Protocols for high risk pregnancies an evidence based approach

GalanDepartment of Obstetrics and Gynecology,University of Colorado School of Medicine,Aurora, CO, USASreedhar GhaddipatiDepartment of Obstetrics and Gynecology,Division of Maternal Feta

Protocols for High-Risk Pregnancies

An Evidence-Based Approach

Professor and Chairman, Emeritus

Department of Obstetrics & Gynecology

Georgetown University School of Medicine

Washington, DC, USA

Catherine Y Spong MD

Bethesda, MD, USA

Charles J Lockwood MD, MHCM

Dean, Morsani College of Medicine

Senior Vice President, USF Health

Professor of Obstetrics and Gynecology and Public Health

University of South Florida

Tampa, FL

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Protocols for high-risk pregnancies : an evidence-based approach / edited by John T Queenan, Catherine Y Spong, Charles J Lockwood – Sixth edition.

A catalogue record for this book is available from the British Library.

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Cover image: ©iStock.com/stereohype

Set in 9.5/13pt Meridien by Laserwords Private Limited, Chennai, India

1 2015

List of Contributors, ix

Preface, xiii

Part I Concerns in Pregnancy

1 Tobacco, Alcohol, and the Environment, 3

Jorge E Tolosa, George Saade

2 Ionizing Radiation, 14

Robert L Brent

3 Depression, 27

Kimberly Yonkers

Part II Antenatal Testing

4 Prenatal Detection of Fetal Chromosome Abnormality, 35

10 Sickle Cell Disease, 88

Marc R Parrish, John Morrison

11 Isoimmune Thrombocytopenia, 97

Richard L Berkowitz, Sreedhar Ghaddipati

v

Part IV Obstetric Problems

34 First Trimester Vaginal Bleeding, 281

Richard M.K Adanu

Population Family and Reproductive Health

Department, University of Ghana School of

Public Health, Accra, Ghana, Africa

Brenna L Hughes (Anderson)

Department of Obstetrics and Gynecology,

Warren Alpert Medical School of Brown

University/Women & Infants Hospital,

Providence, RI, USA

Raul Artal

Department of Obstetrics, Gynecology and

Women’s Health, Saint Louis University,

St Louis, MO, USA

Vincenzo Berghella

Department of Obstetrics and Gynecology,

Division of Maternal-Fetal Medicine, Thomas

Jefferson University, Philadelphia, PA, USA

Richard L Berkowitz

Department of Obstetrics and Gynecology,

Division of Maternal Fetal Medicine, Columbia

University Medical Center, New York, NY, USA

Robert L Brent

Alfred I duPont Hospital for Children, Thomas

Jefferson University, Wilmington, DE, USA

Joshua A Copel

Departments of Obstetrics, Gynecology and

Reproductive Sciences, and Pediatrics, Yale

School of Medicine, New Haven, CT, USA

F Garry Cunningham

Department of Obstetrics and Gynecology,

University of Texas Southwestern Medical

Center, Dallas, TX, USA

Mary E D’Alton

Department of Obstetrics and Gynecology, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, New York, NY, USA

Mara J Dinsmoor

Department of Obstetrics and Gynecology, NorthShore University Health System, Evanston, IL, USA

Department of Obstetrics and Gynecology, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA

Patrick Duff

Department of Obstetrics and Gynecology, University of Florida College of Medicine, Gainesville, FL, USA

Henry L Galan

Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, CO, USA

Sreedhar Ghaddipati

Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Columbia University Medical Center, New York, NY, USA

ix

x List of Contributors

Robert Gherman

Division of Maternal Fetal Medicine, Frannklin

Square Medical Center, Baltimore, MD, USA

Alessandro Ghidini

Perinatal Diagnostic Center, Inova Alexandra

Hospital, Alexandria, VA, USA

Jane Hitti

Department of Obstetrics and Gynecology,

University of Washington, Seattle, WA, USA

G Justus Hofmeyr

Department of Obstetrics and Gynecology,

Frere Maternity Hospital/University of the

Witwatersrand/University of Fort Hare/

Eastern Cape Department of Health, Bhisho,

South Africa

Fred M Howard

Department of Obstetrics and Gynecology,

University of Rochester School of Medicine

and Dentistry, Rochester, NY, USA

Andra H James

Division of Maternal-Fetal Medicine,

Department of Obstetrics & Gynecology,

Duke University, Durham, NC, USA

Jeffrey R Johnson

Women and Children’s Hospital, Buffalo,

NY, USA

Mark B Landon

Department of Obstetrics and Gynecology,

The Ohio State University College of Medicine,

Columbus, OH, USA

Charles J Lockwood

Dean, Morsani College of Medicine

Senior Vice President, USF Health

Professor of Obstetrics and Gynecology and

Public Health

University of South Florida, Tampa, FL

Men-Jean Lee

Department of Obstetrics & Gynecology, Icahn

School of Medicine at Mount Sinai, New York,

NY, USA

George A Macones

Department of Obstetrics & Gynecology,

Washington University School of Medicine,

St Louis, MO, USA

Kenneth J Moise Jr

Department of Obstetrics, Gynecology and Reproductive Sciences, UT Health School of Medicine, Houston, TX, USA

Thomas R Moore

Department of Reproductive Medicine, Division

of Perinatal Medicine, University of California at San Diego, San Diego, CA, USA

Alan Peaceman

Division of Maternal-Fetal Medicine,

Northwestern University Feinberg School

of Medicine, Chicago, IL, USA

John T Queenan, Jr.

Department of Obstetrics and Gynecology,

University of Rochester Medical Center,

Rochester, NY, USA

Susan Ramin

Department of Obstetrics and Gynecology,

Baylor College of Medicine, Texas Children’s

Hospital Pavilion For Women, Houston, TX, USA

Robert Resnik

Department of Reproductive Medicine, UCSD

School of Medicine, La Jolla, CA, USA

Dwight J Rouse

Maternal-Fetal Medicine Division, Women &

Infants Hospital of Rhode Island, Providence,

RI, USA

Department of Obstetrics and Gynecology,

Warren Alpert School of Medicine at Brown

University, Providence, RI, USA

George Saade

Department of Obstetrics & Gynecology,

Division of Maternal Fetal Medicine,

University of Texas Medical Branch, Galveston,

TX, USA

Michael Schatz

Department of Allergy, Kaiser-Permanente

Medical Center, San Diego, CA, USA

James R Scott

Department of Obstetrics and Gynecology,

University of Utah Medical Center, Salt Lake

City, UT, USA

Jeanne S Sheffield

Division of Maternal-Fetal Medicine, University

of Texas Southwestern Medical Center, Dallas,

TX, USA

Baha M Sibai

Department of Obstetrics and Gynaecology and

Reproductive Sciences, The University of Texas

Medical School at Houston, Houston, TX, USA

Jorge E Tolosa

Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Oregon Health & Science University, Portland, OR, USA Departamento de Obstetricia y Ginecología, Facultad de Medicina, NACER Salud Sexual y Reproductiva, Universidad de Antioquia, Colombia

Katharine D Wenstrom

Division of Maternal-Fetal Medicine, Women & Infants’ Hospital of Rhode Island and Brown Alpert Medical School, Providence, RI, USA

of Medicine, New Haven, CT, USA School of Epidemiology and Public Health, Yale University School of Medicine, New Haven,

CT, USA

Today’s pressures of healthcare reform, rapidly changing technology, formation overload,” and medically sophisticated patients make it essential

“in-to have correct, concise, and relevant information at hand The nature andtraining of physicians instills a constant drive to always try to do the rightthing Therefore, it is necessary to have appropriate, current, and practicalinformation available as protocols to make good decisions Why use pro-tocols? Having a protocol or guideline organizes essential clinical material

in a systematic, logical order and avoids omissions in patient care It is to

this end that we have created the sixth edition of Protocols for High-Risk

Since the fifth edition was published, advances in medicine and ogy have dictated changes in management Thus, in the sixth edition, allprotocols have been reviewed and new protocols added to cover advances

technol-in Doppler and sonography, as well as changes technol-in approach to prematurity,depression, diagnosis and treatment of venous thromboembolism, and fetalgrowth restriction, among others We have included protocols in areas ofcritical importance to the developing world such as malaria, tuberculosis,and chronic iron deficiency anemia

For each protocol, we have invited physicians who are outstandingauthorities on the topics They start with a brief introduction and patho-physiology and write the protocol as if they were working up their patientsand following them through the various stages of management

We required that each protocol is evidence-based to the maximum extentpossible In areas where no clear evidence exists, we have asked the experts

xiii

At Wiley-Blackwell we have enjoyed excellent expertise from MartinSugden, Rob Blundell, Priyanka Gibbons, and their outstanding editorialand production staffs.

This edition, as the others, was created to be practical, cost effective, andclearly presented: a format that is easy to carry with you on rounds andconsultations We have designed this book to help you in your practice.Make it your own!

John T Queenan, MD

Professor and Chairman, Emeritus Department of Obstetrics & Gynecology Georgetown University School of Medicine

Washington, DC, USA

Catherine Y Spong, MD

Bethesda, MD, USA

Charles J Lockwood, MD

Department of Obstetrics and Gynecology and Reproductive Sciences,

University of South Florida, Morsani College of Medicine,

Tampa, FL, USA

Concerns in Pregnancy

P R O T O C O L 1

Tobacco, Alcohol,

and the Environment

Jorge E Tolosa1 ,2 & George Saade3

1 Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Oregon Health & Science University, Portland, OR, USA

2 Departamento de Obstetricia y Ginecología, Facultad de Medicina, NACER Salud Sexual y Reproductiva, Universidad de Antioquia, Colombia

3 Department of Obstetrics & Gynecology, Division of Maternal Fetal Medicine, University of Texas Medical Branch, Galveston, TX, USA

Tobacco

Clinical significance

Globally, 22% of the world’s adult population aged 15 years and over areestimated to be current tobacco smokers, including 36% of men and 8% ofwomen The World Health Organization European and Americas regionshave the highest prevalence of current tobacco smoking among adultwomen There is a stark difference in smoking rates between women oflow income countries (whose tobacco smoking rates are low to very low)and women of middle and high-income countries (whose tobacco smokingrates are high to very high) Global tobacco use continues to shift to lowand middle-income countries, with a recent increase in the rates of tobaccosmoking among women, which is expected to rise to 20% by 2025 About

250 million women worldwide are daily smokers Women 18–19 years oldshow the highest prevalence (17.1%); 26% smoked half a pack or more

of cigarettes a day An estimated 19.8 million women in the United Statessmoke The annual average rate of past month cigarette use in 2012 and

2013 among women aged 15 to 44 who were pregnant was 15.4 percent.Rates of current cigarette use in 2012–2013 among pregnant women aged

15 to 44 were 19.9 percent in the first trimester, 13.4 percent in the secondtrimester, and 12.8 percent in the third trimester The women most likely

to smoke are among the most vulnerable—those disadvantaged by lowincome, low education, and mental health disorders, further exacerbatingthe adverse health effects from smoking on mothers and their offspring.Women in these groups are also less likely to quit smoking when theybecome pregnant and are more likely to relapse after delivery

Tobacco exposure in pregnancy is associated with an increased rate ofadverse outcomes including low birth weight, resulting from preterm birth

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Sixth Edition.

Edited by John T Queenan, Catherine Y Spong and Charles J Lockwood.

© 2015 John Wiley & Sons, Ltd Published 2015 by John Wiley & Sons, Ltd.

3

and/or fetal growth restriction In 2003 in the United States, ers had a rate of 7.7% of low-birth-weight babies compared with 12.4%born to smokers Tobacco dependence is a chronic addictive condition thatrequires repeated intervention for cessation Although a light smoker isdefined as a cigarette smoker of fewer than 10 per day, smoking is unsafe

nonsmok-at all levels, as is exposure to any form of tobacco in pregnancy Tobaccocessation in pregnancy results in reduction in preterm birth, fetal growthrestriction, low birth weight and perinatal death, as well as in improvedneonatal outcomes It is the most important preventable cause of low birthweight

Pathophysiology

Tobacco smoke contains thousands of compounds that may have adverseeffects The major compounds suspected of causing harm to the developingfetus are nicotine and carbon monoxide Nicotine crosses the placenta andcan be detected in the fetal circulation at levels that exceed maternal con-centrations by 15%, while amniotic fluid concentrations of nicotine are88% higher than maternal plasma The actions of nicotine include vaso-constriction and decreased uterine artery blood flow Carbon monoxidealso crosses the placenta rapidly and is detectable in the fetal circulation

at levels that are 15% higher than maternal It has a higher affinity forhemoglobin than oxygen to form the compound carboxyhemoglobin thatshifts the oxygen dissociation curve to the left Consequently, the availabil-ity of oxygen to fetal tissues is decreased Levels of cyanide in the circulationare higher in smokers, a substance that is toxic to rapidly dividing cells Inaddition, smokers frequently have other clinical characteristics that mayaccount for some adverse pregnancy outcomes, such as poor nutrition, andalcohol or drug abuse

Screening for tobacco exposure and increasing tobacco cessation

Smoking cessation interventions for pregnant women result in fewerlow-birth-weight newborns and perinatal deaths, fewer physical, behav-ioral and cognitive problems during infancy and childhood, and importanthealth benefits for the mothers Women who discontinue smoking even

as late as 30 weeks of gestation have infants with higher birth weightthan those who continue smoking In contrast, “cutting down” seems toimprove fetal growth only slightly

Smoking cessation interventions should be included as part of prenatalcare Women are more likely to quit smoking during pregnancy than atany other time in their lives An office-based cessation counseling session

of 5–15 minutes, when delivered by a trained provider with the provision

of pregnancy-specific educational materials, increases rates of cessation

Tobacco, Alcohol, and the Environment 5

among pregnant smokers Trials have shown that a five-step interventionprogram (the 5 As) is effective:

1 Ask pregnant women about smoking status using a multiple-choice

ques-tion method to improve disclosure

2 Advise women who smoke to quit smoking, with unequivocal,

person-alized and positive messages about the benefits for her, the baby andfamily Review the risks associated with continued smoking Congratu-late women who have quit and reinforce the decision by reviewing thebenefits resulting from not smoking

3 Assess the woman’s willingness to make an attempt to quit smoking

within the next 30 days If the woman wants to try to quit, the providershould move to the next step, Assist For women who are unwilling

to attempt cessation, the advice, assessment and assistance should beoffered at each future visit

4 Assist

• Provide self-help smoking cessation materials that contain messages

to build motivation and confidence in support of a cessation attempt

• Suggest and encourage the use of problem-solving methods and skillsfor cessation for issues that the woman believes might adversely influ-ence her attempt to quit Avoid “trigger situations.”

• Arrange social support in the smoker’s environment by helping heridentify and solicit help from family, friends, co-workers and otherswho are most likely to be supportive of her quitting smoking

• Provide social support as part of the treatment This means thatthe counselor is encouraging, communicates care and concern, andencourages the patient to talk about the process of quitting

5 Arrange follow up Smoking status should be monitored throughout

pregnancy, providing opportunities to congratulate and support success,reinforce steps taken toward quitting, and advise those still considering

a cessation attempt

Pharmaceutical cessation aids such as nicotine replacement therapy(NRT), varenicline, or bupropion SR have efficacy as first-line agents in

the general non-pregnant population The use of these medications is not yet

routinely recommended in pregnancy, as there is inconclusive data of their

effectiveness and safety NRT is available in transdermal patch, nasal spray,

chewing gum, or lozenge If used, it should be with extreme cautionand women should be warned of uncertain side effects in pregnancy.Bupropion SR is an atypical antidepressant that has been approved bythe FDA for use in smoking cessation It is contraindicated in patientswith bulimia, anorexia nervosa, use of MAO inhibitors within theprevious 14 days, or a known or history of seizures It carries a blackbox warning due to an association of antidepressant medications withsuicidality in children, adolescents, and young adults under the age of

24 years Varenicline is approved for smoking cessation in the generalpopulation Serious neuropsychiatric symptoms have been associated withits use including agitation, depression, and suicidality The FDA issued apublic health advisory in 2008 cautioning its use in populations with ahistory of psychiatric illness To date, contingency management, or theuse of tangible reinforcement to promote desired behaviors, is the mostpromising technique to achieve smoking cessation and has been shown

to be an effective motivational tool for overcoming other addictions,including alcohol and substance abuse Four small randomized trials and

a recent systematic review of the published literature of contingencymanagement in pregnancy demonstrate an increase in smoking quit ratesand potential beneficial effects in reducing adverse pregnancy outcomes.However, the generalizability of these studies in the U.S and globally islimited especially for women of lower socio-economic status Adequatelypowered randomized controlled trials are needed in the US and globally

to determine the effectiveness and cost-effectiveness of this intervention

An increasing proportion of smokers are now using e-cigarettes, eitherfor nicotine delivery or as an attempt to stop smoking There are limiteddata on e-cigarettes in pregnancy In addition to nicotine, some of thee-cigarettes may contain other chemicals such as preservatives Pregnantwomen should be discouraged from using e-cigarettes

ACOG and other organizations including the Centers for DiseaseControl and Prevention have a number of resources to assist providers

in counseling and managing smokers in pregnancy (CDC’s ing Cessation for Pregnancy and Beyond: A Virtual Clinic: www.smokingcessationandpregnancy.org, ACOG’s Smoking Cessation DuringPregnancy: A Clinician’s guide to helping pregnant women quit smoking:https://www.acog.org/∼/media/Departments/Tobacco%20Alcohol%20and%20Substance%20Abuse/SCDP.pdf, and Clean Air for HealthyChildren: www.cleanairforhealthychildren.org)

Smok-Complications

Pregnancies among women who smoke have been associated withincreased risks for miscarriage, ectopic pregnancy, fetal growth restriction,placenta previa, abruptio placentae, preterm birth, premature rupture ofthe membranes and low birth weight Overall, the perinatal mortality rateamong smokers is 150% greater than that in nonsmokers

The progeny of smoking mothers face additional risks during childhood.There is a strong association between maternal smoking and suddeninfant death syndrome, and a clear dose–response relationship has beendemonstrated Prenatal and postnatal tobacco smoke exposure also hasbeen associated with increased risk of persisting reduced lung function,respiratory infections, and childhood asthma Recent studies suggest that

Tobacco, Alcohol, and the Environment 7

infants born to women who smoke during pregnancy may be at increasedrisk for childhood obesity In addition, there is evidence suggesting aneurotoxic effect of prenatal tobacco exposure on newborn behavior,i.e., being more excitable and hypertonic The behavioral and cognitivedeficits associated with in utero exposure to tobacco seem to continue intolate childhood and adolescence with increased risk for attention-deficithyperactivity disorder and conduct disorder

Follow up and prevention

It is essential to identify the pregnant woman who is a smoker, ideallybefore pregnancy, when the risks associated with smoking in pregnancyshould be discussed and the benefits of smoking cessation emphasized.Cotinine, a metabolite of nicotine, is an accurate assay for nicotine expo-sure when measured in urine and can be part of a cost-effective cessationprogram Studies indicate higher success rates when participants are awarethat compliance is measured with biochemical tests Postnatal relapse ratesare high, averaging 50–60% in the first year after delivery Counselingshould be continued at each postpartum visit including unequivocal, per-sonalized and positive messages about the benefits to the patient, her babyand family resulting from smoking cessation If indicated, pharmacother-apy could be recommended to the lactating woman, after giving consid-eration to the risk for the nursing infant of passage of small amounts ofthe medications through breast milk, compared to the increased risks asso-ciated with smoking for children such as sudden infant death syndrome,respiratory infections, asthma, and middle ear disease

Alcohol

Clinical significance

In the mother, chronic alcohol abuse is associated with pneumonia, tension, hepatitis and cirrhosis, among other serious medical complica-

hyper-tions For the fetus, it is a known teratogen Alcohol exposure in pregnancy

is the leading known cause of mental retardation and the leading preventable cause

of birth defects in Western societies As many as 1 in 100 births are affected in

the United States Fetal alcohol syndrome is characterized by fetal growthrestriction, central nervous system abnormalities and facial dysmorphol-ogy, with an average IQ of 70 Functionally, the spectrum of disease evenwhen fetal alcohol syndrome is not fully expressed includes hyperactiv-ity, inattention, memory deficits, inability to solve problems, and mooddisorders

It has been estimated that the risk of fetal alcohol syndrome is 20% if thepregnant woman consumes four drinks per day, increasing to 50% with

eight drinks per day No safe level of exposure to alcohol has been fied, thus alcohol consumption during pregnancy should be avoided.Public health warnings about the importance of avoiding alcohol in preg-nancy were initiated 30 years ago Despite this, the 2007 National Survey

identi-on Drug Use and Health found that amidenti-ong pregnant women between 15and 44 years of age, 11.6% used alcohol in the previous 30 days and 0.7%were classified as heavy drinkers (five or more drinks on one occasion, on

5 or more days in the last 30 days) and 6.6% reported binge drinking inthe first trimester

Screening for alcohol abuse in pregnancy

Identifying women who drink during pregnancy is difficult While a recentreport reveals that 97% of women are asked about alcohol use as part oftheir prenatal care, only 25% of practitioners use standard screening tools.There is no validated biological marker for alcohol available for use inthe clinical setting Healthcare providers have to rely on self-reported use,resulting in significant underreporting Of available screening tools, theT-ACE is validated for pregnant women

Tolerance (T): The first question is “How may drinks can you hold?” A

pos-itive answer, scored as a 2, is at least a 6-pack of beer, a bottle of wine

or 6 mixed drinks This suggests a tolerance of alcohol and very likely ahistory of at least moderate to heavy alcohol consumption

Annoyed (A): “Have people annoyed you by criticizing your drinking?” Cut down (C): “Have you felt you ought to cut down on your drinking?” Eye opener (E): “Have you ever had a drink first thing in the morning to

steady your nerves or get rid of a hangover?”

These last three questions, if answered positively, are worth 1 point each

A score on the entire scale of 2 or higher is considered positive for excessive

or risk drinking Follow up of a positive screen should include questionsabout volume and frequency A report of more than seven standard drinksper week, less if any single drinking episode involves more than three stan-dard drinks, should be considered at risk A standard drink is defined as 12ounces of beer, 5 ounces of wine, or 1.5 ounces of liquor in a mixed drink.The T-ACE has been reported to identify 90% or more of women engaging

in risk drinking during pregnancy

Treatment of risk drinking in pregnancy

Advice by the healthcare provider is valid, effective and feasible in the ical office setting Brief behavioral counseling interventions with follow

clin-up in the clinical setting have been demonstrated to produce significantreductions in alcohol consumption lasting at least 12 months Practition-ers need to be aware of the possibility of concurrent psychiatric and/or

Tobacco, Alcohol, and the Environment 9

social problems Consultation with mental health professionals and socialworkers is indicated and can be powerful adjuvants to assist women todiscontinue use of alcohol

Brief interventions for pregnancy risk drinking generally involve tematic counseling sessions, approximately 5 minutes in length, whichare tailored to the severity of the identified alcohol problem In the firstintervention, the provider should state her/his concern, give advice,and help to set a goal Educational written materials should be pro-vided Routine follow up is essential and should involve encouragement,information and re-evaluation of goals at each prenatal visit Womenwho are actually alcohol-dependent may require additional assistance toreduce or eliminate consumption during pregnancy For these women,referral for more intensive intervention and alcohol treatment needs

sys-to be recommended No randomized clinical trials for pregnant womenenrolled in alcohol treatment in pregnancy have been conducted to testthe use of pharmacological or psychosocial interventions as reported bythe Cochrane collaboration

Environmental hazards

In 1970, the Occupational Safety and Health Act was implementedwith a surge of interest in the reproductive effects of working andthe workplace While an adult worker with an occupational expo-sure is best served by referral to an occupational medicine specialist,workplace exposures of pregnant women tend to be avoided by occu-pational physicians and the responsibility for these issues thus falls

to the obstetrician In their Guidelines for Perinatal Care, the

Ameri-can Academy of Pediatrics and the AmeriAmeri-can College of Obstetriciansand Gynecologists include environmental and occupational exposuresamong the components of the preconceptional and antepartum maternalassessment and counseling Help is available in the form of TeratogenInformation Services, accessed through local health departments, andvia the databases, such as REPROTOX (http://reprotox.org/) and TERIS(http://depts.washington.edu/∼terisweb/teris/), which were set up toprovide information to physicians and the Teratogen Information Services

on potential teratogens from any source, including the workplace

Physical agents

Heat

The metabolic rate increases during pregnancy, and the fetus’s temperature

is approximately 1∘C above the mother’s Because pregnant women have

to eliminate the physiological excess heat, they may be less tolerant of high

environmental temperatures Exposure to heat and hot environments canoccur in many occupations and industries Few studies specifically addressthe hazards of occupational heat stress in pregnancy Data from animalstudies and fever during pregnancy indicate that core temperature eleva-tions to 38.9∘C or more may increase the rate of spontaneous abortion orbirth defects, most notably neural tube defects Women with early preg-nancy hyperthermic episodes should be counseled about possible effectsand offered alpha-fetoprotein screening and directed sonogram studies.

Chemical exposures

Hairstylists

Hair colorants and dyes contain aromatic amines that may be absorbedthrough the skin These agents are mutagenic but are not teratogenic in ratsand cause embryotoxicity in mice only at high doses that are also mater-nally toxic Permanent wave solutions may cause maternal dermatitis butare not known to be teratogenic in animals

There is no direct evidence that hair dyes and permanent wave solutionsare teratogenic in human pregnancy, but very limited data are available.One study found a higher rate of spontaneous abortion among cosmetol-ogists Exposure to these agents should be minimized by the use of glovesand, if possible, reduction of chronic exposures in the first trimester

Painters and artists

Organic and inorganic pigments may be used in paints The raw materialsfor organic pigments may contain aromatic hydrocarbons, such as ben-zene, toluene, naphthalene, anthracene, and xylene Inorganic pigmentsmay contain lead, chromium, cadmium, cobalt, nickel, mercury, and man-ganese Workers in battery plants and those involved in the removal of oldpaint are also exposed to lead salts

Reproductive concerns about inorganic pigments are focused primarily

on lead, which is readily transferred across the placenta Inorganic leadsalts have been associated with increased spontaneous abortion, infant cog-nitive impairment, and stillbirth rates in humans, and central nervous sys-tem abnormalities and clefting in rodents Women at risk of lead exposureshould be monitored for blood lead levels before becoming pregnant Ifblood lead concentration is greater than 10 micrograms/mL, the patientshould be removed from exposure and chelation considered before preg-nancy Chronically exposed workers will have significant bone lead storesand should remain in a lead-free environment until safe lead levels arereached before attempting pregnancy There is no consensus on how tomanage elevated blood lead levels during pregnancy as chelation will atleast temporarily elevate blood lead levels by releasing bone stores Further,

Tobacco, Alcohol, and the Environment 11

the chelating agent, calcium edetate, may be developmentally toxic, ably by decreasing zinc stores

prob-Solvent workers

Some organic hydrocarbons may cause a fetal dysmorphogenesis syndromecomparable to fetal alcohol syndrome if ingested in large amounts This hasbest been evaluated for gasoline, in a group of individuals who habitually

“sniffed” the fuel for its euphoric effects An excess of mental retardation,hypotonia, and microcephaly was found in the offspring The effects oflower levels of gasoline are not known Similar effects were reported withtoluene sniffing

Ethylene glycol is another solvent used in a large number of industrialprocesses (paint, ink, plastics manufacture) No human studies exist, but inrodents many studies report abnormal development and skeletal and cen-tral nervous system abnormalities If a woman has a considerable exposurelevel as determined by blood and urine levels or abnormal liver functiontests, increased monitoring of fetal development is recommended

Pesticide workers

Pesticides are often encountered in agricultural workers and landscapeartists Two common agents are carbaryl and pentachlorophenol A sus-pected workplace exposure may be quantitated by urine levels Humanstudies for these agents are not available but animal studies suggest thathigh doses, particularly those that produce maternal toxicity, may impairreproductive success and be responsible for skeletal and body wall defects.These outcomes may be related to maternal toxicity and may not be aspecific developmental effect

Exposure to inhalational anesthetics

The studies that have suggested an association between occupational sure to inhalational anesthetics and adverse reproductive outcomes havebeen heavily criticized The available scientific evidence, while weak, doeslead to concern over occupational exposure to inhalational anesthetics inthe trace concentrations encountered in adequately scavenged operatingrooms Recommending limitation of exposure may be reasonable in envi-ronments where scavenging equipment is not available, such as some den-tists’ offices

expo-Other occupational hazards

Air travel

The environment in passenger cabins of commercial airlines is maintained

at the equivalent of 5000–8000 feet While living at high altitude hassignificant effects on maternal and fetal physiology, air travel has not been

associated with harmful fetal effects because of the short duration of mostflights Adequate hydration is essential as the humidity is also reduced

to less than 25% in most cabins Intermittent ambulation and changingposture is recommended in order to prevent deep vein thrombosis.Reports indicate that flight attendants experience twice the incidence

of first trimester spontaneous abortions as other women, but not otheremployed women Most airlines restrict the working air travel of flightattendants after 20 weeks of gestation, and restrict commercial airlinepilots from flying once pregnancy is diagnosed Counseling for womenwith medical or obstetric complications should be individualized It should

be noted that air travel could contribute to background radiation The nitude of in-flight exposure to radiation depends on altitude and the solarcycle A round trip between New York and Seattle can result in exposure

mag-to 6 mrem (0.06 mSv), well below the safe upper limit accepted by mostexperts Because the effect may be cumulative, frequent flyers need tokeep track of their exposure Patients and physician can consult the FAA’sradiation estimation software (http://jag.cami.jccbi.gov./cariprofile.asp)

to calculate the exposure and the National Oceanic and AtmosphericAdministration (http://www.sec.noaa.gov) to check for solar flares

Suggested reading

Tobacco

Fiore MC, Jaén CR, Baker TB, et al Treating Tobacco Use and Dependence: 2008 Update.

Clinical Practice Guideline Rockville, MD: US Department of Health and Human vices, Public Health Service, May 2008.Hamilton, BE., Martin, JA., Ventura, SJ (2013) Births: Final data for 2011 National vital statistics reports 61(5) Hyattsville, MD: National Center for Health Statistics Retrieved July 2, 2013, from http://www.cdc.gov /nchs/data/nvsr/nvsr62/nvsr62_01.pdf.

Ser-Chamberlain C, O’Mara-Eves A, Oliver S, Caird JR, Perlen SM, Eades SJ, Thomas

J Psychosocial interventions for supporting women to stop smoking in pregnancy Cochrane Database of Systematic Reviews 2013, Issue 10 Art No.: CD001055 DOI: 10.1002/14651858.CD001055.pub4.

Smoking cessation during pregnancy Committee Opinion No 471 American College of

Obstetricians and Gynecologists Obstet Gynecol 2010;116:1241–4 (Reaffirmed 2013).

U.S Department of Health and Human Services The Health Consequences of Smoking:

50 Years of Progress A Report of the Surgeon General Atlanta, GA: U.S Department

of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2014 Printed with corrections, January 2014.

Likis FE, Andrews JC, Fonnesbeck CJ, Hartmann KE, Jerome RN, Potter SA, Surawicz

TS, McPheeters ML Smoking Cessation Interventions in Pregnancy and Postpartum Care Evidence Report/Technology Assessment No.214 (Prepared by the Vanderbilt Evidence-based Practice Center under Contract No 290-2007-10065-I.) AHRQ Publi- cation no 14-E001-EF Rockville, MD Agency for Healthcare Research and Quality; February 2014 www.effectivehealthcare.ahrq.gov/reports/final.cfm.

Tobacco, Alcohol, and the Environment 13

World Health Organization WHO Recommendations for the Prevention and Management of Tobacco Use and Second-Hand Smoke Exposure in Pregnancy Geneva: World Health Orga-

nization; 2013.

U.S Department of Health and Human Services Substance Abuse and Mental Health Services Administration Center for Behavioral Health Statistics and Quality National Survey on Drug Use and Health, 2013 Inter-University Consortium for Political and Social Research (ICPSR) [distributor].

Alcohol

At-Risk Drinking and Illicit Drug Use: Ethical Issues in Obstetric and Gynecologic Practice ACOG Committee Opinion No.422 American College of Obstetricians and Gynecolo-

gists Obstet Gynecol 2008;112:1449–1460.

Chang G Screening and brief intervention in prenatal care settings Alcohol Res Health

2004;28(2):80–84.

Lui S, Terplan M, Smith EJ Psychosocial interventions for women enrolled in alcohol

treatment during pregnancy Cochrane Database Syst Rev 2008;(3).

Sokol RJ, Martier S, Ager J The T-ACE questions: practical prenatal detection of

risk-drinking Am J Obstet Gynecol 1989;160:863–70.

Substance Abuse and Mental Health Services Administration Results from the 2007 National Survey on Drug Use and Health (www.oas.samhsa.gov/nsduh/reports.htm).

Environmental agents

Barish RJ In-flight radiation exposure during pregnancy Obstet Gynecol 2004;103:

1326–30.

Chamberlain G Women at work in pregnancy In: Chamberlain G (ed.) Pregnant Women

at Work New York: Macmillan, 1984.

Frazier LM, Hage ML (eds) Reproductive Hazards of the Workplace New York; Chichester:

John Wiley & Sons, 1998.

Mittlemark RA, Dorey FJ, Kirschbaum TH Effect of maternal exercise on pregnancy

outcome In: Mittlemark RA, Drinkwater BL (eds) Exercise in Pregnancy, 2nd edn

Bal-timore: Williams & Wilkins, 1991.

Paul M (ed.) Occupational and Environmental Reproductive Hazards: A Guide for Clinicians.

Baltimore: Williams & Wilkins, 1993.

Scialli AR The workplace In: Scialli AR (ed.) A Clinical Guide to Reproductive and mental Toxicology Boca Raton: CRC Press, 1992.

Develop-Ionizing Radiation

Robert L Brent

Alfred I duPont Hospital for Children, Thomas Jefferson University, Wilmington, DE, USA

In 2013, an extensive update of radiation risks was published by theNational Council on Radiation Protection and Measurements (NCRP

174, 2013) The new material dealing with the preconception andpostconception risks of ionizing will be summarized in this protocol.Ionizing radiation associated with medical procedures is typically theradiation exposure that causes the greatest concern and anxiety to preg-nant women However, if imaging examinations are medically indicatedand performed with proper equipment and careful technique, then thepotential immediate benefit to the health of the patient and the embryo

or fetus will outweigh the radiation risks Most diagnostic medical ing procedures in radiography, computed tomography (CT), conventionalfluoroscopy, and nuclear medicine subject the embryo or fetus to absorbeddoses of less than 0.1 Gy (10 rad) Doses delivered to the embryo or fetusduring fluoroscopically guided interventional procedures and during thecourse of radiation therapy may be higher

imag-Preconception ionizing radiation risks

There is no convincing direct evidence of heritable disease in the offspring

of humans attributable to ionizing radiation, yet radiation clearly inducesmutations in microbes and somatic cells of rodents and humans, and trans-generational effects in irradiated drosophila and mice are established Itwould be imprudent to ignore the possibility of human germ-cell mutation.However, the data indicated that the risk is not measurable in humans.The inheritance of mutations is a process that, in theory, has both abackground component that is intrinsic in an individual and an inducedcomponent that results from environmental exposures such as ionizingradiation A very small but undefined fraction of hereditary human dis-ease is attributable to the environmental agents with mutagenic potential

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Sixth Edition.

Edited by John T Queenan, Catherine Y Spong and Charles J Lockwood.

© 2015 John Wiley & Sons, Ltd Published 2015 by John Wiley & Sons, Ltd.

14

Ionizing Radiation 15

In the absence of adequate human data, modeling and extrapolation haveguided radiation protection

Genetic risk is generally estimated using three components:

• doubling dose for radiation-induced germ-cell mutations in mice;

• background rate of sporadic genetic disease in humans; and

• population-genetics theory and experience

One additional consideration is that some deleterious mutations taneous or as a result of preconception radiation exposure) would not beexpressed as effects in an offspring because they are lethal to the developingova (eggs) or sperm or to the developing embryo because of defective ova

(spon-or sperm, a consideration that has been described as biological filtration.There is little to no convincing or consistent evidence among the offspring

of childhood cancer survivors, atomic-bomb survivors, environmentallyexposed populations, or occupationally exposed workers for an excess ofcytogenetic syndromes, single-gene disorders, malformations, stillbirths,neonatal deaths, cancer, or cytogenetic markers that would indicate anincrease of heritable genetic mutations in the exposed parents

James V Neel, M.D., Ph.D., a geneticist, spent a major part of his scientificlife studying the genetic effects of the atomic bomb in the children of theexposed parents (Neel 1990, Annual Review in Genetics 24: 327–362).Studies of eight indicators in the children of the atomic bomb survivorsand suitable controls suggested that the genetic doubling dose for thespectrum of acute gonadal radiation (experienced by survivors of theatomic bombings) is in the neighborhood of 2.0 Gy For extrapolation tothe effects of chronic radiation Neel used a dose rate factor of 2, resulting

in a doubling dose estimate of 4.0 Gy Using the specific locus test of

Russell (Russell 1956, 1965, 1976) Russell et al 1958; Schull et al 1981,

Neel concluded that his estimate of the doubling dose was acceptable

It would be impossible to demonstrate this risk in a human populationexposed to less than 0.1 Gy (10 rad) You would need tens of thousands

of exposed humans in the study Preconception gonadal (sperm, ova)exposure to diagnostic radiological tests are unlikely to have a measurablegenetic risk

Exposure during pregnancy

What are the reproductive and developmental risks of in utero exposures

to ionizing radiation exposure?

1 Birth defects, mental retardation and other neurobehavioral effects,

growth retardation and embryonic death are deterministic effects(threshold effects) This indicates that these effects have a NOAEL(no adverse effect level) Almost all diagnostic radiological procedures

provide exposures that are below the NOAEL for these developmentaleffects Diagnostic radiological studies rarely exceed 0.1 Gy (10 rad),while the threshold for congenital malformations or miscarriage is morethan 20 rad (0.2 Gy) (Table 2.1).

2 For the embryo to be deleteriously affected by ionizing radiation when

the mother is exposed to a diagnostic study, the embryo has to be exposedabove the NOAEL in order to increase the risk of deterministic effects.This rarely happens when pregnant women have X-ray studies of thehead, neck, chest or extremities

3 During the pre-implantation and pre-organogenesis stages of embryonic

development, the embryo is least likely to be malformed by the effects ofionizing radiation because many of the cells of the very young embryoare omnipotential and can replace adjacent cells that have been delete-riously affected This early period of development has been designated

as the “all or none” period

4 Protraction and fractionation of exposures of ionizing radiation to the

embryo decrease the magnitude of the deleterious effects of deterministiceffects

5 The increased risk of cancer following high exposures to ionizing

radia-tion exposure to adult popularadia-tions has been demonstrated in the atomicbomb survivor population Radiation-induced carcinogenesis is assumed

to be a stochastic effect (non-threshold effect), so that there is retically a risk at low exposures While there is no question that highexposures of ionizing radiation can increase the risk of cancer, the magni-tude of the risk of cancer from embryonic exposures following diagnosticradiological procedures is very controversial Recent publications andanalyses indicate that the risk is lower for the irradiated embryo thanfor the irradiated child which surprised many scientists interested in this

theo-subject (Preston et al 2008).

Evaluating the risks

The responsibility of evaluating risks of environmental toxicants to thepregnant patient and her embryo frequently is the responsibility of theobstetrician When evaluating the risks of ionizing radiation, the physician

is faced with several different clinical situations, as outlined below

1 The pregnant patient presents with clinical symptoms that need to be

evaluated What is the appropriate utilization of diagnostic radiologicalprocedures that may expose the embryo or fetus to ionizing radiation?

A pregnant or possibly pregnant woman complaining of nal bleeding, abdominal or back pain, or an abdominal or pelvic massthat cannot be attributed to pregnancy deserves the appropriate studies

gastrointesti-Ionizing Radiation 17

Table 2.1 Radiation exposure and risk at different gestational phases

Stage, Gestation weeks Effect

First and second weeks post first

day of the last menstrual period

(LMP) (Prior to conception)

First two weeks post first day of the last menstrual period This is a preconception radiation exposure Mother has not yet ovulated

Third and fourth week of

gestation (First two weeks post

conception)

Minimum human acute lethal dose (from animal studies) approximately 0.15–0.20 Gy Most sensitive period for the induction of embryonic death

Fourth to eighth week of

gestation (Second to sixth

week post conception)

Minimum lethal dose (from animal studies) at 18 days post conception is 0.25 Gy (25 rad).

After 50 days post conception, more than 0.50 Gy (50 rad) predisposes embryo to the induction of major malformations and growth retardation.

Minimum dose for growth retardation at 18–36 days is 0.20–0.50 Gy (20 rad-50 rad and at 36–110 days is 0.25–0.5 Gy (25–50 rad) But the induced growth retardation during this period is not as severe as during mid-gestation from similar exposures Eighth to fifteenth week of

gestation

Most vulnerable period for irreversible whole body growth retardation, microcephaly and severe mental retardation Threshold for severe metal retardation is 0.35–0.50 Gy (35–50 rad) (Schull and Otake 1999) Miler indicated that the threshold was more than

50 rad (1999) Decrease in I.Q may occur at lower exposures but is difficult to document There is no increased risk for mental retardation with exposures less than 0.10 Gy

Sixteenth week to term of

gestation

Higher exposures can produce growth retardation and decreased brain size and intellect, although the effects are not as severe as what occurs from similar exposures during mid-gestation There is no risk for major anatomical malformations The threshold dose for lethality (from animal studies) from 15 weeks to term is more than 1.5 Gy (150 rad).

Minimum dose for severe mental retardation at 15 weeks to term is more than1.50 Gy, but decrease in I.Q can occur at lower exposures.

There is no evidence that radiation exposure in the diagnostic ranges (less than 0.10 Gy, less than

10 rad) is associated with measurably increased incidence of congenital malformation, stillbirth, miscarriage, growth, and mental retardation.

to diagnose and treat her clinical problems, including radiological studies.Furthermore, these studies should not be relegated to one portion of themenstrual cycle if she has not yet missed her period The studies should

be performed at the time they are clinically indicated whether or not thewoman is in the first or second half of the menstrual cycle

2 The patient has completed a diagnostic procedure that has exposed her

uterus to ionizing radiation Her pregnancy test was negative She nowbelieves she was pregnant at the time of the procedure What is yourresponse to this situation?

Explain that you would have proceeded with the necessary X-ray nostic test whether she was pregnant or not, since diagnostic studies thatare indicated in the mother have to take priority over the possible risk toher embryo, because almost 100% of diagnostic studies do not increasethe risks to the embryo (Table 2.1) Secondly, she must have been veryearly in her pregnancy, since her pregnancy test was negative At thistime, obtain the calculated dose to the embryo and determine her stage

diag-of pregnancy If the dose is below 0.1 Gy (10 rad) (0.1 Sv), you can informthe mother that her risks for birth defects and miscarriage have not beenincreased In fact, the threshold for these effects is 20 rad (0.2Gy) at themost sensitive stage of embryonic development (Tables 2.1 and 2.2) Of

Table 2.2 Risk of less than 0.1 Gy (less than 10 rad).

than 0.1 Gy (less than

10 rad) exposure Risk of very early pregnancy

loss, before the first missed

period

350,000/10 6 pregnancies 0

Risk of spontaneous abortion

in known pregnant women

150,000/10 6 pregnancies 0 Risk of major congenital

late-onset genetic disease

100,000/10 6 Very low risk is in next

generation and there is not measurable increase with small populations

Growth retardation 30,000/10 6 pregnancies 0

Ionizing Radiation 19

course, you are obligated to tell her that every healthy woman is at riskfor the background incidence of birth defects and miscarriage, which is3% for birth defects and 15% for miscarriage

3 A woman delivers a baby with serious birth defects On her first

post-partum visit, she recalls that she had a diagnostic x-ray study early inher pregnancy What is your response when she asks you whether thebaby’s malformation could be caused by the radiation exposure?

In most instances, the nature of the clinical malformations will rule outradiation teratogenesis At this time, a clinical teratologist or radiationembryologist could be of assistance On the other hand, if the exposure

is below 0.1 Gy (10 rad), it would not be scientifically supportable to cate that the radiation exposure was the cause of the malformation Asmentioned before, the threshold for malformations is 0.20 Gy (20 rad)exposure The nature of the malformation would enter into this analysis

indi-In order to appropriately and more completely respond to these tions, the obstetrician should rely on the extensive amount of informationthat has accumulated on the effects of radiation to the embryo There is noenvironmental hazard that has been more extensively studied or on whichmore information is available (Tables 2.1 and 2.2)

ques-Radiation risks to the embryo

There is no question that an acute exposure to ionizing radiation above0.5 Gy represents a significant risk to the embryo, regardless of the stage

of gestation The threshold dose for low LET ionizing radiation that results

in an increase in malformations is approximately 0.02–0.1 Gy (Table 2.1).Although congenital malformations are unlikely to be produced by radi-ation during the first 14 days of human development, there would be asubstantial risk of embryonic loss if the dose is high From approximatelythe 18th day to the 40th day postconception, the embryo would be atrisk for an increased frequency of anatomical malformations if the embry-onic exposure is greater than 20–25 rad (0.2–0.25 Gy) Up until about the15th week, the embryo maintains an increased susceptibility to central ner-vous system (CNS) effects, major CNS malformations early in gestation andmental retardation in mid-gestation Of course, with very high doses, morethan 1 Gy, mental retardation can be produced in the latter part of gesta-tion While it is true that the embryo is sensitive to the deleterious effects ofthese mid-range exposures of ionizing radiation, the measurable effects falloff rapidly as the exposure approaches the usual exposures that the embryoreceives from diagnostic radiological procedures less than 0.1 Gy (10 rad).The threshold of 20 rad at the most sensitive stage of development (20–25days postconception) is raised by protraction of the radiation exposure,

for example, following several clinical diagnostic radiological proceduresoccurring over a period of days.

That is why the recommendation of most official organizations, includingthe National Council on Radiation Protection and Measurements (NCRP),indicates that exposures in the diagnostic range will not increase the risk ofbirth defects or miscarriage The risks of radiation exposure to the humanembryo when the exposure exceeds the no-effect dose (20 rad) are:

• Embryonic loss

• Growth retardation

• Congenital malformations

• Carcinogenesis (the magnitude of the risk is controversial)

• Microcephaly and mental retardation

Because all of the above effects are threshold phenomena, except for cinogenesis, radiation exposure below 0.1 Gy (10 rad) literally presents nomeasurable risk to the embryo Even if one accepts the controversial con-cept that the embryo is more vulnerable to the carcinogenic effects of radi-ation than the child, the risk at these low exposures is much smaller thatthe spontaneous risks Furthermore, other studies indicate that Stewart’sestimate of the risk involved is exaggerated

car-Table 2.2 compares the spontaneous risks facing an embryo at conceptionand the risks from a low exposure of ionizing radiation

Therefore, the hazards of exposures in the range of diagnosticroentgenology less than 0.1 Gy (10 rad) present an extremely lowrisk to the embryo, when compared with the spontaneous mishapsthat can befall human embryos (Table 2.2) Approximately 30–40% ofhuman embryos abort spontaneously (many abort before the first missedmenstrual period) Human infants have a 2.75% major malformationrate at term, which rises to approximately 4–6% once all malformationsbecome manifest When the data and risks are explained to the patient,the family with a wanted pregnancy invariably continues with thepregnancy

The difficulty that frequently arises is that the risks from diagnostic ation are evaluated outside the context of the significant normal risks ofpregnancy Furthermore, many physicians approach the evaluation of diag-nostic radiation exposure with either of two extremes: a cavalier attitude

radi-or panic The usual procedures in clinical medicine are ignradi-ored, and anopinion based on meager information is given to the patient Frequently, itreflects the physician’s bias about radiation effects or his or her ignorance ofthe field of radiation biology We have patient records in our files of scores

of patients who were not properly evaluated but were advised to have anabortion following radiation exposure

Ionizing Radiation 21

Evaluating the patient

After thorough evaluation in most instances, the dose to the embryo isestimated to be less than 0.1 Gy (10 rad) and frequently is less than 1 rad(0.01 Gy) Our experience has taught us that there are many variablesinvolved in radiation exposure to a pregnant or potentially pregnantwoman Therefore, there is no routine or predetermined advice thatcan be given in this situation However, if physicians take a systematicapproach to the evaluation of the possible effects of radiation exposure,they can help the patient make an informed decision about continuing thepregnancy This systematic evaluation can begin only when the followinginformation has been obtained:

• Stage of pregnancy at the time of exposure

• Menstrual history

• Previous pregnancy history

• Family history of congenital malformations and miscarriages

• Other potentially harmful environmental factors during the pregnancy

• Ages of the mother and father

• Type of radiation study, dates and number of studies performed

• Calculation of the embryonic exposure by a medical physicist or tent radiologist when necessary

compe-• Status of the pregnancy: wanted or unwanted

An interpretation should be made of the information, with both patientand counselor arriving at a decision The physician should place a summary

of the information in the medical record It should state that the patienthas been informed that every pregnancy has a significant risk of problemsand that the decision to continue the pregnancy does not mean that thecounselor is guaranteeing the outcome of the pregnancy The use of amnio-centesis and ultrasound to evaluate the fetus is an individual decision thatwould have to be made in each pregnancy but is rarely indicated

The carcinogenic effects of radiation

The carcinogenic risk of in-utero radiation is an important topic that not be addressed completely in this protocol Alice Stewart published theresults of her case–control studies indicating that diagnostic radiation frompelvimetry increased the risk of childhood leukemia by 50% (Table 2.2).That would change the risk of childhood leukemia from four cases per100,000 to six cases per 100,000 in the population of exposed fetuses.This has been a very controversial subject A recent publication by Preston

can-et al (2008) presented data from the in utero population of the A-bomb

survivors, which indicated that the embryo was less vulnerable to the

Table 2.3 Parameter estimates and 95% confidence intervals for solid cancer excess risks for atomic-bomb survivors in the in utero and childhood cohorts

Risk Estimates

(per unit weighted

organ dose) ∗, †

Cohort Age at Exposure

ERR Gy −1 In utero 0.3 (0.0–2.0) 0.5 (0.0–2.4) 0.4 (0.0–2.0)

Early childhood 1.3 (0.6–2.2) 2.2 (1.3–3.4) 1.7 (1.1–2.5) EAR (104 PY Gy) −1 at

50 y of age

In utero 4.3 (0.001–36) 9.2 (0.002–65) 6.8 (0.002–48) Early childhood 36 (16–63) 76 (49–100) 56 (36–79)

∗ Weighted organ doses are the estimated absorbed dose from gamma rays plus 10 times the estimated absorbed dose from neutrons In this report, the weighted organ dose is presented in gray; it has also been reported in the literature in sievert.

† For the in utero cohort, weighted uterine dose; for the early childhood cohort, weighted colon dose.

The excess relative risk (ERR) is the ratio of the excess risk of a specified disease to the probability

of the same effect in the unexposed population.

The excess absolute rate (EAR) is the excess rate of a specified disease in a specified population

among exposed persons per unit dose In radiation-exposed populations, the EAR is designated as the number of excess cases of a specific disease in radiation-exposed persons per 10,000 persons-years per gray [(10 4 PY Gy) −1 ].

The excess absolute risk (of solid tumors) is much greater for irradiated children than for exposed

embryos.

Source: Preston et al 2008 Adapted with permission of Oxford University Press.

oncogenic effects of ionizing radiation than the child (Table 2.3) Patientscan be told that the fetal risks are extremely small, so small that we cannotmeasure the risks because that would require a large exposed population.The risk of cancer in offspring that have been exposed to diagnostic x-rayprocedures while in utero has been debated for 55 years High doses at highdose rates to the embryo or fetus (e.g., more than 0.5 Gy) increase the risk

of cancer This has been demonstrated in human epidemiology studies aswell as in mammalian animal studies Most pregnant women exposed todiagnostic x-ray procedures or the diagnostic use of radionuclides receivedoses to the embryo or fetus less than 0.1 Gy (10 rad) The risk of cancer inoffspring exposed in utero at a low dose such as less than 0.1 Gy (10 rad) iscontroversial and has not been definitively determined

Research at the University of Rochester in 1951 demonstrated that therat embryo was less vulnerable to the carcinogenic risks of ionizing radia-tion than the postnatal animal The use of chemical carcinogens such asurethane also indicated that the postnatal animal was more vulnerablethan the embryo to the carcinogenic risks of some chemical carcinogens

In the 1950s, Stewart and others published numerous case–controlstudies that indicated that the embryo was the most vulnerable organ-ism to the carcinogenic effects of low exposures of ionizing radiation

Ionizing Radiation 23

(pelvimetry) There are 17 cohort studies of pregnant women exposed

to diagnostic radiological studies, none of which were positive, howevermany of the studies contained too few subjects to negate the impact of

the many case control studies In 2008, Preston et al published the results

of the in utero exposed population to the atomic bomb, which indicatedthat the embryo was less vulnerable to the carcinogenic effect of ionizingradiation (Table 2.3)

The Preston et al (2008) study is important because it demonstrates that

radiation exposure in utero is associated with increased risks of adult-onsetsolid tumors, which was not new information

The difference in ERRs and EARs between the two cohorts suggests that lifetime cancer risks at 57 y of age following in utero exposure are lower than risks for early childhood exposure

However, the investigators state, “additional follow-up of this cohort isnecessary before definitive conclusions can be made about the nature of the

risks for those exposed in utero” (Preston et al 2008) Mortality follow-up

for the in utero cohort, however, was available from 1950 and indicated

no deaths from childhood leukemia (Delongchamp et al 1997) Another

limitation is the small numbers of cancers in each dose category in the

in utero cohort Nevertheless, this investigation is the only cohort studywith long-term, continuous, active follow-up of a population with in uteroradiation exposure and high-quality estimated doses for each subject

At this time (2014), diagnostic imaging procedures utilizing ionizing ation that are clinically indicated for the pregnant patient should be per-formed because the clinical benefits outweigh the potential carcinogenicrisks However, when it has been determined that the procedure is neces-sary, it should be tailored to effectively manage the dose to the embryo orfetus (i.e., use only the least amount of radiation necessary to achieve theclinical purpose)

radi-The background risk for lethal cancers is 23% (23,000 per 100,000 viduals) due to the background spontaneous incidence of cancer That isthousands of times greater than the estimated cancer risks of low dose radi-ation to the developing embryo, with the possibility that there might not

indi-be an increase risk

Diagnostic or therapeutic abdominal radiation

in women of reproductive age

In women of reproductive age, it is important for the patient and physician

to be aware of the pregnancy status of the patient before performing anytype of x-ray procedure in which the ovaries or uterus will be exposed If

the embryonic exposure will be 0.1 Gy (10 rad) or less, the radiation risks

to the embryo are very small when compared with the spontaneous risks(Table 2.2) Even if the exposure is less than 0.1 Gy (10 rad), this expo-sure is far from the threshold or no-effect dose of 20 rad The patient will

accept this information if it is offered as part of the preparation for the x-ray

studies at a time when both the physician and patient are aware that apregnancy exists or may exist The pregnancy status of the patient should

be determined and noted

Because the risks of less than 0.1 Gy (10-rad) fetal irradiation are so small,the immediate medical care of the mother should take priority over therisks of diagnostic radiation exposure to the embryo X-ray studies that areessential for optimal medical care of the mother and evaluation of medi-cal problems that need to be diagnosed or treated should not be postponed.Elective procedures such as employment examinations or follow-up exam-inations, once a diagnosis has been made, need not be performed on apregnant woman even though the risk to the embryo is not measurable

If other procedures (e.g., MRI or ultrasound) can provide adequate mation without exposing the embryo to ionizing radiation, then of coursethey should be used Naturally, there is a period when the patient is preg-nant but the pregnancy test is negative and the menstrual history is of littleuse However, the risks of less than 0.1 Gy (10 rad) or less are extremelysmall during this period of pregnancy (all or none period, first two weekspostconception) The patient will benefit from knowing that the diagnosticstudy was indicated and should be performed in spite of the fact that shemay be pregnant

infor-Scheduling the examination

In those instances in which elective X-ray studies need to be scheduled, it isdifficult to know whether to schedule them during the first half of the men-strual cycle just before ovulation or during the second half of the menstrualcycle, when most women will not be pregnant The genetic risk of diagnos-tic exposures to the oocyte or the embryopathic effects on the preimplantedembryo is extremely small, and there are no data available to compare therelative risk of less than 0.1 Gy (10 rad) to the oocyte or the preimplantedembryo If the diagnostic study is performed in the first 14 days of the men-strual cycle, should the patient be advised to defer conception for severalmonths, based on the assumption that the deleterious effect of radiation

to the ovaries decreases with increasing time between radiation exposureand a subsequent ovulation? Physicians are in a quandary because theymay be warning the patient about a very-low-risk phenomenon On the

concep-exposures before conceiving additional offspring.”

Because the patients exposed during diagnostic radiological proceduresabsorb considerably less than 25 rad, the recommendations made here may

be unnecessary, but it involves no hardship to the patient or physician.Because both the NCRP and ICRP have previously recommended that elec-tive radiological examinations of the abdomen and pelvis be performedduring the first part of the menstrual cycle (10-day rule, 14-day cycle) toprotect the zygote from possible but largely conjectural hazards, the recom-mendation to avoid fertilization of recently irradiated ova perhaps meritsequal attention

Importance of determining pregnancy status

of patient

If exposures less than 0.1 Gy (10 rad) do not measurably affect the exposedembryos, and it is recommended that diagnostic procedures should be per-formed at any time during the menstrual cycle, if necessary, for the medicalcare of the patient, why expend energy to determine the pregnancy status

of the patient?

There are several reasons why the physician and patient should share theburden of determining the pregnancy status before performing an x-ray ornuclear medicine procedure that exposes the uterus:

1 If the physician is forced to include the possibility of pregnancy in the

differential diagnosis, a small percentage of diagnostic studies may nolonger be considered necessary Early symptoms of pregnancy maymimic certain types of gastrointestinal or genitourinary disease

2 If the physician and patient are both aware that pregnancy is a possibility

and the procedure is still performed, it is much less likely that the patientwill be upset if she subsequently proves to be pregnant

3 The careful evaluation of the reproductive status of women undergoing

diagnostic procedures will prevent many unnecessary lawsuits Evenmore important, the patient will have more confidence if the decision

to continue the pregnancy is made before the medical x-ray dure is performed, because the necessity of performing the procedurewould have been determined with the knowledge that the patientwas pregnant.

proce-In every consultation dealing with the exposure of the embryo to nostic studies involving ionizing radiation (X-ray, CT scans, use of radionu-clides) in which her reproductive risks or developmental risks for her fetushave not been increased by the radiation exposure, the patient should beinformed that every healthy woman with a negative personal and geneticfamily reproductive history has background reproductive risks which are3% for birth defects and 15% for miscarriage We cannot change thesebackground risks, which every women faces

diag-Suggested reading

Brent RL Biological factors related to male mediated reproductive and developmental

toxicity In: Olshan, AF and Mattison, DR (Eds) Male-Mediated Developmental Toxicity.

Plenum Press, New York, pp 209–242, 1994.

Brent, R.L Saving lives and changing family histories: Appropriate counseling of nant women and men and women of reproductive age, concerning the risk of radiation

preg-exposures during and before pregnancy Am J Obstet Gynecol 2009;200(1):4–24 Brent RL, Frush DP, Harms RW, et al Preconception and prenatal radiation exposure:

Health effects and protective guidance NCRP Report No 174 Recommendations of the National Council on Radiation Protection and Measurements, 342 pp., May 24, 2013.

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P R O T O C O L 3

Depression

Kimberly Yonkers1,2,3

1 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

2 Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA

3 School of Epidemiology and Public Health, Yale University School of Medicine, New Haven,

CT, USA

Clinical significance

Approximately 20% of women suffer from a depressive disorder at somepoint in their lives The risk of being depressed is greatest for women dur-ing their reproductive years and thus clinicians may encounter a pregnantwoman with pre-existing depression or a woman who becomes depressedduring her pregnancy Some research finds an association between mater-nal depression and particular perinatal complications, including pretermbirth and/or delivery of a low-birth-weight baby, although there aredissenting results These findings, along with the potentially devastatingtoll that a major depressive episode (MDE) has on a mother, underscorethe need to treat depressed pregnant women However, when the neededtreatment is pharmacotherapy, there are additional concerns becauseantidepressants, and the anxiolytics that are often used concurrently, arelinked with adverse perinatal and fetal outcomes Researchers note a risk

of fetal malformations although this appears to be a small risk that haslargely centered on atrial and ventricular septal defects and only withsome antidepressants Other worrisome associations include delivery of

an infant who is preterm or small for gestational age, as well as a verysmall increased likelihood of persistent pulmonary hypertension Theevidence for a number of these outcomes among women treated withantidepressants in pregnancy is mixed, with the strongest support forpreterm birth However, even the smallest risk can lead to apprehension

on the part of patients and uneasiness for their prescribing physicians

Protocols for High-Risk Pregnancies: An Evidence-Based Approach, Sixth Edition.

Edited by John T Queenan, Catherine Y Spong and Charles J Lockwood.

© 2015 John Wiley & Sons, Ltd Published 2015 by John Wiley & Sons, Ltd.

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