Fosterfysiologi Obligatorisk obstetrikk-kurs Oslo Januar 2019

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1 Fosterfysiologi Obligatorisk obstetrikk-kurs Oslo Januar 2019 Torvid Kiserud Overskrifter i forelesningen 1. kasus som introduserer klinisk fysiologi 2. Fostersirkulasjonens tilpasning til intrauterine forhold 3. Hvordan placenta, sirkulasjon og fosterlever organiserer fostervekst 4. Akutt hypoksi akutt tilpasning 5. Vedvarende hypoksi kronisk tilpasning 6. Akutt hypovolemi akutt tilpasning 7. Fosteralderens betydning for responsene To artikler skal være lastet opp sammen med denne forelesningsoversikten, dvs. en oversiktsartikkel om fostersirkulasjon supplert med en artikkel om fosterets hjerteminuttvolum og fordelingen til placenta hos normale og vekst-hemmede foster. Kan du dette har du en god oversikt. Noen momenter i undervisningen 1. Kasuistisk introduksjon. Du kan her notere deg momenter fra demonstrasjonen: 2. Fostersirkulasjonens tilpasning til intrauterine forhold. Figurene blir sentrale i forståelsen: Via sinistra: Oksygen-rikt blod fra placenta føres gjennom umbilikalvenen (UV), shuntes gjennom ductus venosus (DV) og direkte inn i foramen ovale (FO) via vena cava inferiors

2 (IVC) innmunning i forkammeret. Dermed kommer rikt oksygenert blod til venstre forkammer (LA), videre til venstre ventrikkel (LV) som fører blod via aorta (AO) ascendens til koronararteriene (myokard) og carotidene (hjerne-forsørgning). Via dextra: sørger for at Lavt oksygenert blod fra IVC og vena cava superior (SVC) føres til høyre forkammer (RA) og høyre ventrikkel (RV) videre til pulmonaltrunkus (AP). Herfra shuntes blodet gjennom ductus arteriosus (DA) hvor de ti banene forenes i aorta descences (AO). De tre shuntene (ductus venosus, foramen ovale og ductus arteriosus) er vesentlig for normal fosterutvikling, men også viktige kompensasjonsmekanismer f.eks. ved hypoksi og hypovolemi. Sagittal insonering med ultralyd viser umbilikalvenen (UVV) fortsette inn i ductus venosus i nesten vertikal retning inn i VCI i det denne munner inn i hjertet med naturlig retning mot venstre atrium (LA) på venstre side av atrie septum (AS). Fargeskissen angir hvordan oksygenrikt blod fra ductus venosus og oksygenfattig blod fra abdominale vena cava inferior kan løpe side om side med minimalt med blanding. 3. Placenta skaffer ressursene, sirkulasjonen transporterer og fosterleveren (metabolsk hjerne) informeres og produserer vekstfaktorer for differensiert organvekst i fosteret,

3 4. Effekt av akutt hypoksi Akutt hypoksi utløser en prioritert omfordeling av blodforsyningen hos fosteret. Responsen er best utviklet i siste trimester (figuren kopiert fra Arne Jensen 1991) 5. Effekt av persisterende hypoksi (Etter A Bocking) Blir hypoksiene vedvarende (mange timer, døgn) blir metabolismen redusert, spesielt i de lavest prioriterte organene, her vist ved signifikant reduksjon i DNA syntese fosterlungene, muskulatur og thymus. Dette reduserer oksygen-behovet og reduserer anaerob forbrenning.

4 6. Effekt av føtal hypovolemi (Etter PL Toubas 1981) 15% blødning hos fosteret gir katastrofale sirkulasjonsforhold der selv viktige organer (binyrer, hjerte, hjerne og placenta) har minimal eller ingen kompensatorisk økning andelen av de reduserte ressursene. 7. Fosteralders betydning Det er opplagt at sirkulasjon og dens reguleringsmekanismer er i endring fra uke til uke tilpasset de forskjellige stadienes størrelse og metabolske behov og evner. Det er godt illustrert i nedenstående resultater av adrenalin-målinger gjort under hypoksi ved forskjellige

5 alderstrinn (Arne Jensen 1992). Forsøkene er opprinnelig gjort på lammefoster, men her er fosteralderen forsøkt omregnet til tilsvarende svangerskapsuker (u) for humane foster.

6 Seminars in Fetal & Neonatal Medicine (2005) 10, 493e503 Physiology of the fetal circulation Torvid Kiserud a,b, * a Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Bergen, Bergen, Norway b Fetal Medicine Unit, Department of Obstetrics and Gynaecology, Haukeland University Hospital, Bergen, Norway KEYWORDS Circulation; Blood flow; Fetus; Placenta; Ductus venosus; Ductus arteriosus; Foramen ovale; Liver Summary Our understanding of fetal circulatory physiology is based on experimental animal data, and this continues to be an important source of new insight into developmental mechanisms. A growing number of human studies have investigated the human physiology, with results that are similar but not identical to those from animal studies. It is time to appreciate these differences and base more of our clinical approach on human physiology. Accordingly, the present review focuses on distributional patterns and adaptational mechanisms that were mainly discovered by human studies. These include cardiac output, pulmonary and placental circulation, fetal brain and liver, venous return to the heart, and the fetal shunts (ductus venosus, foramen ovale and ductus arteriosus). Placental compromise induces a set of adaptational and compensational mechanisms reflecting the plasticity of the developing circulation, with both short- and long-term implications. Some of these aspects have become part of the clinical physiology of today with consequences for surveillance and treatment. ª 2005 Elsevier Ltd. All rights reserved. Introduction Many of the mechanisms described in animal experiments also occur in the human fetus, but with differences. The reasons for variation are many, e.g. a sheep fetus has a different anatomy compared with a human fetus, with a longer intrathoracic inferior vena cava (IVC), a smaller * Department of Obstetrics and Gynaecology, Haukeland University Hospital, N-5021 Bergen, Norway. Tel.: C ; fax: C address: torvid.kiserud@kk.uib.no brain, the fetal liver is positioned differently, two umbilical veins, a higher temperature, a lower Haemoglobin (Hgb), a higher growth rate and a shorter pregnancy. Ultrasound in obstetrics has been used increasingly to provide physiological data from human fetuses, and this is reflected in the present review. Blood volume The blood volume in the human fetus is estimated to be 10e12% of the body weight, compared with 7e8% X/$ - see front matter ª 2005 Elsevier Ltd. All rights reserved. doi: /j.siny

7 494 T. Kiserud in adults. 1 The main reason for this difference is the large pool of blood contained within the placenta; a volume that reduces as gestation progresses. The calculated blood volume of 90e105 ml/kg in fetuses undergoing blood transfusion during the second half of pregnancy 2 is probably an underestimate. Other studies have indicated a volume of 110e115 ml/kg, which is more in line with experimental sheep studies. 3 The estimated volume of 80 ml/kg contained within the fetal body is marginally more than that in adults. Compared with adults, the fetus is capable of much faster regulation and restoration of the blood volume due to high diffusion rates between fetal compartments. 1 Arterial and venous blood pressure The mean arterial pressure in human fetuses was measured to be 15 mmhg during cordocentesis at gestational weeks 19e21. 4 Intra-uterine recording of the intraventricular pressure in the human fetus suggests that the systemic systolic pressure increases from 15e20 mmhg at 16 weeks to 30e 40 mmhg at 28 weeks. 5 There was no obvious difference between the left and right ventricles. This increase was also seen for diastolic pressure, which was %5 mmhg at 16e18 weeks and 5e 15 mmhg at 19e26 weeks. Umbilical venous pressure, recorded during cordocentesis and corrected for amniotic pressure, increased from 4.5 mmhg at 18 weeks to 6 mmhg at term. 6 Cardiac performance Structural details of the heart are organized during the embryonic period but are dependent on the physical environment, including blood flow, in order to develop normally. The myocardium grows by cell division until birth, and growth beyond birth is due to cell enlargement. The density of myofibrils increases particularly in early pregnancy and the contractility continues to improve during the second half of pregnancy. 7 The two ventricles perform differently in pressure/volume curves and when tested with intact peripheral vasculature. 8 The fetal heart has limited capacity to increase stroke volume by increasing diastolic filling pressure, the right ventricle even less than the left, as they are already operating at the top of their function curves. The FrankeStarling mechanism does operate in the fetal heart, which is apparent during arrhythmias. 9 Adrenergic drive also shifts the function curve to increase stroke volume. However, increased heart rate may be the single most prominent means of increasing cardiac output in the fetus. The two ventricles pump in parallel (Fig. 1) and the pressure difference between them is minimal compared with postnatal life. 5 However, experimental studies show some variation in pressure and velocity waves between the two sides, ascribed to the difference in compliance of the great arteries and downstream impedance (upper body vs lower body and placenta). 10 Some of the stiffness of the fetal myocardium is attributed to the constraint of the pericardium, lungs and chest wall, 11 all of which have low compliance before air is introduced. However, with the shunts in operation and a metabolism capable of extracting oxygen at low saturation levels, the fetal heart appears to be a very flexible, responsive and adaptive structure. Cardiac output and distribution The fetal systemic circulation is fed from the left and right ventricles in parallel. The left ventricle is predominantly dedicated to the coronary circulation and upper body, while the right ventricle is the main distributor to the lower part of the body, the placenta and the lungs. When using outerinner diameter measurements of the vessels, the combined cardiac output (CCO) is reported to be 210 ml/min at mid-gestation and 1900 ml/min at 38 weeks 12 (Table 1). When using inner diameters, these numbers are lower. 13 The right ventricular output is slightly larger than that of the left ventricle, and pulmonary flow in the human fetus is larger (mean 13e25%) than in the classical fetal lamb studies (%10%). Interestingly, a developmental transition in fetal haemodynamics seems to occur at 28e32 weeks when the pulmonary blood flow reaches a maximum with a simultaneous change in oxygen sensitivity in the pulmonary vasculature. 12,14 Another study found that less blood was distributed to the fetal lungs (11%), 13 which is more in line with previous experimental studies. The three shunts (ductus venosus, ductus arteriosus and foramen ovale) are essential distributional arrangements that make the fetal circulation a flexible and adaptive system for intra-uterine life. A classical concept describes the pathway of oxygenated blood as the via sinistra (Fig. 1) leaving the umbilical vein through the ductus venosus to reach the foramen ovale, left ventricle and aorta, thus feeding the coronary

8 Physiology of the fetal circulation 495 Figure 1 Pathways of the fetal heart and representative oxygen saturation values (in brackets). The via sinistra (red) directs well-oxygenated blood from the umbilical vein (UV) through the ductus venosus (DV) (or left half of the liver) across the inferior vena cava (IVC), through the foramen ovale (FO), left atrium (LA) and ventricle (LV) and up the ascending aorta (AO) to reach the descending AO through the isthmus aortae. De-oxygenated blood from the superior vena cava (SVC) and IVC forms the via dextra (blue) through the right atrium (RA) and ventricle (RV), pulmonary trunk (PA) and ductus arteriosus (DA). CCA, common carotid arteries; FOV, foramen ovale valve; LHV, left hepatic vein; LP, left portal branch; MHV, medial hepatic vein; MP, portal main stem; PV, pulmonary vein, RHV, right hepatic vein; RP, right portal branch. Copied and modified with permission from ref. 16 and cerebral circuits. Conversely, a via dextra directs de-oxygenated blood from the caval veins through the tricuspid valve, pulmonary trunk and ductus arteriosus to reach the descending aorta, largely bypassing the pulmonary circuit. Oxygen saturation gives a picture of distribution and blending of flows in the central fetal circulation (Fig. 1). The lowest saturation is found in the abdominal IVC, and the highest saturation is found in the umbilical vein. 10 Interestingly, the difference between the left and right ventricles is only 10%, and this increases to 12% during hypoxaemia. The small difference between the left and right ventricles is due to the abundant volume of oxygenated blood presented to the foramen ovale. In addition to the ductus venosus blood flow, the umbilical blood passing through the liver has had a modest reduction in saturation and represents another sizeable volume of oxygenated blood flowing in much the same direction as the ductus

9 496 T. Kiserud Table 1 Combined cardiac output and distribution in human fetuses during the second half of pregnancy according to Rasanen et al. 12 % of combined cardiac output at gestational age 20 weeks 30 weeks 38 weeks Combined cardiac output 210 (ml/ min) 960 (ml/ min) 1900 (ml/ min) Left ventricle Right ventricle Foramen ovale Lungs Ductus arteriosus venosus towards the foramen ovale. In addition to some blending, the abundance of oxygenated blood will cause a spillover to the right side when reaching the foramen ovale with its crista dividens (limbus) (Fig. 2). Ductus venosus and liver circulation In the human fetus, the ductus venosus is a slender trumpet-like shunt connecting the intra-abdominal umbilical vein to the IVC at its inlet to the heart. The inlet of the ductus venosus, the isthmus, is the restrictive area with a mean diameter of 0.5 mm at mid-gestation and hardly exceeds 2 mm for the rest of a normal pregnancy. 15,16 The umbilical venous pressure ranges from 2 to 9 mmhg 6 (the portocaval pressure gradient), and causes the blood to accelerate from a mean of 10e22 cm/s in the umbilical vein to 60e85 cm/s as it enters the ductus venosus and flows towards the IVC and foramen ovale. 17,18 The blood flow with the highest oxygenation, coming from the ductus venosus, also has the highest kinetic energy in the IVC and predominantly presses open the foramen ovale valve to enter the left atrium, i.e. the preferential streaming described in animal studies. 19 While 30% of the umbilical blood is shunted through the ductus venosus at mid-gestation, this fraction is reduced to 20% at 30 weeks and remains so for the rest of the pregnancy, but with wide variations (Fig. 3). 16 These results are similar to those of another study, 20 but are at variance with experimental animal studies, admittedly using a different technique, which showed that approximately 50% was shunted through the ductus venosus. 19,21 The redistributional mechanisms of increased shunting during hypoxaemia described in animal experiments also seem to operate in the human fetus. 22,23 Figure 2 The foramen ovale acts as a flow distributor of the inferior venous inlet. (a) Ultrasound scan shows the inferior vena cava (IVC) and left and right atria (LA, RA). The atrial septum (AS) with its crista dividens (postnatal: limbus) faces the inlet of the IVC to divide the ascending column of blood. The terminal portion of the IVC expands, more to the left side, to receive blood from the liver and ductus venosus (DV). The high velocity, its position to the left and steep direction (b) makes the DV blood preferentially press open the foramen ovale valve (FOV) to enter the LA. IVC blood directed more anteriorly arrives predominantly in the RA. Increased pressure in LA or a premature apposition of FOV to the AS would divert more blood to the right. Reproduced with permission from ref. 36 The ductus venosus is under tonic adrenergic control, and distends under the influence of nitroxide and prostaglandins. 24,25 The most extensive dilatation is seen during hypoxaemia, leading to

10 Physiology of the fetal circulation 497 Figure 3 The fraction of umbilical venous return shunted through the ductus venosus in low-risk pregnancies is 30% at mid-gestation but approximately 20% at 30e40 weeks, signifying the developmental importance of the fetal liver receiving 70e80% of the umbilical blood. Reproduced with permission from ref. 16 a 60% increase of the diameter in fetal sheep. 25 However, the changes in diameter are not restricted to the isthmus but also include the entire length of the vessel, which has a far greater impact on resistance. 25,26 The shunt obliterates within 1e3 weeks of birth in term infants, although this takes longer in premature births and in cases with persistent pulmonary hypertension or cardiac malformation. 27e29 In contrast to the ductus arteriosus where increased oxygen tension triggers the closure, no trigger has been found for the ductus venosus. 24 Equally important to the active regulatory mechanism is the passive regulation based on fluid dynamics, i.e. viscosity and pressure. 30 Blood velocity in the ductus venosus is high and has Newtonian properties with low viscosity (similar to water). In contrast, liver tissue represents a huge capillary cross-section with a low blood velocity. At low velocities, the blood is non-newtonian with an accordingly high viscosity (and resistance) and a closing pressure of 1e4 mmhg. It follows that an increase in haematocrit leads to increased viscous resistance in the low-velocity venous liver flow and has little effect on the high-velocity flow in the ductus venosus. Thus, the change in haematocrit alone leads to a shift of umbilical venous flow from the liver to the ductus venosus. Along the same lines, variation in the umbilical venous pressure affects the two pathways differently. 30 A reduction in venous pressure reduces liver perfusion more than ductus venosus flow, as a further reduction in an already low velocity in the large cross-section of the portal vasculature implies a considerable increase in viscous resistance. The result is a higher degree of shunting. In addition to these fluid dynamic determinants, the neural and endocrine regulation of the hepatic vascular bed also play a role. 31 The portal vasculature shows a more pronounced constricting response to adrenergic stimulation compared with the ductus venosus. 32 It all combines to make a distribution system that is extremely sensitive to both active and passive regulation, which is in line with the substantial normal variation of shunting seen in human fetuses. 16,33 The physiological role of the ductus venosus is not well understood. The shunting seems more prominent in early pregnancy than after 30 weeks of gestation. The low degree of shunting through the ductus venosus during the last 8e10 weeks of pregnancy implies that approximately 80% of the umbilical blood perfuses the liver, signifying a very high developmental priority of the umbilical liver perfusion compared with the ductus venosus. 16 However, during hypoxic challenges, the priority seems to be different. Fetuses maintain a higher degree of ductus venosus shunting, probably as a redistributional adaptation to hypoxic pressure, ensuring oxygenation of the heart and brain. 21 The cost for responding to such needs could be permanently altered liver development. 34 It should be borne in mind that oxygen extraction in the liver is rather modest (10e15% reduction in oxygen saturation), 35 which means that blood coming from the median and left hepatic vein are important contributors of oxygenated blood. Actually, the position and direction of the left hepatic venous blood under the Eustachian valve (IVC valve) favour this blood to be delivered at the foramen ovale. 36 Although agenesis of the ductus venosus has been linked to abnormalities and fetal demise, 37 agenesis is also found in fetuses that have exhibited normal growth. 16 Experimental obliteration of the vessel seems to have little haemodynamic effect, 38 but causes an increase in insulin-like growth factor 2 and increases the growth of fetal organs. 39 Recent studies have indicated that the fetal umbilical flow to the liver towards the end of pregnancy is influenced by the maternal nutritional state and diet. 40 Umbilical venous flow constitutes 75% of the venous supply to the liver, with the remaining 25% coming from the main portal

11 498 T. Kiserud stem. 41 In human fetuses, the arterial supply to the liver is not known but it seems to have a more prominent role during compromise. 42 Doppler examination of the ductus venosus is increasingly used to identify hypoxaemia, acidosis, cardiac decompensation and placental compromise, and is a promising tool for timing the delivery of critically ill fetuses. 43,44 Increased pulsatility, mainly caused by the augmented atrial contraction wave, signifies increased atrial contraction due to adrenergic drive, or increased venous filling pressure, or both. In early pregnancy, the augmented a-wave in the ductus venosus is associated with an increased risk of chromosomal aberration and has been suggested as a secondary screening test. 45,46 Foramen ovale A defect in the atrial septum is commonly associated with left-right or right-left shunting in postnatal life. It is conceivable that this concept is carried over to describe the function of the foramen ovale in the fetus, 47 but this is not a fair representation of the actual haemodynamics. Rather, the inferior venous inlet to the heart should be viewed as a column of blood that ascends between the two atria from below. 36,48 This column hits the interatrial ridge, the crista dividens, and is divided into a left and right arm (Fig. 2). The left arm fills the windsock, formed between the foramen ovale valve and the atrial septum, to enter the left atrium. The right arm is directed towards the tricuspid valve and joins the flow from the superior vena cava and coronary sinus to form the via dextra. This is an equilibrium easily influenced by changes in pressure on the two sides. Increased resistance and pressure of the left side is instantaneously reflected in increased diversion of blood to the right side. In contrast to the hypertrophy of the left ventricle seen in aortic stenosis in adults, fetal stenosis commonly leads to a shift of blood volume from left to right at the level of the foramen ovale, with corresponding development of left-sided hypoplasia and compensatory growth of the right ventricle. The developing ventricle responds to the demands of the afterload and is stimulated by the blood volume of the preload. However, for the left side of the heart, the foramen ovale is an important limiting factor, particularly in cases of a maldeveloped foramen or a premature closure. 49 Under physiological conditions, it is not the ovalshaped hole of the septum that constitutes the restricting area for the flow to the left atrium, but the horizontal area between the foramen ovale valve and the atrial septum above the foramen ovale. 50 Interestingly, the growth of this area is somehow blunted after 28e30 weeks of gestation compared with the cross-section of the IVC. This effect coincides with changes in fetal lung perfusion 12 and ductus venosus shunting, 16 and may signify a transition into a more mature circulatory physiology. Ductus arteriosus and pulmonary circulation The ductus arteriosus constitutes a wide muscular vessel connecting the pulmonary arterial trunk to the descending aorta (Fig. 4). 51 During the second trimester, the velocity in the ductus arteriosus increases more than that in the pulmonary trunk, reflecting the development of the wind-kessel function of the pulmonary trunk. 52 During the Figure 4 (a) The ductus arteriosus (arrow) is a sizeable connection between the pulmonary trunk (PA) and the aorta (AO) in fetal rats. (b) Indomethacin induces severe constriction. Reproduced with permission from ref. 51

12 Physiology of the fetal circulation 499 second half of pregnancy, 40% or less of the CCO is directed through the ductus arteriosus 12,13 (Table 1). The lungs receive 13% of the CCO at mid-gestation and 20e25% after 30 weeks, 12 which is more than that reported in fetal sheep experiments 10 and a more recent human study. 13 Normally, the shunt closes 2 days after birth, 53 but a patent duct is a common clinical problem. An increase in oxygen tension is regarded as the main trigger for its closure. 24 The vessel is under the general influence of circulating substances, particularly prostaglandin E 2, which is crucial in maintaining patency. 54 Sensitivity to prostaglandin antagonists is at its highest in the third trimester and is enhanced by glucocorticoids and fetal stress. 55 Nitric oxide has a relaxing effect prior to the third trimester. The increased reactivity of the ductus arteriosus in the third trimester makes it vulnerable to prostaglandin synthase inhibitors, such as indomethacin, which may cause severe and longlasting constriction. 55,56 The ductus arteriosus bypasses the pulmonary circuit, but the distribution between these two pathways depends heavily on the impedance of the pulmonary vasculature, which is under the control of prostaglandin I 2 and modified by a series of substances. 24 In an elegant study, Rasanen et al. showed how reactivity in the pulmonary vascular bed increased in the third trimester. 14 While fetuses at gestational age 20e26 weeks showed no changes during maternal hyperoxygenation, fetuses at 31e36 weeks had lower impedance in the pulmonary arteries assessed by the pulsatility index, and increased pulmonary blood flow. Correspondingly, the blood flow in the ductus arteriosus was reduced. Brain circulation Differences in circulation physiology between animal experiments and human fetuses are likely to be greatest when concerning the brain, as the human brain is relatively larger than in other species. In a study of human previable fetuses weighing 12e272 g (probably corresponding to 10e 20 weeks of gestation), it was found that the brain received approximately 15% of the systemic venous return (equal to the CCO less the pulmonary circuit). 33 The proportion directed to the brain increased with low arterial ph, increased pco 2 and reduced placental perfusion. A study of the primate Macaca mulatta at an advanced stage of gestation found that 16% of the CCO was distributed to the brain, and this fraction increased to 31% during hypoxic challenge. 21 Both of these studies reflect redistributional preferences to the brain during hypoxaemia and acidosis. Clinical obstetrics has taken advantage of such brain-sparing mechanisms, and uses the increased diastolic blood velocity recorded in the middle cerebral artery as a marker of compensatory redistribution of blood to the brain. 57 Fetoplacental circulation In the fetal sheep, 45% of the CCO is directed to the umbilical arteries and placenta. 58 This percentage is less in exteriorized human fetuses, but it increases from 17% at 10 weeks to 33% at 20 weeks of gestation. 33 These results overestimate the placental fraction as the CCO calculation was based on systemic venous return, not including the pulmonary venous return. Secondly, the measurements were not performed under strict physiological conditions. Doppler studies of low-risk pregnancies have found similar results; one-third of the fetal CCO is directed to the placenta at 20e32 weeks of gestation, 59,60 but this decreases to approximately one-fifth beyond 32 weeks of gestation. 60 The introduction of Doppler ultrasound made it possible to assess umbilical venous blood flow 61 in the human fetus in utero. Recent longitudinal observations in low-risk pregnancies have found that the umbilical blood flow increases from a mean of 36 ml/min at 20 weeks to 265 ml/min at 40 weeks of gestation. 62 Umbilical flow normalized for fetal weight is at its highest (117 ml/min/ kg) at 25 weeks and at its lowest at 41 weeks (63 ml/min/kg) of gestation. These results are in accordance with earlier studies applying thermodilution at birth. 63 The fact that human umbilical flow is considerably lower than that in the fetal sheep is not disconcerting as fetal sheep have a higher growth rate, a higher temperature and a lower Hgb. Resistance to flow is mainly determined by the peripheral vascular bed of the placenta. This vasculature has no neural regulation and catecholamines have little effect on the vasculature. Endothelin and prostanoid have a constricting effect 64 and nitric oxide has a vasodilatory effect, 65 but the exact role of humoral regulation is not fully understood. 66 Placental blood flow has been found to be fairly stable and chiefly determined by arterial blood pressure. 10 The substantial increase in the vascular cross-section during late gestation accounts for a reduction in impedance and the corresponding fall in umbilical artery pulsatility seen in longitudinal studies. 67 Placental vasculature is believed to account for 55% of the umbilical

13 500 T. Kiserud resistance. 68 The waveform recorded by Doppler measurement in the umbilical artery reflects this downstream impedance and is used extensively to identify placental compromise. 69 Watershed areas and the compromised circulation The watershed area in the brain circulation has long been used to explain certain lesions of neonates, and a concept of a watershed at the isthmus of the aorta, the left portal vein and the foramen ovale with its crista dividens has been proposed recently. It has long been known that fetuses with critical aorta stenosis or hypoplastic left heart syndrome direct ductus arteriosus blood in a retrograde direction through the isthmus aortae to feed the aortic arch. Recent studies have highlighted the isthmus aortae as a watershed between the aortic arch and the ductus arteriosus in anatomically normal fetuses. 70,71 Since this watershed also reflects the difference in impedance between the cerebral circuit and that of the placenta and lower fetal body, the blood velocity pattern across the isthmus with various degrees of reversed flow was suggested to be an indicator of placental compromise. Similarly, the direction of flow in the left portal vein (Fig. 1) is suggested to reflect compromised venous return demanding a compensatory increase of blood from the main portal stem to maintain portal and umbilical pressure, with the result being a cessation of umbilical venous flow to the left portal branch, and, at a more advanced stage of compromise, reversed flow that permits splanchnic blood to enter the ductus venosus. 72 A third watershed, the foramen ovale (Fig. 2), differs from the two former watersheds. It distributes blood to the left and right atria by dividing the ascending venous blood into two arms at the crista dividens. The horizontal area between the foramen ovale valve and the atrial septum is thought to be the restricting area for flow to the left atrium. 50 In cases with increased venous return (e.g. arteriovenous malformation), an increased volume of blood is diverted to the right side, leading to increased growth of the right ventricle. In cases of abnormally small foramen ovale, the left side of the heart develops less in size (one of the possible mechanisms leading to hypoplastic left heart syndrome). These concepts are in need of detailed studies to make them clinically relevant. Circulatory regulation Circulatory responses to hypoxaemia and hypovolaemia have been particularly well studied in animals during the last trimester of pregnancy, 73 but even during mid-gestation and earlier, there seem to be neural and endocrine responses in addition to the prominent direct effect on cardiac function caused by hypoxic insults. 74,75 A hypoxic insult in late pregnancy activates a chemoreflex mediated by the carotid bodies (and, to a lesser extent, the aortic bodies), causing an immediate vagal effect with reduced heart rate and a sympathetic vasoconstriction. 76 This is followed by endocrine responses (e.g. adrenaline and noradrenaline) maintaining vasoconstriction (a-adrenergic), increasing heart rate (b-adrenergic) and reducing blood volume with renin release and increased angiotensin II concentration. The responses involve angiotensinevasopressin mechanisms, and increased concentrations of adrenocorticotrophic hormone, cortisol, atrial natriuretic peptide, neuropeptide Y and adrenomedullin orchestrate a circulatory redistributional pattern that maintains placental circulation and gives priority to the adrenal glands, myocardium and brain 73 (Fig. 5). In clinical medicine, this translates into a frequently visualized coronary circulation, 77 a shift in lefteright ventricular distribution, 78 a cerebral circulation with high diastolic flow, 57 and an increased impedance in the pulmonary circulation 79 during circulatory compromise. Sustained hypoxia forces an adaptational shift to less oxygen demand, reduced DNA synthesis Figure 5 Redistribution of fetal combined cardiac output during acute hypoxaemia caused by reduced uterine blood flow. Based on ref. 58

14 Physiology of the fetal circulation 501 and growth, with a gradual return towards normal concentrations of blood gases and endocrine status, 80 although with a residual deviation that may have a longlasting effect on fetal and newborn life. There is an increasing awareness that even subtle differences in the development of autocrine, paracrine, endocrine and metabolic functions induced by nutritional or circulatory variations during pregnancy could have lasting effects with increased risks of cardiovascular and endocrine diseases in adult life. 81 Practice points Which of the two ventricles takes a larger volume load? From where comes the blood in the left atrium? How much of the umbilical venous return is shunted through the ductus venosus in the human fetus? In what sense is the aortic isthmus a watershed? Research directions More information on human fetal circulation is expected to substitute animal experimental studies as the basis for clinical medicine. More detailed adaptational pattern is expected to give a better background for fetal surveillance. More detailed knowledge of human fetal responses and adaptation is expected to unveil the mechanisms involved in in utero conditioning of health risk in adult life. References 1. Brace RA. Regulation of blood volume in utero. In: Hanson MA, Spencer JAD, Rodeck CH, editors. The circulation, Fetus and neonate. Physiology and clinical application, vol. 1. Cambridge: Cambridge University Press; p. 75e Nicolaides KH, Clewell WH, Rodeck CH. Measurement of fetoplacental blood volume in erythroblastosis fetalis. Am J Obstet Gynecol 1987;157:50e3. 3. Brace RA. Fetal blood volume response to intravenous saline solution and dextrane. Am J Obstet Gynecol 1983;143: 777e Castle B, Mackenzie IZ. In vivo observations on intravascular blood pressure in the fetus during mid-pregnancy. In: Rolfe P, editor. Fetal physiological measurements. London, Boston, Durban, Singapore, Toronto, Wellington: Butterworths; p. 65e9. 5. Johnson P, Maxwell DJ, Tynan MJ, Allan LD. Intracardiac pressures in the human fetus. Heart 2000;84:59e Ville Y, Sideris I, Hecher K, Snijders RJM, Nicolaides KH. Umbilical venous pressure in normal, growth-retarded, and anemic fetuses. Am J Obstet Gynecol 1994;170:487e Thornburg KL, Morton MJ. Development of the cardiovascular system. In: Thorburn GD, Harding R, editors. Textbook of fetal physiology. Oxford: Oxford University Press; Reller MD, Morton MJ, Reid DL, Thornburg KL. Fetal lamb ventricles respond differently to filling and arterial pressures and to in utero ventilation. Pediatr Res 1987;22: 519e Lingman G, Dahlström JA, Eik-Nes SH, Marsál K, Ohlin P, Ohrlander S. Hemodynamic evaluation of fetal heart arrhythmias. Br J Obstet Gynecol 1984;91:647e Rudolph AM. Distribution and regulation of blood flow in the fetal and neonatal lamb. 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16 Physiology of the fetal circulation Kiserud T, Rasmussen S, Sethi V. Fetal blood flow distribution to the placenta. Ultrasound Obstet Gynecol 2003; 22: Gill RW. Pulsed Doppler with B-mode imaging for quantitative blood flow measurement. Ultrasound Med Biol 1979; 5:223e Acharya G, Wilsgaard T, Berntsen GKR, Maltau JM, Kiserud T. Reference ranges for umbilical vein blood flow in the second half of pregnancy based on longitudinal data. Prenat Diagn 2005;25:99e Stembera ZK, Hodr J, Janda J. Umbilical blood flow in healthy newborn infants during the first minutes after birth. Am J Obstet Gynecol 1965;91:568e Poston L. The control of bloodflow to the placenta. Exp Physiol 1997;82:377e Sand AE, Andersson E, Fried G. Effect of nitric oxide donors and inhibitors of nitric oxide signalling on endothelin- and serotonin-induced contractions in human placental arteries. Acta Physiol Scand 2002;174:217e Poston L, McCarthy AL, Ritter JM. Control of vascular resistance in the maternal and feto-placental arterial beds. Pharmacol Ther 1995;65:215e Acharya G, Wilsgaard T, Berntsen GKR, Maltau JM, Kiserud T. Reference ranges for serial measurements of umbilical artery Doppler indices in the second half of pregnancy. Am J Obstet Gynecol 2005;192:937e Adamson SL. Arterial pressure, vascular input impedance, and resistance as determinants of pulsatile blood flow in the umbilical artery. Eur J Obstet Gynecol Reprod Biol 1999;84:119e Alfirevic Z, Neilson JP. Doppler ultrasonography in high-risk pregnancies: systematic review with meta-analysis. Am J Obstet Gynecol 1995;172:1379e Fouron JC, Zarelli M, Drblik P, Lessard M. Flow velocity profile of the fetal aortic isthmus through normal gestation. Am J Cardiol 1994;74:483e Sonesson S-E, Fouron J-C. Doppler velocimetry of the aortic isthmus in human fetuses with abnormal velocity waveforms in the umbilical artery. Ultrasound Obstet Gynecol 1997;10:107e Kiserud T, Kilavuz Ö, Hellevik LR. Venous pulsation in the left portal branch e the effect of pulse and flow direction. Ultrasound Obstet Gynecol 2003;21:359e Iwamoto HS. Cardiovascular effects of acute fetal hypoxia and asphyxia. In: Hanson MA, Spencer JAD, Rodeck CH, editors. The circulation, Fetus and neonate physiology and clinical application, vol. 1. Cambridge: Cambridge University Press; Iwamoto HS, Kaufman T, Keil LC, Rudolph AM. Responses to acute hypoxemia in fetal sheep at 0.6e0.7 gestation. Am J Physiol 1989;256:H613e Kiserud T, Jauniaux E, West D, Ozturk O, Hanson MA. Circulatory responses to acute maternal hyperoxaemia and hypoxaemia assessed non-invasively by ultrasound in fetal sheep at 0.3e0.5 gestation. Br J Obstet Gynaecol 2001;108: 359e Hanson MA. Do we now understand the control of the fetal circulation? Eur J Obstet Gynecol Reprod Biol 1997;75: 55e Chaoui R. The fetal heart-sparing effect detected by the assessment of coronary blood flow: a further ominous sign of fetal compromise. Ultrasound Obstet Gynecol 1996;7: 5e al-ghazali W, Chita SK, Chapman MG, Allan LD. Evidence of redistribution of cardiac output in asymetrical growth retardation. Br J Obstet Gyanecol 1989;96:697e Rizzo G, Capponi A, Chaoui R, Taddei F, Arduini D, Romanini C. Blood flow velocity waveforms from peripheral pulmonary arteries in normally grown and growth-retarded fetuses. Ultrasound Obstet Gynecol 1996;8:87e Bocking AD. Effect of chronic hypoxaemia on circulation control. In: Hanson MA, Spencer JAD, Rodeck CH, editors. The circulation, Fetus and neonate physiology and clinical application, vol. 1. Cambridge: Cambridge University Press; Barker DJP, Sultan HY. Fetal programming of human disease. In: Hanson MA, Spencer JAD, Rodeck CH, editors. Growth, Fetus and neonate physiology and clinical application, vol. 3. Cambridge: Cambridge University Press; p. 255e74.

17 Ultrasound Obstet Gynecol 2006; 28: Published online 6 July 2006 in Wiley InterScience ( DOI: /uog.2832 Fetal cardiac output, distribution to the placenta and impact of placental compromise T. KISERUD*, C. EBBING*, J. KESSLER* and S. RASMUSSEN* *Department of Clinical Medicine, Section of Obstetrics and Gynaecology, University of Bergen, Department of Obstetrics and Gynecology, Haukeland University Hospital and Locus of Registry Based Epidemiology, Norwegian Birth Registry, Bergen, Norway KEYWORDS: blood flow; cardiac output; circulation; echocardiography; fetus; growth restriction; placenta; ultrasound ABSTRACT Objectives Intrauterine growth restriction is a common clinical problem, but the underlying hemodynamic changes are not well known. Our aim was to determine the normal distribution of fetal cardiac output to the placenta during the second half of pregnancy, and to assess the changes imposed by growth restriction with various degrees of placental compromise. Methods A cross-sectional study of 212 low-risk pregnancies with a gestational age of weeks constituted the reference population. A second group of 64 pregnancies with an estimated fetal weight 2.5 th percentile constituted the study group. Ultrasound measurements of inner diameters and velocities at the fetal left and right ventricular outlets and intra-abdominal umbilical vein were used to determine combined left and right cardiac output (CCO) and the fraction distributed to the placenta. Placental compromise was graded according to umbilical artery waveform: pulsatility index normal, > 97.5th percentile, or absent/reversed end-diastolic velocity. Regression analysis and Z-score (SD-score) statistics were used to establish normal ranges and to compare groups. Results During gestational weeks the normal CCO/kg was on average 400 ml/min/kg and the fraction directed to the placenta was on average 32%, while after 32 weeks it was 21%. In intrauterine growth restriction the CCO/kg was not significantly different, but the fraction to the placenta was lower (P < 0.001). This effect was more pronounced in severe placental compromise (P < 0.001). Conclusions Normally, one third of the fetal CCO is distributed to the placenta in most of the second half of pregnancy, and one fifth near term. In placental compromise this fraction is reduced while CCO/kg is maintained at normal levels, signifying an increased recirculation of umbilical blood in the fetal body. Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. INTRODUCTION Intrauterine growth restriction (IUGR) is one of the major challenges in antenatal care and an important determinant for perinatal mortality and morbidity 1.Low birth weight has also been associated with increased risk of cardiovascular diseases and Type 2 diabetes in adult life 2. Although impaired maternal nutrition may influence birth weight and health in later life, the effect on birth weight is rather modest. This suggests that additional powerful mechanisms, of which placental compromise is probably the most common, are involved in the clinically important group of growth-restricted fetuses seen during the second and third trimesters. Experimental data suggest that restriction in placentation leads to impaired fetal growth 3, and a sustained reduction in oxygen delivery imposed by a restriction in the maternal or fetal circulation of the placenta leads to down-regulation of DNA synthesis and fetal growth 4. In the human fetus, IUGR and compromised placenta are commonly linked to an augmented pulsatility of the umbilical artery. The extreme finding of absent or reversed end-diastolic flow (ARED) in the umbilical arteries is associated with a perinatal mortality rate of 36% 5. These fetuses show signs of increased afterload 6 and circulatory redistribution 7. Thus, the circulatory pattern of these fetuses is emerging, but some fundamental pieces of information on the underlying hemodynamics are still lacking. One of these is the proportion of fetal cardiac output distributed to the placenta. In 1971, Abraham Rudolph et al. 8 showed Correspondence to: Prof. T. Kiserud, Department of Clinical Medicine, Section of Obstetrics and Gynaecology, Haukeland University Hospital, N-5021 Bergen, Norway ( torvid.kiserud@kk.uib.no) Accepted: 29 November 2005 Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. ORIGINAL PAPER

18 Placental fraction of CCO 127 that, under experimental conditions, roughly one third of the combined left and right cardiac output (CCO) was directed towards the umbilical circulation at midgestation in human pregnancies, and a later Doppler study 9, under physiological conditions, points in the same direction, although a low number of observations towards the end of pregnancy made the statistics at this point less reliable. As for compromised pregnancies causing umbilical hemodynamic compromise and fetal growth impairment, the fraction of fetal CCO directed to the placenta is not known. The aim of this study was to determine the fetal cardiac output and its distribution to the placenta in normal pregnancies during the second half of pregnancy, and to assess the changes imposed by IUGR with various degrees of placental compromise. METHODS Reference population The reference population consisted of 212 women with low-risk pregnancies recruited, after written consent, to a cross-sectional study acknowledged by the Regional Committee for Ethics in Medical Research. Excluded were those with an obstetric history of previous hypertensive complications, IUGR, placental abruption and history of smoking, diabetes, hypertension or any general chronic disease. Gestational age was assessed at the routine ultrasound examination at weeks of gestation. Fetuses with malformations and known chromosomal aberrations were not included. One participant withdrew after cardiac malformation and trisomy 21 was identified during the study examination, and another due to social reasons. The median gestational age at birth was (range, to 42+ 2) weeks. The median birth weight was 3665 (range, ) g, and in terms of percentiles for the Norwegian population, it was 50 th percentile (range, 1 99 th percentiles). The umbilical venous flow in this group has been presented previously and forms the reference ranges for the present study 10. In this study, we established new reference ranges for the blood flow in the cardiac outlets, left right ventricular output differences, CCO, CCO/kg and the placental fraction of CCO in order to compare these with the results of growth-restricted fetuses. IUGR group This group consisted of 66 women recruited into the study when fetal biometry (biparietal diameter and middle abdominal diameter) identified an estimated fetal weight 2.5 th percentile. Gestational age was determined by crown rump length before 12 weeks of gestation, biparietal diameter at the routine scan at weeks, or certain information of a regular last menstrual period (LMP). In cases of a discrepancy of 10 days between the gestational age determined by the second-trimester scan and that calculated from a certain LMP, we relied on LMP because growth impairment was assumed to start early, affecting size at the week scan. Twins, chromosomal aberrations, malformations and infections in the present pregnancy excluded participation. Those with a birth weight > 10 th percentile were excluded, leaving 64 for statistical analysis. These 64 had been examined at a median gestational age of weeks (range, to 39+ 5) weeks, and delivered at a median gestational age of (range, to 40+ 6) weeks. The median lag between examination and delivery was 3 (interquartile range (IQR), 1 7; range, 0 85) days. The majority of neonates were delivered by Cesarean section (47/64). In total there were 29 girls and 35 boys, with a median birth weight of 1870 (range, ) g. Of these, 51 were < 2.5 th percentile, seven were between 2.5 th and 5 th percentiles, and six were between 5 th and 10 th percentiles according to gender-specific birth-weight charts 11. Three deaths occurred at delivery or in the delivery room (birth weights of 270, 280 and 350 g). Of the remaining 61, seven had an Apgar score of < 7at1minandtwohadascoreof < 7 at 5 min, 31 were admitted to the neonatal intensive care unit, and 19 required respiratory support. Sonography The participants were examined during a 45-min session using a Vingmed CFM 800 (GE Vingmed, Horten, Norway) ultrasound machine equipped with a multifrequency mechanical sector transducer (center frequency, 5 MHz) with color Doppler and pulsed Doppler facilities (4 MHz). The spatial peak temporal intensity was set at 45 mw/cm 2 for pulsed Doppler. The inner diameter (D) of the aorta and the pulmonary artery was measured at an insonation angle perpendicular to the vessel wall, between the open semilunar valves, in a zoomed image (Figure 1). The optimal frame for measurement was searched in the memory buffer. For the aorta, the procedure was repeated three times or more in 163/174 cases, and an average of 5.2 (median, 5; IQR, 4 6; range, 1 14) times. For the pulmonary artery the measurement was repeated three times or more in 168/177 cases, and an average of 5.5 (median, 5; IQR, 4 7; range, 1 13) times. The calculated mean diameters were used in the statistical analysis. In a separate axial insonation, the sample volume was placed at the ostia of the aorta and pulmonary artery and the maximum velocity during systole was recorded for 2 4 s during fetal quiescence. The angle of insonation was kept as low as possible; for the aorta it was 0 in 153 recordings and the median was 10 (IQR, 2 18) in the 27 remaining recordings, while for the pulmonary artery it was 0 in 153 recordings and the median was 14 (IQR, 8 33) in the remaining 24. The systolic time-velocity integral (TVI) and heart rate (HR) were calculated as an average of four to six cardiac cycles. Left and right ventricular output were calculated as π (D/2) 2 TVI HR. The CCO was calculated as the sum of the two, and the normalized CCO was calculated by dividing this by the fetal weight. The Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

19 128 Kiserud et al. the 95% CI of the mean to half or less, depending on the diameter 12. The same approach was used for the umbilical venous flow assessment. Statistical analysis Figure 1 Doppler recording (a,c) and diameter measurement (b,d) at the level of the aortic ostium (a,b) and at the pulmonary arterial ostium (c,d) in a fetus at 30 weeks of gestation. difference between left and right ventricular output was calculated as a percentage of the CCO. For the intra-abdominal umbilical vein the D was determined as an average of four or more measurements made before the first portal branches with an angle of insonation perpendicular to the vessel wall 10. The weighted mean blood velocity (V wmean ) was recorded during 2 4 s in a separate insonation along the axis of the vessel with an expanded sample volume. The angle of insonation was 0 in 56 recordings and the median was 16 (IQR, 10 24) in the remaining 141. The fetoplacental blood flow was calculated as π (D/2) 2 V wmean, and its fraction of the CCO was calculated as a percentage. In all fetuses, the fetal weight at the time of examination was estimated on the basis of the weight percentile at birth 10. In addition, the umbilical artery blood velocity was recorded in the free loop, the pulsatility index (PI ua ) was calculated from five to six waveforms, and ARED was noted. Increasing waveform alteration was taken as increasing hemodynamic compromise of the placenta and the participants were grouped accordingly into those with normal PI ua, those with PI ua > 97.5 th percentile, and those with ARED. Measures were taken to restrict random error. One person did all measurements (T.K.) in both groups. The intraobserver variation, calculated as the coefficient of variation for the diameter measurement, was 8.4% (95% CI, ) for the aorta and 7.7% (95% CI, ) for the pulmonary artery. The corresponding intraclass correlations were 94% (95% CI, 92 95) and 97% (95% CI, 96 97), respectively. In order to further control error, the diameters were determined as a mean of three or more repeat measurements, which we have shown to reduce To produce means, fractional polynomial regression models were fitted to the ln-transformed data and SDs were modeled by the method of scaled absolute residuals 13. The 10 th percentile was calculated as mean SD and the 90 th percentile as mean SD using back-transformed values. To achieve a normal distribution, the outcome measures of the growth-restricted fetuses were ln-transformed and SD scores (Z-scores) were calculated based on ln-transformed mean and SD values of the normally grown fetuses. Analysis of variance and 95% CIs were used to assess differences. P 0.05 was regarded as statistically significant. The intraobserver coefficient of variation for repeated diameter measurements of the aorta and pulmonary artery was studied in 141 and 145 participants of the reference group with four or more observations, respectively. The intraobserver variation was also analyzed as the intraclass correlation. The SPSS statistical package (SPSS, Chicago, IL, USA) was used except for the intraobserver coefficient of variation, which was carried out according to the logarithmic method of Bland 14. RESULTS Of the 210 examined successfully in the reference group, we obtained measurements of the umbilical flow in 195 and measurements from the cardiac outlets in 181, with complete sets in 170. Fetal movements, unfavorable position, maternal obesity and time constraints were the reasons for incomplete data. Of the 64 growthrestricted fetuses included, we obtained umbilical flow measurements in 62 and measurements in the heart in 32, with complete sets for output calculation in 29. In addition to the reasons for missing data mentioned for the low-risk group, fetuses with IUGR were examined for a shorter time, and priority was given to the umbilical circulation. Figures 2 and 3 show the diameters of the aorta and pulmonary artery measured at the ostia between open valves at gestational ages of weeks. The relationship is almost linear. In fetuses with IUGR these diameters tended to be less than they were in the reference group (Figures 2 and 3, Table 1). The pulmonary arterial diameter was significantly smaller in fetuses with IUGR and normal PI ua compared with the reference group, while the severely affected fetuses with ARED flow before 32 weeks of gestation maintained a normal pulmonary arterial diameter (Table 1). Normal left and right ventricular output and the results for growth-restricted fetuses are shown in Figures 4 and 5. Those with IUGR had lower output on both the left and the right sides, but without significant differences between Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

20 Placental fraction of CCO 129 (a) 10 (b) Aortic diameter (mm) Aortic diameter (mm) Gestational age (completed weeks) Gestational age (completed weeks) Figure 2 Diameter of the fetal aorta measured at the ostium between the open valvular leaflets in (a) 181 low-risk pregnancies and (b) 32 pregnancies with intrauterine growth restriction and various degrees of placental compromise, showing those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were different from the reference group (P < 0.001). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3,andSD= GA, where GA is gestational age in weeks. Data were ln-transformed. (a) 12 (b) Pulmonary arterial diameter (mm) Pulmonary arterial diameter (mm) Gestational age (completed weeks) Gestational age (completed weeks) Figure 3 Diameter of the fetal pulmonary artery measured at the ostium between valvular leaflets in (a) 179 low-risk pregnancies and (b) 32 pregnancies with intrauterine growth restriction and various degrees of placental compromise, showing those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were different from the reference group (P < 0.001). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3,andSD= GA, where GA is gestational age in weeks. Data were ln-transformed. Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

21 130 Kiserud et al. Table 1 Combined cardiac output (CCO) and its distribution in intrauterine growth restriction (IUGR) compared with normal fetuses using Z-score (SD-score) statistics Measurement/fetus Mean SE 95% CI n Overall P Aortic diameter Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Aortic flow Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Pulmonary arterial diameter Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Pulmonary arterial flow Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED CCO Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED CCO/kg Normal IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Left-right flow difference Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Umbilical flow Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Umbilical flow/kg Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED Placenta/CCO flow fraction Normal < IUGR, PI ua normal IUGR, PI ua > 97.5 th p IUGR, ARED IUGR fetuses were grouped according to umbilical artery waveform, i.e. pulsatility index normal (PI ua ),PI ua > 97.5 th percentile (p.), or absent/reversed end-diastolic flow (ARED). the three sub-groups classified according to the umbilical artery waveform (Table 1). Comparing left and right ventricular output (Figure 6), there was a shift towards higher volume load in the right ventricle, this effect being augmented during the last weeks of pregnancy. The combined values before 32 weeks of gestation showed a 13% greater load in the right than in the left ventricle, and the corresponding difference after 32 weeks was 26%. In fetuses with IUGR there was a significant overall shift towards greater load in the right ventricle compared with the reference group (Figure 6 and Table 1). However, when divided into subgroups, fetuses with IUGR and normal PI ua were not different from the reference population. On the other hand, those with IUGR and PI ua > 97.5 th percentile shifted the distribution significantly to the right compared with the reference Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

22 Placental fraction of CCO 131 (a) 1000 (b) Aortic flow (ml/min) Aortic flow (ml/min) Gestational age (completed weeks) Gestational age (completed weeks) Figure 4 Left ventricular output (aortic flow) in (a) 175 low-risk pregnancies and (b) 30 pregnancies with intrauterine growth restriction and various degrees of placental compromise, showing those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were different from the reference group (P < 0.001). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3,andSD= GA, where GA is gestational age in weeks. Data were ln-transformed. (a) 1800 (b) Pulmonary arterial flow (ml/min) Pulmonary arterial flow (ml/min) Gestational age (completed weeks) Gestational age (completed weeks) Figure 5 Right ventricular output (pulmonary arterial flow) in (a) 173 low-risk pregnancies and (b) 31 pregnancies with intrauterine growth restriction and various degrees of placental compromise, showing those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were different from the reference group (P < 0.001). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3.andSD= GA, where GA is gestational age in weeks. Data were ln-transformed. group (95% CI of the Z-scores, 0.46 to 1.68 vs to 0.16), but also compared with those with IUGR and normal PI ua (95% CI, 0.93 to 0.29) (Table 1). Fetuses with IUGR and ARED in the umbilical artery showed the same tendency but did not reach significance, their numbers being small (Table 1). Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

23 132 Kiserud et al. (a) 100 (b) Left right difference (%) Left right difference (%) Gestational age (completed weeks) Gestational age (completed weeks) Figure 6 Difference between left and right ventricular output, calculated as the percentage of the combined left and right output, showing a dominance of the right ventricle, in (a) 170 low-risk pregnancies and (b) 29 fetuses with intrauterine growth restriction. These fetuses were subdivided to show those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were different from the reference group (P < 0.001). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3,and SD = GA, where GA is gestational age in weeks. Left right flow difference was ln-transformed. (a) 2000 (b) CCO (ml/min) CCO (ml/min) Gestational age (completed weeks) Gestational age (completed weeks) Figure 7 Fetal combined left and right cardiac output (CCO) in (a) 170 low-risk pregnancies, and (b) 29 pregnancies with intrauterine growth restriction and various degrees of placental compromise, showing those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were different from the reference group (P < 0.001). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 1,andSD= GA, where GA is gestational age in weeks. Data were ln-transformed. The mean fetal CCO was 80 ml/min at 18 weeks and 1370 ml/min at 40 weeks (Figure 7). In fetuses with IUGR the CCO was less (Figure 7 and Table 1). The CCO/kg was on average 400 ml/min/kg during the entire second half of the normal pregnancy and this was no different from that in the group with IUGR, Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

24 Placental fraction of CCO 133 (a) 1200 (b) CCO/kg (ml/min/kg) CCO/kg (ml/min/kg) Gestational age (completed weeks) Gestational age (completed weeks) Figure 8 Fetal normalized combined cardiac output (CCO/kg) in ml/min/kg for (a) 170 low-risk pregnancies and (b) 29 pregnancies with intrauterine growth restriction and various degrees of placental compromise, showing those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). The growth-restricted fetuses were not different from the normal group (P = 0.485). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3,andSD= GA, where GA is gestational age in weeks. Data were ln-transformed. (a) 450 (b) Umbilical venous flow (ml/min) Umbilical venous flow/kg (ml/min/kg) Gestational age (completed weeks) Gestational age (completed weeks) Figure 9 (a) Umbilical venous flow in 62 growth-restricted fetuses was lower than that in the reference group (P < 0.001). (b) The effect was also present when flow was normalized for fetal weight (UV flow/kg) (P < 0.001). Growth-restricted fetuses were divided into groups, showing various degrees of placental compromise: those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line for the UV flow was y = ln(ga) GA 2,andSD= GA, and that for the regression line for the UV flow/kg was y = GA GA 3, and SD = GA, where GA is gestational age in weeks. All data were ln-transformed. or any sub-group of placental compromise (Figure 8 and Table 1). Umbilical blood flow was less in growth-restricted compared with normal fetuses (P < 0.001) (Figure 9), and there was a significant effect of increasing hemodynamic compromise of the placenta (Table 1). This effect was less pronounced when umbilical flow was normalized for fetal weight, but was still significant (Figure 9 and Table 1). Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

25 134 Kiserud et al. (a) 80 (b) Placenta/CCO flow fraction (%) Placenta/CCO flow fraction (%) Gestational age (completed weeks) Gestational age (completed weeks) Figure 10 The fraction of fetal combined cardiac output (CCO) directed to the placenta calculated as a percentage of CCO (a) in 164 low-risk pregnancies. (b) The 29 fetuses with intrauterine growth restriction directed a lower proportion of CCO to the placenta (P < 0.001), particularly in extreme degrees of compromise. Growth-restricted fetuses were divided into groups, showing various degrees of placental compromise: those with normal umbilical artery pulsatility index (PI) ( ), those with PI > 97.5 th percentile ( ) and those with absent or reversed end-diastolic blood velocity ( ). Lines indicate 10 th, 50 th and 90 th percentiles. The equation for the regression line was y = GA GA 3 ln(ga), andsd= GA, where GA is gestational age in weeks. Data were ln-transformed. The fraction of CCO directed to the placenta in normally grown fetuses was on average 32% before 32 weeks, and 21% beyond 32 weeks (Figure 10). In general, growth-restricted fetuses distributed less of the CCO to the placenta (P < 0.001) (Figure 10 and Table 1). While growth-restricted fetuses with normal PI ua distributed a similar fraction of the CCO to the placenta compared with their normal peers, this was not the case for those that had hemodynamic compromise. Those with PI ua > 97.5 th percentile and particularly those with ARED flow in the umbilical artery had a reduced fraction of CCO distributed to the placenta (Table 1), implying an increased recirculation of umbilical blood in the fetal body. DISCUSSION In this study we showed that fetuses normally direct one third of their cardiac output to the placenta during the second half of pregnancy and one fifth during the last couple of months. Interestingly, this implies an increase in recirculation of umbilical blood in the fetal body towards the end of pregnancy. Furthermore, this effect is augmented in placental compromise. Growth-restricted fetuses direct a reduced volume of blood towards the placenta, both in absolute and in relative terms, while maintaining a relatively normal cardiac output. The effect seems to increase with the degree of placental compromise and signifies a more extensive recirculation of umbilical blood within the fetal body. The distribution of volume load within the fetal heart also seems to be affected. Although experimental data 15,16 and some studies in humans 17 suggest that the normal dominance of the right ventricle is cancelled during challenge, our study supports that in fetuses with increased pulsatility of the umbilical artery the right ventricle actually takes an increased proportion of the load 18,19. This is in keeping with other mechanisms seen in such fetuses: reduced size of and shunting through the foramen ovale 7,20, increased resistance in the pulmonary circuit 21, with correspondingly less venous return to the left heart, and retrograde blood flow at the aortic isthmus 7,22 to further supply the aortic arch and carotid arteries with right ventricular blood via the ductus arteriosus. A shift to the left of the watershed area between portal and umbilical venous supply to the liver 23,24 andanaugmented blood velocity in the hepatic artery 25 will change the fetal circulation in the same direction. These are mechanisms of redistribution but also of increased recirculation of umbilical blood in the fetal body, which correspond to more extensive oxygen extraction. On average, the oxygen concentration in the umbilical vein measured in the IUGR fetus during cordocentesis is lower than that in their normal peers 26. The fraction of fetal CCO directed to the placenta found in this study is in line with the two previous studies that examined this issue in humans, but with an important difference: the placental fraction was less (one fifth) near term. The study of Rudolph et al. 8 using the microsphere technique found an average 33% Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

26 Placental fraction of CCO 135 distribution of the CCO to the placenta at mid-gestation, but did not include higher gestational ages. Due to the method of calculating CCO (pulmonary venous return was not included) and the conditions not being strictly physiological (the fetuses were exteriorized), the results have awaited verification. Our study, applying a different technique, presents very similar results indeed; 32% of the CCO was directed to the placenta during gestational weeks In the second study, Sutton et al. 9 used Doppler ultrasound in physiological pregnancies to show that the placental fraction of the CCO is one third for the second half of pregnancy. Fewer numbers included and calculation of umbilical venous flow using maximum velocity (which tends to overestimate flow if not corrected for the parabolic velocity profile) may explain some of the differences from our study in late pregnancy. The normal fetal CCO found in our study had a similar pattern during the second half of pregnancy to that described in previous studies Compared with those using leading edges (inner outer diameter) for the vessel cross-section measurement, our results of CCO are lower (1300 vs ml/min at 38 weeks) 29 ; our results are more in agreement with those using inner diameters in their calculation, as they are for CCO/kg (400 vs. 425 ml/min/kg) 30. The 6% difference may be ascribed to technique (this study measured between valves at the ostium), or to chance. Knowing the variability of such measurements in the fetus 31,32, particularly diameter measurements, we restricted error by repeating measurements 12,33 and by using a single operator. Coefficients of variation of 8.4 and 7.7%, and intraclass correlations of 94 and 97% for the diameter of the aorta and pulmonary artery, respectively, ensured that the study gave a fair representation of normal and abnormal flows. We acknowledge that having cardiac outflow measurements in less than half of the IUGR group might represent a limitation of the study, with a possible selection bias. A successful examination is least likely in small fetuses with oligohydramnios in overweight mothers; in our setting we believed that time constraints for such mothers and fetuses (which, due to clinical reasons, tended to be examined for a shorter period than did the low-risk group) were the main reason for the low success rate. The fact that umbilical venous flow was obtained successfully in 62/64 cases underscores the point that due to time limitation, the lower priority of cardiac measurements gave fewer results. In short, one third to one fifth of the fetal CCO circulates the normal placenta; in comparison, the compromised placenta shrinks this fraction, both in absolute and in relative terms, thus driving the circulation towards increased recirculation of umbilical blood within the fetal body. We believe this reflects an increased vulnerability in much the same way as does the low oxygen concentration found in growth-restricted fetuses. ACKNOWLEDGMENT The study was supported by the Norwegian Research Council. REFERENCES 1. Kramer MS, Olivier M, McLean FH, Willis DM, Usher RH. Impact of intrauterine growth retardation and body proportionality on fetal and neonatal outcome. Pediatrics 1990; 86: Barker DJP, Hales CN, Fall CHD, Osmond C, Phipps K, Clark PMS. Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth. Diabetologia 1993; 36: Robinson JS, Kingston EJ, Jones CT, Thorburn GD. Studies on experimental growth retardation in sheep. The effect of removal of endometrial caruncles on fetal size and metabolism. JDev Physiol 1979; 1: Bocking AD. Effect of chronic hypoxaemia on circulation control. 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Cardiovasc Res 1991; 25: Kiserud T, Rasmussen S, Skulstad SM. Blood flow and degree of shunting through the ductus venosus in the human fetus. Am J Obstet Gynecol 2000; 182: Skjaerven R, Gjessing HK, Bakketeig LS. Birthweight by gestational age in Norway. Acta Obstet Gynecol Scand 2000; 79: Kiserud T, Saito T, Ozaki T, Rasmussen S, Hanson M. Validation of diameter measurements by ultrasound. Intra-observer and inter-observer variation assessed in vitro and in the fetal sheep. Ultrasound Obstet Gynecol 1999; 13: Royston P, Wright EM. How to construct normal ranges for fetal variables. Ultrasound Obstet Gynecol 1998; 11: Bland JM. How should I calculate a within-subject coefficient of variation? mb55/meas/cv.htm [Accessed 22 September 2005]. 15. Thornburg KL, Morton MJ. Filling and arterial pressures as determinants of RV stroke volume in the sheep fetus. Am J Physiol 1983; 244: H656 H Rudolph AM. Distribution and regulation of blood flow in the fetal and neonatal lamb. Circ Res 1985; 57: al-ghazali W, Chita SK, Chapman MG, Allan LD. Evidence of redistribution of cardiac output in asymmetrical growth retardation. BrJObstetGynaecol1989; 96: Reed KL, Anderson CF, Shenker L. Changes of intra-cardiac Doppler blood flow velocities in fetuses with absent umbilical artery diastolic flow. Am J Obstet Gynecol 1987; 157: Weiner Z, Farmakides G, Schulman H, Penny B. Central and peripheral hemodynamic changes in fetuses with absent end-diastolic velocity in umbilical artery: Correlation with Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

27 136 Kiserud et al. computerized fetal heart rate pattern. Am J Obstet Gynecol 1994; 170: Kiserud T, Chedid G, Rasmussen S. Foramen ovale changes in growth-restricted fetuses.ultrasound Obstet Gynecol 2004; 24: Rizzo G, Capponi A, Chaoui R, Taddei F, Arduini D, Romanini C. Blood flow velocity waveforms from peripheral pulmonary arteries in normally grown and growth-retarded fetuses. Ultrasound Obstet Gynecol 1996; 8: Sonesson S-E, Fouron J-C. Doppler velocimetry of the aortic isthmus in human fetuses with abnormal velocity waveforms in the umbilical artery. Ultrasound Obstet Gynecol 1997; 10: Kiserud T, Kilavuz Ö, Hellevik LR. Venous pulsation in the left portal branch the effect of pulse and flow direction. Ultrasound Obstet Gynecol 2003; 21: Kilavuz Ö, Vetter K, Kiserud T, Vetter P. The left portal vein is the watershed of the fetal venous system. JPerinatMed2003; 31: Kilavuz Ö, Vetter K. Is the liver of the fetus the 4th preferential organ for arterial blood supply besides brain, heart, and adrenal glands. JPerinatMed1999; 27: Soothill PW, Nicolaides KH, Campbell S. Prenatal asphyxia, hyperlactaemia and erythroblastosis in growth retarded fetuses. BMJ (Clin Res Ed) 1987; 294: Kenny JF, Plappert T, Saltzman DH, St John Sutton MG. Changes in intracardiac blood flow velocities and right and left ventricular stroke volumes with gestational age in the normal fetus. Circulation 1986; 74: De Smedt MCH, Visser GHA, Meijboom EJ. Fetal cardiac output estimated by Doppler echocardiography during midand late gestation. Am J Cardiol 1987; 60: Rasanen J, Wood DC, Weiner S, Ludomirski A, Huhta JC. Role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy. Circulation 1996; 94: Mielke G, Benda N. Cardiac output and central distribution of blood flow in the human fetus. Circulation 2001; 103: Beeby AR, Dunlop W, Heads A, Hunter S. Reproducibility of ultrasonic measurement of fetal cardiac haemodynamics. Br J Obstet Gynaecol 1991; 98: Simpson JM, Cook A. Repeatability of echocardiographic measurements in the human fetus. Ultrasound Obstet Gynecol 2002; 20: Kiserud T, Rasmussen S. How repeat measurements affect mean diameter of the umbilical vein and the ductus venosus. Ultrasound Obstet Gynecol 1998; 11: Copyright 2006 ISUOG. Published by John Wiley & Sons, Ltd. Ultrasound Obstet Gynecol 2006; 28:

28 Innhold Perinatale infeksjoner Grete A.B. Kro Mikrobiologisk avdeling OUS Rikshospitalet 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Perinatale infeksjoner Informasjon om perinatale infeksjoner Oversiktsslide Under oppdatering

29 Nasjonal faglig retningslinje for bruk av antibiotika andre.. Innhold 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Perinatale infeksjoner To vanlige problemstillinger Oversiktsslide Diagnostikk 1. Gravid som har infeksjonssymptomer 2. Funn hos foster

30 Virusinfeksjoner; det vanlige og det farlige.. Bakterielle infeksjoner; det vanlige og det farlige.. Influensa eller annen viral luftveinsinfeksjon CMV Parvovirus Toxoplasmose Enterovirus (Coxsackievirus) Varicella Hepatitt B og C HIV Rubella Herpes simplex Zika.. «Vanlige bakterielle infeksjoner» Gruppe B streptokokker Bakteriell vaginose Aerob vaginitt Klamydia Gonorè Listeria Tuberkulose Resistente bakterier; MRSA, VRE, ESBL Hvilke prøver vil du ta? Hvilke prøver vil du ta? Prøve fra evt infeksjonsfokus f.eks luftveier, sår, placenta, fostervann, urin Prøve fra evt infeksjonsfokus f.eks luftveier, sår, placenta, fostervann, urin Blodprøver: Infeksjonsmarkører? Serum til antistoffer og EDTA fullblod til PCR undersøkelser OBS! Ulike transportmedier for ulike materialer og undersøkelser. Blod er ikke blod for laboratoriet.. Virusdiagnostikk PCR versus antistoff/serologi Serologi eller PCR? PCR Antistoff/serologi Prøve fra der agens finnes; sårsekret, fostervann, placenta, fullblod Serumprøve

31 Kliniske opplysninger.. Kliniske opplysninger.. Gravid uke 20 5 dager feber og leddsmerter Ingen konsensus om standardpakke? Toxoplasma IgG Parvovirus IgG Rubella IgG CMV IgG? Parvovirus IgG Parvovirus IgM Parvovirus PCR CMV IgG CMV IgM Toxoplasma IgG Toxoplasma IgM Rubella IgG Rubella IgM Evt Enterovirus PCR Evt Varicella Evt Zika dersom reise.. To vanlige problemstillinger Infeksjon hos foster? 1. Gravid som har infeksjonssymptomer 2. Funn hos foster CMV Parvovirus Toxoplasmose Herpes Varicella Syfilis Rubella Enterovirus (Coxsackievirus) Zika.. Prøver fra mor Infeksjon hos mor nå? Hatt infeksjon tidligere i svangerskapet? Screeningprøve tidlig i svangerskapet? Tidligere svangerskap? Infeksjon hos foster? Prøver ved fødselogså til virusanalyser! CMV Parvovirus Toxoplasmose Herpes Varicella Syfilis Rubella Enterovirus (Coxsackievirus) Zika.. Prøver fra mor Prøver fra foster? Fostervann Placenta Navlestrengsblod Urin- eller spyttprøve av barnet ved spm om CMV

32 Innhold Parvovirus B19 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause Viktig fordi: Hyppigere enn vi tror.. Føtal infeksjon kan gi anemi- behandling mulig Negative antistoff (IgG og IgM) utelukker ikke sikkert infeksjon 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Parvovirus B19 Parvovirus B19 Gir 5.barnesykdom: Ofte asymptomatisk. Lett feber. Utslett ansikt- kropp. Leddsmerter Smitte: Dråpesmitte. Mest smittsomt ca 7 dager FØR utslett Hos foster- hyppigst skader <20. svangerskapsuke Parvovirus infiserer fostadier til røde blodceller gir anemi Fosterdød (< 20 uker: 10%) Hydrops foetalis (uke 9-20: 3%) Inkubasjonstid 4-21 dager Parvovirus B19 Parvovirus B19 Påvisbar antistoffproduksjon kan mangle hos gravide Behandling Ingen antiviral behandling finnes Blodtransfusjon til foster ved alvorlig anemi Det bør gjøres parvovirus PCR i tillegg til IgG og IgM ved mistanke om parvovirusinfeksjon

33 Eksempel Gravid uke 36 Spørsmål om parvovirus infeksjon hos foster Kvinnen: IgG positiv og IgM negativ Kan infeksjon i svangerskapet utelukkes? Tidligere prøver!!! Innhold Hepatitt B 1. Oversikt infeksjoner 2. Diagnostikk Obs! Kvinner fra endemiske områder 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Hepatitt B Er den gravide smitteførende? Smitte fra virusbærende mor til barnet under fødselen er hyppig (35-90 %) Hepatitt B s Antigen Hepatitt B s Antistoff Hepatitt B core Antistoff Perinatal smitte gir ofte kronisk infeksjon OBS! Barn som er perinatalt eksponert for hepatitt B, skal ha immunglobulin umiddelbart etter fødsel og starte HBV-vaksinasjon En del av selve viruset Surface Beskytter Core Gjennomgått Positiv = smitteførende Alene = vaksine

34 Innhold Toxoplasmose 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Parasitten Toxoplasma gondii Kort periode med parasitter i blodet. Bare i denne perioden kan fosteret smittes? Parasitten forblir i kroppen etter smitte ikke aktiv form 39 Toxoplasmose- husk IgM kan vedvare leeeeeeeeeeenge Finnes tidligere prøver? Påvist IgM er ikke ensbetydende med infeksjon i aktuelt svangerskap Avvent svar fra utvidet serologisk analyse Ikke skriv i journal at pasienten har toxoplasmose før dette er ENDELIG avklart 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom Innhold 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering

35 Cytomegalovirus (CMV) Hvorfor CMV diagnostikk? CMV er vanligste infeksiøse årsak til utviklingsavvik i nervesystemet i industrialiserte land* CMV er vanligste infeksiøse årsak til sensorinevralt hørselstap i industrialiserte land* Seronegative småbarnsmødre spesielt utsatt for smitte Finne årsak til symptomer/funn Behandling/oppfølging ETTER fødselen Antiviral behandling? Oppfølging i barneårene * Kenneson A,Cannon MJ. Review and meta-analysis of the epidemiology of congenital 43 cytomegalovirus infection. Rev Med Virology 2007; 17: IgM Bare ca 50% av IgM positive har primær CMV infeksjon Forekomst av CMV-infeksjon i svangerskapet Gravide i Norge: ca 40% seronegative 45 Sallie R. Permar et al. J. Virol. 2018;92:e Forekomst av CMV-infeksjon i svangerskapet Gravide i Norge: ca 40% seronegative Transmisjon til foster Primærinfeksjon: 30-40% Reaktivering/reinfeksjon: <1 % Sallie R. Permar et al. J. Virol. 2018;92:e Sallie R. Permar et al. J. Virol. 2018;92:e

36 Diagnostikk foster 1. Ultralyd Intrauterin vekstretardasjon 1. Ultralyd 2. CMV DNA påvisning i fostervann 49 Microcephali Annet CNS: ventriculomegali, intracerebrale calcifikasjoner, periventriculær ekkogenisitet, corticale eller cerebellare malformasjoner m.fl. Hepatomegali, splenomegali, ascites, ekkogenisitet i tarm Merk: CMV sykdom er ofte IKKE synlig på ultralyd REF Congenital cytomegalovirus infection in pregnancy ; a review of prevalence, clinical features,diagnosis and prevention. Naing ZW, Scott GM, and Shand A et al. Australiand and New Zealand Journal of Obstetrics and Gynaecology 2016; 56:9-18 REF: Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, diagnosis, and therapy. Rawlinson WD, Boppana SB, and Kimberlin DW et al. Lancet Infectious Diseases 2017 Jun;17(6):e177-e188. REF: Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management. Luck SE, Wieringa JW, and Blázquez-Gamero D et al ; ESPID Congenital CMV Group Meeting, Leipzig Pediatr Infect Dis J Dec;36(12): CMV DNA påvisning i fostervann Ved CMV infeksjon og etablert nyrefunksjon Fostervannsprøve til CMV DNA påvisning (PCR) Vurderes og tas av fostermedisiner CMV skilles ut i urinen og kan påvises i fostervann Tidligst 6-8 uker etter mors antatte smittetidspunkt Sensitivitet 45-80% Gestasjonsalder minst uker, helst >23 51 Dersom CMV ikke påvises i fostervannsprøve: Rutinemessig spytt- og urinprøve til CMV PCR innen 3 uker etter fødselen 52 Behandling av foster? Innhold Antivirale midler? Ganciclovir/valganciclovir: Mulig effekt. Trygt? Kasuistikker er publisert. Studier trengs. Aciclovir/valaciclovir: Bare litt effekt på CMV, men regnes som trygt. Spesifikt CMV hyperimmunoglobulin? Usikker effekt Mulig bivirkninger Studier trengs Pr dags dato er internasjonal konsensus: Ingen behandling anbefalt 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering REF: Congenital cytomegalovirus infection in pregnancy and the neonate: consensus recommendations for prevention, 53 diagnosis, and therapy. Rawlinson WD, Boppana SB, and Kimberlin DW et al. Lancet Infectious Diseases 2017 Jun;17(6):e177-e188.

37 Kasuistikk Kvinne 37 år Gravida 1, Para 0 Svangerskapsvarighet 31 uker Spørsmål om premature rier Urinprøve: neg Dyrkning vaginalsekret Andre prøver? Ikke vannavgang eller blødning. UL: alt normalt Tiltak? Hvilke prøver vil du ta? Neonatal sepsis Vaginas bakterielle mikrobiom Tidlig neonatal sepsis (<72 t etter fødsel) Smittes Transplacentalt Oppadstigende fra vagina Ved passasje gjennom fødselskanalen Vanligste bakterier: Gruppe B streptokokker 43% av alle 73% av terminbarn 9% dødelighet E.coli 29% av alle 81% av preterme 33% dødelighet = normalflora Et komplekst økosystem Påvirkes av oral- og tarmflora Barriære - hindrer sykdom Ref: Shane AL et al Lancet 2017 Ubalanse i vaginalflora Assosiert med: Spontanabort Preterm fødsel Postpartuminfeksjon Pelvic inflammatory disease Bakteriell vaginose Aerob vaginitt Soppinfeksjon

38 Innhold Bakteriell vaginose 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus Endret flora i vagina hos ca 25% av kvinner i fertil alder Lactobasiller Gardenerella vaginalis Anaerober (Adopobium, Bacteriodes, Prevotella, Mobiluncus m.fl.) Mycoplasma og Ureaplasma 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Østrogen- Glycogen- Lactobasiller- melkesyre- ph Aerob vaginitt (AV) Aerob vaginitt Vaginal inflammasjon Lave nivå av lactobasiller Flora domineres av aerobe bakterier Bakterier fra tarmflora: Gruppe B streptokokker, S.aureus (gule stafylokokker), E.coli, andre Enterobacteriaceae (f.eks Klebsiella), Enterokokker Diagnostikk basert på mikroskopi av våtpreparat Vaginal dyrkning: bekrefte diagnosen, ekskludere candidainfeksjon Ikke det samme som bakteriell vaginose! Gulaktig purulent illeluktende utflod (ikke fiskelukt..) Kløe Dyspareuni Rødhet/inflammasjon i mucosa Overfladiske ulcerasjoner Negativ KOH test Aerob vaginitt Aerob vaginitt Prevalens: 3-9 % av lav-risiko svangerskap Etiologi og patogenese uklar Gir risiko for Preterm fødsel Chorioamnionitt Betennelse i navlesnoren (funisitt) Profylaktisk behandling av gravide med AV for å redusere risiko for preterm fødsel? Clindamycin reduserer ikke risiko Kekki M et al Obstet Gynecol 2001 McGregor JA et al Am J Obstet Gynecol 1994 Clindamycin reduserer risiko Kiss H et al BMJ 2004 Larsson PG et al BJOG 2006 Lamont RF et al Obstet Gynecol 2003 Ugwumadu A et al Lancet 2003 Hva med probiotika?

39 Behandling Innhold Mål for behandling Reetablere sunn laktobasilldominans vedvarende Strategier Drepe skadelige bakterier Tilføre sunne bakterier Endre vertsfaktorer Problem ved behandling Biofilm: resistent mot antibiotika Residiv etter antibiotikabehandling Resistente bakterier selekteres Nivåene av Lactobasiller blir ikke tilstrekkelig høye 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose og aerob vaginitt 7. Vaginalprøve til dyrkning 8. Oppsummering Vaginalprøve til dyrkning Normalflora eller ikke; det er spørsmålet Prøvesvar med og uten kliniske opplysninger.. Prøvetagning Skriv problemstilling på rekvisisjonen!!! Unngå forurensing av sterile prøvematerialer

40 Innhold HUSK! 1. Oversikt infeksjoner 2. Diagnostikk 3. Noen virus + en parasitt 1. Parvovirus 2. Hepatitt B 3. Toxoplasma gondii 4. Cytomegalovirus 4. Pause 5. Vaginas bakterielle mikrobiom 6. Bakteriell vaginose 7. Aerob vaginitt 8. Oppsummering Kliniske opplysninger!! Ha en venn på mikrobiologen.. Gravid uke 20 3 dager feber og leddsmerter Ingen konsensus om standardpakke Toxoplasma IgG Rubella IgG CMV IgG Parvovirus IgG Parvovirus IgG Parvovirus IgM Parvovirus PCR CMV IgG CMV IgM CMV PCR Toxoplasma IgG Toxoplasma IgM Rubella IgG Rubella IgM Evt Enterovirus PCR Evt Varicella Evt Zika ESBL Viktig fordi: Blir mer og mer hyppig i Norge Konsekvens for behandling av pasienten ved infeksjon Skal ha smitteverntiltak

41 ESBL ESBL quiz Hva er det egentlig? Hva er ESBL? Veldig smittsomme bakterier Veldig resistente bakterier Bakterieenzymer Extended Spectrum Beta Lactamase Enzymer (β-laktamaser) ESBL quiz Når bør du tenke på ESBL? Inaktiverer Smal virkn. Bredspektret β-laktam-antibiotika: Penicilliner eks: penicillin G, kloksa-/dikloksacillin Cefalosporiner 1. generasjon (eks: cefalotin) 2. generasjon (eks: cefuroksim) 3. generasjon (eks: cefotaksim, ceftazidim) (4. generasjon) Karbapenemer eks: meropenem Bakteriene er i tarmflora Ikke eradikasjon Karianne W. Gammelsrud 2014 ESBL ESBL

42 ESBL ESBL Praktisk konsekvens dersom en gravid har ESBL? Praktisk konsekvens dersom en gravid har ESBL? Smittevern Behandling ved sykdom ESBL ESBL Vanlig ESBL Super ESBL Slutt

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60 Døgnrytme hos fosteret og antenatal CTG Har fosteret en døgnrytme? Jörg Kessler Kvinneklinikken Haukeland Universitetssykehus Forskningsgruppe for svangerskap, fosterutvikling and fødsel Klinisk institutt 2 Universitetet i Bergen Har fosteret en døgnrytme? Har fosteret en døgnrytme? Synkronisert glukose opptak i SCN mor og foster N=18/26 Gestasjonsalder uker Reppert, S. M. et al (1984). Neuroscience Letters, 46(2), Lunshof, S. et al. (1998). AJOG.178(2), Hvordan undersøke? Døgnrytme hjertefrekvens Transabdominal EKG basert Holter registrering Sletten et al., submitted

61 Døgnrytme gutter vs jenter Døgnrytme gutter vs jenter Jentefostre samordnet populasjonsrytme Guttefostre stor interindividuell variasjon Sletten et al., submitted Sletten et al., submitted Antenatal CTG Når tar vi CTG? Før fødsel Ingen rier, kynnere Mange normale «Stikkprøve» Under fødsel Rier Mange unormale Kontinuerlig Innkomst Sammentrekninger/ rier Screening Hypoksi, akutt/kronisk Hvorfor? Hvordan? Doppler ultralyd, trykkprobe Registrering i minst 20 minutter Papirhastighet 1 cm/min Anemi/ hypovolemi Infeksjon Måle mors puls! Pulsoxymeter

62 Fortolkning Variabilitet Deselerasjoner Akselerasjoner Variabilitet Basalfrekvens Korttidsvariabilitet - maskinell utregning - kan ikke bedømmes visuelt - angis i millisekunder Langtidsvariabilitet - båndbredde - visuell bedømning - angis i slag/min 500 ms HF: 120/min 480 ms HF: 125/min STV= 500 ms ms = 20 ms Korttidsvariabilitet Korttids- og langtidsvariabilitet STAN S31, Neoventa, Mølndal Dawes-Redman algoritme STV i loggen: gjennomsnittsverdi fra start inntil aktuelle tidspunkt Direkte sammenheng STV: kvantitativt hjelpemiddel Pardey, AJOG 2002; 186: Basalfrekvens CTG og svangerskapsalder Langtidsvariabilitet Korttidsvariabilitet CTG og svangerskapsalder Amorim-Costa (2016) Park (2001) Serra (2009) Akselerasjoner Park, Int J OG 2001; 74: Serra, et al. (2009). Ultrasound Obstet Gynecol: 34(1), Amorim-Costa et al. Acta Obstet Gynecol Scand, 95(10),

63 Fortolkning Fortolkning: Normal CTG FIGO RCOG/NICE ACOG/NICHHD SOGC Antepartum Intrapartum Felles klassifikasjonssytem ante- og intrapartum Felles klassifikasjonssytem ante- og intrapartum Ayres-de-Campos, Int J OG 2010; 110:1-6 Liston et al. J Obstet Gynecol Can 2007; 29: Veileder NGF, 2014 Liston et al. J Obstet Gynecol Can 2007; 29: S3-56 Fortolkning: Normal CTG Antenatal CTG - prediktiv verdi Mortalitet/Morbiditet Falsk negativ Falsk positiv % 55-90% Reaktiv CTG => tilnærmet 100% sannsynlighet for ikkehypoksisk foster Reaktivitet! Non-reaktiv CTG => 10-45% sannsynlighet for hypoksisk foster Veileder NGF, 2014 Liston et al. J Obstet Gynecol Can 2007; 29: S3-56 Signore et al. Obstet Gynecol 2009; 113: Fortolkning: Ikke normal CTG Korttidsvariabilitet - intervensjon N=3563 fostre N= CTG >4 ms: normalt 3-4 ms: intensiver overvåking <3ms: vurder forløsning Veileder NGF, 2014 Liston et al. J Obstet Gynecol Can 2007; 29: S3-56 Dawes, G. S.et al.(1992). Obstetrics and Gynecology, 80(4),

64 Ikke normal CTG - hva så? Kasus 1 Krever ALLTID ytterlige tiltak Diagnostikk Overvåkning Tiltak - Fortsette CTG - Ultralyd - Vekst - Sirkulasjon - Innleggelse - Induksjon - Forløsning Hva er årsaken? Plan for oppfølging og behandling Veileder NGF, 2014 Liston et al. J Obstet Gynecol Can 2007; 29: S3-56 Kasus 2 Antenatal CTG - nytteverdi Potensielt unngåelige dødsfall Neonatale kramper Grivell et al (2015). Cochrane Database Syst Rev, (9), CD Computer CTG - nytteverdi Perinatal mortalitet Estimated fetal weight [g] Del av et test batteri Umbilical artery PI Potensielt unngåelige dødsfall Grivell et al (2015). Cochrane Database Syst Rev, (9), CD Short-term variation (ms) Gestational age [weeks] Gestational age (weeks) Middle Cerebral artery PI Gestational age (weeks) Gestational age (weeks)

65 Intrapartum fosterovervåkning Fosterets oksygen status og målet med fosterovervåkning Under graviditeten lever foster med lav O 2 i blodet, normal CO 2 og uten acidose. Under fysiologisk fødsel utvikles noe hypoksi og relativ placentas insuffisiens: Branka M.Yli Målet med fosterovervåkning under fødselen identifisere fostre med risiko for å utvikle komplikasjoner på grunn av hypoksi under fødselen Utvikling av O 2 mangler Hvorfor asfyksi skader i Norge? Hypoksemi: redusert O 2 i blod Hypoksi: redusert O 2 i vevene Asphyksi: når hypoksi affiserer sentrale organer: hjertet, hjernen og binyrene Haugen G et al Circul Res

66 Hvorfor asfyksiskader i Norge? Intrapartum overvåkning Pinard stetoskop/doppler. CTG 1968 Etter vannavgang CTG kombinert med: Skalp ph 1963 Skalp laktat 1990-årene Foster EKG (STAN) 2000 Blodsirkulasjon Fetal Circulation shunt based :the most the O 2 -rich blood to the heart and brain 65% O 2 saturation O 2 55% Kiserud T et al Prenatal Diagnosis 200; CO 2 Blod fra fosteret avfall via navleateriene til placenta 85 % 35 % Blod til fosteret via navlevene (surstoff, ernæring, hormoner) Ductus venosus- Foramen ovale Ductus arteriosus 2

67 Acid-bases values in the healthy term foetus before birth and neonates after birth, along with the adult values for comparison Living on the top of Mount Everest! Umbilical vein Umbilical cord Umbilical cord vein Adult artery d before birth a artery after birth after birth ph > ( ) b 7.35 ( ) b pco 2 (kpa) < ( ) b 5.2 ( ) b BDecf (mmol/l) < ( ) b 3.5 ( ) b po 2 (kpa) > ( ) c 3.5 ( ) c The fetus lives in low O 2 environment a Results obtained by cordocentesis b Median (2.5th- 97.5th percentile). From the 13,181 term neonates, spontaneous vaginal deliveries, no epidural analgesia, no induction, and 5 minute Apgar score 7. c Data from 1145 term neonates with 5 minute Apgar score 7 after spontaneous vaginal deliveries d 95 % reference interval, from Laboratory Book Department of Medical Biochemistry, Oslo University Hospital,Rikshospitalet. Does the fetus spends months with inadequate oxygenation? Sir John Bracroft 1946 Hvilke mekanismer sikrer fetal oksygenering? Hemoglobin F ( HbF)har større affinitet for O 2 ved samme po 2 CTG Oksygen-dissosiasjons kurven er venstre-forskjøvet Økt konsentrasjon av Hb (40%), øker O 2 transport kapasitet Høyere hjertefrekvens hos fostre Høy perfusjonsrate av både sentrale and perifere organer Voksen Hb Det mest brukte obstetriske prosedyre!! 89% av fødsler» ACOG 2009, Chen rt.al AJOG

68 u u u CTG Kontinuerlig overvåkning God sensitivitet: alle fleste med hypoksi vil ha unormal CTG Dårlig spesifisitet: alle fleste unormale CTG skyldes ikke hypoksi Intrapartum CTG vs lytting av fosterlyd Metaanalyse: 12 Randomiserte Kontrolerte Studier (RCT) ( 2 høy kvalitet) > forlosninger keisersnitt (RR 1.66, 95 % CI ) instrumentele forløsninger (RR1.16, 95% CI ) neonatale kramper (RR 0.50,95%CI ) (-) perinatal mortalitet (RR 0.85, 95%CI ) (-) CP (RR 1.74,95%CI ) Bruk av skalp ph endret ikke forskjellen i neonatale kramper eller andre resultater Alfirevic Z et al, Cochrane Library 2006 RCT- tidsperspektiv Melbourne 1976 Denver 1979 Copenhagen 1985 Denver 1976 Sheffield 1978 Melbourne 1981 Dallas 1986 Dublin 1985 Seattle 1987 Pakistan 1989 Athens 1993 WHO, FIGO, RCOG Kontinuerlig CTG anbefales for høyrisiko kasus WHO, Lancet 1985;2:436 FIGO, Int J Gynecol Obstet 1995;49:213 RCOG. The use of elctronic fetal monitoring. RCOG press, London fødsel trengs for å finne ut effekt på perinatal mortalitet 4

69 Hva evaluerer vi på CTG? Variabilitet Reaktivitet Frekvens Deselerasjoner Rier Variabilitet Den viktigste indikator for fosterets well being Sentrale nervesystemets evner til å overvåke og finjustere sirkulasjons apparatet gjennom det autonome nerve systemet Normal mellom 5-25 slag Måler: Båndbredden Legemidler: effekt på variabilitet og frekvens Mg, Steroider Betablokkere Sedativa Nedsatt variabilitet 5

70 Hypoksi: effekt på variabiliteten Variabilitet ofte: Initialt økt Senere nedsatt Fravær Fravær av variabilitet: hjertemuskulaturens evne til å reagere er redusert, og fosteret har ingen evner å finmodulere sirkulasjon 6

71 Nedsatt variabilitet-sent i hypoksiutviklingen Preterminal variabilitet-alvorlig asfyksi SINUSOIDALvariabilitetpatologisk CTG Sinusformede bølger med amplituden av 5-15 bpm, sjelden større, frekvens på 2-5 sykluser per minutt, stabil baslinje og ingen områder med normal FHR variabilitet eller reaktivitet. Modanlou and Freeman Sinusoidal varabilitet Forekomst 0.3 to 1.7% Ikke perioder med normal CTG ALTID PATOLOGISK CTG Anemi hos fostre! Modanlou HD Murata Y; Sinusoidal heart rate pattern: Reappraisal of its definition and clinical significance. Obstet Gynaecol Res Jun;30(3):

72 Pseudosinusoidal- ikke forveksle normal CTG Forekomst 15% Svangerskap og fosterfrekvens The high inter-fetal variability and considerable intra-fetal consistency suggests the possible value of using each fetus as its own reference in serial assessments! 1 Amorim-Costa (2016) 2 Serra (2009) 3 Park (2001) Foster sutter på tommel (2016) Murphy KW et al. BJOG 1991 Hva er normal fosterfrekves? Bruk foster som egen kontroll: sjekk altid fosterfrekvensen fra starten og samelign med siste kontrollene og på Helsekortet 2 dager etter Frekvens? Frekvens 120 8

73 Hypoksi: effekten på frekvensen Langsom utvikling av hypoksi Sympaticus: Stresshormoner Tahykardi Langsom reaksjon Rask utvikling av hypoksi Parasympa*cus: Vagus Bradykardi Rask reaksjon Deselerasjoner Deselerasjoner Risikrone- tidlige deselerasjoner Uniforme (forhold til riene, begynner før eller etter at rien er nådd sin maksimum) Tidlige (N) Variable (Varighet, slagtap) Ukompliserte <1 min, slagtap < 60 (N) < 1min, slagtap > 60 (A) Eksperimenter av Edward Hon i fødsel med trykk på fosterhodet med ringpessarene introdusert i vagina viste raske korte deselerasjoner som varer i 15 sek Sene (P) Kompliserte > 1 min (P) HON EH. The electronic evaluation of the fetal heart rate. Preliminary report

74 Deselerasjoner Deselerasjoner: Forstyrrelser i placentasirkulasjon (volum Volumreseptor i hjerte ) Navlesnor kompresjoner Utero-placentær insuffisiens Kompliserte variable deselerasjoner(kvd) Hvor mange KVD per 20 min = Patologisk CTG? Okkludert navlesnor 1 min / 5 min (4 KVD/20 min) 4 timer: Okkludert navlesnor 1 min / 25 min (8 KVD/20 min)4 timer: BT fall etter 4.okklusjon stabiliserer seg, nytt fall på slutten 10

75 2 min / 5 min Prograssiv hypotensjon BT fall allerede etter 3. oklusjon Progressiv acidose ph 6,82 BD 22,9 Avsluttet gjn.snitt :116, 3 min dvs 23 okklusjoner Total deselerasjoner areal ( mange UKD+KVD) Hypoksi- sene deselerasjoner Akutt / kronisk feto-placentar insuffisiensaktivering av kjemoreseptorer VIKTIGST særlig i kombinasjon med f.eks økt frekvens, redusert variabilitet o.v. 11

76 Sene deselerasjoner Infrared spektroskopi:lys basert måling av cerebral oksygenering Cerebral konsentrasjon av oxsyhemoglobin- deoxihemoglobin Sene deselerasjoner signifikant reduksjon i cerebral oksygenering Aldrich CJ et al. BJOG 1995 Sameshima H et al,unselected low-risk pregnancies and the effect of continuous intrapartum fetal heart rate monitoring on umbilical blood gases and cerebral palsy Jan;190(1): Rier Rier: effekten på sirkulasjonen Basal tonus (under 30 mmhg) Maksimal trykk Frekvens Varighet Fosteret trenger sec mellom riene for å komme seg etter den nedsatte gassutvekslingen Myometrium: 2-3 ganger Intrauterin trykk Spiral arterie: mmhg Intervillous rom Stasis Hypoksemia Hyperkapnia Acidemia Uterinhulen: mmhg 12

77 Optimalt tid mellom kontraksjoner Uterin hypertoni (tachysystoli): Infrared spektroskopi:lys basert måling av cerebral oksygenering Cerebral konsentrasjon av oxsyhemoglobin- deoxihemoglobin >5 kontraksjoner/10 min i 30 min periode ACOG Det må 2,3 min mellom kontraksjoner for a unngå signifikat oksygenfall i hjerne!! Sammenhengende/koblede kontraksjoner Økt basaltonus mellom kontraksjoner Økt basaltonus! Pleebles DM et al BJOG 1995 For mange rier-gir hypoksi- bruk oksytocin riktig! Viktig: Tids faktor. < 5 rier/10min 5 rier/10m >5 rier/10m Tids faktor under pågående utvikling av hypoksi: ph faller: 0,01/min Anoksia (skulder dystoci) ph faller opp til 0,04/min* Hypotension/ Ischemi i tillegg (abruptio placentae,uterus ruptur, skulder dystoci) Luttkus et al 2004 * Myers re at al 1972 Kathleen Rice Simpson, Dotti C. James: Effects of oxytocin-induced uterine hyperstimulation during labor on fetal oxygen status and fetal heart rate patterns; American Journal of Obstetrics and Gynecology Volume 199, Issue e1-34.e5 13

78 Rier Myometrium: 2-3 ganger Intrauterin trykk Spiral arterier Spiral mmhg arterier: mmhg Intervlilløs Rom Uterin hulen: Stasis mmhg Hypoksemia Hypoksemia Hyperkapnia Hyperkapnia Acidemia Acidemia Neonatal utfall i forhold til lengde av aktiv trykketid n = 22,812 kasus Pushing time (min) n(%) ph <7 OR (95% CI) n(%) ph <7 or BDecf >12 or 5 Apgar <7 OR (95% CI) <15 12(0.2) 1 41(0.6) (0.5) 3.2 (1.7-6) 73(1.1) 1.8 ( ) (0.8) 4.7 (2.5-9) 94(1.6) 2.4 ( ) + aktiv trykking (0.6) 3.8 ( ) 38(1.9) 2.7 ( ) (1.3) 7.3 ( ) 18(2.5) 3.5 ( ) Sirkulasjon til spiral arteriene er kraftig redusert Hypoksia Hyperlaktemia Acidose 120 3(0.9) 5.1 ( ) 41(2.3) 3.3 ( ) Multilevel regression analyses after adjustment for parity, induction of labor, epidural use, birth weight and gender Yli BM et al. How does the duration of active pushing in labor affect neonatal outcomes? JPM 2011 Lengde av trykketid i forhold til navlearterie ph<7.00 What about spontaneous pushing (open glottis )? Time of active pushing (min) p<0.001 Pearson s chi-square test ODR 32.8% ODR 7.8% p<0.001 ph<7.00 ph³ min ( 9-107) 23 min ( 5-87) Yli BM et al. How does the duration of active pushing in labor affect neonatal outcomes? JPM 2011 Respiratory efforts typically involve breathing with an open glottis, rather than a closed glottis, such as the case during a VM When women push spontaneously, they begin to push from their resting respiratory volume, and they push multiple times per contraction (3 5) for 3 to 5 seconds per effort, followed by about 2 seconds of breaths and the release of air. Vocalization requires that the glottis is open. Prins M, Boxem J, Lucas C, Hutton E.,. BJOG 2011;118:

79 Valsalva pushing is frequently used in the second stage of labour, but the evidence for this pushing technique is not clear. Objectives :To critically evaluate any benefit or harm for the mother and her baby of Valsalva pushing versus spontaneous pushing in the second stage of labour. Prins M, Boxem J, Lucas C, Hutton E.,. BJOG 2011;118: Valsava pushing modifies pelvic floor function when measured using urodynamic studies several months following childbirth. Prins M, Boxem J, Lucas C, Hutton E.,. BJOG 2011;118: Konklusjon Uterus er muskel- høy laktat-stivner! Det støttes ikke rutinemessig bruk av Valsalva i den II stadie av fødselen. Valsalvas metoden har en negativ effekt på urodynamiske faktorer. Varigheten av II stadie av fødsel er kortere med Valsalva men den kliniske betydningen av dette funnet er usiker! Laktat konsentrasjonen: høyere i myometrietblodet enn i skjellettmuskler hos kvinner i fødsel Ved langsom framgang ph myometriet er lavere ph=7,35 sammenlignet med kvinner med elektiv sectio ph=7,47 Wray S Qunby et al

80 Myometriet patologisk rimønster Langsom framgang/dysfunksjonell fødsel Abnorme rier, dårligere eksport av laktat og metabolitter Laktat akkumuleres Ristyrken avtar i denne situasjonen og fødselsforløpet stagnerer ph synker: Det påvirker kalsiumtransporten inn i myocytene Uterus mister kontraksjonsstyrke ved høye laktat verdier og lav ph i kapillarblod i myometrie Hyppigst årsak til SC ved P0 20 % av alle fødsler med levende barn har protrahert forløp ( langsom framgang). Zhu B. et al.labor dystocia and its association with interpregnancy interva AJOG 2006 Denmark: multisenter studie,lav risiko P0, term: 37% Kjaergaard HI et al. Incidence and outcomes of dystocia in the active phase of labor in term women with spontaneous labor onset. Acta Obstet Gynecol Scand. 2009;88(4): nulliparous Quenby et al. Dysfunctional labor and myometrial lactic acidosis. Obstet Gynecol. 2004;103: Årsaker til dysfunksjonel fødsel Hovedårsaker: Ikke effektive rier --> protrahert forløp Malposisjon (feilinnstilling) Cefalopelvic dysproposjon (mekanisk misforhold) Laktat i fostervannet 60 kvinner med elektivt keisersnitt, biopsier fra myometrietoppdaget laktat transport proteiner :MCT-1, MCT-4. Myometriet produserer store mengder laktat både ved aerobe forhold (bidirectional ) og anaerobe forhold (unidirectional ) Under aktivitet passerer laktat frem og tilbake via MCT1 og MCT4, meget liten passiv diffusjon Betran AP et al Paediat Perinat Epidemiol 2007; 21; Fostervann inneholder store mengder laktat. Laktatkonsentrasjon i fostervannet 4-6 x større enn i mors blod eller fosterets blod. Åkerud et al. Am J Physiol Endocrinol Metab,

81 Samarin was given to help the uterus recover from the muscular changes associated with labor dystocia Each package of Samarin original has an active substance of sodium bicarbonate 2.13g and tartaric acid, citric acid, sodium, potassium and silica. Two bags of Samarin was mixed in a glass of water (200ml) and ingested during a couple of minutes by the laboring woman 1h before stimulation with oxytocin started. Kjønn av fostre In the multivariate analysis, male gender was found to be significantly associated with first stage: OR 1.76, 95% CI , p = second stage: OR 1.73, 95% CI , p < 0.01 pathological fetal heart tracing patterns, ph < 7.1, and Apgar scores at 1'< 7. CONCLUSIONS:Trend of a lower clinical performance of male neonates compared with females. In addition, the relation between fetal heart rate patterns during all stages of labor and fetal gender showed an independent association between male gender and abnormal fetal heart monitoring during labor. 17

82 Hva slags pasient har vi? CTG tolkning Risiko mor? Risiko fostre? Risiko under fødsel? Risikofaktorer hos mor: Risikofaktorer hos foster: Risikofaktorer under fødsel: Preeklampsi Preterm fødsel ( <37 SU) Stimulering med oxytocin (CTG) Etter vurdering STAN Overtidig svangerskap: 294 dager Vekstrestriksjon Feber hos mor Diferensiering er mangefult Tidlegare alvorlige kompikasoner ved Oligohydramnion Misfarget fostervann svangerskap eller fødsel Tidligere sectio, eller andre operative inngrep på Unormale funn ved Doppler-u.s. i art. Vannavgang over 18 timer med spontan uterus umbilicalis, a.cerebri media eller ductus fødselstart venosus Indusert fødsel Immunisering Protrahert forløp 30% overflyttes til avdeling for å overvåkes! Berniz S et al BJOG 2011 Mistanke om infeksjon hos mor Tvillingsvangerskap Rikelig vaginalblødning Blødning før fødsel (utover tegningsblødning) Mors alder: fra år etter vurdering f.eks paritet Mors BMI > 40 Sjeldne sv kontroller (<4per svang) Medisinske sykdommer: Høy blood trykk Hjerte/lungesykdommer Diabetes mellitus Gestasjonell diabetes Autoimun sykdom (SLE) Alvorlig anemi Andre tilstander etter vurdering Mistanke om mindre fosterbevegelser Epidura,spinalanalges,PCB: ved innkomst CTG de første 30 min fra oppstart Setepresentasjon Mistanke om avvikende hjertelyd ved Andre tilstander etter vurdering auskultasjon Abnormal uterin aktivitet Avvikende eller patologisk CTG ved innkomst NGF Veileder: Fødselsovervåking % av de som fikk medhold for asfyksi var antenatalt definert som lav risiko! Andreasen S et al.acta Obstet Gynecol Scand Nov 18

83 CTG Konstant med variasjoner Periodisk Ø Frekvens Ø Variabilitet Ø Akselerasjoner Ø Deselerasjoner(evn) CTG CTG (modifisert FIGO) Normalt Avvikende Patologisk Preterminalt Minimumstid 20 minutter for tolkning 1 cm i minuttet Rier Variabilitet Reaktivitet Frekvens Deselerasjoner 19

84 CTG (FIGO) Rier Minimumstid 20 minutter for tolkning 1 cm i minuttet Rier Variabilitet Reaktivitet Frekvens Deselerasjoner Åpningstiden(starten) 2-3 / 10 min sekunder Åpningstiden( slutten) 4-5/10 min 90 sekunder Uterin hypertoni (tachysystole): >5 kontraksjoner/10 min Sammenhengende/koblede kontraksjoner Økt basaltonus mellom kontraksjoner Abnormal rie-frekvens!! CTG (modifisert FIGO) Minimumstid 20 minutter for tolkning 1 cm i minuttet Rier Variabilitet Reaktivitet Frekvens Deselerasjoner Økt basaltonus! 20

85 Variabilitet Normalt: 5-25 slag/min Avvikende: >25 slag/min (saltatorisk) Variabilitet Patologisk: Sinusoidalt mønster eller < 5 slag/min i mer enn 1 time eller < 5 slag/min i mer enn 40 min Preterminalt: Ingen variabilitet (2 slag/min) og reaktivitet, med eller uten deselerasjoner eller bradykardi CTG (modifisert FIGO) Reaktivitet / Akselerasjoner Minimumstid 20 minutter for tolkning 1 cm i minuttet Rier Variabilitet Reaktivitet Frekvens Deselerasjoner Definisjon: Intermitterende økning i hjertefrekvensen >15 slag, >15 sek Preterme: >10 slag >10 sek Ikke regelmessig!! 21

86 Reaktivitet / Akselerasjoner Normalt reaktiv CTG: >2 akselerasjoner /20 min Vaginal undersøkelse: sjekke reaktivitet Fetal stimulasjon: stimulere det autonom nerve systemet og fremkalle akselerasjoner. Pålitelig møte å ekskludere acidose! Preterminalt: Ingen variabilitet (2 slag/min) og reaktivitet med eller uten deselerasjoner eller bradykardi Sannsynligheten for lav skalp ph er 2% dersom akselerasjon! Skupski DW et al Obstet Gynecol 2002 CTG (modifisert FIGO) The majority of fetuses are not acidemic even when the FHR trace is pathological and stimulation tests are only helpful when accelerations are provoked. Minimumstid 20 minutter for tolkning 1 cm i minuttet Rier Variabilitet Reaktivitet Frekvens Deselerasjoner 22

87 Basallinjefrekvens Frekvens Definisjon: Fosterhjertets frekvens mellom rier, registrert i minst 10 minutter Normal: slag/min (preterme 160) Avvikende: slag/min; slag/min; Kort episode med bradykardi Patologisk : >170 slag/min; Bestående bradykardi Bradykardi CTG (modifisert FIGO) Kort episode med bradykardi <100 slag/min i > 3 min <80 slag/min i > 2 min Bestående bradykardi <100 slag/min i >10 min <80 slag/min i > 3 min uten stigende tendens Minimumstid 20 minutter for tolkning 1 cm i minuttet Rier Variabilitet Reaktivitet Frekvens Deselerasjoner 23

88 Deselerasjoner Deselerasjoner Definisjon: Uniforme Variable: Fall i hjertefrekvens >15 slag, >15 sekunder Preterme >10 slag, >10 sekunder Forholder seg til riene. Ikke stor slagtap Forholder seg IKKE til riene. Rask tap av slag, ofte betydelig slagtap. Deselerasjoner Uniforme (forhold til riene, begynner før eller etter at rien er nådd sin maksimum) Variable (Varighet, slagtap) Tidlige Uniforme Sene Variable UVD UVD>60 slagtap KVD. Tidlige (N) Ukompliserte <1 min, slagtap < 60 (N) < 1min, slagtap > 60 (A) Sene (P) Kompliserte > 1 min (P) Normalt CTG Patologisk CTG Normalt CTG Avvikende/ Patologisk CTG 24

89 CTG Stmulasjons test Vaginal undersøkelse: få akselerasjon! (reaktiv) Fetal stimulasjon: stimulere det autonom nerve systemet og fremkalle akselerasjoner. Pålitelig møte å ekskludere acidose! Progresjon over tid!!! Sannsynligheten for lav skalp ph er 2% dersom akselerasjon! Skupski DW et al Obstet Gynecol 2002 STAN: ST-ANalyse STAN : ST-ANalyse av foster-ekg Kontinuerlig overvåkning Tradisjonell CTG registrering kombinert med automatisk ST-segment analyse av fosterets EKG i overvåkning av fullbårne fostre under fødsel ST økning ST senkning (Bifasisk ST) 25

90 EKG Komplekset ST-intervall forandringer (eventer) ST-intervall elevasjon ST-intervall senkning ST intervallet Episodisk ST event < 10 min Baslijie ST event >10 min Bifasiske eventer Patologisk CTG ST eventer 2 nivåer avhengig av CTG klassifisering 1. CTG klassifisering Intervensjon ØPreterminal CTG: Ikke vent med ST flagg! Forløs! ST information Patologisk CTG uten ST flagg i utdrivnigs:den: Avvente maksimum 60 min : Forløs! Barnet bør bli født innen 90 min! 26

91 STAN testet + anbefaling i Norge Ak#v fødsel, e-er vannavgang Graviditet 36+0 Risiko svangerskap og fødsel Senest start avslutning av åpnings#d Startes helst fra normal CTG (siste 30 min), Hvis start med patologisk CTG-ikke vist ny-e av STAN CTG/STAN Kontinuerlig overvåkning Definert intervensjons tid J Normalt CTG: K Avvikende CTG: K Patologisk CTG: se bort fra ST henelser STAN retningslinje STAN retningslinje L Preterminal: forløs umiddelbart Viktig: Tids faktor Når det er indikasjon for tiltak CTG/ST event Åpningstiden: 20 minutter: Tiltaket skal hjelpe innen 20 min, hvis ikke CTG bedre seg - må du forløse! Ved start av andre stadiet (10 cm): forløsning innen 20 min! Trykketiden: Umiddelbart forløsning! Indikasjon for tiltak ut fra CTG alene Patologisk CTG uten ST flagg i andre stadiet. Avvente maksimum 60 min : Forløs! Barnet bør bli født innen 90 min! Preterminal CTG: Ikke vent med ST flagg! Forløs! Forløsning kan ta lengre tid en forventet! Kompliserte vaginale forløsninger Mislykket forsøk på operativ vaginal forlosning før Keiser snitt Tidligere sectio, nå ny, teknisk mer krevende 27

92 USA RCT 74,39% ekskludert USA CTG veileder:3 klasser «Category II tracings,( yellow zone) are the most frequent seen in >80% of laboring women, are quite variable in their significance and can include FHR patterns from the most benign to the most threatening!» Anthony M. Vintzileos, AJOG september 2016Volume 215, Issue 3, Pages

93 10 meta-analysis (ST analysis + CTG vs CTG alone) 10 metaanalysis CTG +FBS +ST vs CTG+FBS (CTG alone) 8% reduction of operative vaginal deliveries 36% reduction of metabolic acidosis RCTs Gold standard for assessing new technology, BUT do not typically reflect everyday practice Observational studies Reduction in adverse perinatal outcomes > 20 studies Less FBS Operative interventions Learning curve Need for real-world evidence 29

94 STAN Observetional Clinical studies Ny artikkel! 19 published studies11 land (S, N, F, DK, NL, B, D, I, GB,USA, Singapore) > patients Positiv experiance comfirmed results from RCT Aksepted by health care personal and and patients Kwee A et al 2004 Ross MG et al 2004 Devoe LD et al 2006 Noren et al 2006 Welin AK et al 2007 Vayssiere C et al 2007 Massoud et al 2007 Doria T et al 2007 Palmgren N et al 2007 Kale et al 2008 Melin M et al 2008 Rzepka et al 2010 Noren H et al 2010 Ragupathy et al 2010 Doret M et al 2011 Timonen S 2012, 2018 Kessler J et al 2013 Chandraharan E et al ST eventer 2 nivåer avhengig av CTG klassifisering The study was conducted at the Turku University Hospital, Finland, with 3,400-4,200 annual deliveries. The study population consisted of 42,146 deliveries during the study period In the whole study population ph <7.05 : 1.5% % (RR, 0.54; 95% CI, ), CS : 17.2% -14.1% (RR, 0.82; 95% CI, ) FBS : 1.75% -0.82% (RR, 0.47; 95% CI, ) When the two study periods were compared: ST analysis group cord metabolic acidosis : 1.0% to 0.25% (RR, 0.33; 95% CI, ) ØPreterminal CTG: Ikke vent med ST flagg! Forløs! Patologisk CTG uten ST flagg i utdrivnigs:den: Avvente maksimum 60 min : Forløs! Barnet bør bli født innen 90 min! 30

95 Når kan STAN begynne å varsle? Bifasiske: allerede etter 3 kryss, hvis det foreligge signifikant (2 eller 3) ST senkning Fetal skalpblodprøve (FBS) Basislinje og episodiske: etter at baslinje er bestemt : Trengs 10 kryss innen 10 min. Tidspunkt når baslinje er bestemt står i loggen FBS: Skalp ph Ikke kontinuerlig overvåkning, må repeteres Invasiv FBS + CTG vs..ctg Kun en RCT ( 695) som direkte sammenlignet CTG vs. CTG+FBS- ingen forskjeller Haverkamp AD et al. AJOG 1979 FBS: Ikke testet protokoll for indikasjon/hyppighet av FBS Westgate J et al. BJOG 1994 Ikke definert protokoll Tas ikke når indikasjon i 33% Tas uten indikasjon i 39% Becker HJ et al. BJOG 2011 Definert protokoll Tas etter protokoll i 58% Hvor mange FBS per pasient? NICE ved 3. overlege beslutning 31

96 1-2 FBS versus 3 FBS FBSs-n 1070 laboring women median of two samplings (range 1-8) Results No differences in Apgar score <7 at 5 min No difference metabolic acidemia in umbilical art. 23% CS in 1-2 FBS vs 42% 3 FBS (OR 2.05;95%C.I ) Tidskrevende Tidskrevende The interval between the decision to perform the procedure and obtaining the result and evaluated. The median time for FBS was 10 min. When cervical dilatation was 4 cm samples took approximately 30% longer to obtain. 32

97 Tolking av FBS analyseverdier Normal: ph > 7,25 Laktat 4,2 Forventet laktat verdier under fødsel Lactate 4-10 cm The mean lactate 1.7 +/- 0.8 mmol/l No difference was seen in lactate in early compared to late first stage of labor Pushing time (lactate increases 1mmol/30 min pushing) Preacidotisk: ph 7,21-7,24 Laktat 4,2-4,7 Ny prøve etter min., eller vurder forløsning om det har vært raskt fall siden siste prøve Acidotisk:. ph < 7,20 Laktat > 4,8 Rask forløsning iverksettes Labor The mean lactate umbilical artery immediately after delivery 3.7 +/- 1.2 mmol/l. Nordstrøm L et al.acta 1994, Nordstrøm L et al. BJOG cases Normal CTG and 5 Apgar score 9,0 The reference interval of fetal scalp lactate during second stage is from mmol/l; median 2.5 mmol/l (LactateProTM) Lactate intermediate/pathological CTG (p <0.001) Lactate P0, use of epidural or oxytocin (p <0.001) Lactate durition of active pushing time Parity, epidural, oxytocin and active pushing time together, had equal influence on lactate values (p <0.001). increase in scalp lactate of mmol/l for every min of bearing down: 1,5 mmol/ time 33

98 Take home massage! Differensiering er mangefult! Tilstedeværelse, omsorg og kommunikasjon er veldig viktig! Lære seg CTG/STAN /FBS Forstå klinikken Forstå når en normal fødsel går til patologi og handle ut fra dette Diskutere med kollega- klar hvem som eier pasient Overvåke helt til slutten av fødsel Handle rask hvis det er indikasjon Vurderer alltid hele pasient! Sjekkliste for fødselsovervåkning Hva slags risiko har pasienten? Tekniske karakteristika: 20 min lang, god signal kvalitet? Ekstern CTG? US1/US2(US2 for tvillinger og adipøse pasienter). Intern CTG? Se på: Rier: frekvens/varighet, typer, basaltonus (maks 5/10 min) Frekvensen: minst 10 min, og mellom riene Variabiliteten: saltatorisk, sinusoidal,nedsatt 40 min/60 min, frævarende Akselerasjoner: til stedet Deselerasjoner: Uniforme (tidlige, sene); Variable (UVD,KVD) CTG klassifiseres som: Normal Avvikende Patologisk Preterminal Dokumenter! Forandres CTG seg over tid: fra en patologisk mønster til en annen patologisk mønster? Fra patologisk til preterminal: Følg med nøye! Skaff tilleggs informasjon! Dokumenter! Tiltak: Fysiologiske tiltak: stoppe oksytocin, riedempende medikamenter hvis hyperton uterus væske til mor, feber nedsettende hvis feber, stillingsendring eller forløsning. Evaluerings tiltak: skalp blodprøve, akselerasjon ved palpasjon Tid: Er det forløsning indikasjon. Forløs raskt! VURDER alltid hele pasient! Hvis flere risikofaktorer tenk på alle i vurdering av forløpet! Ofte sier en etter uønsket utfall: Lett å være etterpåklok Hvis man vurderer hele risiko,kan man bli etterpåklok på forhånd! Gynekol hist BMI Alder Paritet Med. syk Sv. Syk IVF Sv lengde Forløp Overvåking Tid IMPORTANT! Absence of evidence is not evidence of absence Studies that have found no statistically significant difference in outcome, may not have been large enough to exclude them. To conclude that they prove ineffectiveness of treatments is clearly misleading... Altman DG, Bland JM. BMJ 1995;311:485 34