Ebook Keelings fetal and neonatal pathology (5th edition) Part 2

(BQ) Part 2 book Keelings fetal and neonatal pathology presentation of content: The respiratory system, the alimentary tract and exocrine pancreas, liver and gallbladder, the urinary system, the reproductive system, the endocrine system, the reticuloendothelial system,...and other contents.

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T.Y Khong, R.D.G Malcomson (eds.), Keeling’s Fetal and Neonatal Pathology, DOI 10.1007/978-3-319-19207-9_17

or cause iatrogenic damage Most side effects are minor problems, but some can be serious and may result in a major handicap, long-term sequelae, or death of the infant Invasive antenatal investigation and treatment and the increasingly complex interventions in neona-tology have resulted in the appearance of new types and patterns of pathology Recognition

of side effects, especially with the advent of newly developed therapeutic strategies in the neonatal intensive care unit, is very important, and the clinician must be alert and carefully monitor these children This is important to minimize side effects and serious damage The pathologist is sometimes the ﬁ rst to recognize these adverse effects but should be very well informed about the therapeutic interventions and therapies that were performed before beginning an examination to be able to recognize these side effects

Keywords

Iatrogenic disease • Iatrogenic pathology • Lesions • Amniocentesis • Chorionic villus sampling (CVS) • Cordocentesis • Fetoscopy • Fetal surgery • Maternal drugs • Teratogenic

• Organogenesis • Over-the-counter medicines (OTCs) • Birth injuries • Cesarean section

• Neonatal therapy • Infection • Monitoring • Vascular cannulation • Blood sampling

Injury is a feature of all medical practice, but it is perhaps

nowhere more accepted as an unavoidable consequence of

therapy than in obstetric and neonatal medicine Treatment is

usually beneﬁ cial, but therapeutic procedures may

some-times result in adverse side effects or cause iatrogenic

dam-age Most side effects are minor problems, but some can be

serious and may result in a major handicap, long-term

sequelae, or death of the infant [ 1 3 ]

The development of new therapeutic strategies may result

in not previously observed combinations of pathology

Invasive antenatal investigation and treatment and the

increasingly complex interventions in neonatology have resulted in the appearance of new types and patterns of pathology Recognition of side effects, especially with the advent of newly developed therapeutic strategies in the neo-natal intensive care unit, is very important, and the clinician must be alert and carefully monitor these children This is important to minimize side effects and serious damage Over the last decades, neonatal care has been very successful, especially with the impressive improvement of survival of very premature infants The pathologist is sometimes the ﬁ rst

to recognize these adverse effects but should be very well informed about the therapeutic interventions and therapies that were performed before beginning an examination to be able to recognize these side effects All medical devices, like tubes, catheters, etc., should, of course, be left in situ after death It is equally important to perform a thorough autopsy

P G J Nikkels , MD, PhD

Department of Pathology , University Hospital Utrecht ,

Utrecht , The Netherlands

e-mail: p.g.j.nikkels@umcutrecht.nl

17

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as completely as is permitted Only in these circumstances is

valuable information not lost and the optimal and early

detection of serious side effects made possible If these

con-ditions are met, the pathologist can contribute markedly to

the improvement in the quality of care for children The

decline in autopsy rates, however, could make it more difﬁ

-cult to determine the incidence of iatrogenic lesions [ 4 ]

A recent study estimated that preventable complications

accounted for at least 4,400 deaths per year among

hospital-ized children in the USA [ 1 ] Children younger than 30 days

were at particular risk of complications [ 2 ] Gestational age,

birth weight, severity of initial illness as assessed by the

Score for Neonatal Acute Physiology and Perinatal Extension

(SNAPPE II), and length of stay were signiﬁ cantly

associ-ated with iatrogenic events Furthermore, univariate analysis

for environmental characteristics showed that type of shift,

but not nursing workload, was signiﬁ cantly associated with

iatrogenic events [ 5 ]

The role of the pathologist in the investigation of child death

is central to the monitoring of iatrogenic pathology and brings

with it considerable responsibilities in the light of potential

medicolegal consequences and the need to recognize new

problems It is vital that the pathologist should be familiar in

identiﬁ cation of iatrogenic lesions and should record with great

care unusual ﬁ ndings in cases where novel therapeutic

modali-ties are being employed Iatrogenic lesions may be of varying

degrees of clinical signiﬁ cance Many, perhaps the majority,

are minor and accepted as a consequence of intervention, while

others represent serious complications and medical mishaps or

reﬂ ect poor clinical judgment Perinatal autopsy examinations

provide a vital opportunity to monitor any potential teratogenic

effects of drug therapy In addition the ability to keep very ill

babies alive in neonatal intensive care has resulted in the

matu-ration or evolution of pathological processes in various organs

resulting in the development of new patterns of pathology,

which need to be recorded and explained

As discussed by deSa, iatrogenic lesions can be classiﬁ ed

in three categories: (1) the lesion can be directly traced to the

procedure or is a direct consequence of the procedure; (2)

lesions are an untoward complication of the initial

proce-dures (a procedure used to treat one complication may cause

another); and (3) complex lesions evolved from earlier

lesions, including lesions related to prolonged survival and/

or an improved outcome, i.e., lesions related to therapeutic

success One lesion may affect the other, and sometimes it is

difﬁ cult to determine the pathogenesis of the lesions [ 6 ]

Iatrogenic Lesions in the Prenatal Period

There is a large literature regarding the safety of the various

invasive procedures employed in antenatal diagnosis In

gen-eral it appears that midtrimester amniocentesis is the safest

procedure, while chorionic villus sampling (CVS) and early amniocentesis have a slightly higher incidence of subsequent pregnancy loss of approximately of 0.6–2 % [ 7 9 ] CVS on the other hand should not be performed before 10 weeks’ gestation due to a possible increase in risk of limb reduction defects [ 9 ] Amniocentesis can give rise to hemorrhage and infection and sometimes puncture marks on the skin, liver laceration, or lung damage Injection of dyes (i.e., methylene blue) in the amniotic sac in twins to study which amniotic sac was punctured ﬁ rst is associated with jejunal atresia [ 10 –

12 ] Umbilical cordocentesis can be associated with cord hematomas, but this is extremely rare

Ultrasonography

Modern ultrasound machines have enormously increased the potential for prenatal intervention and diagnosis The use of ultrasound in obstetrics is now routine practice, but there is no evidence that the use of ultrasound at diagnostic intensities has any deleterious effect on the fetus or the mother [ 13 – 15 ] Detailed scanning is operator dependent and ultrasound diag-noses are not infallible Some anomalies can be identiﬁ ed with a very high success rate (e.g., neural tube defects), but others (such as cardiac defects) are much more difﬁ cult to identify and diagnose Accordingly, the real risk would appear

to be related to the skill of the operator and resultant noses rather than dangers of standard equipment [ 16 ]

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) is now a routine tum and neonatal diagnostic tool particularly in instances of complex congenital malformation It is of particular value in the assessment of lung size in cases of congenital diaphrag-matic hernia (CDH), central nervous system abnormalities including hydrocephalus, and some cardiac malformations There is no evidence that MRI scanning has any deleterious effect on the fetus or the progress of a pregnancy

con-P.G.J Nikkels

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415uncommon with adequate aseptic technique Secondary infec-

tion may lead to intrauterine fetal demise or spontaneous

abor-tion due to intra-amniotic infecabor-tion and chorioamnionitis In

addition it is known that fetal exposure to intra-amniotic

inﬂ ammation is associated with the development of cerebral

palsy in survivors [ 17 , 18 ] In the case of women who are

rhe-sus negative, it is necessary to provide anti-D treatment in order

to prevent rhesus isoimmunization In assessing the potential

complications of amniocentesis, it is important to differentiate

between midtrimester and early (9–14 weeks’ gestation)

amniocentesis as the range of complications varies Early

amniocentesis, at 9–14 weeks’ gestation, is associated with

increased risk to fetal development Although the procedure is

technically similar to midtrimester amniocentesis, the ﬂ uid

volume around the fetus is much smaller and it can be more difﬁ

-cult to obtain a sample The incidence of unsuccessful attempts

may be as high as 20 % There is clear evidence that the

inci-dence of talipes is greater in the children of women undergoing

amniocentesis prior to 14 weeks’ gestation [ 19 , 20 ]

Amniocentesis performed prior to 15 weeks had a signiﬁ cantly

higher miscarriage rate than chorionic villus sampling or

midtrimester amniocentesis and also increased the risk of

tali-pes equinovarus [ 20 , 21 ] Midtrimester amniocentesis is

asso-ciated with a signiﬁ cant increase in spontaneous and induced

preterm delivery for which the etiology remains unclear [ 22 ]

Recent data show a procedure-related miscarriage rate of 0.5–

1.0 % for amniocentesis [ 9 ], while a recent review of studies

incorporating more than 68,000 midtrimester amniocentesis

procedures concluded that the procedure-related excess

preg-nancy loss rate was 0.6 % [ 23 ]

Signiﬁ cant fetal injury following midtrimester

amniocen-tesis is not common Small cutaneous scars resulting from

direct needle puncture are described but are seldom of

sig-niﬁ cance Internal injuries of the fetus have also been

described following inadvertent trauma [ 24 ] These injuries

include fatal hemorrhage; intra-abdominal pathology in the

form of ileal atresia and peritoneal adhesions; limb

anoma-lies resulting from arterial injury, constrictions, and

amputa-tions; and intrauterine fetal demise secondary to amniotic

bands and disruptive brain injury [ 25 – 29 ]

More signiﬁ cant sequelae of midtrimester amniocentesis

relate to potential impairment of lung development and

mat-uration with an increased risk of respiratory distress

syn-drome (RDS) and neonatal pneumonia [ 30 ] It was suggested

that the fetal problems resulted from removal of amniotic

ﬂ uid and possibly from chronic amniotic ﬂ uid leakage that

had not been noted by the patient

Chorionic Villus Sampling

The need for early diagnosis of karyotypic or metabolic

dis-orders thus permitting technically safer and easy medical

termination of pregnancy has driven the development of rionic villus sampling (CVS) Samples can be obtained either

cho-by a transcervical or a transabdominal approach The abdominal approach has the advantage for some practitio-ners in that the technique is similar to that used for amniocentesis in which practitioners are familiar In a recent review, it was demonstrated that the miscarriage rates (i.e., spontaneous loss and procedure-related loss) after amnio-centesis and CVS were 1.4 % and 1.9 %, respectively This difference may be explained by the difference in gestational age at the time of the procedures The miscarriage rate was inversely correlated with the number of procedures per-formed by the practitioners [ 31 ] It is hardly surprising that there is a signiﬁ cant incidence of fetomaternal hemorrhage following chorionic villus sampling by either technique [ 32 ,

trans-33 ] This can lead to maternal rhesus sensitization in dences of incompatibility or to a worsening of maternal immunization in a preimmunized patient Patients are there-fore checked for the need to receive anti-D immunoglobulin The range of complications of chorionic villus sampling are wide and, while most are fortunately of minor clinical sig-niﬁ cance, some in individual cases can be more serious, giv-ing rise to fetal anomaly particularly in the case of early chorionic villus sampling Firth and colleagues reported a cluster of limb reduction defects in babies of a series of women who underwent chorionic villus sampling before 9 completed weeks’ gestation [ 34 ] Two subsequent studies identiﬁ ed similar pathologies, and it was proposed that these limb abnormalities were the result of vascular disruption and hypoxic tissue damage related to the needle movements [ 35 ,

inci-36 ] In expert hands, using good ultrasound visualization and care with the needle, the risk is extremely remote

A long-term follow-up of infants in pregnancies that had transcervical chorionic villus sampling or amniocentesis concluded that there was no difference in the incidence of congenital malformations, neonatal morbidity, pediatric morbidity, or functional disturbance between the two patient groups [ 37 ]

Cordocentesis

Fetal blood sampling is now a well-established procedure, which has applications in a number of clinical situations The usual sampling site is the placental insertion of the umbilical cord, but other sites that can be employed include the fetal cord insertion, the fetal intrahepatic vein, and the fetal heart Needle insertion (20- or 22-gauge spinal needle)

is under continuous ultrasound visualization It is important that the fetal heart is observed throughout the procedure as fetal bradycardia indicates fetal distress and the site of nee-dle insertion is observed during and after procedure in order

to assess hematoma formation in the cord root and the invariable

17 Iatrogenic Disease

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blood leakage from the puncture site (Fig 17.1 ) Sampling is

more problematic below 18 weeks’ gestation, and there is a

higher rate of pregnancy loss in these early gestation

preg-nancies [ 38 ] The speciﬁ c indications are the provision of

rapid and uncontaminated fetal karyotype, the investigation

and management of rhesus hemolytic disease, and the

inves-tigation and management of hematological disorders

includ-ing autoimmune idiopathic thrombocytopenia and

hemoglobinopathies Fetal intrauterine infection can also be

investigated using fetal blood samples

Many pregnancies where fetal blood sampling is done

are, by deﬁ nition, high risk This complicates assessment of

fetal loss related to the procedure alone Loss rate estimates

have been in the range of 1–2 % [ 39 , 40 ] In one major study,

the fetal loss rate for structurally normal fetuses was 1 %, but

this increased to 25 % in a group of fetuses with nonimmune

hydrops fetalis [ 41 ]

Fetoscopy and Fetal Surgery

Fetoscopic intrauterine interventions can be separated into

two broad categories The ﬁ rst is obstetric endoscopy, which

includes surgical interventions on the placenta, umbilical

cord, and fetal membranes, and the second is endoscopic

fetal surgery [ 42 ]

Obstetric Endoscopy

The most frequent obstetrically related intervention is

treat-ment of the complications of twin-twin-transfusion

syn-drome (TTTS) using a Nd:YAG laser or diode to coagulate

the intertwin anastomoses [ 43 ] Given that TTTS can

com-plicate up to 15 % of monochorionic pregnancies and will

present with a mortality rate of 80 % or more without

inter-vention, laser coagulation is the treatment of choice for

TTTS Laser therapy is normally offered to patients between

15 and 26 weeks of gestation If performed correctly, laser treatment results in a reversal of hemodynamic disturbances associated with TTTS in the following days after treatment Main complications after laser treatment include intrauterine fetal death of either fetus (13–30 %) and preterm rupture of membranes (10 %) Persistence of overt TTTS due to anasto-moses missed during surgery (2–14 %) and twin-anemia- polycythemia sequence (2–13 %) can occur, but the rate of these complications is critically dependent upon the sur-geon’s experience [ 43 ] The reported survival rates for at least one twin range from 76 to 88 %, and the reported inci-dence of severe neurodevelopmental impairment at 2 to 5 years of age is 13–17 % including a cerebral palsy rate of 6–7 % [ 43 ] A short cervical length (−15 mm) may indicate

a higher risk of preterm delivery Amniodrainage is a tive treatment that may prolong pregnancy by reducing the risks of polyhydramnios and relieve maternal discomfort In cases of severe TTTS before 26 weeks’ gestation, amniod-rainage has been reported to be associated with survival rates

pallia-of 51–60 % for at least one fetus and a rate pallia-of neurological handicap of 29 % Serial amniodrainage beyond 26–28 weeks’ gestation may prolong pregnancy in late TTTS cases with normal Doppler Amniodrainage performed before laser treatment increases the risk of complications and results in poorer outcome [ 43 ]

Closed Fetal Surgery

One of the ﬁ rst forms of closed interventions was the ment of shunts for drainage of pathological ﬂ uid collections

place-in the fetus Pleural effusions and dilatations of the urplace-inary tract resulting from obstruction at all levels from the pelvi-ureteric junction to the posterior urethra are amenable to intrauterine drainage [ 44 ] In these cases, the decision to per-form a drainage procedure is dependent on the exclusion of karyotypic anomaly and other serious fetal anomalies In poor prognosis cases, which in untreated situations result in

100 % fetal loss, the survival rate is in the order of 30 % Abdominal wall hernia has been reported as an uncommon complication of uterovesical amniotic shunt treatment for obstructive uropathy The hernias were amenable to postna-tal repair In a report of three cases, the authors noted that while the drainage of urine into the amniotic sac improved pulmonary development in all three patients, two of the three had renal failure requiring dialysis after birth [ 45 ] Survival seemed to be higher in fetuses receiving vesicoamniotic shunting, but the size and direction of the effect remained uncertain, such that beneﬁ t could not be conclusively proven Results suggest that the chance of newborn babies surviving with normal renal function is very low irrespective of whether

or not vesicoamniotic shunting is done [ 46 ]

In terms of surgery on the fetus, an increasingly frequent indication is severe congenital diaphragmatic hernia as well

as myelomeningocele Overall maternal safety is high, but

Fig 17.1 Small hematoma at the placental cord insertion following

fetal blood sampling

P.G.J Nikkels

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417rupture of the membranes and preterm delivery remain a

problem [ 47 ] Fetuses with isolated severe congenital

dia-phragmatic hernia are treated with fetoscopic endoluminal

tracheal occlusion, generally performed at approximately

26–28 weeks’ gestation [ 48 ] It involves the percutaneous

placement of an inﬂ atable balloon in the fetal trachea under

sono-endoscopic guidance The balloon prevents egress of

lung ﬂ uid, causing airway stretch, which in turn results in

lung growth The balloon is preferentially removed in utero

at approximately 34 weeks by tracheoscopy or ultrasound-

guided puncture Alternatives are ex utero intrapartum

treat-ment or, at the latest, after birth by tracheoscopy or

ultrasound-guided needle puncture through the neck Fetal

intervention for severe congenital diaphragmatic hernia is

associated with neonatal morbidity that is comparable with

that of an expectantly managed group but with less severe

disease [ 48 ] It should be cautioned, however, that the

cur-rently available evidence suggests that although there is lung

enlargement following in utero tracheal occlusion, this

appears to be due to abnormal dilatation of peripheral lung

saccules with pooling of mucin The lung remains

structur-ally abnormal with low radial alveolar counts and

abnor-mally large alveolae The treatment did not prevent the

development of lung pathology typically associated with

pulmonary hypoplasia [ 49 ]

Intrauterine fetal therapy has also been used for large

solid sacrococcygeal teratomas Vascular ﬂ ow to the tumors

was interrupted by fetoscopic laser ablation, radiofrequency

ablation, or interstitial laser ablation with or without

vascu-lar coiling [ 50 ] This treatment is often complicated by

intra-uterine death or premature birth Survival in fetuses with

hydrops was 30–45 % and without hydrops 67 % [ 50 ]

It can be expected that closed fetal surgical procedures

will increase dramatically in number and scope in the next

5–10 years as improved endoscopic techniques and the

development of speciﬁ c fetoscopic instruments together with

better management of tocolysis becomes available [ 42 , 51 ]

A recognized hazard of techniques that breach the amniotic

sac is rupture of the membranes with amniotic ﬂ uid leak or

premature delivery Most cases can be expected to seal

spon-taneously if infection does not develop, but active

interven-tions to plug leaks either with an amnio patch of platelets and

cryoprecipitate or application of ﬁ brin sealant have been

suc-cessfully reported [ 52 ]

Open Fetal Surgery

Many of the more complex fetal anomalies that severely

com-promise the fetus to the point where extrauterine existence is

called into question are as yet not amenable to repair by

closed techniques Because survival rates are so poor, these

conditions have led to the development of open fetal surgical

techniques Urinary tract obstruction, diaphragmatic hernia,

congenital pulmonary airway formation, amniotic band

sequence, myelomeningocele, and sacrococcygeal teratoma have all been the subject of fetal surgery over the last 10 years Randomized controlled trials (RCTs) have demonstrated an advantage for open fetal surgery of myelomeningocele and for fetoscopic selective laser coagulation of placental vessels

in twin-to-twin transfusion syndrome The evidence for other fetal surgery interventions, such as tracheal occlusion in con-genital diaphragmatic hernia, excision of lung lesions, fetal balloon cardiac valvuloplasty, and vesicoamniotic shunting for obstructive uropathy, is more limited [ 53 ] The aim of postnatal myelomeningocele surgery is not to reverse or pre-vent the neurologic injury, but to palliate The neurologic defects result from primary incomplete neurulation and sec-ondary chronic in utero damage to the exposed neural ele-ments through mechanical and chemical trauma In utero repair to decrease exposure and alter the antenatal course of neurologic destruction was conceived Through animal mod-els and human pilot studies, the feasibility of fetal spina biﬁ da repair was demonstrated Subsequently, a prospective ran-domized multicenter trial revealed a decreased need for shunting, reversal of hindbrain herniation, and preservation of neurologic function when performed before 26 weeks of ges-tation, making in utero repair an accepted care alternative for select women carrying a fetus with spina biﬁ da [ 54 ] Of mothers who had open maternal-fetal surgery, 40 % experi-enced complications One had uterine dehiscence, and another had uterine rupture requiring urgent delivery at 36 weeks In subsequent pregnancies, 20 % of open maternal-fetal surgery cases were complicated by uterine rupture, and 8 % of ex utero intrapartum treatment patients had uterine dehiscence Future reproductive capacity and complication rates in subse-quent pregnancies following ex utero intrapartum treatment procedure are similar to those seen in the general population

In contrast, mid-gestation open maternal-fetal surgery remains associated with relatively morbid complications All had good maternal-fetal outcome [ 55 ]

Maternal Medication During Pregnancy

Maternal drug therapy poses risks to the fetus at all stages of development Current standards for testing of potential ther-apeutic agents for developmental toxicity have prevented any repetition of the thalidomide tragedy, and there have been no reported episodes of new unrecognized teratogens released into routine therapeutic use for more than two decades Although the deleterious effects of some agents may appear idiosyncratic, the recognition and understanding

of certain principles regarding the harmful effects of drugs in general serve to guard against complacency We now recog-nize that agents that bind to steroid hormone receptors, the aryl hydrocarbon receptor, or retinoid receptors are potential developmental toxins with likely teratogenic effects

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There is no effective maternal-fetal barrier against drugs

ingested by pregnant women Although for some substances

the transplacental dispersion is concentration dependent

(i.e., dependent on the maternal dose ingested), it must be

remembered that the placenta is a dynamic organ capable of

facilitated and active transport by carrier molecules, which

may well increase placental transfer of a given substance

to a greater extent than simple diffusion would permit [ 56 ]

Thus, it is possible that a drug or other molecule can achieve

a higher concentration in the placenta and fetus than would

normally be determined by the maternal serum concentration

The harmful effects of drugs are substantially determined

by the stage of development of the conceptus at the time of

exposure Thus, developmental toxicity results from

expo-sure in the embryonic period during which there is major

organogenesis This critical period extends from fertilization

until approximately 60 days postconception, and the pattern

of abnormality reﬂ ects the phase of organogenesis during the

time of exposure Six principal teratogenic mechanisms are

suspected to be associated with medication use: folate

antag-onism, neural crest cell disruption, endocrine disruption,

oxi-dative stress, vascular disruption, and speciﬁ c receptor- or

enzyme-mediated teratogenesis [ 57 ] In the fetal period (i.e.,

60 days postfertilization until birth), drugs may exert their

deleterious inﬂ uence by changes in the growth and

func-tional development of organs Drugs given late in pregnancy

or during labor may also cause problems in the progress of

labor or in the neonate postpartum It should also be

remem-bered that certain classes of drugs have long half-lives and

can be teratogenic for months after the cessation of maternal

therapy, e.g., retinoic acid analogues

Maternal ingestion of drugs that may affect the fetus can

occur in the following circumstances:

1 Inadvertently without the mother realizing she is

pregnant

2 Taken in diagnosed pregnancy without consideration or

knowledge of the risks involved

3 Therapeutic administration in the knowledge of

preg-nancy in the ﬁ rst trimester

4 Therapeutic administration in the knowledge of

preg-nancy in the second and third trimesters

5 Maternal administration of drugs intended to have a

ther-apeutic effect on the fetus

6 Maternal therapies during labor

7 Maternal treatment postpartum in breastfeeding mothers

It has been calculated that approximately one-third of all

pregnant women receive at least 1 course of drug therapy

during pregnancy [ 58 ] This apparently high rate, given the

widespread understanding of the risks of drug ingestion in

pregnancy, is a gross understatement of the true incidence

of fetal exposure in the ﬁ rst trimester to pharmacological

agents as self-treatment by proprietary “over-the-counter”

medications (OTCs) or continuation of prescribed therapy is frequent prior to the mother or her medical advisers knowing she is pregnant This may be particularly critical given the fact that exposure is occurring during the phase of organo-genesis, which is the period of greatest risk to the embryo

As it is not possible to conduct clinical trials of the effects of drugs in humans in early pregnancy, we rely on the results of anecdotal occurrence or therapeutic disasters to identify terato-genic agents and only a small number of drugs are defi nitely regarded as known teratogens if administered in the fi rst tri-mester of pregnancy It should also be noted that teratogenic effects may be dose dependent or may require the coadminis-tration of other agents or synergistic infl uences if serious sequelae are to ensue An additional complication in assessing the teratogenic effect of any agent is the background rate of congenital malformation in the community as a whole, some of which may be teratogenic in its own right, which is in the order

of 1–2 % of all pregnancies An example of this diffi culty is the thalidomide experience where it is now clear that some cases of limb reduction defect were in fact Robert’s syndrome and not the result of thalidomide exposure in the mother This has become apparent when children of apparent thalidomide vic-tims are born with identical patterns of limb defi ciency A sig-nifi cant proportion, perhaps 10 %, of congenital abnormalities result from environmental infl uences including preexisting maternal conditions, infective agents, mechanical disruptions, and chemicals, while in the majority of instances the etiology is unknown [ 59 – 61 ] Also, we are continually exposed to numer-ous chemicals in the environment for which the teratogenic potential is largely unknown It has been estimated that only approximately 5 % of the 60,000 or more chemicals in com-mercial use have been assessed for their teratogenic potential

In future, sophisticated structural analyses of chemicals may provide a means of predicting teratogenic potential and permit

a rapid assessment of risk for any given agent [ 62 ] Only a few representative examples will be described here, and the reader

is referred to other sources for a general review and more detailed information [ 63 , 64 ]

Over-the-Counter Medicines (OTCs)

Many pregnant women use over-the-counter medications at some stage in their pregnancy In many instances, this use is in the critical developmental stages of the ﬁ rst trimester Werler

et al [ 65 ] reported that in the USA, 65 % of women had used acetaminophen, 15 % had used ibuprofen, and 4 % had used other drugs such as pseudoephedrine, aspirin, and naproxen during pregnancy This rate of consumption exposes a huge population of developing babies to a vast array of agents With such large numbers, even a small toxic effect will give rise to

a clinically important and avoidable rate of potentially deleterious results Pain medication when taken in the ﬁ rst 2 gestational months of pregnancy is reported as strongly

P.G.J Nikkels

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419 associated with stillbirths due to congenital anomalies and to

be positively associated with all stillbirths [ 66 ] Implicit in

these ﬁ ndings is a potential explanation for a number of

unex-plained congenital anomalies and stillbirths, and it is clear that

more must be done to monitor the use of OTCs in pregnancy if

these risks to pregnancy are to be removed [ 67 ]

Teratogenic Drugs

The serious effects of thalidomide on the fetus are well known

[ 68 ] Folic acid antagonists used as cytotoxic agents in cancer

chemotherapy are also known to have serious effects on the

developing embryo [ 69 – 71] Of more immediate clinical

import are commonly used agents that are proven teratogens

Examples of these include phenytoin, warfarin, retinoids,

car-bamazepine, lithium, sodium valproate, and danazol

The teratogenic effect of anticonvulsant drugs was ﬁ rst

described in relation to phenytoin by Meadow [ 72 ] It is

probable that other related compounds may have potentially

harmful effects, and it has been suggested that there may be

a potentiation of phenytoin effects with co-treatment with

barbiturates Children exposed to phenytoin present with a

variety of malformations including dysmorphic facies,

digi-tal hypoplasia, nail hypoplasia, growth deﬁ ciency, and

men-tal deﬁ ciency More serious structural defects of organs such

as the heart are also occasionally identiﬁ ed [ 73 – 77 ] Of

par-ticular interest in relation to the effects of phenytoin is the

apparent variation in the susceptibility of a fetus The risk of

a fetus exposed to phenytoin developing the full spectrum of

effects is approximately 10 %, with perhaps a third of fetuses

having lesser abnormalities Numerous studies now suggest

that the fetal susceptibility depends on the fetal genotype,

with inherited defects in phenytoin detoxiﬁ cation

contribut-ing to the increased sensitivity to the drug [ 78 – 82 ]

Warfarin embryopathy was ﬁ rst recognized in 1975—

although previous case reports had described similar

pathol-ogy in the babies of mothers with valve prostheses receiving

anticoagulation—and is now well characterized [ 83 – 85 ]

Despite the condition being well recognized, new cases still

occur [ 86 – 88 ] Approximately one-third of exposed fetuses

will be born with the classical features of nasal hypoplasia,

depressed nasal bridge, and stippled calciﬁ cation of the

epiphyses A signiﬁ cant proportion will also have mental

retardation and a variety of other abnormalities are

recog-nized The critical period of exposure appears to be between

6 and 9 weeks, but there is debate as to the additional risks

from exposure in the second and third trimesters with reports

of central nervous system abnormalities [ 89 ]

Retinoic acid embryopathy was ﬁ rst reported by Rosa [ 90 ],

and subsequently the spectrum of structural defects in

prena-tally exposed children has been described [ 91 ] Retinoids are

potent teratogens and give rise to craniofacial, cardiovascular,

and central nervous system abnormalities A particularly

important feature of retinoic acid embryopathy is the term teratogenic potential of some retinoic acid analogues used therapeutically, particularly for the management of skin disease, e.g., etretinate Some analogues may be teratogenic in excess of 12 months after the cessation of therapy

Non-teratogenic Drug Effects

Drugs administered to mothers outside the period of genesis can disrupt structural and functional growth and development of organs Examples include the angiotensin- converting enzyme (ACE) inhibitors, sex hormones, anti-thyroid drugs, and beta-blockers Angiotensin-converting enzyme inhibitors are associated with fetal renal abnormali-ties including proximal renal tubular dysgenesis (Fig 17.2 ) giving rise to neonatal renal failure [ 92 – 94 ] Intrauterine growth restriction and skull ossiﬁ cation defects are also frequently present An increased incidence of intrauterine

Fig 17.2 Renal tubular dysplasia secondary to fetal ACE-inhibitor

exposure; the proximal tubules have an immature morphology and glomeruli are crowded

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death, stillbirth, and perinatal death resulting from

oligohy-dramnios and related abnormalities has also been described

in the fetuses of mothers receiving ACE inhibitors

Diethylstilbestrol (DES) was identiﬁ ed as having a

trans-placental carcinogenic affect in females The majority of

female children of mothers who received this drug in

preg-nancy developed vaginal adenosis, and a very much smaller

proportion are at risk of subsequent development of

adeno-carcinoma [ 95 ] Decades later, DES is known to enhance

breast cancer risk in exposed women and cause a variety of

birth-related adverse outcomes in their daughters such as

spontaneous abortion, second trimester pregnancy loss,

pre-term delivery, stillbirth, and neonatal death Additionally,

children exposed to DES in utero suffer from sub/infertility

and cancer of reproductive tissues [ 96] Male fetuses of

exposed mothers developed genital anomalies [ 97 ]

Oral contraceptives, frequently taken in the ﬁ rst trimester

of pregnancy, do not appear to be associated with a risk to the

development of the fetus [ 98 ]

The administration of antithyroid drugs can produce

thy-roid enlargement in the fetus (Fig 17.3 ) These drugs readily

cross the placenta and are thought to act by suppression of

thyroxine production by the fetus with subsequent enhanced

TSH secretion from the pituitary gland [ 99 – 101 ] The use of

beta-blockers in the treatment of essential hypertension in pregnancy is associated with an increased risk of intrauterine growth restriction [ 102 ] Neonates of mothers treated with the beta-blocker labetalol for severe preeclampsia have a higher risk of hypotension and patent ductus arteriosus [ 103 ] There are relatively few instances where maternal drug therapy inhibits breastfeeding Most drugs will be secreted in the breast milk, but the dose ingested by the baby is usually insufﬁ cient to cause deleterious consequences [ 104 ] Atkinson et al [ 105] provide practical guidelines on the common drugs that pass into breast milk in signiﬁ cant quan-tities and make recommendations as to breastfeeding or drug treatment to be avoided if breastfeeding is intended Among the drugs that should be avoided in these circumstances are amiodarone, aspirin, barbiturates, benzodiazepines, and car-bimazole Cytotoxic agents are highly toxic, and breastfeed-ing is contraindicated by mothers on these therapies

The potential for synergistic effects between drugs that are not thought to be teratogenic and other environmental inﬂ uences should not be forgotten Hyperthermia is associ-ated with the development of a variety of birth defects [ 106 ,

107 ] Animal experiments have identiﬁ ed potentiation of the teratogenic effects of hyperthermia by aspirin in non- teratogenic doses [ 108 ] The effect is thought to be due to suppression of prostaglandin E, which is cytoprotective as a result of its induction of heat shock proteins [ 109 ]

Deleterious effects of intrauterine exposure to peutic agents need not be conﬁ ned to structurally identiﬁ -able abnormalities Recent work has raised the issue of more subtle effects that may manifest themselves in terms

thera-of organ function or effects on intellectual development thera-of exposed individuals Antenatal glucocorticoid therapy has reduced the rate of complications seen in preterm deliver-ies Glucocorticoids have important effects on brain devel-opment and in animal studies can be shown to modify the structure and functioning of the brain Recent work has sug-gested that the limbic system (speciﬁ cally the hippocampus) and the hypothalamo-pituitary-adrenal axis are particularly sensitive to steroid exposure in utero with resultant alteration

in behavior and learning performance, and it also reduces life span in an animal model [ 110 , 111 ] There is also increas-ing interest in the impact of prenatal glucocorticoid therapy

on cardiovascular disease later in life [ 112 – 114 ] In an mal model, treatment of pregnant mice with antidepressant drugs (selective serotonin-reuptake inhibitors) affected fetal development, resulting in cardiomyopathy and a higher vul-nerability to affective disorders in a dose-dependent man-ner [ 115] Neonates from mothers treated with selective serotonin- reuptake inhibitors have a higher risk of develop-ing persistent pulmonary hypertension [ 116 ]

Not all harmful drug effects need necessarily be genic or act directly on the fetus Antibiotic prophylaxis for group B streptococcal infection is widely utilized, particularly

Fig 17.3 Thyroid enlargement in a fetus at 20 weeks’ gestation

exposed to carbimazole

P.G.J Nikkels

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in the USA The recommended treatment protocols include

the use of penicillin G or ampicillin It has been shown that

the antepartum use of ampicillin in this context appears to

result in an increased incidence of early-onset neonatal

sep-sis with non-group B streptococcal organisms that are resep-sis-

resis-tant to ampicillin [ 117 ] A study of Towers et al highlighted

the increased frequency of antibiotic utilization in pregnancy

from a level of less than 10 % in 1991 to 16.9 % in 1996

[ 118 ] The implications for antibiotic resistance and

subse-quent difﬁ culties in neonatal care are obvious

Drugs in Labor and Effects on the Fetus

Obstetric analgesia and anesthesia have the potential to affect

the progress of labor, the fetus in utero, and the neonate after

delivery The use of epidural anesthesia can have signiﬁ cant

deleterious effects on the progress of labor There is a

decrease in uterine performance with increased need for

oxy-tocin augmentation, prolongation of the ﬁ rst and second

stages of labor, and increased risk of operative delivery

(cesarean section) [ 119 – 122] Both anesthetic gases and

analgesic agents such as opiates pass readily across the

pla-centa and into the fetus These agents can cause respiratory

depression, which may complicate the early neonatal period

[ 120 , 123 ] The reader is encouraged to consult recent review

articles on problems in obstetric anesthesia [ 124 ]

Complications of the Intrapartum Period

The pattern of complications that arise in relation to labor and

delivery are the result of the interaction of maternal factors, the

intrauterine well-being of the fetus and its position, and the

decisions made by medical and nursing staff as to the manner

of delivery It cannot be overemphasized that “birth injury”

and related defects are as often the result of the fetal condition

as they are the consequence of apparent errors of judgment on

the part of medical and nursing staff supervising and

manag-ing the delivery Therefore, pathologists should proceed with

caution in attributing apparent traumatic abnormalities,

par-ticularly related to the head and intracranial lesions, as being

solely the responsibility of the attendants at a delivery

Some facets of intrapartum asphyxia can be due to or

accentuated by clinical decision-making, but frequently

asphyxiated babies are in poor condition as a result of

pre-partum intrauterine pathology affecting the placenta or have

congenital defects that impair their capacity to withstand the

normal rigors of labor The complexities of this area are

reviewed by Wigglesworth [ 125 ]

Serious birth injuries do occur, however, and many of these

are wholly traumatic in nature The breech presentation is most

likely to be associated with traumatic lesions O’Mahony et al

reviewed singleton delivery intrapartum- related deaths in which traumatic cranial or cervical spine injury or diffi cult delivery was a signifi cant feature [ 126 ] They identifi ed that the vast majority of cases meeting the criteria for inclusion in the study presented with fetal compromise prior to delivery Where cranial and traumatic injury was seen, it was typically associ-ated with a diffi cult instrumental delivery together with ill-judged persistence with attempts at vaginal delivery

Elective cesarean section delivery is associated with a ber of initial problems in the neonate In the emergency situa-tion, the underlying pathology requiring urgent delivery by this route usually supersedes those abnormalities that result from cesarean section alone and that are manifest in babies born electively by this route and particularly those born prematurely

Extracranial Hemorrhage

Edema and bleeding into the soft tissues of the scalp and extracranial tissues is not uncommon and most usually is of little clinical consequence Caput succedaneum is the accu-mulation of ﬂ uid and blood in the skin and superﬁ cial soft tissues of the scalp and usually affects the presenting part of the head over the vertex It is thought to develop as the cervi-cal canal compresses the skull during the passage of the head through the birth canal This swelling usually subsides in a few days Chinon is a somewhat similar lesion resulting from the application of a ventouse extractor with soft tissue edema underlying the area held by the extractor cap In this instance, the edema and hemorrhage is more tightly localized than with a caput succedaneum Subaponeurotic or subgaleal hemorrhage originates deep to the epicranial aponeurosis, and substantial hemorrhage can accumulate in this layer and

be associated with serious clinical consequences including hypovolemic shock [ 127 ] (Fig 17.4 )

Fig 17.4 Massive subgaleal hemorrhage occurring after ventouse extraction

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Cephalhematoma is hemorrhage underlying the

perios-teum over the surface of the skull bones This is usually a

lesion limited by the boundaries of the individual skull bone

plates, and thus the volume of hemorrhage is usually much

less than that seen in subaponeurotic hemorrhages Simple

lin-ear fractures of the parietal bone are not infrequent in instances

of cephalhematoma [ 128 ] (see Fig 15.22 ) Boﬁ ll et al reported

the development of cephalhematoma in 37 of 322 cases of

delivery employing the vacuum extractor [ 129 ] All of these

extracranial ﬂ uid accumulations and hemorrhages have been

associated with the use of the ventouse vacuum extractor,

par-ticularly in instances of multiple applications as a result of

technical failures in the procedure [ 130 – 132 ] Extradural

hem-orrhage is also often associated with skull fracture but is

usu-ally of minor severity and is located between the periosteum

and the inner surface of the skull bones

Skull Fractures

Fracture of the skull is most usually associated with forceps

delivery but can also be seen as a result of pressure of the

skull against the prominences of the maternal pelvis Skull

fracture has also been reported as a consequence of use of the

ventouse vacuum extractor [ 133 ] Minor depressed skull

frac-tures, most typically of the parietal bone, are usually of little

clinical import Similarly linear fractures involving only one

skull bone usually do not lead to signiﬁ cant clinical sequelae

It is likely therefore that the frequency of skull fracture is

higher than the reported incidents Dupuis et al reported that

in a series of 68 cases of neonatally diagnosed depressed skull

fracture managed in their unit, no fewer than 18 cases were of

a “spontaneous” etiology, i.e., not associated with

instrumen-tal delivery or use of the vacuum extractor [ 134 ]

More signiﬁ cant and more typical of a true traumatic birth

injury is a multiradiate fracture of the skull bones, most

typi-cally affecting the parietal bones and frequently bilateral

These injuries are associated with signiﬁ cant intracranial

hemorrhage as a result of tearing of subdural veins and of the

venous sinuses Serious intracranial injury is more likely to

be associated with instrumental delivery [ 134 ]

In cases where a traumatic delivery results in formation of a

leptomeningeal cyst, an associated fracture may grow in size in

the neonatal period A case has also been reported of expanding

fontanelle secondary to delivery trauma with leptomeningeal

cyst formation following use of the ventouse extractor [ 135 ]

Occipital Osteodiastasis

Wigglesworth and Husemeyer describe a serious fracture of

the occipital bone resulting from disruption of the

relation-ship between the squamous and lateral parts of the occipital

bone, which are joined by cartilage and do not fuse until the second year of life [ 136 ] Pressure on the suboccipital region during delivery causes inward displacement of the squamous portion of the bone with resultant tearing of the underlying venous sinuses and subsequent hemorrhage often associated with direct injury to the cerebellum In recent times, this has not been a frequently reported pathology, although it is more likely to occur in vaginal breech delivery Minor forms of this traumatic lesion can easily be missed unless speciﬁ cally excluded by direct and careful inspection The diagnosis can also be made on lateral skull or cervical spine roentgeno-grams showing speciﬁ c changes in the area of the innomi-nate synchondrosis [ 137 ]

Subdural Hemorrhage

This results from tearing of the bridging veins in the subdural space but can also follow tentorial and venous sinus hemor-rhage resulting from precipitant or traumatic delivery However, the presence of unilateral and bilateral subdural hemorrhage is not necessarily indicative of excessive birth trauma [ 138 ] Subdural hemorrhage has also been described following the use of vacuum extraction [ 139 , 140 ]

Although many of these hemorrhages appear to be related

to instrumental delivery and in particular the use of the uum extractor, it should not be forgotten that these lesions have also been described as arising in utero and not related to the delivery process Petrikovsky et al reported seven cases

vac-of cephalhematoma and caput succedaneum not related to labor [ 141 ] Subdural hemorrhage arising in utero and identi-

ﬁ ed in stillborn babies and antenatal subdural hemorrhage that resulted in intrauterine death were described several times [ 142 – 145 ] In some cases, this was due to a severe fetal thrombocytopenia [ 146 ]

Extracranial Injuries

A large variety of additional injuries are reported related to birth These include fractures, hemorrhage into soft tissues and related to major organs, and injuries to the spinal cord and nerves The risk factors and other morbidities associated with the development of these injuries include birth weight greater than 4 kg, prolonged second stage of labor, use of epidural anesthesia and oxytocin, forceps delivery, shoulder dystocia, and fetal compromise as evidenced by meconium passage in labor and low Apgar scores [ 147 – 149 ]

Fractures

Clavicular fractures are seen particularly in difﬁ cult ies of large infants or in cases of shoulder dystocia (Fig 17.5 ) They are not uncommon in breech presentations Published

deliver-P.G.J Nikkels

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423reports give variable incidence rates for this complication in

the range 0.5–1.65 % of deliveries [ 147 , 149 – 152 ]

Diagonal fractures of the middle third of the long bones,

most frequently the femur and humerus, are well recognized

(Fig 17.6a, b ) They are seen with normal deliveries but also

more commonly in instances of breech presentation

Fractures of the vertebrae are extremely rare, although again

they are seen with breech delivery

Visceral Injuries

Hemorrhage related to intra-abdominal organs such as the

liver, spleen, kidney, and adrenal is not infrequent The most

common pattern of hemorrhage is a subcapsular hematoma

of the liver Rupture of this capsule may give rise to a peritoneum and death Subcapsular hematomas are also seen

hemo-in stillborn fetuses and also hemo-in fetuses aborted for somal abnormality or congenital malformation Capsular rupture of the spleen is less common but can give rise to hemoperitoneum Traumatic renal and adrenal hemorrhage

chromo-is extremely rare

Injuries to the Spinal Cord

Spinal cord injuries are more likely to occur during breech delivery and have become less frequent with the increasing use of cesarean section in breech presentations [ 153 ] They are also seen, but much less frequently, in cephalic presenta-tions with injuries arising during delivery of the shoulder The mechanism of injury is a combination of excessive lon-gitudinal traction while the head is hyperextended and pos-sibly ischemic damage related to either stretching with spasm or occlusion of the vertebral arteries [ 154 ] Spinal cord injuries have also been described after an uncompli-cated vaginal delivery [ 155 ]

Peripheral Nerve Injuries

Injuries to the brachial plexus are probably the most mon peripheral nerve injuries An Erb’s palsy results when the ﬁ fth and sixth cervical nerves are damaged, and Klumpke’s paralysis results when the seventh and eighth cer-vical and ﬁ rst thoracic nerves are injured In Klumpke’s paralysis, there is also a Horner’s syndrome as a result of the

Fig 17.5 Birth injury healing midclavicular fracture at 11 days of age

Fig 17.6 ( a ) Humerus fracture in 37 weeks’ gestational age neonate with gracile bones due to a congenital muscular disorder ( b ) Humerus

frac-ture in a 30-week gestational age neonate due to translucent bones associated with massive perivillous ﬁ brin deposition in the placenta

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damage to the ﬁ rst thoracic nerve Occasionally phrenic

nerve palsy may occur with resultant diaphragmatic

paraly-sis and respiratory distress [ 156 ]

Perlow and colleagues report an incidence of facial nerve

injury of 0.6 per 1,000 live births and brachial plexus injury

of 0.9 per 1,000 live births [ 147 ]

These peripheral nerve injuries are frequently but not

exclusively associated with shoulder dystocia where the

shoul-der impacts against the symphysis pubis or the sacral

promon-tory during delivery The fetal manipulation techniques

required for the delivery of a case of shoulder dystocia are not

associated with an increased incidence of nerve injuries or

fractures [ 148 ] The main clinical risk factors are a large baby

(thus the infants of diabetic mothers are at risk) and precipitant

delivery with failure of truncal rotation and persisting A-P

alignment of the shoulders However, the majority of cases

occur in babies who are not overtly large, and it is therefore

not necessarily possible to predict in advance the risk for an

individual labor and baby [ 157 – 161 ]

Complications Related to Cesarean

Section Delivery

Babies born following cesarean section are at risk not only

from the underlying pathological process necessitating this

mode of delivery but also develop complications that result

from the loss of the beneﬁ ts of a vaginal delivery

The vast majority of cesarean sections are performed for

sound clinical reasons in the maternal and/or fetal interest

However, a not insigniﬁ cant number appear to result for

per-haps less clinically rigorous reasons One study reported that

19.8 % of 3,150 elective cesarean sections were cases where

a trial of vaginal delivery was considered appropriate but the

mother requested an operative delivery [ 162 ] In addition, in

women with 1 prior cesarean, planned elective repeat

ean section compared with planned vaginal birth after

cesar-ean was associated with a lower risk of fetal and infant death

or serious infant outcome [ 163 ]

The incidence of respiratory distress syndrome and also of

transient tachypnea of the newborn is increased in babies born by

the cesarean route [ 164 , 165 ] Cesarean section delivery has been

identiﬁ ed as an independent risk factor for the development of

respiratory distress syndrome [ 166 ] The etiology appears to be

the retention of a relative excess of ﬂ uid within the lungs at the

time of delivery Normal vaginal delivery is associated with an

adrenaline surge, which leads to a reduction in lung ﬂ uid volume

[ 167 , 168 ] In addition there is increased synthesis of surfactant

Passage through the birth canal imparts a strong external

com-pressive force on the thorax and aids the displacement of ﬂ uid

from the lungs [ 169 , 170 ] The loss of these physiological

pro-cesses is associated with retention of excess liquor, reduced lung

vital capacity, and lower mean thoracic gas volume [ 171 , 172 ]

Complications of Neonatal Therapy

The diverse patterns of pathology that are seen in neonates result in part from the immaturity of these patients, both those born at term and premature neonates, and the unavoid-able consequences of invasive and often highly aggressive therapeutic modalities invoked in their care The rate of iat-rogenic events is about 57 % at gestational ages of 24–27 weeks, compared with 3 % at term [ 173 ] Many neo-nates who require active therapeutic intervention are extremely ill and represent very-high-risk therapeutic chal-lenges to neonatologists Any pathological lesions or com-plications that develop in these infants may be the result of instrumentation, procedures required for monitoring, or the damaging effects of primary pathologies of prematurity or pathologies resulting directly from therapeutic intervention

In an observational prospective study including all neonates admitted to an academic tertiary neonatal center, the incidence of iatrogenic events was 25.6 per 1,000 patient days In this study, 34 % of lesions were preventable and

29 % were severe Two of the 267 iatrogenic events were fatal, but neither was preventable The most severe iatrogenic events were nosocomial infections and respiratory events Cutaneous injuries were frequent but generally minor, as were medication errors The major risk factors were low birth weight, gestational age, length of stay, a central venous line, mechanical ventilation, and support with continuous positive airway pressure (CPAP) [ 174 ] Superimposed on these pathological processes are developments in the genesis

of lesions, which only become apparent as critically ill nates survive for prolonged periods before their ultimate, and often inevitable, demise Thus, pathological lesions are now seen that would not have been apparent to preceding genera-tions of pathologists involved in perinatal and neonatal medicine

The whole spectrum of pathological appearances that are seen in neonatal medicine varies as new therapeutic modalities are introduced and older treatments are aban-doned It is therefore incumbent on pathologists to pay particular attention to the patterns of therapy employed and to record with care and accuracy the abnormalities seen Only in this way can potentially serious deleterious consequences of innovative treatments be identiﬁ ed at an early stage thus avoiding unnecessary or unacceptable injury to patients

It should not be forgotten, however, that standard and routine interventions can cause cosmetic or functionally deleterious lesions during neonatal intensive care Skin damage is not infrequent and usually trivial [ 173 ] The major risk factors for severe skin damage are low birth weight, gestational age, length of stay, a central venous line, mechanical ventilation, and support with continuous positive airway pressure [ 173 ]

P.G.J Nikkels

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Respiratory System

The most signiﬁ cant patterns of iatrogenic pathology in

neo-nates relate to the need for ventilatory support in premature

neonates or neonates who have other causes of respiratory

distress and hypoxemia Over the last several years, the range

of options available to neonatologists for maintenance of

oxygenation has increased dramatically with the

concomi-tant development of iatrogenic lesions The majority of these

techniques maintain the need for intubation of the proximal

airways, but techniques of cardiopulmonary bypass have

also been introduced into neonatal units

Injuries Caused by Endotracheal Intubation

Cutaneous erythema and superﬁ cial ulceration around the

nose and mouth are very common in intubated neonates

This results both from the use of adhesive tape and from

direct irritation of the poorly keratinized skin of premature

infants, which withstands friction poorly Nasal intubation

by endotracheal tubes and also by nasogastric tubes can give

rise to more serious pathology, and large-bore endotracheal

tubes can cause signiﬁ cant damage to the nasal septum

(Fig 17.7 )

Abnormalities of primary dentition have also been

identi-ﬁ ed in infants intubated for prolonged periods and are

thought to be the result of pressure effects of the

endotra-cheal tube on the gingival margin [ 175 ] Grooves and

cleft-ing of the palate have been described in patients with

long-term endotracheal intubation Fadavi and colleagues

reported on a group of 52 prematurely born children who,

when examined between the ages of 2 and 5 years,

demon-strated signiﬁ cant palatal deformities and abnormalities of

dentition [ 176 ] These are thought to arise from direct

pres-sure effects of the tube Alternative mechanisms have been

suggested [ 177 ] Pape et al described deformity of the skull

and associated cerebellar hemorrhage secondary to venous

infarction in patients in whom face masks were secured by

Velcro bands [ 178 ]

The physical process of intubation can damage the

phar-ynx, esophagus, and upper airway structures, although

fortu-nately these injuries—usually perforations or tears—are rare

[ 179 ] (Fig 17.8 ) Sapin et al reported the outcome in a series

of ten patients, ﬁ ve of whom were managed conservatively

while the remainder required surgical interventions, and it

was noted that the outcome was not always favorable,

princi-pally as a result of concomitant pathology of prematurity

[ 180 ]

Foci of ulceration of the larynx in the region of the

vocal cords or subglottic region are frequently seen

(Fig 17.9 ) The majority of these lesions are superﬁ cial

and heal without signiﬁ cant scarring or ﬁ brosis after the

removal of the endotracheal tube The lesions appear to be

the result of direct pressure effects of the tube and its

inﬂ ated cuff More rarely the ulceration is deep and heals

by ﬁ brosis with narrowing of the airways following scar formation and shrinkage [ 181] O’Neill estimated that laryngeal or tracheal stenosis occurred in 1.5 % of cases at risk and that intubation for periods of greater than 4 weeks’ duration was a predisposing factor [ 182 ] Perichondritis and chondromalacia affecting the arytenoid and cricoid cartilages have been described as a sequel to prolonged intubation [ 183 ]

Ulcerative foci in the tracheal mucosa are rarely seen and usually present as a vertical row of shallow ulcers on the anterior midline surface of the tracheal rings These clearly result from direct contact with the endotracheal tube The selection of a tube of an appropriate size should mitigate against this development More common is squa-mous metaplasia of the anterior portion of the tracheal mucosa in those parts of the trachea in contact with the tube (Fig 17.10 ) This metaplastic change in response to direct irritation may theoretically interfere with the mucociliary escalator and thus with mucus clearance from the proximal

Fig 17.7 Ulceration of the nasal septum after endotracheal intubation

Trang 14

airways This could predispose to infection and appears to

be a lesion that persists for some considerable time after

removal of the endotracheal tube The repeated use of

suc-tion as part of the standard endotracheal toilet in neonatal

intensive care can also result in tracheal and upper

bron-chial injury if the aspirating cannula is inserted too far

dis-tally It is generally accepted that it is not necessary to

aspirate the bronchi but merely to keep the tube itself clear

Mucociliary activity of the airways distal to the end of the

tracheostomy tube keeps the proximal major airways clear

without need for suction in otherwise uncomplicated

situa-tions Subglottic mucous cysts have been described in

patients with long-standing endotracheal intubation and

may compromise airway patency after removal of the

endo-tracheal tube [ 184 ]

It is clear that endotracheal intubation can give rise to a

number of pathological processes, but the appropriate

selec-tion of tube size, gentle handling without excessive vigor

in aspiration of the tube, and use of humidiﬁ ed ventilating

gases greatly minimize the risk of these developments

Patent Ductus Arteriosus

Increased mortality and chronic lung disease in infants with persistent symptomatic patent ductus arteriosus (PDA) suggest that surgical ligation remains an important treatment modality for preterm infants [ 185 ] However, some observational studies showed that ligation of PDA in preterm infants is in some stud-

Fig 17.8 Laryngeal mucosal tear with false passage formation

fol-lowing “difﬁ cult” endotracheal intubation

Fig 17.9 Larynx opened posteriorly; ulceration is present in the

mid-line anteriorly and on both sides below the vocal folds; intubation injury

Fig 17.10 Cross section of trachea; epithelial squamous metaplasia is

present in the anterior half

P.G.J Nikkels

Trang 15

427ies associated with increased chronic lung disease, retinopathy

of prematurity, and neurodevelopmental impairment at

long-term follow-up However, insufﬁ cient adjustment for postnatal,

pre-ligation confounders, such as intraventricular hemorrhage

and the duration and intensity of mechanical ventilation,

sug-gests the presence of residual bias due to confounding by

indi-cation and obliges caution in interpreting the ligation-morbidity

relationship [ 186 ] There is also a strong association with ﬂ uid

overload and the development of chronic lung disease Thus,

any failure to recognize or manage the development of

pulmo-nary edema can be expected to increase the risk of chronic lung

disease in a ventilated neonate Very rarely a left-sided,

iatro-genic vocal fold paralysis secondary to recurrent laryngeal

nerve injury can occur as a complication of ligation of patent

ductus arteriosus, and neonates with a birth weight less than

1 kg are most vulnerable [ 187 ]

Complications of Assisted Ventilation

Neonatal respiratory disease results from the

interrelation-ship between the maternal health, the presence or absence of

prematurity, and the consequences of medical interventions

Prematurity is the most important etiological factor in the

development of respiratory distress syndrome and results

from factors linked to maternal health and obstetric care The

combination of prematurity and medical interventions results

in other pathological consequences including pneumothorax,

pulmonary interstitial emphysema, and chronic lung disease

[ 6] The etiology and spectrum of iatrogenic injury is

reviewed by Clark [ 188 ]

Respiratory Distress Syndrome and Chronic

Lung Disease

Respiratory distress syndrome is very common in the early

neonatal period, occurring in up to 7 % of newborn infants

The risk decreases with each advancing week of gestation

At 37 weeks, the chances are three times greater than at

39–40 weeks’ gestation [ 189 ] In 1967 a new chronic

respi-ratory disease, bronchopulmonary dysplasia (BPD), that

developed in premature infants exposed to mechanical

ven-tilation and oxygen supplementation was described [ 190 ]

Twenty years later, clinically signiﬁ cant respiratory

symp-toms and functional abnormalities persisted into

adoles-cence and early adulthood in a cohort of survivors of

bronchopulmonary dysplasia as reviewed by Baraldi and

Filippone [ 191 ] The pathology of chronic lung disease is

very heterogeneous and will involve abnormalities in the

airways, blood vessels, and interstitial tissues [ 192 ] and is

discussed further in Chap 20 (pages 552–554)

Today, newborns consistently survive at gestational ages

of 23 to 26 weeks—8 to 10 weeks younger than the infants

in whom bronchopulmonary dysplasia was ﬁ rst described

New mechanisms of lung injury have emerged, and the

clini-cal and pathologiclini-cal characteristics of pulmonary

involve-ment have changed profoundly, although its natural history

and outcome into adulthood are still largely unknown [ 191 ] What is now considered the “old” bronchopulmonary dys-plasia was originally described in slightly preterm newborns with the respiratory distress syndrome who had been exposed

to aggressive mechanical ventilation and high oxygen centrations Diffuse airway damage, smooth-muscle hyper-trophy, neutrophilic infl ammation, and parenchymal fi brosis refl ected extensive disruption of relatively immature lung structures The “new” form of bronchopulmonary dysplasia

con-is more likely a developmental dcon-isorder The infants are now delivered several weeks before alveolarization begins, and infants at risk for new bronchopulmonary dysplasia often have only mild respiratory distress syndrome at birth But

at this early developmental stage, even minimal exposure

to injurious factors may affect the normal processes of monary microvascular growth and alveolarization The his-topathologic lesions of severe airway injury and alternating sites of overinfl ation and fi brosis in “old” BPD have been replaced in “new” BPD with the pathologic changes of large, simplifi ed alveolar structures, a dysmorphic capillary con-

pul-fi guration, and variable interstitial cellularity and/or pul-fi proliferation Airway and vascular lesions, when present, tend to occur in infants who over time develop more severe disease The concept that “new” BPD results in an arrest in alveolarization should be modifi ed to that of an impairment

bro-in alveolarization, as evidence shows that short ventilatory times and/or the use of nCPAP allows continued alveolar for-mation [ 193 , 194 ] The histology of chronic lung disease of neonates now reﬂ ects more basic disorder of normal pulmo-nary development with deﬁ ciency of structural elements and excessive development of mesenchymal components The subject is reviewed by Bland [ 195 ]

The most important etiological association with chronic lung disease is respiratory distress syndrome, but also sig-niﬁ cant are oxygen toxicity, positive pressure ventilation, patent ductus arteriosus, and pulmonary air leak Infection can also play an important contributory role in the evolution

of the pathological processes Although the changes of chopulmonary dysplasia can be produced in animals exposed

bron-to high levels of oxygen only, reviewed by D’Angio and Ryan [ 196 ], the practical reality is that the condition was not seen to any extent in neonates before the advent of assisted mechanical ventilation It therefore represents an archetypal iatrogenic pathology Advances in neonatal intensive care and in particular the antenatal use of corticosteroids and postnatal surfactant therapy have modiﬁ ed the pattern of neonatal chronic lung disease such that the classical progres-sion of bronchopulmonary dysplasia is seen infrequently

Oxygen Toxicity

High oxygen concentrations in inspired or ventilated air have dramatic effects on the cells of the airways and lungs, most particularly the alveolar type 2 epithelial cells [ 197 ] The evidence for the injurious effect of pure oxygen is clear, but

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what is much less certain is that oxygen concentrations of

90 % or less cause signiﬁ cant injury [ 198 ] Oxygen induces

tissue injury by increasing formation of free radicals, which

are highly reactive and which react with membrane lipids

and other intracellular constituents Many of the antioxidant

defense mechanisms of the neonate are immature, and the

neonate is unable to respond by dramatically increasing

anti-oxidant enzyme activity when challenged with hyperoxia

[ 199 , 200 ]

Positive Pressure Ventilation

There is considerable evidence in support of the view that

intermittent positive pressure ventilation (IPPV) is the main

etiological factor in BPD The signiﬁ cance of positive

pres-sure ventilation in the genesis of chronic lung disease and

BPD was recognized by Barnes et al [ 201 ] Tooley deﬁ ned

the relationship more clearly [ 202 ] Peak inspiratory

pres-sures in the excess of 35 cm of water were highly associated

with signiﬁ cant and serious BPD [ 203 ] The full spectrum of

pathology will develop with IPPV in the absence of

hyper-oxia Nasal IPPV reduces the incidence of symptoms of

extubation failure and need for reintubation within 48 h to

1 week more effectively than nasal continuous positive

pres-sure ventilation; however, it has no effect on chronic lung

disease or mortality [ 204 ]

Pulmonary Air Leak

Central to the process of ventilation is the requirement to

deliver oxygenated gas to the air-blood interface in the lung

periphery This requires ventilating pressures sufﬁ cient to

achieve alveolar expansion, and in situations of prematurity

with surfactant deﬁ ciency, this pressure must be maintained

throughout the ventilatory cycle in order to prevent alveolar

collapse with loss of capacity for gaseous exchange

Although ventilation pressures are maintained at the lowest

level commensurate with adequate oxygenation, the

pres-sures are always such as to increase the risk of pulmonary air

leakage This becomes particularly likely if pulmonary

compliance falls and ventilation pressures have to rise signiﬁ

-cantly In the author’s experience, some degree of passage of

air into the interstitial tissues of the lung is universal in

ven-tilated neonates Pulmonary air leaks are secondary to

alveo-lar distension, but the sites of tissue rupture are difﬁ cult to

identify in babies who have been ventilated for prolonged

periods or who have developed signiﬁ cant additional

pathol-ogies prior to their presentation for postmortem examination

Alveolar overdistension is particularly associated with high

transpulmonary pressure swings, air trapping, and uneven

alveolar ventilation Air leaking from the gaseous spaces will

track along preformed anatomical pathways particularly

around bronchi, bronchioles, and perivascular tissues The

air may be localized to only one lobe, may extend into the

mediastinum and soft tissues of the head and neck, or may

rupture directly into the pleural cavity giving rise to a

pneu-mothorax Extrathoracic extension of pneumomediastinum

is well recognized

Pneumothorax

A spontaneous pneumothorax is seen in up to 1 % of babies at the time of birth [ 205 ] The vast majority of pneumothoraces are related to pulmonary pathology secondary either to prema-turity or other disorders requiring ventilation The instance of pneumothorax increases as the level of respiratory support increases [ 206 ] The application of positive expiratory pres-sure in an effort to maintain alveolar distension in situations of surfactant deﬁ ciency is associated with increased incidence of pneumothoraces [ 207 ] High inﬂ ation pressures and mean air-way pressures greater than 12 cm of water are associated with increased risk of pneumothorax [ 208 , 209 ] The incidence of air leaks and pneumothorax has been reduced by the use of surfactant [ 210 ] Another well- recognized disorder that pre-disposes to pneumothorax is the development of active expira-tory efforts by the infant during the positive pressure plateau

of assisted ventilation, i.e., “ﬁ ghting the ventilator” [ 208 ] The incidence of neonates ﬁ ghting the ventilator can be increased

by therapeutic protocols, and logically attention to ventilation rate and duration of ventilation time can mitigate against this pathology indicating that there is an iatrogenic component outside the presence of abnormal pressures applied to the air-ways Increasing the ventilation rate has a beneﬁ cial effect in lowering the rate of pneumothoraces and reduces the inci-dence of active expiration and ﬁ ghting the ventilator [ 211 ,

212 ] The use of high- frequency jet oscillation has also onstrated a signiﬁ cantly lower incidence of pulmonary air leak and pneumothoraces [ 213 , 214 ]

Pulmonary Interstitial Emphysema

Interstitial air leak may be localized to one lobe of a lung but more commonly affects both lungs In both instances, the presence of pulmonary interstitial emphysema (PIE) can be recognized macroscopically by the presence of air blebs under the pleural surfaces of the lung (Fig 17.11 ) Sectioning

of the lung will also reveal small cystic spaces in relation to interlobar septa and the larger interstitial tissue planes PIE is

a potentially serious condition causing lung splinting with impaired ventilation and hypoxemia Rarely the accumula-tion of gas around one lobe of the lung may be sufﬁ cient to cause compromise of the lung (Fig 17.12 ) and even medias-tinal shift giving rise to signiﬁ cant respiratory embarrass-ment This has been treated by lobectomy, but it is more common to attempt management by variation of ventilatory care using high-frequency ventilation and withdrawal of pos-itive end expiratory pressure [ 215 ] Other surgical, therapeu-tic treatments have involved direct insertion of chest drains into the larger subpleural blebs, the use of linear pleuroto-mies, or ipsilateral occlusion of the bronchus [ 216 – 218 ] Zerella and Trump reported a series of PIE decompressions

by thoracotomy with lysis of the individual blebs of air [ 219 ]

P.G.J Nikkels

Trang 17

Seventeen of the 31 patients treated survived the procedure,

with the mortality being more common in those neonates

with poor clinical prognostic features

Extrapulmonary Air Leakage

Pneumomediastinum is not uncommon in cases of RDS

requiring ventilation Postmature infants are at increased

risk In some instances, air may track into the soft tissues of

the neck giving rise to subcutaneous emphysema Most

usu-ally the patients are asymptomatic or have mild respiratory

signs Pneumopericardium frequently occurs with

pneumo-mediastinum, with air entry into the pericardial sac probably

adjacent to the pericardial reﬂ ection near the ostia of the

pul-monary veins Pneumopericardium is rarely asymptomatic

and usually causes cardiac embarrassment with tamponade-

like symptoms Pneumoperitoneum can arise as a result of

air accumulation within the chest with dissection via the

diaphragmatic foramina into the intraperitoneal space It is

more usually associated with the infants who already have

pneumothorax or pneumomediastinum Unless the abdomen

is under tension, there is no need for active treatment

Pulmonary Gas Embolism

Pulmonary gas embolism is a rare complication of positive

pressure ventilation [ 220 ] The embolism results from direct

communication between the airways and small vascular channels [ 221 ] The lesion is more likely in situations where there is laceration of lung tissue perhaps as a result of instru-mentation (see below) that favors reversal of the intrabron-chial pressure-pulmonary venous pressure gradient [ 222 ] Pulmonary gas embolism is usually fatal [ 223 ]

Other Ventilator Injury

High-frequency jet ventilation in which aliquots of gas are

ﬁ red into the airways via an endotracheal tube and cannula

at a rate of 200–600 per minute has been associated with the development of necrotizing tracheobronchitis charac-terized by the development of tracheal, mucosal, and sub-mucosal ischemic injury Mucosal inﬂ ammation, erythema, and erosion are relatively minor patterns of injury, but more serious tracheal necrosis and resultant tracheal obstruction are reported [ 224 – 226] The lesions are not simply the result of direct impact of the gas jet, as they have been reported when the tracheal wall was not in the line of the jet [ 227] Not dissimilar tracheal lesions have also been reported with other high-frequency ventilation systems Inﬂ ammatory endobronchial polyps have been seen in chil-dren who have had a history of mechanical ventilation in the neonatal period [ 228 ] The authors suggest that these lesions result from airway trauma, but it is not clear as to

Fig 17.11 Interstitial emphysema involving both lobes of the left

lung; gas bubbles are visible through the pleura There is gas

accumula-tion at the right hilus

Fig 17.12 Interstitial emphysema; large accumulations of gas distort

lung architecture

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whether this was the result of suction cannulation direct

injury or pressure effects

Special Techniques

Extracorporeal Membrane Oxygenation (ECMO)

Extracorporeal membrane oxygenation (ECMO) is a form

of cardiopulmonary bypass that has been introduced into

neonatal intensive care as a method of oxygenation for

neo-nates with respiratory failure [ 229 ] ECMO avoids the

com-plications of barotrauma secondary to positive pressure

ventilation [ 230 ] There are two forms of ECMO: the ﬁ rst,

veno-arterial (VA), involves the creation of a circuit with

blood taken from the right jugular vein and returned via the

right common carotid artery, and the second, venovenous

(VV), involves blood taken from the right jugular vein and

returned usually through the femoral vein [ 231 – 233 ] VA

ECMO is more advantageous in that there is approximately

80 % cardiopulmonary bypass, and thus there is a dramatic

reduction in the level of respiratory support required A

dis-advantage is that there is a potential for embolization of

blood clot or air into the arterial circulation and in particular

to the central nervous system In addition, the ligation of the

carotid artery or the attempted reconstruction of the carotid

artery following decannulation can give rise to additional

complications [ 234 , 235 ] With VV ECMO, there is no

car-diopulmonary bypass and the infant is dependent on good

myocardial function Femoral vein ligation after

decannula-tion may give rise to obstrucdecannula-tion of venous drainage to the

limb and consequent edema In both forms of ECMO, the

venous blood is oxygenated outside the body and returned

by a pump after passing through a heat exchanger The

patient is required to be heparinized and sedated throughout

the treatment

Children who survived neonatal treatment with ECMO

often encounter neurodevelopmental problems at school

age [ 236 ] Congenital diaphragmatic hernia (CDH) is now

the most common indication for ECMO Most patients—

except those with CDH—have normal lung function and

normal growth at older age Maximal exercise capacity is

below normal and seems to deteriorate over time in the

CDH population [ 236] The results of the UK trial of

ECMO revealed the successful nature of the therapy but

also indicates the high morbidity and mortality that results

from the underlying presenting primary pathologies as

most infants eligible for ECMO are critically ill [ 237 ]

Complications related to ECMO are not infrequent and

may, in a minority of cases, be serious It is important to

note that pathology established prior to the commencement

on ECMO—particularly that related to the lung and

result-ing from prematurity, hypoplasia, and barotrauma—will

progress through the usual stages despite the cessation of

ventilation while on VA ECMO and will manifest itself in

survivors later in childhood in the form of hyperinﬂ ation,

airway obstruction, and lower oxygen saturations with exercise [ 238 , 239 ]

Of all the indications for the use of ECMO, those patients with acute respiratory failure secondary to meconium aspira-tion syndrome appear to have the best outcome both in terms

of survival rate and subsequent respiratory health [ 240 ] Venovenous ECMO has been shown to be an optimum thera-peutic modality for meconium aspiration syndrome [ 241 ] Cerebrovascular complications result from microemboli, with microinfarcts and the increased risk of hemorrhage Studies have demonstrated dramatic effects on cerebral per-fusion during VA ECMO with marked reduction in arterial

ﬂ ow, particularly if there is any obstruction in the venous cannula [ 242 ] Neurodevelopmental defects may be manifest

in survivors and can result from the primary pathology and from the complications of ECMO therapy [ 243 ] The reported frequency of brain abnormality as identifi ed by var-ious neuroimaging modalities varies between 28 and 52 % of ECMO-treated neonates and is associated with functional defi ciency in childhood [ 244 , 245 ] However, it appears that most newborn infants who received ECMO therapy for acute respiratory failure (of which the majority will be meconium aspiration syndrome) will have normal neural developmental screening assessment at 1–1½ years of age [ 246 , 247 ] Cardiovascular complications, including myocardial stun and infarction, have an adverse effect on survival during ECMO [ 248 ] Hemorrhage is a signifi cant complication in

up to a third of patients, and sepsis is predictably a concern Mechanical problems related to the ECMO circuit have been reported in up to 20 % of cases [ 249 , 250 ] Extracorporeal membrane oxygenation is a labor-intensive and expensive therapeutic modality that should be limited to a few dedi-cated centers

Nitric Oxide

The addition of nitric oxide to ventilating gases to promote vascular relaxation in the pulmonary vascular bed is increas-ingly being employed in neonates with persisting pulmonary hypertension Nitric oxide was identifi ed as the endothelium- derived vasodilator factor by Ignarro and coworkers [ 251 ] Subsequently, its central role in control of vascular tone and the related chemistry have been defi ned It is a major factor in the transition from the high-resistance state of the fetal pulmo-nary circulation to the low-resistance “adult” state [ 252 , 253 ] The effi cacy of inhaled nitric oxide in reducing pulmo-nary vascular resistance is unquestioned, but the effects are frequently short-lived, and pulmonary hypertension recurs after cessation of nitric oxide therapy A recently reported multicenter randomized control trial of inhaled nitric oxide therapy for premature neonates with severe respiratory fail-ure has concluded that the treatment does not decrease the rate of death or rate of development of bronchopulmonary dysplasia in critically ill premature infants weighing less than 1,500 g [ 254 , 255 ]

P.G.J Nikkels

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431 There are several observed and theoretical concerns regard-

ing the toxicity of nitric oxide It binds avidly to hemoglobin

where it is quickly inactivated with the resultant formation of

methemoglobin, inorganic nitrate, and nitrite [ 256 ] Under

certain conditions, nitrogen dioxide and peroxynitrite free

radicals can form [ 257 ] Nitrogen dioxide is toxic to lung

tis-sue and can cause pulmonary edema Peroxynitrite, by its

oxi-dant capacity, damages lipid membranes and surfactant and

will bind to nucleic acid and proteins at tyrosine residues

forming nitrotyrosine with a theoretical risk of teratogenicity

and mutagenicity [ 258 – 263 ] The real risk of long-term

sequelae, particularly of a teratogenic and

mutagenic/carcino-genic nature, is likely to be small but is as yet undeﬁ ned The

passage of time will be the test in this regard

Liquid Ventilation

Perﬂ uorocarbons dissolve large quantities of oxygen and

carbon dioxide at atmospheric pressure At normal

atmo-spheric pressure conditions, a saturated solution of perﬂ

uo-rocarbon contains approximately 15 vol.% of oxygen [ 264 ]

Ventilation by instillation of perﬂ uorocarbon into the

air-ways is being increasingly employed in neonatal and adult

intensive care where there is a need for respiratory support

and augmentation [ 265] However, there is no evidence

from randomised controlled trials to support or refute the

use of partial liquid ventilation in children with acute lung

injury or acute respiratory distress syndrome [ 266 ] The

treatment appears to be remarkably devoid of complication,

and the histological appearances of liquid ventilated lung

tissue are remarkable for their “normality,” as a result

pre-sumably of the removal of exudate and damaging cytokines,

the expansion of alveolar saccules with enhancement of

blood-gas interface surface area, and the avoidance of the

barotrauma associated with positive pressure ventilation

Hemodynamic embarrassment and lactic acidosis have been

reported during liquid ventilation [ 267 , 268 ] However,

there is now a very large literature reporting the use of liquid

ventilation in a number of clinical scenarios both in children

and adults, and there is no evidence of any signiﬁ cant

dele-terious consequence related to the treatment alone

Complications of Pharmacological Interventions

in Neonatal Lung Disease

Surfactant Therapy

The administration of exogenous surfactant given either

pro-phylactically or as a “rescue” therapy has had a considerable

impact upon the incidence and severity of respiratory

dis-tress syndrome and chronic lung disease in premature

neo-nates The results of rescue therapy are less dramatic than

those of prophylactic therapy Toxicity from the various

forms of animal and artiﬁ cial surfactant appears to be

minimal, and, in particular, antibodies are not formed to the

bovine and porcine animal-derived surfactants [ 269 ]

Surfactant therapy is also effective in the management of other forms of neonatal respiratory disease in which the efﬁ -ciency of endogenous surfactant is altered by aspirated mate-rial or inﬂ ammatory exudate The cholesterol, free fatty acids, and bilirubin in meconium show a dose-dependent interference with surfactant function, which can be over-come by endogenous surfactant therapy

The sole signiﬁ cant complication is a higher incidence of massive pulmonary hemorrhage, particularly following the use of Exosurf in small babies weighing less than 700 g [ 270 ,

271 ] A meta-analysis of 29 trials was conducted by Raju and Langenberg and conﬁ rmed an association between massive pulmonary hemorrhage and synthetic but not natural surfac-tant [ 272 ] The large Osiris study showed pulmonary hemor-rhage to occur in 5–6 % of babies treated with Exosurf [ 273 ]

Indomethacin

Recovery from otherwise uncomplicated respiratory distress syndrome is complicated by signiﬁ cant shunting through a patent ductus arteriosus in approximately 20 % of cases [ 274 ] Indomethacin is routinely utilized to close the ductus arteriosus and is successful in 75–80 % of cases [ 275 ] The drug has several side effects, including reduction of renal output and ﬂ uid retention [ 276] In addition it has been shown to be associated with an increased risk of gastrointes-tinal perforation and hemorrhage and also with disorders of coagulation [ 277 – 279 ]

A potentially more serious consequence of indomethacin therapy used as antenatal tocolytic drug is mediated by its effect on cerebral hemodynamics The drug causes a marked decline in cerebral blood fl ow, cerebral oxygen delivery, and cerebral blood volume and may also reduce the oxygenation of the brain [ 280 , 281 ] The development of cystic brain lesions and interventricular hemorrhage has also been associated with indomethacin therapy [ 282 , 283 ] In doses of 50–150 mg per day as tocolytic agent, no adverse side effects were seen, and it did not have an effect on the ability to autoregulate the cerebral circulation [ 284 ] A randomized controlled trial confi rmed the effects of indomethacin on cerebral blood fl ow and demon-strated that ibuprofen, while having a similar therapeutic ben-

eﬁ t in closure of a patent ductus arteriosus, was not associated with disordered cerebral hemodynamics [ 285 ]

Antioxidant Therapy

Vitamin E and superoxide dismutase treatment have been used in the management of evolving chronic lung disease Trials have shown no beneﬁ t of vitamin E in the prevention

of bronchopulmonary dysplasia, but the incidence of tal sepsis and necrotizing enterocolitis has been shown to be higher in neonates receiving vitamin E therapy for 8 days or longer [ 286] Vitamin E decreases the oxygen-dependent intracellular killing ability of neutrophils and may result in a decreased resistance of preterm infants to infective organ-isms [ 287 ]

neona-17 Iatrogenic Disease

Trang 20

A similar theoretical risk arises with the use of

antioxi-dant superoxide dismutase treatment, which may affect the

bactericidal activity of neutrophil polymorphs

Complications of Chest Drains

Perforation of the lung by chest drains is not uncommon and

has been reported in approximately 25 % of cases in some

studies [ 288 ] This complication is more likely to occur in

situ-ations of poor pulmonary compliance and with lungs that

become full and voluminous as a result of signiﬁ cant

intersti-tial air leak and intra-alveolar hemorrhage The avoidance of

sharp trocar insertion and utilization of blunt dissection for the

insertion of chest drains minimizes the incidence of direct

pul-monary perforation by the drain tube Injury to the thoracic

duct causing chylothorax [ 289 ], cardiac trauma with

tampon-ade [ 290], and phrenic nerve injury [ 291 – 293] are also

reported Direct lung puncture can give rise to bronchopleural

ﬁ stula formation, which may require surgical repair [ 294 ]

Infection

The subject of infection is dealt with in detail elsewhere in

this book (Chap 9 ) Unlike the fetus, which is protected in

utero to a substantial degree, the neonatal period represents

the time of greatest vulnerability to infection Passage

through the birth canal exposes the neonate to a complex

bacteriological and virological environment with numerous

virulent pathogens, some of which colonize the maternal

genital tract, e.g., ß hemolytic Streptococcus

The premature neonate or a baby born with hypoxemia is

at particular risk A combination of an immature

immuno-logical system and other major system functional deﬁ cits

increases the risk of infection The wide range of therapeutic

measures employed in the neonatal intensive care

environ-ment (e.g., endotracheal intubation and the insertion of

vas-cular cannulae) breach the fragile local defense mechanisms

of the neonate and create portals of entry for infectious

agents, which almost invariably are more likely to be

patho-genic than those microorganisms that would be encountered

outside the hospital environment

Complications Related to Monitoring,

Vascular Cannulation, and Blood Sampling

Intermittent and continuous monitoring of multiple

parame-ters using various monitoring devices to display and record

cardiorespiratory function and other modalities is an

essen-tial feature in neonatal intensive care Inherent with any

sys-tem involving machines is the possibility that as a result of

some deﬁ ciency in setting up the equipment or some

equip-ment failure, inappropriate information can be proffered to

nursing and medical staff It is important that all monitoring

devices are checked regularly and that all staff are aware of the common system faults that may arise

Arteries

Arterial blood sampling and monitoring of blood gases are

an essential part of neonatal intensive care The target range for PaO 2 , PaCO 2 , and pH requires relatively tight control if the deleterious consequences of hypoxemia, hyperoxemia, alkalosis, and acidosis are to be avoided The development

of indwelling arterial lines permits neonatologists to take frequent samples or to continuously monitor a number of parameters The routine method of obtaining arterial blood is

to insert an umbilical arterial catheter (UAC) This is usually straightforward in the early days after delivery, but as with all vascular cannulation, there is the potential for endothelial trauma and associated thrombosis Resultant thrombosis in the aorta or iliac arteries is common and is reported with a frequency of between 24 % and 95 % in infants investigated

by angiography and seen in 3.5–48 % of cases coming to necropsy [ 295 ] Occasionally the aorta thrombosis results

in occlusion of the inferior mesenteric artery with ing enterocolitis as a result [ 296 , 297 ] A small amount of adherent thrombus can be identifi ed in relation to almost every umbilical arterial catheter, but serious thrombosis with ischemic damage to related organs is extremely rare Usually the thrombus is small and associated with the exter-nal wall of the catheter—often adherent to the catheter tip Thrombosis is more commonly seen in catheters with a side hole, and this is thought to be related to the presence of a dead space between the side hole and end hole of the catheter tip Given the frequency with which umbilical arterial cannu-lae are inserted in neonates, it is comforting to note that the incidence of serious complication is very low if attention is given to the optimum positioning of the catheter in the aorta and if recognized standard procedures of catheter manage-ment are followed The danger area for the risk of serious embolization of intra-abdominal organs is in the zone from T12 to L3/4 [ 298 ] In this area, the arteries to the kidneys and intestines take origin The theoretical risks of emboliza-tion from catheters that are positioned above T12 with sub-sequent increased risk of NEC do not appear to present as a clinical problem [ 299 ] The low positioning of the cannula tip can give rise to obstruction of blood fl ow to the lower limbs [ 300 ] Signifi cant complications of umbilical arte-rial cannulation, although rare, are very serious and include aortic thrombosis [ 301 , 302 ] (Fig 17.13 ); thrombotic epi-sodes affecting the lower limbs [ 303 ] (Fig 17.14 ), the kid-neys [ 304 ], and the gastrointestinal tract [ 305 ] (Fig 17.15 ); damage to the bladder or urachus with urinary leakage in the peritoneal cavity [ 306 ]; development of aortic aneurysmal dilatation [ 307 ]; and spinal cord injury including the devel-opment of paraplegia [ 308 – 310 ]

necrotiz-P.G.J Nikkels

Trang 21

Gluteal skin necrosis as a complication of umbilical

arte-rial catheterization has also been described [ 311 , 312 ], but

others have implicated the prolonged contact with alcohol-

based skin cleansing agents or infusion of hyperosmolar

solutions as a causative factor [ 313 – 315 ]

Cannulation of peripheral arteries is occasionally utilized

when an umbilical arterial cannula cannot be inserted

Peripheral arterial cannulae, unlike those inserted via the

umbilical artery, should not be used for infusion purposes as

this gives rise to arterial spasm It is vital to check that there

are good collateral blood supplies distally before cannulation

of radial, ulnar, or posterior tibial arteries Simmons et al

reported ischemic brain injury secondary to cannulation of

the temporal arteries, presumably as a result of arterial spasm

in the territory of the ipsilateral external carotid artery [ 316 ]

Lin et al report their experience of complications resulting

from femoral arterial catheterization in pediatric patients

[ 317 ] Nonischemic complications had a good outcome, but

a small proportion of children presenting with ischemic complications did not regain normal circulation to the limb despite surgical interventions—although no limbs were lost Gamba et al reported a neonatal unit experience of vascu-lar injuries in a study group of 2,898 extremely low- and

Fig 17.13 Massive aortic thrombosis following umbilical arterial

catheterization

Fig 17.14 Gangrene of the perineum and lower limb caused by

mas-sive aortic thrombosis

Fig 17.15 Infarction of the colon following aortic thrombosis

Trang 22

low-weight neonates [ 318] The incidence of signiﬁ cant

pathology—e.g., arteriovenous ﬁ stulae, carotid artery

trauma, and limb ischemia—was strongly correlated with

birth weight; 2.6 % of low-birth-weight babies suffered

sig-niﬁ cant iatrogenic vascular pathology as compared with

0.3 % of neonates weighing more than 1,500 g

Intermittent arterial puncture should be less frequently

required in neonatal intensive care where continuous monitoring

catheters or umbilical arterial catheters permitting intermittent

sampling are in situ The risk of introduction of infection into the

repeated arterial puncture area and also of direct vascular injury

is obvious Fortunately these complications are relatively rare as

is the risk of distal ischemic secondary to arterial spasm

Veins

Cannulation of umbilical veins is associated with a high

frequency of complications (Figs 17.16 and 17.17 )

Umbilical vein thrombosis was extremely common following

catheterization and particularly frequent after the infusion

of hypertonic solutions [ 319 ] The frequency and pattern of thrombotic and embolic complications were related to the positioning of the end of the catheter Typically the umbili-cal venous cannulae are positioned in the right atrium but may occasionally be in the thoracic inferior vena cava Occasionally this may result in perforation of the right atrium with tamponade [ 320 , 321 ] Malposition of the cannula tip

in the portal vein with subsequent portal vein thrombosis and subsequent hepatic necrosis was reported by Larroche [ 322 ] There is a high risk of liver necrosis when an umbili-cal venous catheter is used in combination with a congeni-tal anomaly of the venous duct like hypoplasia or agenesis (Fig 17.18a, b ) More chronic consequences of portal vein thrombosis included portal hypertension with splenomegaly

or hematemesis [ 323 , 324 ]

More commonly, venous catheters are inserted in temic veins and positioned in the subclavian, femoral, and superior vena cava territories for the purposes of parental alimentation The principal complication with these lines appears to be a high risk of bacterial and fungal coloniza-tion with dissemination of infection [ 325 ] Thrombosis related to the tip of the cannulae and propagation of the thrombus into the superior vena cava and heart are also not uncommon An infrequent but well-recognized com-plication of venous catheterization is perforation of the myocardium [ 326 ]

Fig 17.16 Thromboembolus straddles a pulmonary arterial

bifurca-tion following umbilical venous cannulabifurca-tion

Fig 17.17 Venous infarction of the left kidney secondary to inferior

vena caval thrombosis after umbilical venous catheterization

P.G.J Nikkels

Trang 23

Other Causes of Complications

Burns

Neonatal skin is more sensitive than adult skin to burning

Burns have been reported in instances of prolonged exposure

to warming devices at temperatures as low as 42 °C, and

sec-ond-degree burns have been reported following resuscitation

under infrared heating lamps and by using a defective

transil-lumination device [ 327 – 329 ]

Topical Preparations

The high surface area-to-volume ratio of small neonates combined

with the relative fragility and poor keratinization of neonatal

skin increases the potential for absorption of topical preparations

Hexachlorophene

A classical example of this risk was hexachlorophene, which

was formerly used as a bacteriostatic agent and was applied

as a whole-body application for cleansing purposes

Abnormalities of the central nervous system were ﬁ rst

identi-ﬁ ed in experimental animals in the form of spongiform degeneration after repeated applications of hexachlorophene [ 330 ] Similar changes were identiﬁ ed by Powell et al in the brains of six preterm infants who had received at least four whole-body exposures to hexachlorophene [ 331 ] Shuman

et al found similar abnormalities in the brains of 17 of 248 babies who were all of low birth weight and who had experi-enced repeated applications of 3 % hexachlorophene solution [ 332 ] This experience should serve as a warning of the spe-cial conditions of neonatal skin This obsolete therapy and others were discussed in a recent paper by Halliday [ 333 ]

Alcohol-Based Cleansing Solutions

Wilkinson et al and Harpin and Rutter identiﬁ ed the quences of prolonged exposure of the skin to alcoholic solu-tions of chlorhexidine and industrial methylated spirits [ 314 ,

conse-315 ] These exposures resulted in superﬁ cial skin necrosis in the areas exposed to the alcoholic solutions (Fig 17.19 ) Harpin and Rutter also demonstrated the absorptive capacity of the skin by ﬁ nding high blood levels of ethanol and methanol in some of the babies exposed to methylated spirits [ 315 ]

a

b

Fig 17.18 ( a ) Severe hypoplasia of the venous duct, ( left ) overview of the venous system in the liver with the pinpoint lumen of the venous duct

( arrow ) in detail ( right ) ( b ) Liver necrosis in the right upper lobe in association with severe hypoplasia of the venous duct

Trang 24

Systemic Treatments

The major risk with regard to drugs administered

systemi-cally is inadvertent computation errors and subsequent drug

overdose [ 334 ] This is undoubtedly a much more frequent

occurrence than the literature would cause one to believe

[ 335 ] A lot has been done to try to ensure the safe use of

medicine [ 336 , 337 ]

Antibiotics

Antibiotics are a major cause of drug-induced renal disease

as a result of direct toxicity or immunologically mediated

injury Antibiotics are widely used in neonatal intensive

care (e.g., aminoglycosides, glycopeptide, beta-lactams,

etc.), and all show varying potential for nephrotoxicity In

most instances, this will be reversible on discontinuation of

treatment [ 338 , 339 ]

Diuretics

Diuretics such as furosemide, chlorothiazide, and tone are frequently used in the management of chronic lung disease Furosemide can provide dramatic improvements in lung compliance and reduction of airway resistance [ 340 ,

spironolac-341 ] Prolonged therapy with chlorothiazide and tone has been reported to improve the outcome in patients with severe bronchopulmonary dysplasia [ 342 ] However, whether the use of diuretics is also benefi cial for the new bronchopulmonary dysplasia is not yet well studied [ 343 ] Furosemide administration may cause hyponatremia and hypocalcemia Chronic diuretic therapy is associated with hypercalciuria, renal calcifi cation, and nephrolithiasis The renal calcifi cation is composed of calcium oxalate and cal-cium phosphate [ 344 ] This may be associated with demin-eralization of bones Renal calcifi cation is more common in immature infants receiving longer courses of treatment and has been reported in infants receiving long-term furosemide therapy—renal function may remain compromised in some patients [ 345 ] The calcifi cation usually resolves spontane-ously following discontinuation of treatment, but active therapy with chlorothiazide may be utilized to increase uri-nary calcium excretion and promote the resolution of calci-

spironolac-ﬁ cation [ 344] Other complications of chronic diuretic therapy include hyperchloremia, metabolic alkalosis, and ototoxicity [ 346 – 349 ]

Steroids

Steroids are utilized in the treatment of chronic lung disease and give rise to improvement in lung function, although effects on survival and the long-term outcome are less clear [ 350 , 351 ] Numerous side effects of steroid therapy have been reported, and it appears important that sepsis and patency of the ductus arteriosus are excluded prior to instiga-tion of treatment Depression of immune function is a poten-tially serious consequence of steroid therapy, but studies have provided confl icting results as to the signifi cance in neonates [ 352 , 353 ] Steroids are associated with gastroin-testinal complications including hemorrhage, peptic ulcer-ation, and gastric perforation [ 354 , 355 ] Signifi cant hypertension can follow steroid therapy and will persist for several days after treatment has been discontinued [ 356 ,

357 ] Hypertensive encephalopathy has been associated with steroid-induced hypertension Dexamethasone has been associated with a transient myocardial hypertrophy and hypertrophic obstructive cardiomyopathy [ 358 , 359 ] The cardiac pathology resolved completely after cessation of treatment Dexamethasone is also known to have a catabolic effect in preterm infants causing a rise in urea secondary to catabolism of muscle tissue [ 360 , 361 ] The risk of adrenal suppression following prolonged use of exogenous steroid therapy in premature babies appears to be very small [ 362 ]

Fig 17.19 Dorsal cutaneous necrosis following prolonged contact

with an alcohol-based skin cleansing agent

P.G.J Nikkels

Trang 25

However, suppression of the hypothalamic pituitary access at

the pituitary level has been identiﬁ ed in prolonged

dexa-methasone therapy [ 363] Neonatal dexamethasone

treat-ment for chronic lung disease has been shown to impair

cerebral cortical gray matter development and

neurodevelop-mental impairment in a primate model and preterm newborns

[ 364 , 365 ] No long-term effects on neurocognitive outcome

have yet been shown for hydrocortisone treatment; however,

the outcome of this therapy has to be evaluated in

random-ized trials [ 366 , 367 ]

Tolazoline

An alpha-adrenergic blocking agent used in the management

of pulmonary hypertension, tolazoline, is associated with the

development of gastrointestinal ulceration and hemorrhage

[ 368 , 369 ] (Fig 17.20 )

Prostaglandin E1

This drug is used to maintain the patency of ductus arteriosus

in neonates with cyanotic congenital heart disease Heffelﬁ nger et al reported the development of pulmonary arteritis following prostaglandin E1 therapy and proposed a causal relationship [ 370 ] The development of cortical hyper-ostosis following long-term administration of prostaglandin E1 in infants with cyanotic congenital heart disease is well known [ 371 ] Prolonged prostaglandin treatment is also asso-ciated with signs of gastric-outlet obstruction, disturbed ﬂ uid-electrolyte parameters, and high leukocyte counts [ 372 ]

Total Parenteral Nutrition

Intravenous alimentation is widely used in pediatric practice, most particularly in neonates with gastrointestinal pathology including necrotizing enterocolitis Increasingly it is being employed in neonatal intensive care units to supplement the oral feeding of very small neonates Most neonates with severe respiratory illnesses will have ileus and delayed gas-tric emptying This plus the high frequency of gastroesopha-geal reﬂ ux makes enteral nutrition potentially problematic Intravenous alimentation in the form of either supplementa-tion of enteral feeding or as total parenteral nutrition (TPN) involves the intravenous infusion of solutions of amino acids, sugar, and lipid emulsion with additional vitamins and trace elements added Amino acid and calcium infusions are intensely irritant if they leak out the vascular compartment The most frequent complication relates to infection by bacte-ria and fungi colonizing the intravenous line Disturbances of liver function and cholestasis are well-recognized complica-tions of prolonged total parenteral nutrition Peden et al were the ﬁ rst to draw attention to the hepatic complications

of total parenteral nutrition in infants [ 373 ] The ment of TPN-associated cholestasis is related to the duration

develop-of treatment and correlates inversely with the gestational age and birth weight It is a diagnosis of exclusion given the numerous other causes of neonatal cholestasis that are pos-sible The morphological appearances are not speciﬁ c and are variable [ 374 , 375 ] Infants are more susceptible to TPN- related hepatocellular injury, are more likely to develop

fi brosis, and progress to high-stage fi brosis more rapidly than older children and adults [ 376] Typically there is marked cholestasis affecting liver cells, and canaliculi and cholestatic hepatocyte rosettes are frequently present (see page 612) Bile plugs may be present in interlobar bile ducts Steatosis is infrequent The portal tracts usually exhibit a very light mixed infl ammatory infi ltrate Prolonged therapy

is associated with a periportal ductular reaction and sive fi brosis Surgical intervention performed during TPN-associated cholestasis may exacerbate liver injury [ 377 ] The use of fat emulsion in intravenous alimentation is associated with additional specifi c and potentially very serious adverse consequences Barson et al fi rst described pulmonary lipid

Fig 17.20 Multiple discreet ulcers in the gastric mucosa; at necropsy,

the stomach and duodenum were ﬁ lled with blood

Trang 26

embolism in patients received lipid infusions [ 378 ]

Subsequently, lipid infusions were shown to be associated

with a fall in PaO 2 [ 379 ] Randomized prospective control

trials in preterm neonates receiving intralipid demonstrated

longer requirement for oxygen therapy and intermittent

posi-tive pressure ventilation and also a higher rate of

develop-ment of chronic lung disease [ 380 , 381 ] Cooke showed that

intravenous lipid was a precursor of chronic lung disease in

low-birth-weight infants [ 382 ]

The reticuloendothelial system takes up lipid droplets in

macrophages following lipid emulsion administration In

animals this has been shown to result in defective neutrophil

and macrophage function, and intralipid treatment may

increase the risk of staphylococcal epidermidis sepsis and

coagulase-negative staphylococcal bacteremia in very

low-birthweight newborns [ 383 – 386 ] The principles and

com-mon complications of parenteral nutrition in the newborn

were reviewed recently [ 387 ]

Blood Transfusion

Potential complications related to blood transfusion are

very numerous They range from technical and procedural

errors in crossmatching, insertion of intravascular lines,

problems with volume, and the potential for disturbance of

body temperature to more speciﬁ c factors within the

trans-fusion itself [ 388 , 389 ]

Infection

No blood product can be regarded as entirely free from the

risk of infection with any of a number of viral agents

(cytomegalovirus [CMV], hepatitis viruses, human immunodeﬁ

-ciency virus [HIV]), and in more recent times, the question

of the potential risk of exposure to prions—the infectious

agent in spongiform encephalopathy (Creutzfeldt-Jakob

dis-ease [CJD] and new variant CJD)—has been raised

However, for all practical purposes, the risk of infection is

extremely low for patients in the “developed” world as a

consequence of rigorous screening of blood donors and

donations for infectious agents [ 390 – 393] Recipients of

infected blood have a high risk of established infection Dike

et al reported that 76 % of a cohort of patients who received

hepatitis C virus (HCV)-positive blood prior to the

establish-ment of the 1991 screening system became infected as

evi-denced by the detection of HCV RNA in the recipients of the

blood donations [ 394 ]

The position in developing countries is less assured with high rates of infectivity in the population in general and in donations [ 395 ] The cost of screening tests is a serious bur-den in many countries, and the risk of infection from blood products is signiﬁ cant

Transfusion-transmitted CMV infection is potentially serious in immunocompromised patients Neonates, particu-larly those who are premature, have suboptimal immune sys-tems and with the additional stresses of other neonatal disorders are at risk of serious illness rather than the more usual asymptomatic seroconversion Again, screening of blood given to immunocompromised patients signiﬁ cantly reduces the risks [ 396 , 397 ]

Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease (GVHD)

is rare but carries a very high mortality The condition results from the proliferation of donor T lymphocytes in an immunocompromised host incapable of their elimination Irradiation of blood products is the method currently employed to inhibit the proliferative capacity of T lympho-cytes in blood, and this is routine if a patient is known to be immunocompromised Despite this, fatal immunodeﬁ -ciency can still follow the development of GVHD after blood transfusion The clinical presentation is typical of GVHD in other clinical settings, e.g., bone marrow trans-plantation [ 389 , 396 , 398 ]

Skeletal Abnormalities

Rachitic changes in the ribs of premature infants with ratory pathology characterized by expansion of the epiphy-ses and costochondral junctions, angulation of the ribs, and occasional rib fractures are well described [ 399 ] (Fig 17.21 ) These abnormalities have been attributed to the results of low intake of calcium and vitamin D, with these deﬁ ciencies being accentuated by the administration of sodium bicarbon-ate and the use of furosemide, which increases calcium excretion A number of hormones and other agents may cause hypocalcemia and are present in very sick low-birthweight neonates [ 400 ] It is likely, therefore, that the etiology

respi-of calcium depletion from the ribs is multifactorial, although calcium supplementation and dietary supplementation will alleviate and ameliorate the pathology These skeletal abnor-malities still occur, especially in extremely low-birth-weight infants [ 401 , 402 ]

P.G.J Nikkels

Trang 27

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T.Y Khong, R.D.G Malcomson (eds.), Keeling’s Fetal and Neonatal Pathology, DOI 10.1007/978-3-319-19207-9_18

ances and more in their molecular biology They probably have a lot more to teach us

There has not been the time for multiple mutations to develop as for adult tumors These tumors are often genomically and chromosomally similar to the host, and morphologically they often appear to recapitulate differentiation The genetic revolution has taken us further into understanding this close association, showing important pathways in cellular differen-tiation genes, imprinting, chromatin remodeling, and noncoding RNA This may explain the issues related to whether these are tumors, or maldevelopment, or both sharing similar largely epigenetic pathways

This chapter is a review of the major tumor types with some discussion of new entities and some of the pathogenetic factors There are too many tumors and too many new discov-eries to cover all the entities in detail, but this is to give a general guide to the topic

Keywords

Neonatal tumors • Congenital • Neoplasia • Oncogenesis • Inherited tumors • Inherited syndromes • Teratogenesis

Tumors presenting in the newborn period are rare, although

any pathologist working near a busy obstetric or neonatal

unit can expect to see occasional cases The incidence is

around 1 in every 12,000–27,500 live births Many of these

tumors are peculiar to infants or behave differently from

their counterparts in older children [ 1 , 2 ] Lack of familiarity

with neonatal tumors may lead to unnecessarily aggressive

therapy or well-intentioned neglect The neonate responds

differently to therapy and is often more sensitive, and the

effect of many cancer therapies on the developing infant can

be severe and permanent Some neonatal tumors may appear

to be aggressive lesions and yet be benign and, conversely, others look benign but may be fatal if incompletely excised Most, but not all, childhood neoplasms have been described in the perinatal period, but the frequency of the different tumors varies greatly with the age of presentation between fetal and neonatal period, early childhood, and later childhood The more common childhood tumors are very rare

in neonates As in children generally, tumors are often chymal rather than epithelial in histogenesis and knowledge

mesen-of normal human development is mesen-often useful As discussed later, there are close links between development and onco-genesis as Willis noted in his textbook, and this is more than just the histological similarities of tumors and fetal develop-ment; it also reﬂ ects the genetic and especially the epigenetic changes The current classiﬁ cation of some of these neonatal conditions as a neoplasm or a developmental abnormality may

A K Charles , MD (Cantab)

Department of Pathology , Sidra Medical and Research Center

& Weill Cornell Medical College in Qatar , Doha , Qatar

e-mail: acharles@sidra.org

18

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overlook the close association of these two processes, how

each of us is not genetically homogeneous, and the fact that

nongenomic changes can indeed be inherited

This chapter cannot be comprehensive but will

concen-trate on the special characteristics of neonatal tumors, which

inﬂ uence their diagnosis and management, and outline some

areas where study of neonatal tumors is of interest to our

understanding of neoplasia in general Some characteristic

lesions not mentioned elsewhere in the text are shown in

Table 18.1 [ 3 6] (Figs 18.1 and 18.2) Neonatal tumors

accounted for 2.6 % of all children’s tumors in one series, of

which 40 % were malignant [ 7 ] About 40 % of malignant

tumors in neonates are evident on the ﬁ rst day of life and

17 % only discovered at autopsy [ 8 ] Most malignant

con-genital tumors present in the ﬁ rst week

A congenital tumor is one that is present at birth, but it is

reasonable to suppose that any tumor presenting in the ﬁ rst

3 months of life was congenital It is now becoming clear

that other childhood tumors—including many leukemias,

Wilms’ tumors, bronchopulmonary blastomas,

neuroblasto-mas, and some germ cell tumors—appear to arise from

abnormal cells or lesions that are already present at the time

of birth Children who present with acute leukemia can be

found to have identical genetic changes in their leukemia and

in the DNA from their Guthrie card or in the leukemia in

their monozygotic twin [ 9] More neonates have these

genetic changes than children who develop leukemia,

imply-ing that many childhood leukemias have precursor cells that

have undertaken the initial genetic steps of neoplastic

pro-gression at birth but do not necessarily progress to

malig-nancy, a situation well described with nephrogenic rests and

Wilms’ tumor, neuroblastoma in situ, and pleuropulmonary

blastoma

Although there is no absolute distinction between the

his-tological types of tumors presenting at birth and in early

infancy, there are clinical differences that make the

distinc-tion worth preserving For example, tumors are now not

infrequently diagnosed in utero by the anatomy scan, and

this has increased the identiﬁ cation of some tumors This

helps the management of the pregnancy and delivery, and

novel approaches such as the ex utero intrapartum treatment

(EXIT) procedure have been introduced Large tumors can

rupture or obstruct delivery or give rise to fetal hydrops, if

vascular, or affect the fetal cardiovascular system The fetal

circulation may be responsible for particular patterns of

metastasis seen in the neonate The outcome often depends

more on the size and site of the lesion than on the histology

Reduced tolerance to drugs and especially radiation may

complicate therapy in very young babies There are also

tumors that are present in neonates and young infants and not

later (e.g., sacrococcygeal teratomas) and conversely other

tumors seen in children and adults but not (yet) described in

neonates (e.g., synovial sarcoma) or very rare (e.g., clear cell

sarcoma of the kidney)

Many of the tumors seen in the newborn are mas, though the distinction between neoplasm, hamartoma, choristoma, and even malformation is often unclear and

Table 18.1 Some lesions recognized in newborns, but not described

elsewhere in the text [ 3 6 ] Anatomical site, tumor Head and neck Thymic cyst Mouth and nasopharynx Gingival granular cell tumor (Fig 18.1 ) Hairy polyp of the oropharynx (Fig 18.2 ) Nasal glioma

Nasopharyngeal brain heterotopia Foregut duplication cyst of tongue Hamartoma of the tongue Sialoblastoma [ 3 ] Salivary gland anlage tumor Skin and subcutis

Neurocristic hamartoma Striated muscle hamartoma Rhabdomyomatous dysplasia [ 4 ] Smooth muscle hamartoma Soft tissue

Neuromuscular choristoma Primitive myxoid mesenchymal tumor [ 5 ] Lung and thorax

Rhabdomyomatous dysplasia of the lung Pulmonary myoﬁ broblastic tumor Massive mesenchymal malformation of lung Thymic hyperplasia

Heart Cardiac ﬁ broma Rhabdomyoma Gastrointestinal Gastrointestinal stromal tumor Leiomyosarcoma

Tailgut cyst Pancreatoblastoma [ 6 ] Gonads

Congenital ovarian cysts Juvenile granulosa cell tumor Gonadoblastoid dysplasia Cystic dysplasia of testis Testis adrenal rest with congenital adrenal hyperplasia Spine

Spinal hamartoma Tails

Bone Osteochondromyxoma of bone Infantile cartilaginous hamartoma of the rib Brain

Hypothalamic hamartoblastoma Miscellaneous

Accessory scrotum

A.K Charles

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may be semantic in some cases It is difﬁ cult to make a

comprehensive classiﬁ cation system for these tumors:

some segregate according to histological type and others

according to usual site of presentation Some of the true

neoplasms of childhood are collectively referred to as

blastomas or embryonic tumors These include

nephro-blastoma (Wilms’ tumor), neuronephro-blastoma, retinonephro-blastoma,

hepatoblastoma, medulloblastoma, pleuropulmonary

blas-toma, and embryonal rhabdomyosarcoma These tumors

tend to recapitulate embryonic tissues and are thought to

arise from genetic changes in immature tissue or persistent

fetal stem cells This explains their unique histology and

restricted age range

Incidence

Benign tumors of the newborn are common, and many are not formally recorded Vascular nevi and hemangiomas are present in 6–25 % of the pediatric population, most being congenital, although they often present after birth Strawberry hemangiomas are more common in very-low-birth-weight babies than controls While most strawberry hemangiomas and many visceral hemangiomas regress, even benign hem-angiomas may cause death, for example, by causing heart failure or a consumptive coagulopathy Melanocytic nevi are found in a few percent of newborn white infants and more commonly in nonwhite infants in contrast to the extreme rar-ity of congenital malignant melanoma [ 10 , 11 ], but the diag-nostic features of malignancy and proliferative nodules within a congenital nevus are not absolute and even genetic studies are not always useful [ 12 ]

It is difﬁ cult to estimate the incidence of malignant genital tumors from the literature Most series are not popu-lation based, and many are not comparable because they include different age ranges (Table 18.2 ) Series extend over many years during which the treatment and classiﬁ cation of tumors have changed

con-Teratomas are the most commonly reported neonatal tumor, but neuroblastoma is the most common malignant tumor followed by leukemias and mesenchymal tumors of various types, renal tumors, and brain tumors and is also the most common fatal congenital tumor [ 13 ] Less-common conditions seen in the neonatal period include Langerhans’ cell histiocytosis, hepatoblastoma, and retinoblastoma Lymphoma, clear cell sarcoma of the kidney, and anaplastic Wilms’ tumor are notable for their extreme rarity in neonates

A study of 17,417 perinatal necropsies carried out in Melbourne over ﬁ ve decades revealed 46 congenital tumors, which included 24 teratomas, most frequently of the head and neck followed by sacrococcygeal and medi-astinal teratoma [ 14 ] Vascular tumors, neuroblastoma, and cardiac rhabdomyoma were next in frequency Of the affected babies, 20 % had developmental anomalies, mainly associated with teratomas Some babies presented with maternal polyhydramnios and/or fetal hydrops, most often with teratoma

Fig 18.1 Granular cell epulis/congenital granular cell tumor Typical

presentation with a female neonate with a 20 mm mass arising from

gingival margin

Fig 18.2 Hairy polyp Term neonate with mass in the mouth arising

from the soft palate consisting of skin-like tissue with hair and adnexal

glands over ﬁ broadipose tissue A cartilage bar was present deep in the

lesion

Table 18.2 Benign and malignant tumors in newborn children and

infants (percentage by tumor type) Tumor Perinatal tumors %

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Pathologists should be aware that standard histological

criteria of malignancy such as high mitotic rate, immature

cells, necrosis, and even vascular invasion do not always

indi-cate malignant behavior in congenital tumors (or for that

mat-ter some childhood tumors) A large population-based study

of infants up to 1 month old in the West Midlands from 1960

to 1989 showed an incidence of benign and malignant

neona-tal tumors of 0.07 per 1,000 live births per year, also with a

predominance of teratoma (mostly benign) followed by

neu-roblastoma and leukemia The 5-year survival rate was 50 %

Congenital tumors were associated with polyhydramnios,

which was not speciﬁ c to any particular tumor type Fifteen

percent of patients had some congenital anomaly [ 15 ]

Etiology

Congenital tumors appear to offer a system in which to study

oncogenesis free from the multiple environmental inﬂ uences

that complicate such studies in adults However, the sperm,

egg, embryo, and fetus are exposed to many chemical,

physi-cal, and infective agents in utero, and the intrauterine

envi-ronment can alter the risk of infant and childhood neoplasia

In recent years, considerable insight has been gained into

the pathogenesis of neoplasms in infants and young children,

and the molecular pathogenetic pathways are beginning to be

understood Genetic accidents are part and parcel of human

mitotic activity The large number and rapidity of cell cycles

required during embryonic and fetal growth provide ample

opportunity for such mistakes The genetic mechanisms

involved in oncogenesis—which include small mutations,

loss of heterozygosity, and changes in genomic imprinting—

are being shown to involve genes and noncoding RNA that

normally regulate the cell cycle and apoptosis and are

impor-tant in development and cellular differentiation Genetic,

chromosomal, syndromic, and environmental associations

that have been recognized in childhood cancer will be

dis-cussed later However, many childhood and infant tumors

have a normal or near normal karyotype, and apart from the

often characteristic translocations that involve oncogene

activation, many of the pathogenetic pathways appear to

involve more subtle, epigenetic, and nongenomic changes

closely related to cell development and differentiation This

is associated with the age of presentation and explains the

lack of the more complex genomic changes more

character-istic of adult tumors It appears that timing of the change in

cell differentiation and the cell type in which the change

occurs are crucial This may explain why the same

transloca-tion, t(12;15), is seen in mesoblastic nephroma and infantile

ﬁ brosarcoma (essentially the same tumor type) and the

secretory analogue tumor of the breast and salivary gland,

which are clearly otherwise unrelated tumors

Many oncogenes are also implicated in development (e.g., retinoblastoma, WT1, sonic hedgehog); the data is showing that the more subtle nongenomic, epigenetic mech-anisms such as imprinting (e.g., IGF2 locus at 11p15), chro-matin remodeling (e.g., SWNF1), and microRNA pathways (e.g., DROSHA and DICER1), as well as cell to cell interac-tion and the cellular microenvironment are crucial in the oncogenesis of these tumors as well as being involved in development and cellular differentiation [ 16 ] Adult tumors usually arise in differentiated tissues (usually epithelial) and require time for mutations to develop by exposure to muta-genic environmental agents

Inherited Tumors

Some childhood tumors are inherited and a greater tion of pediatric tumors are associated with familial predis-position or a syndrome, and this should be considered for all tumors The frequency varies between tumors For example,

propor-40 % of retinoblastomas and a small proportion (1–3 %) of Wilms’ tumors are familial, though 10–15 % of Wilms’ tumor have a germline mutation [ 17 ] Nine percent of retino-blastomas are present at birth, and these are almost always heritable and attributable to a mutation of the retinoblastoma gene on chromosome 13q Sibships affected by leukemia, neuroblastoma, teratoma, hepatoblastoma, or congenital

ﬁ bromatoses have all been reported, but the genes ble are largely unknown Many inherited syndromes predis-pose to tumor development (Table 18.3), although such tumors are not usually present at birth

Malformation Syndromes and Tumors

The association of trisomy 21 and leukemias is well known (see later), though children with Down syndrome appear to have a lower rate of solid tumors than infants with a normal karyotype [ 18 , 19 ] A further group of patients in this study had leukemia and constitutional aneuploidy, mainly trisomy

21 mosaicism Neonatal tumors are reported with trisomies

13 and 18, the latter particularly with nephroblastoma and hepatoblastoma The association of constitutional karyotypic abnormalities and childhood cancer can be helpful in local-izing key genes involved in particular tumor oncogenesis The most frequent association likely to be seen by perinatal pathologists is congenital leukemia associated with trisomy

21 if one excludes malformations caused by the tumor such

as sacrococcygeal teratoma (Table 18.4 )

Several dysmorphic syndromes and malformations carry niﬁ cant risk of childhood cancer (Table 18.5 ) The best known are hemihypertrophy and Beckwith–Wiedemann syndrome (BWS); 10–21 % of children with Beckwith–Wiedemann

sig-A.K Charles

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