Neonatology

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Neonatology

  1. 1. 2.1 The Fetus at TermThe stages of development of the human, from embryo tofetus and finally to newborn baby, are shown in Table 2.1.2.2 Developmental Phases of the FetusThe embryonic phase is a critical stage of development, whensystems undergo important basic development.The third week after conception marks the beginning ofthe embryonic period. It ends at the end of the tenth week,when the embryo comprises three layers from which all or-gans will develop.The second fetal phase begins after the tenth week andcontinues until the end of pregnancy. During this phase, or-gans (liver, kidneys) begin to function.From the 16th to 20th weeks, the fetus undergoes a rapidgrowth spurt. Fat develops under a thin skin. Cardiac outputincreases. Meconium accumulates in the bowel. The fetushiccups and spends time awake and asleep.Fetal development slows down between the 21st and 24thweeks. By the 24th week, the fetus weighs approximately 1,3pounds (0,6 kg).Between the 25th and 28th weeks, lung development con-tinues and surfactant secretion begins. By the 28th week, 90%of fetuses will survive ex utero with appropriate support.From the 29th to the 40th weeks, the amount of body fatrapidly increases. Thalamic brain connections, which mediatesensory input, form. Bones are fully developed. Most of themajor systems and organs are complete. The immune systemdevelops.By weeks 35−40, the fetus is sufficiently developed forlife outside the uterus without any more support than thatwhich would be required by any newborn baby delivered atterm. At 37 weeks, the fetus will continue to add approxi-mately one ounce (28 g) per day to its body weight and it willbe 48−53 cm (19−21 inches) in length at birth.2.3 Fetal Constitutional Characteristics2.3.1 The Central Nervous System (CNS)The CNS is formed by four subdivisions of the neural tube thatdevelop into distinct regions of the central nervous system.The neural tube is initially open both cranially and cau-dally. These openings close during the fourth week. Failure ofclosure of these neuropores can result in neural tube defectssuch as anencephaly or spina bifida.The dorsal part of the neural tube comprises the alar plate,which is primarily associated with sensation. The ventral partof the neural tube comprises the basal plate, which is primarilyassociated with motor control.The spinal cord is a long, thin, tubular bundle of nervoustissue and support cells that extend from the brain. The brainand spinal cord together make up the central nervous system.The spinal cord functions primarily for the transmission ofneural signals between the brain and the rest of the body, butalso contains neural circuits that independently control numer-ous reflexes and central pattern generators.D. Arduini ( )Department of Obstetrics and GynecologyUniversity of Rome Tor Vergata, Rome, Italy7G. Buonocore et al. (eds.), Neonatology. A Practical Approach to Neonatal Diseases.© Springer-Verlag Italia 2012Table 2.1 The stages of development of the human fetus, from embryoto newbornFetus at term1. Development phases of the fetus2. Fetal constitutional characteristics3. Diagnosis of fetal well-being4. Fetal injuries5. Fetal response to injuries6. Postnatal development2The Development from Fetus to NewbornDomenico Arduini and Marianne Vendola
  2. 2. 2.3.2 The Fetal CirculationThe essential difference between the circulatory system of afetus and that of the baby after birth is that the lungs are notin use: the fetus obtains oxygen and nutrients from the motherthrough the placenta and the umbilical cord. Blood from theplacenta is carried to the fetus by the umbilical vein. A largeproportion enters the fetal ductus venosus and passes to theinferior vena cava, while the remainder enters the liver fromvessels on its inferior border. The branch of the umbilical veinthat supplies the right lobe of the liver joins the portal veinand blood then passes to the right atrium. In the fetus, thereis an opening between the right and left atria (the foramenovale), and most of the blood flows from the right into theleft atrium, thus bypassing pulmonary circulation. The ma-jority of blood flow is then into the left ventricle from whereit is pumped through the aorta to supply the various organs.Blood then flows from the aorta through the internal iliac ar-teries to the umbilical arteries, and re-enters the placenta,where carbon dioxide and other waste products from the fetusare taken up and enter the maternal circulation. A small pro-portion (about 4%) of the blood from the right atrium doesnot enter the left atrium, but enters the right ventricle and ispumped into the pulmonary artery. In the fetus, a connectionbetween the pulmonary artery and the aorta, called the ductusarteriosus, directs most of the blood away from the lungs(which are not being used for respiration at this point as thefetus is suspended in amniotic fluid).An important concept of the fetal circulation is that fetalhemoglobin has a higher affinity for oxygen than adult he-moglobin, which facilitates diffusion of oxygen from the ma-ternal circulation to the fetus. The circulatory system of themother is not directly connected to that of the fetus, so gasexchange takes place at the placenta. Oxygen diffuses fromthe placenta to the chorionic villus, an alveolus-like structure,from which it is then carried to the umbilical vein. Fetal he-moglobin enhances the fetal ability to draw oxygen from theplacenta because the oxygen dissociation curve is shifted tothe left, which has the effect of oxygen being taken up at alower concentration than by adult hemoglobin. This enablesfetal hemoglobin to take up oxygen from adult hemoglobinin the placenta, which has a lower partial pressure of oxygenthan at the lungs after birth.A developing fetus is highly susceptible to anomalies ofgrowth and metabolism, increasing the risk of birth defects.2.3.3 Fetal MetabolismA continuous placental supply of glucose provides the sub-strate for energy metabolism to the fetus, and this convertsafter birth to intermittent feeding. While the fetus is dependenton maternal glucose as the main source of energy, it can alsouse lactate, free-fatty acids, and ketone bodies under someconditions (e.g. starvation or hypoxia). Fetal glucose utiliza-tion is augmented by insulin produced by the developing fetalpancreas in increasing amounts as gestation proceeds; this en-hances glucose utilization in insulin-sensitive tissues (skeletalmuscle, liver, heart, adipose tissue), which increase in massand thus glucose requirement during late gestation. Glucose-stimulated insulin secretion increases with gestation. Glyco-gen stores are maximal at term, but even the term fetus onlyhas sufficient glycogen available to meet energy needs for8−10 hours, and this store can be depleted even more quicklyif demand is high.At 27 weeks’gestation, only 1% of a fetus’sbody weight is fat; this increases to 16% at 40 weeks. Inade-quate glucose substrate can lead to hypoglycemia and fetalgrowth restriction. In cases of intrauterine growth restriction,fetal weight-specific tissue glucose uptake rates and glucosetransporters are maintained or increased, while synthesis ofamino acids into protein and corresponding insulin-likegrowth factor (IGF) signal transduction proteins are de-creased. These observations demonstrate the mixed phenotypeof the intrauterine growth restriction (IUGR) fetus that has anenhanced capacity for glucose utilization, but a diminishedcapacity for protein synthesis and growth. Excess substratecan also lead to problems, as with infants of diabetic mothers(IDM). Thus, the normal fetus has a considerable capacity toadapt to changes in glucose supply [1].2.3.4 Regulation of Fetal GrowthFetal growth depends on many different aspects, mostly in-fluenced by maternal and uteroplacental factors.2.3.4.1 Role of the Mother in Fetal Growth RegulationFetal growth and development are influenced by genetic aswell as environmental factors. Maternal genes have an im-portant specific influence on fetal growth; for example, ma-ternal height is a major determinant of fetal size, representinguterine capacity and the potential for growth. Although thebirth weights of siblings are similar and correlate, environ-mental influences are also important in determining growth.Maternal constraint refers to the limited capacity of the uterusto support fetal growth and is important in limiting fetal over-growth and subsequent dystocia, to ensure the mother’s ca-pacity for future successful pregnancies [2].Maternal Nutrient IntakeThe mother is the supplier of oxygen and essential nutrientsto the fetus via the placenta. Maternal diet, caloric intake, andmetabolic function have an important role in supplying nu-trients to the fetus. Increased caloric intake is necessary dur-ing the second and third trimesters to allow for fetal and8 D.Arduini and M.Vendola
  3. 3. placental growth [3]. A Cochrane systematic review of sixrandomized controlled trials found that balanced protein-en-ergy supplementation reduced the risk of small for gestationalage (SGA) neonates by approximately 30% [4]. Glucose isan important nutrient in the control of fetal growth. Studiesof diabetic women have shown that low blood glucose levelsduring pregnancy as a result of excessively tight glycemiccontrol lead to a greater incidence of SGA neonates, whereashigh blood glucose levels increase the likelihood of macro-somia [5].Maternal Uterine Artery Blood FlowIncreased uterine blood flow is essential to meet the meta-bolic demands of the growing uterus as well those of the pla-centa and fetus [6]. Uterine artery blood flow increases bymore than three-fold during pregnancy, partly influenced byan increased artery diameter and reduced resistance to flow.In addition to increased uterine blood flow during normalpregnancy, new blood vessels develop in the uterus, promotedby the placental hormones human chorionic gonadotropin(hCG) [7] and IGF-II [8]. Using Doppler assessment of uter-ine arterial flow at 23 weeks’ gestation, Albaiges et al [9]found that that increased uterine artery blood flow resistancewas associated with an increased risk of an SGA baby.Maternal Smoking and Drug UseMaternal cigarette smoking is associated with reduced birthweight. Early reports suggested a doubling of the rate of lowbirth weight in babies of smokers compared with those ofnon-smokers and a dose-dependent effect with increasingnumber of cigarettes smoked. More recent studies demon-strated a 3.5-fold increased risk of SGA infants in womenwho smoked during pregnancy [10], with a greater effect onlow birth weight with increasing maternal age [11]. Growthrestriction is usually symmetrical with reduced weight, headcircumference, and abdominal circumference. The use ofdrugs, such as cocaine and marijuana, also has significantnegative effects on fetal growth. Cocaine use contributes toan increased rate of low birth weight and a reduction in meanbirth weight of at least 100 g.Maternal HypoxiaMaternal hypoxia influences fetal growth. Its effect is inde-pendent of socioeconomic status, prematurity, maternalsmoking, pregnancy-induced hypertension, and parity. Thecombination of hypoxia and pregnancy appears to be impor-tant in altering maternal physiology, including changes in im-mune pathways [12]. Maternal hypoxia affects placental anduterine blood flow, which contribute to reduced nutrient trans-port to the fetus [13].Maternal Inflammatory DiseasesThe presence of maternal inflammatory disease may con-tribute to reduced fetal growth. Several inflammatory diseasesare associated with reduced fetal growth, including rheuma-toid arthritis [14], inflammatory bowel disease, systemic lupuserythematosus, and periodontal disease [15]. Women with ac-tive inflammatory arthritis during pregnancy have smaller ba-bies compared with healthy women or women whose diseaseis in remission [16], suggesting that active inflammation dur-ing pregnancy may contribute to reduced fetal growth. Mater-nal health influences the maternal state during pregnancy withimplications for fetal growth. In addition to inflammatory dis-eases, many other maternal factors, including preeclampsia[17], anemia [18], infections and alcohol consumption, influ-ence fetal growth via changes in placental function.2.3.4.2 Role of the Placenta in Fetal Growth RegulationThe placenta receives and transmits endocrine signals be-tween the mother and fetus and is the site of nutrient andwaste exchange. Adequate placental growth is essential foradequate fetal growth. Several aspects of placental functionare critical for human fetal growth and development, includ-ing adequate trophoblast invasion, an increase in uteropla-cental blood flow during gestation, transport of nutrients suchas glucose and amino acids from mother to fetus, and the pro-duction and transfer of growth-regulating hormones. In-creased blood flow during pregnancy increases the flow ofnutrients from mother to fetus, and uteroplacental blood flowhas been shown to be reduced by up to 50% in women withpreeclampsia [19]. Doppler velocimetry is used to detect in-creased vascular resistance in the uterine arteries, which oc-curs as a result of abnormal trophoblast invasion of the spiralarteries. In addition, examination of the fetal circulation, par-ticularly umbilical artery waveforms, may reflect placentalinsufficiency [20]. Umbilical vein blood flow, measured byDoppler ultrasound, is decreased in IUGR fetuses, represent-ing reduced perfusion of the fetal tissues.Placental Hormone ProductionDuring human pregnancy, the placenta is an important en-docrine organ. It produces hormones, including estrogens andprogesterone, hCG, human growth hormone (GH) variant,and human placental lactogen. Some of these play a role inthe regulation of fetal growth. Fetal insulin promotes growthof the fetus, acting as a signal of nutrient availability [20]. In-sulin deficiency results in reduced fetal growth, as the fetaltissues decrease their uptake and utilization of nutrients.There is also a relationship between increased insulin produc-tion and increased fetal growth. It has been proposed that thefetus increases its own production of insulin in response tomaternal hyperglycemia, and that this increase in fetal insulin2 The Development from Fetus to Newborn 9
  4. 4. is responsible for the increased growth and macrosomia ob-served in diabetic pregnancies.2.4 Diagnosis of Fetal Well-beingDuring pregnancy, women are generally offered non-invasivescreening tests, such as blood tests, ultrasound and car-diotocography (CTG) (to detect the fetal heartbeat and uterinecontractions, usually monitored during the third trimester), toevaluate the baby’s health. Alternatively, more invasive tests,such as chorionic villous sampling or amniocentesis, may beperformed.Obstetric ultrasound is usually used to:• diagnose pregnancy;• assess possible risks to the mother (miscarriage or molarpregnancy);• check for fetal malformation;• determine intrauterine growth restriction;• note the development of fetal body parts;• check the amniotic fluid and the umbilical cord.Generally an ultrasound examination is ordered wheneveran abnormality is suspected or following a schedule similarto that outlined below:• 7 weeks Confirm pregnancy, determine expected date ofdelivery;• 11–13 weeks Evaluate the possibility of Down syndrome;• 20−22 weeks Perform a scan to assess anatomic integrity;• 32 weeks To evaluate fetal growth, verify the position ofthe placenta and perform the Doppler study to establishfetal well-being.Three- dimensional (3-D) and four- dimensional (4-D) ul-trasound techniques are used to provide additional imagingof fetal structures. Today 3-D ultrasound is most commonlyperformed for the visualization of the baby’s face. However,it has the potential to become part of routine care and manyhospitals use the 3-D ultrasound to detect fetal anomalies, es-pecially of the heart and of the CNS (Fig. 2.1).2.5 Fetal InjuriesIt is important during fetal development to maintain goodfetal oxygen delivery to avoid irreversible fetal compromise.Fetal hypoxia from any cause leads to conversion from aero-bic to anaerobic metabolism, which produces less energy andmore acid. If the oxygen supply is not restored, the fetus dies.Hypoxia may be:1. Hypoxemic hypoxia: reduced placental perfusion with ma-ternal blood and consequent decrease in fetal arterialblood oxygen content due to low pO2.2. Anemic hypoxia: reduced arterial blood oxygen contentdue to low fetal hemoglobin concentration.3. Ischemic hypoxia: reduced blood flow to the fetal tissues.Making this diagnose can be difficult, and some episodesof hypoxia before and during birth may pass unnoticed at thetime, but may affect the central nervous system and not be-come evident until much later in life.2.5.1 Causes of HypoxiaTwo major categories of neurological injury can be observedin the full-term infant: (1) hypoxic-ischemic encephalopathy(HIE) and (2) intracranial hemorrhage (ICH). Brain hypoxiaand ischemia due to systemic hypoxemia, reduced cerebralblood flow (CBF), or both are the primary pathophysiologicalprocesses that lead to an hypoxic-ischemic encephalopathy.The first compensatory adjustment to an hypoxic-is-chemic (asphyxic) event is an increase in CBF due to hypoxiaand hypercapnia. This is associated with a redistribution ofcardiac output so that the brain receives an increased propor-tion of the cardiac output. This is followed by a slight increasein systemic blood pressure (BP) due to increased release ofepinephrine. In the fetus suffering from acute asphyxia (hy-poxic ischemia), if early compensatory adjustments fail, cere-bral blood flow (CBF) may become pressure-passive andbrain perfusion becomes dependent on systemic BP. As BPfalls, CBF falls below critical levels, and a diminished bloodsupply in the brain leads to insufficient oxygen to meet itsneeds and intracellular energy failure.Neuronal injury in hypoxic ischemia is an evolvingprocess. During the early phases of brain injury, brain temper-ature drops, and there is local release of neurotransmitters, suchas γ-aminobutyric acid transaminase (GABA). The magnitude10 D.Arduini and M.VendolaFig. 2.1 Reconstructed 3-D imaging of the eyes, palate and mandiblefrom the fetal profile
  5. 5. of the final neuronal damage depends on both the severity ofthe initial insult and damage due to energy failure, injury dur-ing reperfusion, and apoptosis. The extent, nature, severity,and duration of the primary injury are all important in deter-mining the magnitude of the residual neurological damage.Intracranial hemorrhage in the full-term infant can be in-traventricular, subarachnoid, subdural, or intracerebellar.There is often ventilatory disturbance and hypoxia becauseof varying neurological depression. Intraventricular hemor-rhage (IVH), which is unusual in term infants, may be asso-ciated with evidence of intrapartum asphyxia, but may alsobe clinically silent and underdiagnosed, causing later deficitsor hydrocephalus [21].Approximately 20% of neonatal HIE is primarily relatedto antepartum events that lead to hypoxic ischemia. Maternalconditions such as hypotension, placental vasculopathy, andinsulin-dependent diabetes mellitus may predispose the fetusto intrapartum hypoxic ischemia because there is little reserveto compensate for the stresses of labour [22]. Intrapartumevents such as prolapsed cord, abruptio placentae, and trau-matic delivery have been linked to 35% of cases of HIE.Because of the limitations in determining the actual timingof the insult, it may be difficult to identify the antepartumcontribution separately from the intrapartum. Other eventsbesides intrapartum hypoxia may be responsible for HIE orCP, as less than 25% of these infants have symptoms of hy-poxic ischemia at birth [23].The true incidence of intracranial hemorrhage (ICH) inutero has not been determined. Significant subarachnoid hem-orrhage can occur with intrapartum hypoxia, or may resultfrom trauma at delivery. It can be isolated or associated withsubdural bleeding and cerebral contusion. The presentationis variable but generally includes CNS depression, irritability,and seizures. When subarachnoid hemorrhage is associatedwith other signs of physical injury and is caused by a difficultdelivery, outcome is frequently poor.In fetal hypoxemia, there is a redistribution of blood flow.This results in an increased blood supply to the brain, my-ocardium, adrenal glands and reduced perfusion of the kid-neys, gastrointestinal tract and the lower extremities. Thereis preferential delivery of nutrients and oxygen to vital organs,compensating for a diminished placental supply [24]. Thiscompensation is manifest as cerebral vasodilatation and thereis an increase in the pulsatility index (PI) in cerebral vessels.The PI index is an arterial blood-flow velocity waveformindex designed to quantify the pulsatility or oscillations ofthe waveform. It is calculated by the formula PI = (Vmax –Vmin)/Vmax mean, where Vmax is the peak systolic veloc-ity, Vmin is the minimum forward diastolic velocity in uni-directional flow, or the maximum negative velocity indiastolic flow reversal, and Vmax mean is the maximum ve-locity averaged over one cardiac cycle (Figs. 2.2 and 2.3).Cerebral vasodilatation produces a decrease in left ventricularafterload, while increased placental and systemic resistanceresult in an increased right ventricular afterload. In severe2 The Development from Fetus to Newborn 11Fig.2.2 Flow velocity waveforms from the middle cerebral artery in anormal fetusFig.2.3 Flow velocity waveforms from the middle cerebral artery in agrowth-restricted fetusFig.2.4 Color Doppler examination of the ductus venosus with normalflow velocity waveformsFig. 2.5 Abnormal DV wave form with reversal of flow during atrialcontraction and markedly increased pulsatility systole (S), diastole (D),atrial contraction (a)
  6. 6. hypoxemia, there is also redistribution of umbilical venousblood towards the ductus venosus (Figs. 2.4 and 2.5). Conse-quently, blood flow in the umbilical vein, which contributesto the fetal cardiac output, is increased. In contrast, a reducedafterload is associated with an increase in peak diastolic for-ward flow, indicating that fetal systemic vascular resistancehas a major influence on venous return and filling patterns ofthe right heart. Increased placental resistance and peripheralvasoconstriction cause an increase in right ventricular after-load, and thus ventricular end-diastolic pressure increases.This may result in highly pulsatile venous blood flow wave-forms and umbilical venous pulsations due to the transmis-sion of atrial pressure waves through the ductus venosus.2.6 Fetal Response to InjuryDuring normal development, cardiovascular and circulatoryfunctions progress from fetal life, which is characterized bylow PaO2 (20−24 mmHg; 2.66−3.19 kPa) through transition atbirth, to normoxemia after birth (PaO2 70−80 mmHg;9.31–10.64 kPa); the fetus and newborn are clearly able tothrive despite their “hypoxic” environment.Adaptive responsesby the cardiovascular, metabolic and endocrine systems, allowfairly severe intrauterine hypoxic stress to be tolerated, withthe fetus having relatively normal growth and development.However, severe acute or chronic intrauterine hypoxic stressin utero can cause compromised circulation, organ dysfunction,and threaten survival or intact survival.At the time of transitionto extrauterine life, signs of a depressed circulatory system be-cause of intrauterine hypoxia may become apparent becauseof the increased metabolic demands at birth, and loss of pla-cental gas exchange [25]. Acute hypoxemia produces variouscirculatory adaptations in the fetus that enhance fetal survival,including the development of tachycardia, hypertension, re-distribution of blood flow toward the brain, myocardium andadrenals, and depression of fetal breathing and skeletal muscleactivity. The fetal heart also has a greater capacity for anaero-bic metabolism than the adult heart [26].The neonatal brain is more resistant to acute hypoxia thanthe brain of an older child or adult. Nevertheless, hypoxiaaffecting the fetus or newborn is a major cause of mortalityand chronic neurologic disability. The outcome for infantssustaining cerebral hypoxia and ischemia is influenced bymany factors, including the duration and severity of theevent, and associated infectious, traumatic, or metabolic (es-pecially hypoglycaemic) derangements [27]. Repetitiveepisodes of severe hypoxia may cause global neuronal, cor-tical, midbrain, and cerebellar damage, even if there has beeninitial “sparing” of the CNS.Damage may cause cerebral palsy and developmental dis-abilities in later life. The fetus of a high-risk pregnancy mayexperience such damage before birth, with recovery of bio-chemical markers of distress, such as metabolic acidosis sothat these are not apparent after birth [27]. If myocardial con-tractility is impaired following severe or sustained hypoxia,the resultant reduction in cardiac output may further compro-mise cerebral blood flow and other organ perfusion. Again,depending on the degree of insult, this can be associated withacute myocardial dilatation and consequent tricuspid regur-gitation, myocardial ischemia, and hypotension.Renal impairment is commonly reported following a gen-eralised hypoxic-ischemic insult at birth. The degree of insultvaries in effect from oliguria with minor electrolyte abnor-mality and minimally elevated creatinine, to complete renalfailure requiring dialysis.An elevated blood concentration of liver enzymes, as amarker of hepatocellular injury due to perinatal hypoxia, isalso common after acute hypoxia, but irreversible liver dam-age is rare.Fetal cardiovascular and endocrine responses may be al-tered, both in acute and in chronic hypoxia. Recurrence ofmild hypoxia may occur in pregnancies where the blood flowto placenta, uterus, and fetus is repeatedly compromised byphysiological and environmental influences. In chronic hy-poxia, fetal growth restriction is not uncommon, and depres-sion of growth factors during hypoxia has an importantprotective effect in conserving fetal substrate for energy asopposed to growth needs [28, 29]. The full-term infant, whilemore likely to survive a severe hypoxic-ischemic insult atbirth than a preterm infant (approximately 70% vs 30%), isalso more likely to have significant long-term morbidity [30].2.7 Postnatal Development2.7.1 Adaptation to Extrauterine LifeWith the first breath after birth, changes in the cardiopul-monary system occur. The first challenge for a newborn is theprovision of oxygen by independent breathing instead of uti-lizing placental oxygen. With the first breaths, there is a fallin pulmonary vascular resistance, and an increase in the sur-face area available for gas exchange. As the pulmonary vas-cular resistance falls, there is a corresponding increase insystemic vascular resistance due to loss of the low-resistanceplacental circulation. These two changes result in a rapid re-distribution of blood flow to the pulmonary vascular bed fromapproximately 4% to 100% of the cardiac output, with an in-crease in blood oxygen delivery. The consequent increase inpulmonary venous return results in the left atrial pressurebeing slightly higher than the right atrial pressure, whichcloses the foramen ovale. This changed flow pattern resultsin decreased blood flow across the ductus arteriosus and thehigher blood oxygen content stimulates the constriction andultimately the closure of this fetal circulatory shunt. The um-bilical vein and the ductus venosus close off within two tofive days after birth, leaving behind the ligamentum teres andthe ligamentum venosus of the liver, respectively.12 D.Arduini and M.Vendola
  7. 7. These cardiovascular system changes result in a transitionfrom fetal to adult circulation pattern. During this transition,some types of congenital heart disease that were not sympto-matic in utero when there was a fetal circulation will presentwith cyanosis or respiratory signs (see Chapters 75 and 76).2.7.2 The Preterm FetusIn Europe and many developed countries, the preterm birthrate is generally 5–9%, and in the USA it has risen to 12–13%in the last decades. There are three categories of preterm birth:(1) spontaneous preterm births are the 40–45% preterm birthsthat follow preterm labour of spontaneous (i.e. idiopathic)onset; (2) 25–30% preterm births occur after premature rup-ture of the membranes; (3) the remaining 30–35% are pretermbirths that are induced for obstetric reasons. Full-term preg-nancy is from 37 to 41 completed weeks and babies born justa few weeks earlier usually do not experience any problemsrelated to their slight prematurity. However, the more prema-ture these infants are, the more serious are the complications.The term intrauterine growth restriction (IUGR) describesa condition in which the fetus is smaller than expected for thenumber of weeks of pregnancy. Newborn babies with IUGRare often described as small for gestational age (SGA).Afetuswith IUGR often has an estimated fetal weight below thetenth percentile and may be born at term (after 37 weeks ofpregnancy) or prematurely (before 37 weeks). IUGR refersto a condition in which a fetus is unable to achieve its genet-ically determined potential size. This functional definitionseeks to identify a population of fetuses at risk of poor out-come. The clinician’s challenge is to identify IUGR fetuseswhose health is endangered in utero because of a hostile in-trauterine environment and to monitor and intervene appro-priately. Increasingly, data support the notion that long-termconsequences of IUGR last well into adulthood. These indi-viduals are predisposed to the development of a metabolicsyndrome later in life, manifesting as obesity, hypertension,hypercholesterolemia, cardiovascular disease, and type 2 di-abetes. Several hypotheses suggest that intrauterine malnu-trition results in insulin resistance, loss of pancreatic beta-cellmass, and an adult predisposition to type 2 diabetes. Althoughthe causative pathophysiology is uncertain, the risk of a meta-bolic syndrome in adulthood is increased among individualswho were IUGR at birth [31]. In addition to an increased riskfor physical sequelae, mental health problems have beenfound more commonly in children with growth restriction.2.7.3 DiagnosisFetal arterial Doppler studies are useful in the differential di-agnosis of SGA fetuses. In normal pregnancies, umbilical ar-tery (UA) resistance shows a continuous decline as the preg-nancy progresses; but this does not occur in fetuses with utero-placental insufficiency.The most commonly used measure of gestational age-spe-cific UAresistance is the systolic-to-diastolic ratio of flow, thePulsatility Index (PI), which increases with worsening disease.As the insufficiency progresses, end-diastolic velocity is lostand eventually reversed. The status of UAblood flow supportsthe diagnosis of IUGR and provides early evidence of circu-latory abnormalities in the fetus, helping clinicians to identifythese high-risk fetuses. UA Doppler measurements may helpthe clinician decide whether a small fetus is truly growth re-stricted and to identify a small fetus at risk of chronic hypox-emia. In hypoxemic fetuses with impaired placental perfusion,the PI in the umbilical artery is increased and the fetal middlecerebral artery PI is decreased; consequently, the PI ratio ofthe umbilical artery to middle cerebral artery (UA/MCA) isincreased. However, the UA/MCA ratio does not appear tocorrelate significantly with outcome after 34 weeks.Investigations of the venous vascular system have becomeincreasingly important in the assessment of fetal myocardialfunction, and different indices are used to evaluate the bloodflow velocity during the different phases of the cardiac cyclein the ductus venosus. Reference values for ductus venosusflow velocities are represented by ventricular systole (Swave) and diastole (D wave), the lowest forward velocity dur-ing atrial contraction (A wave). Different indices are calcu-lated, e.g., the S/A ratio. The most important parameter whichrepresents the final stage of disease is the abnormal reversalof blood flow velocities in the ductus venosus, inducing anincrease in the S/A ratio, mainly due to a reduced A compo-nent of the velocity waveforms. Reference values should beused for ductus venosus flow velocities during ventricularsystole (S wave) and diastole (D wave), the lowest forwardvelocity during atrial contraction (A wave) and different cal-culated indices as the S/A.In the inferior vena cava, there is an increase of reverseflow during atrial contraction with progressive fetal deteriora-tion, suggesting a higher pressure gradient in the right atrium.(Figs. 2.6 and 2.7). A high venous pressure induces a reducedvelocity at end-diastole in the umbilical vein, causing typical2 The Development from Fetus to Newborn 13Fig.2.6 Doppler examination of the inferior vena cava with normal flowvelocity waveforms
  8. 8. end-diastolic pulsations. The development of these pulsationsis close to the onset of abnormal fetal heart rate patterns and isfrequently associated with acidemia and fetal endocrinechanges. At this stage, there may be an increased coronaryblood flow velocity compared with that seen in normallygrown third-trimester fetuses and, if the affected fetus is notdelivered, intrauterine death may occur within a few days.2.7.4 Fetal Hemodynamic AspectsAlthough the usual definition of preterm birth is birth before37 weeks’ gestation, a useful pragmatic definition for a “pre-mature” infant is one who has not yet reached the level offetal development that generally allows life outside thewomb. In the normal human fetus, several organ systems ma-ture between 34 and 37 weeks, and the fetus reaches adequatematurity by the end of this period. One of the main organsgreatly affected by premature birth is the lung.In umbilical venous blood, mild hypoxemia may be man-ifest through an absence of hypercapnia or acidemia. In severeuteroplacental insufficiency, the fetus cannot compensate he-modynamically, and hypercapnia and acidemia increase expo-nentially [32]. Hypoxemic growth-restricted fetuses alsodemonstrate a range of hematological and metabolic abnor-malities, including erythroblastosis, thrombocytopenia, hypo-glycemia, deficiency in essential amino acids, hyper-triglyceridemia, hypoinsulinemia and hypothyroidism. Lowbirth weight increases the risk for perinatal mortality (deathshortly after birth), asphyxia, hypothermia, polycythemia,hypocalcemia, immune dysfunction, neurologic abnormalities,and other long-term health problems [33].2.7.5 Timing of Delivery and ManagementIn August 2004, The Lancet published data on brain develop-ment in survivors of the multicenter Growth Restriction Inter-vention Trial (GRIT) [34]. The aim of this study was toidentify compromised fetuses between 24 and 36 weeks’ges-tation and answer the question of whether it was safer to de-liver them immediately or to delay until there was no clinicaldoubt that delivery was necessary. Five-hundred and eighty-eight such fetuses were identified in 69 hospitals in 13 Euro-pean countries. In the GRIT study, the 24 week gestationbabies were very different from those at 36 weeks. In the ab-sence of severe congenital abnormalities, the current infantmortality after 32 weeks’ gestation is low: the causes of thisrare event include asphyxia, necrotising enterocolitis and in-fection; respiratory distress syndrome is rare in this group. Bycontrast, before 32 weeks, and particularly in the extremepreterm fetus, there is a much higher mortality, and the levelsof morbidity were recently emphasised by the EPICure Study,in which 49% of surviving infants born at less than 26 weeks’gestation had some disability at 30 months of age and 19%were severely disabled [35]. The EPICure study reached someimportant conclusions. It demonstrated that 44% of infantsborn at 25 weeks’gestation survived to discharge, whereas de-livery at 22 weeks almost invariably resulted in neonatal death.Neonatologists, obstetricians and parents must increas-ingly recognise that infants born less than 25 weeks’gestationwho survive are at risk of disability at school age. In the EPI-Cure study, only 20% were totally free of disability at schoolage and so the prognosis must be guarded. Disability wasclassified as follows:1. Severe: the child was likely to be highly dependent oncare-givers, e.g., non-ambulant cerebral palsy, profoundhearing loss or blindness.2. Moderate: children who were likely to be reasonably in-dependent, e.g., ambulant cerebral palsy, some hearingloss, some visual impairment.3. Mild: children with neurological signs with minimal func-tional consequences.In the EPICure study, over half of the survivors had mod-erate disability or no disability at school age. In addition,some of the 24% with moderate disability were improvedwith spectacles and hearing aids.There is uncertainty about whether iatrogenic delivery ofthe very preterm (before 33 weeks of gestation) growth re-stricted fetus should be undertaken before the developmentof signs of severe hypoxemia, with a consequent risk of pre-maturity-related neonatal complications, or whether deliveryshould be delayed, incurring risks of prolonged exposure tohypoxia and malnutrition imposed by the hostile intrauterineenvironment [36]. With every week that passes, there is a de-creasing risk of complications including intraventricular hem-orrhage, retinopathy of prematurity and sepsis. However,delay may expose the growth-restricted fetus to ischemic in-jury of the brain, resulting in asphyxia, periventricular leuko-malacia and intraventricular hemorrhage, as well as asignificant risk of intrauterine death. It is important to weighthe risks and benefits of early interventions. This is a dynamicprocess, in which advancements in both fetal and neonatalmedicine are of crucial importance for the appropriate coun-selling of parents and the management of these pregnancies.The GRIT study showed a small increase in fetal deathif the obstetrician delayed delivery, and a small increase in14 D.Arduini and M.VendolaFig. 2.7 Abnormal waveform with increase in reversed flow duringatrial contraction in a growth-restricted fetus
  9. 9. neonatal death if early delivery was chosen. Thus the moni-toring of fetal health is particularly important if there isgrowth restriction. Such fetuses have few metabolic reserves,and sudden death during pregnancy may occur. Labor is anintermittently hypoxic event, and anaerobic metabolism maynot be an option when there are inadequate stores of fat andglycogen.In recent years, placental and fetal arterial Doppler flow-velocity waveforms have guided the timing of delivery.Doppler has been particularly effective in assessing thegrowth-restricted pregnancy and has been a useful adjunctfor the assessment of the very preterm fetus, when car-diotocographical monitoring is unhelpful. However, in thegrowth-restricted hypoxemic fetus, redistribution of well-oxygenated blood to vital organs, such as the brain, heart andadrenals, represents a compensatory mechanism to preventfetal damage, and when the reserve capacities of the circu-latory redistribution reach their limits, fetal deterioration mayoccur rapidly. In clinical practice, serial Doppler investiga-tions estimate the duration and degree of fetal blood flow re-distribution. The onset of an abnormal venous Dopplerrecording indicates deterioration in the fetal condition andiatrogenic delivery should be considered.In conclusion, the goal in the management of the pretermfetus is to deliver the most mature fetus possible, at least at32−34 weeks, in the best condition possible while minimizingthe risk to the mother (Table 2.2). There is lack of a firm ev-idence base and IUGR fetuses remain a challenging problemfor clinicians. Most cases of IUGR occur in pregnancies inwhich no risk factors are present and the clinician must there-fore be alert to the possibility of growth disturbance in allpregnancies. No single measurement secures the diagnosisand a complex strategy for diagnosis and assessment is there-fore necessary. The current therapeutic goals are to optimizethe timing of delivery to minimize hypoxemia and maximizegestational age and maternal outcome.2 The Development from Fetus to Newborn 15Table 2.2 Suggested management of the preterm fetusWhat to do Perform parental counsellingShare any type of decisions with the neonatologist, the anesthesiologist and the couple, personalizing the specific situationFill the informed consent as much detailed as it is possibleConsidering Short-term consequences: RDS, NEC, IVH, PVL, pulmonary dysplasia, sepsisLong-term consequences: cerebral palsy, mental impairment, attention disordersPregnancy age and prognosis ageEtiology of the preterm labour (maternal causes, fetal causes)Maternal mortality related to the type of deliveryFetal presentationObstetric anamnesis of the patientCombination of the multiple factorsWhen Better after 26 weeksUsing corticosteroids between 48 hours and 7 days before deliveryWhere Any hospital with NICUHow Trying to reduce the effects of the hypoxiaBalance maternal and fetal morbidityPreterm delivery is not itself an indication of cesarean section unless associated with maternal or fetal consequencesReferences1. Way W (2006) Recent observations on the regulation of the fetalmetabolism of glucose. J Physiol 572:17−242. Picciano MF (2003) Pregnancy and lactation: physiological adjust-ments, nutritional requirements and the role of dietary supplements.J Nutr 133:1997S–20023. Christian P, Khatry SK, Katz J et al (2003) Effects of alternativematernal micronutrient supplements on low birth weight in ruralNepal: double blind randomised community trial. BMJ 326:5714. Kramer MS, Kakuma R (2003) Energy and protein intake in preg-nancy. Cochrane Database Syst Rev CD0000325. Leguizamon G, von Stecher F (2003) Third trimester glycemic pro-files and fetal growth. Curr Diab Rep 3:323–3266. Kliman HJ (2000) Uteroplacental blood flow. The story of decidu-alization, menstruation, and trophoblast invasion. Am J Pathol157:1759–17687. Zygmunt M, Herr F, Keller-Schoenwetter S et al (2002) Character-ization of human chorionic gonadotropin as a novel angiogenic fac-tor. J Clin Endocrinol Metab 87:5290–52968. Zygmunt M, Herr F, Munstedt K et al (2003) Angiogenesis andvasculogenesis in pregnancy. Eur J Obstet Gynecol Reprod Biol110(Suppl 1):S10–189. Albaiges G, Missfelder-Lobos H, Lees C et al (2000) One-stagescreening for pregnancy complications by color Doppler assess-ment of the uterine arteries at 23 weeks’gestation. Obstet Gynecol96:559–56410. Bamberg C, Kalache KD (2004) Prenatal diagnosis of fetal growthrestriction. Semin Fetal Neonatal Med 9:387–39411. Rich-Edwards JW, Buka SL, Brennan RT, Earls F (2003) Divergingassociations of maternal age with low birthweight for black andwhite mothers. Int J Epidemiol 32:83–9012. Krampl E, Lees C, Bland JM et al (2000) Fetal biometry at 4300 mcompared to sea level in Peru. Ultrasound Obstet Gynecol 16:9–18
  10. 10. 16 D.Arduini and M.Vendola13. Clapp JF (2003) The effects of maternal exercise on fetal oxygena-tion and feto-placental growth. Eur J Obstet Gynecol Reprod Biol110(Suppl 1):S80–8514. Skomsvoll JF, Baste V, Irgens LM, Ostensen M (2002) The recur-rence risk of adverse outcome in the second pregnancy in womenwith rheumatic disease. Obstet Gynecol 100:1196–120215. McGaw T (2002) Periodontal disease and preterm delivery of low-birth-weight infants. J Can Dent Assoc 68:165–16916. Bowden AP, Barrett JH, Fallow W, Silman AJ (2001) Women withinflammatory polyarthritis have babies of lower birth weight. JRheumatol 28:355–35917. Xiao R, Sorensen TK, Williams MA, Luthy DA (2003) Influenceof pre-eclampsia on fetal growth J Matern Fetal Neonatal Med13:157–16218. Allen LH (2001) Biological mechanisms that might underlie iron’seffects on fetal growth and preterm birth. J Nutr 131:S581–58919. Ferrazzi E, Rigano S, Bozzo M et al (2000) Umbilical vein bloodflow in growth-restricted fetuses. Ultrasound Obstet Gynecol16:432–43820. Fowden AL, Forhead AJ (2004) Endocrine mechanisms of in-trauterine programming. Reproduction 127:515–52621. Rohan AJ, Golombek SG (2009) Hypoxia in the term newborn:part three--sepsis and hypotension, neurologic, metabolic andhematologic disorders. MCN Am J Matern Child Nurs 34:224−23322. Volpe JJ (2008) Hypoxic-ischemic encephalopathy: clinical as-pects. In: Volpe JJ (ed) Neurology of the newborn. Elsevier Saun-ders, Philadelphia, pp 400–48023. Task Force on Neonatal Encephalopathy and Cerebral Palsy StaffAmerican College of Obstetricians and Gynecologists with Amer-ican Academy of Pediatrics Staff (2003) Neonatal Encephalopathyand Cerebral Palsy: Defining the Pathogenesis and Pathophysiol-ogy. The American College of Obstetricians and Gynecologists.Washington, DC24. Sheridan C (2005) Intrauterine growth restriction. Aust Fam Physic34:717−72325. Anderson P, Kleiman C, Lister G, Telner N (2004) Cardiovascularfunction during development and response to hypoxia. In: Polin R,Fox W, Abman S (eds) Fetal and neonatal physiology. Saunders,Philadelphia, pp 645−66926. Philipps A (2004) Oxygen consumption and general carbohydratemetabolism of the fetus. In: Polin R, Fox W, Abman S (eds) Fetaland neonatal physiology. Saunders, Philadelphia, pp 465−47827. Bloom R (2006) Resuscitation of the newborn. In: Fanaroff AA,Martin R, Walsh MC (eds) Neonatal-perinatal medicine. Mosby, StLouis28. Noori S, Friedlich P, Seri I (2004) Pathophysiology of shock in thefetus and newborn. In: Polin R, Fox W, Abman S (eds) Fetal andneonatal physiology. Saunders, Philadelphia, pp 772−78129. Seri I, Evens J (2001) Controversies in the diagnosis and manage-ment of hypotension in the newborn infant. Curr Opin Pediatr13:116−12330. Cressens P, Huppi PS (2006) The CNS: hypoxic ischemic en-cephalopathy. In: Fanaroff AA, Martin R, Walsh MC (eds) Neona-tal-perinatal medicine. Mosby, St Louis31. Engle A, Tomashek KM, Wallman C, Committee on Fetus andNewborn (2007) ‘Late preterm’ infants: a population at risk. Pedi-atrics 120:1390−140132. Bastek LA, Sammel MD, Paré E et al (2008) Adverse neonatal out-comes: examining the risk between preterm, late preterm, and terminfants. Am J Obstet Gynecol 199:367.e1–833. Petrini JR, Dias T, Mc Cormick MC et al (2009) Increased risk ofadverse neurological development for late preterm infants. J Pediatr154:169−17634. Thornton JG, Hornbuckle J, Vail A et al (2004) Infant wellbeing at2 years of age in the Growth Restriction Intervention Trial (GRIT):multicentred randomized controlled trial. Lancet 364:513–52035. Wood NS, Marlow N, Costeloe K et al (2000) Neurologic and de-velopmental disability after extremely preterm birth. N Engl J Med343:378–384; comment 343:429–43036. Walter EC, Ehlenbach WJ, Hotchkin DL et al (2009) Low birthweight and respiratory disease in adulthood. A population-basedcase-control study. Am J Respir Crit Care Med 180:176−180

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