In the TRUFFLE (Trial of Randomized Umbilical and Fetal Flow in Europe) study on the outcome of early fetal growth restriction, women were allocated to one of three groups of indication for delivery according to the following monitoring strategies: (1) reduced fetal heart rate (FHR) short-term variation (STV) on cardiotocography (CTG); (2) early changes in fetal ductus venosus (DV) waveform (DV-p95); and (3) late changes in fetal DV waveform (DV-no-A). However, many infants per monitoring protocol were delivered because of safety-net criteria, for maternal or other fetal indications, or after 32 weeks of gestation when the protocol was no longer applied. The objective of the present posthoc subanalysis was to investigate the indications for delivery in relation to 2-year outcome in infants delivered before 32 weeks to further refine management proposals.We included all 310 cases of the TRUFFLE study with known outcome at 2 years' corrected age and seven fetal deaths, excluding seven cases with inevitable perinatal death. Data were analyzed according to the allocated fetal monitoring strategy in combination with the indication for delivery.Overall, only 32% of liveborn infants were delivered according to the specified monitoring parameter for indication for delivery; 38% were delivered because of safety-net criteria, 15% for other fetal reasons and 15% for maternal reasons. In the CTG-STV group, 51% of infants were delivered because of reduced STV. In the DV-p95 group, 34% of infants were delivered because of abnormal DV and, in the DV-no-A group, only 10% of infants were delivered accordingly. The majority of infants in the DV groups were delivered for the safety-net criterion of spontaneous decelerations in FHR. Two-year intact survival was highest in the DV groups combined compared with the CTG-STV group (P = 0.05 for live births only, P = 0.21 including fetal death), with no difference between DV groups. A poorer outcome in the CTG-STV group was restricted to infants delivered because of FHR decelerations in the safety-net subgroup. Infants delivered because of maternal reasons had the highest birth weight and a non-significantly higher intact survival.In this subanalysis of infants delivered before 32 weeks, the majority were delivered for reasons other than the allocated monitoring strategy indication. Since, in the DV group, CTG-STV criteria were used as a safety net but in the CTG-STV group, no DV safety-net criteria were applied, we speculate that the slightly poorer outcome in the CTG-STV group might be explained by the absence of DV data. The optimal timing of delivery of fetuses with early intrauterine growth restriction may therefore be best determined by monitoring them longitudinally, with both DV and CTG monitoring. Copyright © 2016 ISUOG. Published by John WileySons Ltd.

Objective To evaluate preferences and decision‐making among high‐risk pregnant women offered a choice between Non‐Invasive Prenatal Testing (NIPT), invasive testing or no further testing. Methods Nationwide implementation study (TRIDENT) offering NIPT as contingent screening test for women at increased risk for fetal aneuploidy based on first‐trimester combined testing (>1:200) or medical history. A questionnaire was completed after counseling assessing knowledge, attitudes and participation following the Multidimensional Measure of Informed Choice. Results A total of 1091/1253 (87%) women completed the questionnaire. Of these, 1053 (96.5%) underwent NIPT, 37 (3.4%) invasive testing and 1 (0.1%) declined testing. 91.7% preferred NIPT because of test safety. Overall, 77.9% made an informed choice, 89.8% had sufficient knowledge and 90.5% had positive attitudes towards NIPT. Women with intermediate (odds ratio (OR) = 3.51[1.70–7.22], p, What's already known about this topic? NIPT is offered as alternative to invasive testing to screen pregnant women at high risk for fetal aneuploidy.Although NIPT has many advantages, concerns have been raised about the consequences for informed decision‐making. What does this study adds? Implementation of NIPT in a national healthcare‐funded prenatal screening program, accompanied by pre‐test counseling, results in most women having sufficient knowledge and making an informed choiceCompared to women choosing invasive testing, women undergoing NIPT have less intention to terminate the pregnancy for Down syndrome.

Background Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, which may lead to intracranial haemorrhage (ICH), with neurological damage as a consequence. In the absence of screening, FNAIT is only diagnosed after bleeding symptoms, with preventive options limited to a next pregnancy. Objectives To estimate the population incidence of FNAIT and its consequences to prepare for study design of a screening programme. Search strategy An electronic literature search using MEDLINE, EMBASE and Cochrane database, and references of retrieved articles. No language restrictions were applied. Selection criteria Prospective studies on screening for human platelet antigen 1a (HPA-1a) alloimmunisation in low-risk pregnant women. Data collection and analysis Two reviewers independently assessed studies for inclusion and extracted data. Main outcome data were prevalence of HPA-1a negativity, HPA-1a immunisation, platelet count at birth and perinatal ICH. We aimed to compare outcome with and without intervention. Main results HPA-1a alloimmunisation occurred in 294/3028 (9.7%) pregnancies at risk. Severe FNAIT occurred in 71/227 (31%) immunised pregnancies, with perinatal ICH in 7/71 (10%). True natural history data were not found because interventions were performed in most screen-positive women. Authors' conclusions Screening for HPA-1a alloimmunisation detects about two cases in 1000 pregnancies. The calculated risk for perinatal ICH of 10% in pregnancies with severe FNAIT is an underestimation because studies without interventions were lacking. Screening of all pregnancies together with effective antenatal treatment such as intravenous immunoglobulin may reduce the mortality and morbidity associated with FNAIT.

Objective To assess the impact of rapid aneuploidy detection (RAD) combined with fetal karyotyping versus karyotyping only on maternal anxiety and health-related quality of life. Methods Women choosing to undergo amniocentesis were selected into group 1, i.e. receiving a karyotype result only (n = 132) or to group 2, i.e. receiving both the result of RAD and karyotyping (n = 181). Results There were no systematic differences in time of RAD combined with karyotyping versus karyotyping only in terms of anxiety (P = 0.91), generic physical health (P = 0.76, P = 0.46), generic mental health (P = 0.52, P = 0.72), personal perceived control (P = 0.91) and stress (P = 0.13). RAD combined with karyotyping reduced anxiety and stress two weeks earlier compared to karyotyping only. Conclusion RAD as add-on to karyotyping reduces anxiety and stress in the short term but it does not influence overall anxiety, stress, personal perceived control, and generic mental and physical health when compared to a karyotype-only strategy. Copyright (C) 2010 John Wiley & Sons, Ltd.

Objective To assess the reasons and perceptions of women who are offered a choice between karyotyping and standalone rapid aneuploidy detection (RAD) and to compare the impact of both tests on anxiety and health-related quality of life Methods In this prospective comparative study, women undergoing amniocentesis on behalf of their age or for an increased Down syndrome risk were offered a choice between karyotyping (group 1, n = 68) and standalone RAD (group 2, n = 61) Follow-up was 9 weeks post amniocentesis Results The most commonly cited reason for choosing karyotyping was obtaining as much information as possible, while for choosing standalone RAD, it was the short waiting time Prenatal screening (OR 7 09). no knowledge of karyotyping (OR 4 2). and an intermediate perceived risk for chromosomal abnormalities (OR 3 6) were associated with choosing standalone RAD There were no systematic differences in time of karyotyping and standalone RAD in terms of anxiety (P = 0 11). generic physical and mental health (P = 0 94, 0.52, P = 0 66, 0 07). personal perceived control (PPC; P = 0 69). and stress (P = 0 66) Conclusion Offering a choice between karyotyping and standalone RAD does not influence anxiety. stress. PPC. or generic health. Individual choice in prenatal diagnosis meets individual needs and thereby could reduce anxiety and stress Copyright (C) 2010 John Wiley & Sons. Ltd

OBJECTIVE: To determine the incidence and risk factors for neurodevelopmental impairment (NDI) in children with hemolytic disease of the fetus/newborn treated with intrauterine transfusion (IUT). STUDY DESIGN: Neurodevelopmental outcome in children at least 2 years of age was assessed using standardized tests, including the Bayley Scales of Infant Development, the Wechsler Preschool and Primary Scale of Intelligence, and the Wechsler Intelligence Scale for Children, according to the children’s age. Primary outcome was the incidence of neurodevelopmental impairment defined as at least one of the following: cerebral palsy, severe developmental delay, bilateral deafness, and/or blindness. RESULTS: A total of 291 children were evaluated at a median age of 8.2 years (range, 2–17 years). Cerebral palsy was detected in 6 (2.1%) children, severe developmental delay in 9 (3.1%) children, and bilateral deafness in 3 (1.0%) children. The overall incidence of neurodevelopmental impairment was 4.8% (14/291). In a multivariate regression analysis including only preoperative risk factors, severe hydrops was independently associated with neurodevelopmental impairment (odds ratio, 11.2; 95% confidence interval, 1.7–92.7). CONCLUSION: Incidence of neurodevelopmental impairment in children treated with intrauterine transfusion for fetal alloimmune anemia is low (4.8%). Prevention of fetal hydrops, the strongest preoperative predictor for impaired neurodevelopment, by timely detection, referral and treatment may improve long-term outcome.

BACKGROUND: Reduced fetal middle cerebral artery Doppler impedance is associated with hypoxemia in fetal growth restriction. It remains unclear as to whether this finding could be useful in timing delivery, especially in the third trimester. In this regard there is a paucity of evidence from prospective studies.OBJECTIVES: The aim of this study was to determine whether there is an association between middle cerebral artery Doppler impedance and its ratio with the umbilical artery in relation to neonatal and 2 year infant outcome in early fetal growth restriction (26(+0) -31(+6) weeks of gestation). Additionally we sought to explore which ratio is more informative for clinical use.STUDY DESIGN: This is a secondary analysis from the Trial of Randomized Umbilical and Fetal Flow in Europe, a prospective, multicenter, randomized management study on different antenatal monitoring strategies (ductus venosus Doppler changes and computerized cardiotocography short-term variation) in fetal growth restriction diagnosed between 26(+0) and 31(+6) weeks. We analyzed women with middle cerebral artery Doppler measurement at study entry and within 1 week before delivery and with complete postnatal follow-up (374 of 503). The primary outcome was survival without neurodevelopmental impairment at 2 years corrected for prematurity. Neonatal outcome was defined as survival until first discharge home without severe neonatal morbidity. Z-scores were calculated for middle cerebral artery pulsatility index and both umbilicocerebral and cerebroplacental ratios. Odds ratios of Doppler parameter Z-scores for neonatal and 2 year infant outcome were calculated by multivariable logistic regression analysis adjusted for gestational age and birthweight p50 ratio.RESULTS: Higher middle cerebral artery pulsatility index at inclusion but not within 1 week before delivery was associated with neonatal survival without severe morbidity (odds ratio, 1.24; 95% confidence interval, 1.02-1.52). Middle cerebral artery pulsatility index Z-score and umbilicocerebral ratio Z-score at inclusion were associated with 2 year survival with normal neurodevelopmental outcome (odds ratio, 1.33; 95% confidence interval, 1.03-1.72, and odds ratio, 0.88; 95% confidence interval, 0.78-0.99, respectively) as were gestation at delivery and birthweight p50 ratio (odds ratio, 1.41; 95% confidence interval, 1.20-1.66, and odds ratio, 1.86; 95% confidence interval, 1.33-2.60, respectively). When comparing cerebroplacental ratio against umbilicocerebral ratio, the incremental range of the cerebroplacental ratio tended toward zero, whereas the umbilicocerebral ratio tended toward infinity as the values became more abnormal.CONCLUSION: In a monitoring protocol based on ductus venosus and cardiotocography in early fetal growth restriction (26(+0) -31(+6) weeks of gestation), the impact of middle cerebral artery Doppler and its ratios on outcome is modest and less marked than birthweight and delivery gestation. It is unlikely that middle cerebral artery Doppler and its ratios are informative in optimizing the timing of delivery in fetal growth restriction before 32 weeks of gestation. The umbilicocerebral ratio allows for a better differentiation in the abnormal range than the cerebroplacental ratio.

Recent studies have suggested that the fetus is capable of exhibiting a stress response to intrauterine needling, resulting in alterations in fetal stress hormone levels. Intrauterine transfusions are performed by inserting a needle either in the umbilical cord root at the placental surface (PCI), or in the intrahepatic portion of the umbilical vein (IHV). Aim of our study was to test the hypothesis that fetal hormonal changes during intrauterine transfusion are more pronounced when the needle is inserted in the fetal abdomen. Furthermore we aimed to evaluate the effect of fetal analgesia with remifentanil on the fetal stress hormone changes. Exploring the hemodynamic changes following a noxious stimulus, we saw no differences in transfusions through the IHV or the PCI. Remifentanil did not influence the stress hormone changes. We concluded that the stress hormone changes are independent of both site of transfusion and the use of remifentanil. Our results do not confirm nor deny that the fetus is capable to react to a potential painful stimulus, or to show signs of stress or even pain. However, previous research has suggested that presumably painful fetal conditions can lead to alterations in stress reactions after birth. This phenomenon is called ‘fetal programming’. Fetal programming could possibly lead to life-long changes in stress responses and even to increased susceptibility for certain diseases. With the current understanding of fetal pain and fetal analgesia we would advocate the following: 1. Fetal analgesia for invasive procedures should be provided from at least 20 weeks gestation onwards 2. All invasive fetal procedures warrant fetal analgesia, but in procedures involving more than just a single puncture with a thin needle it is obligatory. 3. Analgesics should be given intravenously to the mother. The drug of choice should be ultra-short working (like remifentanil) therefore minimising possible undesirable side-effects to both fetus and mother.