Further reading

Brent RL. Bendectin: review of the medical literature of a comprehensively studied humannonteratogen and the most prevalent tortigen-litigen. Reprod Toxicol 1995;9:337–349.

Brent RL. Environmental causes of human congenital malformations: the pediatrician’s rolein dealing with these complex clinical problems caused by a multiplicity of environmentaland genetic factors. Pediatrics 2004;113:957–968.

Brent RL. Utilization of developmental basic science principles in the evaluation of reproduc-tive risks from pre- and postconception environmental radiation exposures. Teratology1999;59:182–204.

Friedman JM, Polifka JE. TERIS: The teratogen information system. Seattle, WA: Universityof Washington Press, 1999.

Online Mendelian Inheritance in Man, OMIM™. McKusick-Nathans Institute for GeneticMedicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnol-ogy Information, National Library of Medicine (Bethesda, MD), 2000. World Wide WebURL: http://www.ncbi.nlm.nih.gov/omim/

Schardein JL. Chemically induced birth defects. New York: Marcel Dekker; 2002:1109.Scialli AR, Lione A, Padget GKB. Reproductive effects of chemical, physical and biologic

agents. Baltimore, MD: Johns Hopkins University Press, 1995.Sever JL, Brent RL. Teratogen update: environmentally induced birth defect risks. New York:

Alan R Liss, 1986.Shepard TH, Lemire RJ. Catalog of teratogenic agents, 11th edn. Baltimore, MD: Johns

Hopkins University Press, 2004.

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14 Drugs, alcohol abuse, and effects in pregnancyStephen R. Carr and Donald R. Coustan

It is daunting to attempt to study the effect of drugs, medications, or substances ondeveloping fetuses. It requires an understanding of embryology, pharmacology, andmaternal physiology during pregnancy as well as fetal physiology. Studies of illicitsubstance use or abuse of licit substances are hampered by inaccurate reporting aswell as the problem of multiple substance use. Teasing out the individual effects ofa given substance may be challenging indeed. There are numerous compendia avail-able to clinicians describing the effects of marketed pharmaceutical agents.

Alcohol abuse during pregnancy continues to impose a staggering burden onsociety – upwards of US$40 billion per year (in 1998 dollars) in total, or US$2million as a lifetime cost per individual affected with fetal alcohol syndrome (FAS).1

While efforts at establishing a dose–response curve have been stymied by under-reporting and multiple substance use, even low and sporadic alcohol ingestionduring pregnancy increases the risk of congenital anomalies.2 The effects of alcoholon the development of the human fetus may result from increased c-myc proteinand decreased growth-associated protein 43 levels and their effects on normal neu-

Handbook of Clinical Obstetrics: The Fetus & Mother, Third EditionE. Albert Reece, John C. Hobbins

Copyright © 2007 by Blackwell Publishing Ltd

ronal growth and differentiation. As there is no treatment or cure for alcohol-relatedbirth defects, there is no level of alcohol use during pregnancy that can be consid-ered “safe.” The “CAGE,” “T-ACE,” and “TWEAK” questionnaires aid in identi-fying women at risk for risk drinking, after which counseling interventions willdecrease problem drinking by 67%. Drinking cessation at any stage of pregnancybenefits the fetus.

Cocaine is an alkaloid that acts by inhibiting reuptake of norepinephrine anddopamine at presynaptic nerve endings. The elevated dopamine levels are responsi-ble for the euphoria and addictive qualities of cocaine, and the elevated norepi-nephrine levels are responsible for the hypertension and vasoconstriction seen. Bothmaternal and fetal effects of cocaine use stem from its vasoconstrictive properties.These include maternal hypertension, increased risk of placental abruption, andincreased risk of genitourinary tract anomalies. The increased risk of abruption canpersist even if the gravidae stops using cocaine in the first trimester.3

Heroin use during pregnancy does not increase structural teratogenesis, butbehavioral teratogenesis is likely. Infectious comorbidities including the hepatitidesand human immunodeficiency virus (HIV) are substantial. Substitution ofmethadone for heroin use will decrease the risk of low birthweight babies and premature delivery. The neonatal abstinence syndrome will be minimized with amethadone dose of ≤ 20mg/day near delivery.

Maternal smoking during pregnancy increases overall perinatal and neonatal mor-tality by 33%. It is also associated with an increased risk of orofacial clefting anomalies. The “Ask, Advise, Assess, Assist, and Arrange” tool will increasesmoking cessation by 30–70% in smoking gravidae, but is most effective in womenwho smoke ≤ 20 cigarettes per day.

Caffeine is a xanthine and increases intracellular cAMP, altering Ca2+ levels andpotentiating catecholamine action. Caffeine is teratogenic in rodents, inducing limband digit anomalies at doses of 50–80mg/kg. Epidemiologic studies in humansdetected no increase in caffeine-associated congenital anomalies. The associationbetween maternal caffeine intake and spontaneous abortion and/or low birthweightis equivocal.

General

Developmental toxicity of drugs or substances depends on:• dose (total versus chronic infusion versus pulsatile);• route of administration;• physiologic handling of the substance by mother/fetus;• genetic predisposition;• timing of exposure during pregnancy.

Alcohol use in pregnancy

• FAS seen in 0.3–0.4/1000 live births in the US.

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• Effects are secondary to the direct effect of alcohol or its toxic metabolic productacetaldehyde.• Increased c-myc protein and decreased growth-associated protein 43 levels inhibitnormal neuronal growth and differentiation.• Features of FAS: at least one from each of the following categories:4

– Growth restriction, either prenatal or postnatal in onset:Small for gestational age (SGA)/intrauterine growth restriction (IUGR);Failure to thrive/short stature;

– Craniofacial abnormalities:Small eyes;Epicanthal folds;Long philtrum;Midface hypoplasia;

– Central nervous system (CNS) abnormalities:Microcephaly;Developmental delay;Mental retardation;Learning disabilities.

– Alcohol-related birth defects: any of the preceding problems in the offspring ofan alcoholic individual.

Categories of alcohol-related birth defects1 FAS: with confirmed maternal alcohol use and a characteristic pattern of malformations.2 FAS: without confirmed maternal alcohol use, but with the characteristic patternof malformations.3 Partial FAS: with confirmed maternal alcohol use and some components of thecharacteristic malformations.4 Alcohol-related birth defects: the presence of congenital anomalies resulting fromprenatal alcohol exposure.5 Alcohol-related neurodevelopmental disorder (ARND): CNS neurodevelopmen-tal abnormalities, neurological hard or soft signs, or behavioral/cognitive abnor-malities not consistent with background or environment.

Preventing FAS: CAGE, T-ACE, and TWEAKCAGE (≥ two positive answers: increased risk for problem drinking).1 Have you ever felt the need to Cut down drinking?2 Have you ever felt Annoyed by criticism of your drinking?3 Have you ever had Guilty feelings about drinking?4 Have you ever taken a morning “Eye-opener”?

T-ACE (the ability to hold a six-pack of beer or a bottle of wine scores two points on the tolerance question; affirmative answers on the others each score

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one point. A cumulative score of more than two points indicates a high probabil-ity of being a risk drinker).1 How many drinks can you hold? (Tolerance)2 Have you ever felt Annoyed by criticism of your drinking?3 Have you ever felt the need to Cut down drinking?4 Have you ever taken a morning “Eye-opener”?

TWEAK (≥ two points on the TWEAK instrument indicates a high probability ofproblem drinking).5

1 Tolerance: how many drinks does it take before you feel the effects of alcohol?(two points for ≥ three drinks)2 Worry: have close friends or family worried or complained about your drinkingin the past year? (two points for yes)3 Eye-opener: do you sometimes take a drink in the morning when you wake up?(one point for yes)4 Amnesia: are there times when you drink and afterwards cannot remember whatyou said or did? (one point for yes)5 Cut down: do you sometimes feel the need to cut down on your drinking? (onepoint for yes)

Cocaine use in pregnancy

• Cocaine use seen in 8–24% of pregnant women in various studies.• Mechanism of action: inhibition of neurotransmitter reuptake at presynapticnerve terminals.• Effects of cocaine use in pregnancy:6

– Placental abruption;– IUGR;– Premature rupture of the membranes;– Meconium;– Spontaneous abortion;– Intrauterine cerebral infarctions;– Genitourinary (GU) tract anomalies;– Neurobehavioral disorders.

• Increased risk of GU anomalies, with increased trend for other anomalies.• No such thing as a “crack baby.” The effects on neurophysiologic functioning areshort-lived and are correlated with other factors such as alcohol, tobacco, and marijuana.7

Heroin use in pregnancy

Reported effects of heroin on pregnancy• Fetal addiction.• Intrauterine withdrawal/neonatal abstinence syndrome.

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• Symptoms of neonatal withdrawal:– Tremors;– Restlessness;– Hyperreflexia;– High-pitched cry;– Sneezing;– Sleeplessness;– Tachypnea;– Yawning;– Sweating;– Fever;– Convulsions;– Vomiting/diarrhea.

• Low birthweight:– Relative risk (RR) 4.61 (95% CI, 2.78–7.65) in pregnant heroin users;– RR 1.36 (95% CI, 0.83–2.22) in methadone users;– RR 3.28 (95% CI, 2.47–4.39) in women who used both.

• Behavioral teratogenesis.• Sudden infant death syndrome.

Infectious comorbidities associated with drug-seeking behaviors• HIV;• Hepatitides.

Tobacco use in pregnancy

• More than 300 substances in tobacco smoke.• Most effects from nicotine and carbon monoxide.• Smoking increases perinatal mortality (PNM) by 33%.• PNM 23.3/1000 births in non-smokers.• PNM 33.4/1000 births in > 1 pack/day smokers.• Obstetric morbidities seen in pregnant smokers:

– Spontaneous abortion;– Ectopic pregnancy;– Preterm delivery;– Placenta previa;– IUGR/low birthweight (10–15g decrease in birthweight per cigarette smokedper day);– Placental abruption;– Preterm premature rupture of membranes (PPROM);– Sudden infant death syndrome.

• Increased risk of orofacial clefts among smokers.• Prenatal exposure to second-hand smoke manifests as adverse effects on languageskills, and visual and spatial abilities.

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• Brief interventions increase smoking cessation by 30–70%:– Ask: ask the patient to chose a statement that best describes her smoking status:

I’ve smoked < 100 cigarettes in my lifetime;I quit smoking before I found out I was pregnant;I quit smoking after I found out I was pregnant;I still smoke, but I’ve cut down;I still smoke and I haven’t cut down.

– Advise: give clear, firm advice to quit smoking. Stress the benefits to her andthe fetus.– Assess: investigate her willingness to quit.– Assist: offer and encourage coping mechanisms for quitting smoking (identifytrigger situations):

Provide support as part of the treatment;Arrange for social support – involve family and friends;Pregnancy-specific smoking cessation programs.

– Arrange: follow-up is essential. Reassess and re-encourage.

Caffeine use in pregnancy

• Caffeine is a xanthine and exerts effects by increasing intracellular cAMP, alter-ing Ca2+ levels, and potentiating the effects of catecholamines.• Caffeine content of drinks:

– Coffee/tea 100–150mg/cup;– Cola 35–55mg/12-oz can;– Cocoa 200mg theobromine/cup.

• Increases fetal breathing movements.• Causes limb defects in rodents given very large doses:

– Three cases of ectrodactyly in humans associated with 1100–1777mg daily caf-feine intake.– No evidence for congenital malformations or other adverse effect on pregnancyfor caffeine taken in amounts equivalent to less than 10 cups per day.

• Inconsistent effects of caffeine intake on both birth weight and spontaneous abortion.10

References

1 Lupton C, Burd L, Harwood R. Cost of fetal alcohol spectrum disorders. Am J Med Gen(Part C) 2004;127C:42.

2 Martinez-Frias ML, Bermejo E, Rodriguez-Pinilla E, et al. Risk for congenital anomaliesassociated with different sporadic and daily doses of alcohol consumption: a case–controlstudy. Birth Defects Res (Part A) 2004;70:194.

3 Chasnoff D, Griggith DR, MacGregor S, et al. Temporal patterns of cocaine use in preg-nancy: perinatal outcome. JAMA 1989;261:1741.

4 Jones KL, Smith DW. Recognition of the fetal alcohol syndrome in early infancy. Lancet1973;1:999.

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5 Russell M, Martier SS, Sokol R. et al. Screening for pregnancy risk drinking. Alcohol ClinExp Res 1994;18:1156.

6 Little BB, Snell LM, Klein VR, et al. Cocaine abuse during pregnancy: maternal and fetalimplications. Obstet Gynecol 1989;73:157.

7 Frank DA, Augustyn M, Knight WG, et al. Growth, development and behavior in earlychildhood following prenatal cocaine exposure: a systematic review. JAMA2001;285:1613.

8 Walsh RA. Effects of maternal smoking on adverse pregnancy outcomes: examination ofthe criteria of causation. Hum Biol 1944;66:1059.

9 Meyer KA, Williams P, Hernandez-Diaz S, et al. Smoking and oral clefts: exploring theimpact of study design. Epidemiology 2004;15:671.

10 Signorello LB, McLaughlin JK. Maternal caffeine consumption and spontaneous abortion:a review of the epidemiologic evidence. Epidemiology 2004;15:229.

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15 Teratogenic virusesAntonio V. Sison

There are five known teratogenic viruses: cytomegalovirus (CMV), rubella virus,varicella zoster virus (VZV), herpes simplex virus (HSV), and Venezuelan equineencephalitis (VEE) virus. CMV is the most common cause of congenitally acquiredinfection; infections with CMV occur at an annual rate of approximately 500–2500cases per 100000 newborns worldwide. In comparison, the annual incidence ofrubella in the USA in the last few years was approximately 0.05 per 100000 livebirths. Table 15.1 provides a summary of birth defects caused by infection with eachvirus. Recently, the role of parvovirus (Fifth disease) as a teratogenic agent has beenquestioned. Three of the teratogenic viruses (CMV, VZV, and HSV) are her-pesviruses; the fourth member of the herpesvirus group, Epstein–Barr virus, has notbeen implicated as a teratogen.

All of the teratogenic viruses have a significant effect on the central nervous system(CNS; microcephaly, intracranial calcifications) and the eyes (chorioretinitis,cataracts), and many result in multiorgan damage in the affected newborn. Infantswith congenital rubella syndrome (CRS), for example, have findings in many organsystems, such as the CNS, eyes, liver, and lungs. Some viruses cause particular symp-toms in the neonate; for example, cicatricial skin scarring and limb hypoplasia isuniquely found in perinatal infection with VZV, whereas oral ulcerations in theneonate are mostly found with herpesvirus infections. Much of the damage caused by teratogenic viruses is subtle and presents only later in life (i.e., learningdisabilities, psychomotor retardation, hearing loss, diabetes mellitus, and thyroiddisorder).

Diagnosis of congenital infection with teratogenic viruses has generally relied onboth clinical manifestations of the disease in the infant and laboratory techniques.