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in Fetal & Neonatal Medicine 19 (2014) 139 e 152 Contents lists available at ScienceDirect Seminars

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Seminars in Fetal & Neonatal Medicine

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Medicine journal homepage: www.el sevier.com/l ocate/siny Review Counseling women and men regarding exposures to

Review

Counseling women and men regarding exposures to reproductive and developmental toxicants before conception or women during pregnancy

Robert L. Brent *

Thomas Jefferson University, Alfred I. duPont Hospital for Children, Room 308, A/R Building, PO Box 269, Wilmington, DE 19899, USA

308, A/R Building, PO Box 269, Wilmington, DE 19899, USA summary Keywords: Birth defects Counseling Development

summary

Keywords:

Birth defects

Counseling

Development

Environmental toxicants

Pregnancy

Teratology principles

It should be apparent that determining the reproductive risks of an exposure during pregnancy or the cause of a child s congenital malformations is not a simple process. It involves a careful analysis of the medical and scienti c literature pertaining to the reproductive toxic effects of exogenous agents in humans and animals, as well as an evaluation of the exposure and the biological plausibility of the concern of an increased risk or a causal connection between the exposure and a child s congenital malformations. It also involves having available a detailed physical examination of the malformed infant or child and a review of the scienti c literature pertaining to genetic and environmental causes of the malformations in question. Abridged counseling on the basis of super cial and incomplete analyses is a disservice to the family. Experienced counselors understand that their primary task is to educate the pregnant women or family members concerning the risk of an environmental exposure. The counselor should advise them on the options available, but not on which option to select. 2013 Elsevier Ltd. All rights reserved.

1. Introduction

In 1944, during World War II, I received my draft notice for in- duction into the armed forces, which would occur in mid 1945. At the age of 15 years, I applied to the University of Rochester, since I had passed all the high school senior courses which included advanced physics, biology and chemistry. In June 1944, I was a freshman at the University and obtained a part-time position at the Manhattan Project Research facility in Rochester in the genetics and embryology divisions. Whereas all the employees at the University of Rochester were investigating the biological effects of ionizing radiation and the entire research staff had the highest level of se- curity clearance, none of the staff were aware that researchers in Los Alamos were attempting to develop an atomic bomb. After the war ended in 1945, the Manhattan Project became one of the Atomic Energy Commission (AEC) facilities at the University. In 1949, I entered medical school but continued my embryology ra- diation research. The head of the division, Dr James Wilson, offered me the opportunity to be his graduate student in the summer of 1950 and Wilson spent the summer intensively training me in all

* Tel.: þ 1 302 651 6880; fax: þ 1 302 651 6888. E-mail address: rbrent@nemours.org .

1744-165X/$ e see front matter 2013 Elsevier Ltd. All rights reserved.

the experimental techniques used in that division. At the end of the summer, Dr Wilson announced that he had accepted a position at the University of Cincinnati. Rather than close the division, the Administration appointed me the Head of the Division. I had a budget, a technician and secretarial support and I taught the Uni- versity of Rochester medical students embryology during the next four years while I was in Rochester completing my medical and graduate degrees. During these four years my national and inter- national counseling effort began at the University of Rochester. The only other major AEC facility in the country interested in radiation effects on reproduction was at Liane Russell s excellent laboratory in Oak Ridge, Tennessee. However, she was extensively involved in pursuing her research. So the calls and letters all came to Rochester, and then to the Massachusetts General Hospital where I was a resident physician and the Walter Reed Army Insti- tute of Research where I was the head of the Radiation Biology Section for my two years of Army service from 1955 until 1957. I arrived at The Jefferson Medical College in 1957 and have been there for 56 years. In the 1950s there were practically no educa- tional programs in medical school or graduate school that per- tained to the evaluation of the risks of reproductive and developmental toxicants or counseling families with regard to the presence or absence of risks from these exposures. The concept of professional counseling was still in its infancy.

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R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139e152

2. The stages of medical and graduate school education in the

USA: When did counseling with regard to reproductive and

developmental toxicant exposure become a recognized and necessary skill?

Medical education in the USA received a major impetus following the publication of Abraham Flexner s (1910) monograph that was commissioned by the Carnegie Foundation for the Advancement of Teaching [1] . Prior to being contacted by the Car- negie Foundation, Flexner graduated from Johns Hopkins in 1885 at the age of 19 and crystallized in his mind the components of quality higher educational programs: small classes, personal attention and hands-on teaching. He returned to Louisville and founded a med- ical school using these principles. The graduates proved to be em- issaries of what quality education can accomplish. It was these early successes that convinced the Carnegie Foundation that Flexner was the scholar who could improve medical education. Following the implementation of the Flexner Report many rural medical schools closed. Many physicians are unaware that Flexner was not a physician nor did he have an advanced degree. However, he was a brilliant teacher and scholar. Over the next 50 years the Flexner model of medical education evolved into the bioscience model of medical education and med- ical practice. High quality basic science education and research could provide all the answers , so that physicians could diagnose, ameliorate, treat or cure medical problems with which they encountered. Unfortunately, the bioscience model is incomplete and can result in a signi cant portion of the patient population being dissatis ed with their care. This was evident to George Engle at the University of Rochester. He was trained in psychiatry and internal medicines and published many articles about the biopsychosocial model of health care delivery that re ected his interest in psy- chosomatic medicine [2] . At the University of Rochester Engle established the medical psychiatric liaison service staffed by in- ternists and psychiatrists. Engle indicated that he would prefer having physicians with behavioral training rounding on the other clinical services rather than on the psychiatry service. Engle was adamant that you cannot ignore the impact of the environment on the patient s disease or the behavioral defenses available to the patient. It was clear that Engle believed that compassion and empathy were important components of the biopsychosocial model of medical care. Carl Rogers [3 e 5] is probably the most important contributor to the elements of proper counseling since he emphasized the hu- manistic approach to psychological counseling. If the patients or contacts do not sense that the counselor is compassionate or empathetic, their interaction will be less than satisfactory. Exhib- iting genuine compassion and empathy results in a client-centered interaction with much greater success in properly communicating and educating the contact. The client, patient or contact has to believe that the counselor believes that the contact deserves respect, which is demonstrated by exhibiting compassion and re- gard for the contact (unconditional, positive regard) [4] . The fundamental precepts of Rogerian counseling include congruence (being genuine in one s concern), empathy, and unconditional positive regard [4] . A widely accepted component of genuine concern in medical counseling is the responsibility of the counselor to provide core knowledge of the evidence addressing the issue in question. To be genuinely concerned is to seek and provide reliable information. A further adaptation of these principles involves providing an unbiased discussion of the facts surrounding the problem being addressed. Empathy requires some knowledge of, and sensitivity to, the social and cultural position of the persons being counseled.

During the rst 50 years of the twentieth century, the rules of professional counseling were rarely articulated or taught. It was only after the writings of Engle and Rogers that the essential fea- tures of professional counseling were legitimized, whether it per- tained to psychotherapy, medical care and especially for counseling contacts concerning reproductive and developmental risks from environmental exposures.

3. The history of providing counseling to pregnant women exposed to reproductive and developmental toxicants (teratogenesis, congenital malformations), and men and women with preconception exposures (mutagenesis in the gametes and in the offspring in the next generation)

Individual counseling is part of the practice of clinical medi- cine. However, at the beginning of the twentieth century there were very few individuals prepared to counsel patients with re- gard to the risk of reproductive, developmental and mutagenic toxicants. Our laboratory has provided consultations dealing with the risk of various environmental toxicant exposures during or before pregnancy since 1950. In 1960 a group 60 scientists interested in birth defects met at the Slone Kettering Institute in New York City to discuss their common interests in the causes of birth defects and decided to create a Birth Defects Society. In 1961 many of those scientists met in Cincinnati where the charter of the Tera- tology Society was drafted. Within the Teratology Society a pro- portion of the membership was interested in providing counseling to the patient population. There were diverse opinions as to whether individuals who provided counseling should receive training and pass a certi cation examination. That issue was never resolved. However, the problem was partially solved in the 1990s when the Organization of Teratology Services was formed, which frequently meets with the Teratology Society at the latter s annual meeting. In 2005, the name of OTIS was changed to the Organi- zation of Teratology Information Specialists. In Europe the Euro- pean Teratology Society (founded in the 1970s) and European Network of Teratology Information Services (ENTIS) de ne the counseling organizations in Europe having active scienti c and counseling programs, as also happens in Japan and Australia. But none of these organizations professionally certi es individuals to provide counseling, although some members may be certi ed genetic counselors. In North America there are many OTIS members and branches. The Mother Risk program ( Motherrisk.org ) headed by Dr Gideon Koren is located at the Hospital for Sick Children and the University of Toronto. In San Diego, Dr Kenneth Lyon Jones heads the largest program in California; and in Seattle, the TERIS program was initiated with a federal grant obtained by Dr Jan Friedman. With the advent of the Internet, consulting has become more rapid and ef cient. In 2012 the Ask the Expert (ATE) website of the HPS (Health Physics Society) received about 2 400 000 hits. More than 700 000 prepared answers to questions were downloaded. More than 1800 contacts were still quite anxious after reading the website answers and requested a personal consultation. During 2012 our laboratory received its 25 000th consultation. We also receive consultations by letter, telephone and e-mail unrelated to the HPS website. From this extensive experience we have learned that many physicians and other health care counselors are not prepared to counsel patients concerning reproductive and devel- opmental risks. Approximately 6 e10% of the contacts concerned about various environmental toxicants had been provided inaccu- rate information that stimulated unwarranted anxiety that could have resulted in an unnecessary interruption of a wanted pregnancy.

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139 e152

141

4. Role of the counselor in advising families

The counselor must be cognizant of many patients belief that congenital malformations are caused by a drug or medication taken during pregnancy. Counseling patients about reproductive risks requires a signi cant degree of both knowledge and skill. Physi- cians must also realize that erroneous counseling by inexperienced health professionals may be a stimulus to non-meritorious litiga- tion [6 e 8] . Unfortunately, some individuals have assumed that if a drug or chemical causes birth defects in an animal model or in an in-vitro system at a high dose, then it has the potential for producing birth defects at any dose. This may be reinforced by the fact that many teratology studies reported in the literature using several doses have not determined the no-effect dose. Ignoring the basic tenets of teratology ( Box 1 ) appears to occur most frequently in the evaluation of environmental toxic exposures where the exposure was very low or unknown and the agent has been reported to be teratogenic at a very high dose or a maternally toxic dose in animal modes. In most but not all instances, the actual population exposure is revealed to be orders of magnitude below the threshold dose observed in animal studies. This has occurred with 2,4,5,-trichlorophenoxyacetic acid (2,4,5-T, also known as Agent Orange), polychlorinated biphenyls (PCBs), lead, cadmium, pesticides, herbicides, veterinary hormones and some industrial exposures. Unfortunately, environmental disasters have been responsible for birth defects or pregnancy loss in exposed populations (methyl mercury in Japan, PCBs in the Orient, organic mercury in the Middle

Box 1 Principles of teratology.

When evaluating studies dealing with the reproductive and developmental effects of any environmental agent, impor- tant principles should guide the analysis of reproductive human and animal studies. Paramount to this evaluation is the application of the basic science principles of teratology and developmental biology: a

1. Exposure to teratogens follows a toxicological dose e re- sponse curve. There is a threshold below which no effect will be observed, and, as the dose of the teratogen is increased, both the severity and frequency of reproduc- tive effects will increase (deterministic effect; tissue reaction).

2. The period of exposure is critical in determining what effects will be produced and whether any effects can be produced by a known teratogen. Some teratogenic ef- fects have a broad period of sensitivity, others a very narrow one.

3. Even the most potent teratogenic agent cannot produce every malformation.

4. Most teratogens have a confined group of congenital malformations that occur after exposure during a critical period of embryonic development. This confined group of malformations is referred to as the syndrome that describes the agent’s teratogenic effect.

5. Whereas a group of malformations may suggest the possibility of certain teratogens, they cannot definitively confirm the causal agent. On the other hand, the pres- ence of certain malformations can eliminate the possi- bility that a particular teratogenic agent was responsible.

a Source: Brent [52] .

East, lead poisoning in the nineteenth and early twentieth cen- turies) and there are examples of teratogenic drugs and chemicals having been introduced ( Table 1 ) [10 e17] . Therefore, we can never generalize as to whether a chemical or drug is safe or hazardous unless we know the magnitude and stage of the exposure. Before their baby is born, parents may be concerned about the risks of various environmental exposures. If the child is born with congenital malformations they may question whether there was a causal relationship with an environmental exposure.

4.1. Scholarly evaluation

When a counselor responds to a parent s inquiry ( What caused my child s birth defect? ), the physician should respond in the same scholarly manner that would be utilized in performing a differential diagnosis for any clinical problem. Physicians have a protocol for evaluating complex clinical problems; i.e. fever of unknown origin , failure to thrive , congestive heart failure , or respiratory distress ( Box 2 ). If a mother of a malformed infant had some type of exposure during pregnancy, such as a diagnostic radiological examination or medication utilized during pregnancy, the consulting physician should not support or suggest the possibility of a causal relation- ship before performing a complete evaluation ( Box 3 ). Likewise, if a pregnant woman who had not yet delivered had some type of exposure during pregnancy, the consulting physician should not support or suggest the possibility that the fetus is at increased risk before performing a complete evaluation. As mentioned previously, only a small percentage of birth de- fects is due to prescribed drugs, chemicals and physical agents ( Tables 2 and 3 ). Even when the drug is listed as a teratogen, it has to have been administered during the sensitive period of devel- opment for that drug and above the threshold dose for producing teratogenesis. Furthermore, the malformations in the child should be the malformations that are included in the teratogenic syn- drome produced by that drug. It should be emphasized that a recent analysis pointed out that there are no drugs with measurable teratogenic potential in the list of the 200 most prescribed drugs in the USA [17] . After a complete examination of the child and a review of the genetic and teratology medical literature, the clinician must decide on whether the child s malformations are due to a genetic cause or an environmental toxin or agent ( Boxes 1 and 2 ; Table 1 ). The clinician may not be able to conclude, de nitively or presumptively, the etiology of the child s birth defects. This information must then be conveyed to the patient in an objective and compassionate manner. A similar situation exists if a pregnant woman has been exposed to a drug, chemical or physical agent, since the mother will want to know the risk of that exposure to her unborn child. If one wishes to answer the generic question, Is a particular environ- mental drug, chemical or physical agent a reproductive toxicant? then a formal approach is recommended that includes a ve-part evaluation as described in Box 4 .

5.

De ciencies in counseling education and methodology

Some physicians and other health professionals misinform their patients regarding the magnitude of the risk of environmental toxicant exposure during pregnancy [23,29] . Ratnapalan et al. [29] surveyed a large number of general physicians and obstetricians regarding the risk of abdominal computed tomography (CT) scan to pregnant women during the 6th week of gestation ( Table 4 ). Experienced counselors understand that their primary task is to educate the pregnant women or family members concerning the risk of an environmental exposure. The counselor should advise

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R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139e152

Table 1 Developmental toxicants: risks of congenital malformations and abortion in the human.

Developmental

Reported effects or associations and estimated risks

Comments a

toxicant

Alcohol Fetal alcohol syndrome: intrauterine growth retardation, maxillary hypoplasia, reduction in width of palpebral ssures, characteristic but not diagnostic facial features, microcephaly, mental retardation. An increase in spontaneous abortion has been reported but since mothers who abuse alcohol during pregnancy have multiple other risk factors, it is dif cult to determine whether this is a direct effect on the embryo. Consumption of 6 oz of alcohol or more per day constitutes a high risk but it is likely that detrimental effects can occur at lower exposures.

Quality of available information: good to excellent. Direct cytotoxic effects of ethanol and indirect effects of alcoholism. Whereas a threshold teratogenic dose is likely it will vary in individuals because of a multiplicity of factors. Quality of available information: good. Anticancer, antimetabolic agents; folic acid antagonists that inhibit dihydrofolate reductase, resulting in cell death. Quality of available information: good. Effects are dose and stage dependent; stimulates growth and differentiation of sex steroid receptor-containing tissue. Quality of available information: good. Antihypertensive agents; adverse fetal

Aminopterin,

Microcephaly, hydrocephaly, cleft palate, meningomyelocele, intrauterine growth retardation, abnormal cranial ossi cation, reduction in derivatives of rst branchial arch, mental retardation, postnatal growth retardation. Aminopterin can induce abortion within its therapeutic range; it is used for this purpose to eliminate ectopic embryos. Risk from therapeutic doses is unknown but appears to be moderate to high. Masculinization of female embryo: clitoromegaly with or without fusion of labia minora. Non- genital malformations are not a reported risk. Androgen exposures which result in masculinization have little potential for inducing abortion. Based on animal studies, behavioral masculinization of the female human will be rare. The therapeutic use of ACE inhibitors has neither a teratogenic effect nor an abortigenic effect in the rst trimester. Since this group of drugs does not interfere with organogenesis, they can be used in a woman of reproductive age; if the woman becomes pregnant, therapy can be changed during the

methotrexate

Androgens

Angiotensin-converting

enzyme (ACE)

inhibitors

 

rst trimester without an increase in the risk of teratogenesis. Later in gestation these drugs can result in fetal and neonatal death, oligohydramnios, pulmonary hypoplasia, neonatal anuria, intrauterine growth retardation, and skull hypoplasia. Risk is dependent on dose and length of exposure. Caffeine Caffeine is teratogenic in rodent species with doses of 150 mg/kg. There are no convincing data that moderate or usual exposures (300 mg per day or less) present a measurable risk in the human for any malformation or group of malformations. On the other hand, excessive caffeine consumption (exceeding 300 mg per day) during pregnancy is associated with growth retardation and embryonic loss.

Carbamazepine

effects are related to severe fetal hypotension over a long period of time during the second or third trimester.

Quality of available information: fair to good. Behavioral effects have been reported and appear to be transient or temporary; more information is needed concerning the population with higher exposures. Quality of available information: fair to good. Anticonvulsant; little is known concerning mechanism. Epilepsy may itself contribute to an increased risk for fetal anomalies. Quality of available information: fair to good. Cocaine causes a complex pattern of cardiovascular effects due to its local anesthetic and sympathomimetic activities in the mother. Fetopathology is likely to be due to decreased uterine blood ow and fetal vascular effects. Because of the mechanism of cocaine teratogenicity, a well-de ned cocaine syndrome is not likely. Poor nutrition accompanies drug abuse and multiple drug abuse is common. Quality of available information: fair. Excessive bleeding from the chorion is probably related in part to the experience of the operator. Further research is necessary to determine whether CVS is safer for the fetus at certain stages of gestation. Quality of available information: good. Anticoagulant; bleeding is an unlikely explanation for effects produced in the rst trimester. Central nervous system defects may occur any time during second and third trimesters and may be related to bleeding. Quality of available information: fair. Anticancer, alkylating agent; requires cytochrome P450 mono-oxidase activation; interacts with DNA, resulting in cell death. Quality of available information: fair to good. Synthetic estrogen; stimulates estrogen receptor-containing tissue, may cause

Cocaine

Minor craniofacial defects (upslanting palpebral ssures, epicanthal folds, short nose with long philtrum), ngernail hypoplasia, and developmental delay. Teratogenic risk is not known but likely to be signi cant for minor defects. There are too few data to determine whether carbamazepine presents an increased risk for abortion. Since embryos with multiple malformations are more likely to abort, it would appear that carbamazepine presents little risk because an increase in these types of malformations has not been reported. Preterm delivery; fetal loss; placental abruption; intrauterine growth retardation; microcephaly; neurobehavioral abnormalities; vascular disruptive phenomena resulting in limb amputation, cerebral infarctions and certain types of visceral and urinary tract malformations. There are few data to indicate that cocaine increases the risk of rst trimester abortion. The low but increased risk of vascular disruptive phenomena due to vascular compromise of the pregnant uterus would more likely result in mid-gestation abortion or stillbirth. It is possible that higher doses could result in early abortion. Risk for deleterious effects on fetal outcome is signi cant; risk for major disruptive effects is low, but can occur in the latter portion of the rst trimester as well as the second and third trimesters.

Chorionic villous

sampling (CVS)

Low, but increased risk of orofacial malformations and limb reduction defects of the congenital amputation type as seen in vascular disruption malformations in some series. The risk of abortion following CVS is quite low.

Coumarin derivatives

Nasal hypoplasia; stippling of secondary epiphysis; intrauterine growth retardation; anomalies of eyes, hands, neck; variable central nervous system anatomical defects (absent corpus callosum, hydrocephalus, asymmetrical brain hypoplasia). Risk from exposure 10 e 25% during 8th to 14th week of gestation. There is also an increased risk of pregnancy loss. There is a risk to the mother and fetus from bleeding at the time of labor and delivery.

Cyclophosphamide Growth retardation, ectrodactyly, syndactyly, cardiovascular anomalies, and other minor anomalies. Teratogenic risk appears to be increased but the magnitude of the risk is uncertain. Almost all chemotherapeutic agents have the potential for inducing abortion. This risk is dose-related; at the lowest therapeutic doses the risk is small.

Diethylstilbestrol (DES)

Clear cell adenocarcinoma of the vagina occurs in about 1:1000 to 10 000 females who were exposed in utero. Vaginal adenosis occurs in about 75% of females exposed in utero before the 9th week of pregnancy. Anomalies of the uterus and cervix may play a role in decreased fertility and an increased incidence of prematurity although the majority of women exposed to DES in utero can conceive and deliver normal babies. In-utero exposure to DES increased the incidence of genitourinary lesions and

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139 e152

Table 1 ( continued )

143

Developmental

Reported effects or associations and estimated risks

Comments a

toxicant

infertility in males. DES can interfere with zygote survival, but it does not interfere with embryonic survival when given in its usual dosage after implantation. Offspring who were exposed to DES in utero have an increased risk for delivering prematurely, but do not appear to be at increased risk for rst trimester abortion. Diphenylhydantoin Hydantoin syndrome: microcephaly, mental retardation, cleft lip/palate, hypoplastic nails and distal phalanges; characteristic but not diagnostic facial features. Associations documented only with chronic exposure. Wide variation in reported risk of malformations but appears to be 10%. The few epidemiological data indicate a small risk of abortion for therapeutic exposures for the treatment of epilepsy. For short-term treatment, i.e. prophylactic therapy for a head injury, there is no appreciable risk.

misplaced genital tissue which has a greater propensity to develop cancer.

Quality of available information:

fair to good. Anticonvulsant; direct effect on cell membranes, folate, and vitamin K metabolism. Metabolic intermediate (epoxide) has been suggested as the teratogenic agent. Quality of available information: fair. Pregnant animals exposed to EMF do not exhibit consistent or reproducible reproductive effects. There are still questions about biologic effects for frequencies and wave forms of magnetic elds that have not been adequately studied. Quality of available information: fair.

Electromagnetic elds (EMFs)

The data pertaining to video display terminals indicate that the EMF exposures from these units do not present an increased risk for abortion or congenital malformations. The data on power line and appliance exposures are too varied to draw any conclusions, although the risks appear to be small or non-existent. Human exposures to video display terminals and power lines are quite low and are unlikely to have reproductive effects.

Fluconazole

Infectious agents

Fluconazole, a triazole antifungal agent used to treat mycotic infections, is a widely administered medication for vaginal candidiasis. In this latter treatment, it is prescribed as a single dose of 150 mg and has not been associated with increased abnormalities or congenital defects in pregnancy series [18 e 20] Fluconazole is also used to treat more serious mycotic infections at doses of 400 e 800 mg/ day on a continuous basis. During the 1990s, four case reports of infants exposed to this high-dose regimen of uconazole had a distinct and consistent pattern of malformations [21] The constellation of defects consisted of craniosynostosis, orbital hypoplasia, and the rather unique skeletal manifestations of humeral radial synostosis and femoral bowing. The cytotoxic effects and in ammatory responses resulting from fetal infections interfere with organogenesis and/or histogenesis. Fetopathic syndromes are related to the speci c tissue

localization, pathologic characteristics of the infectious agent and the duration of the infection in the embryo and fetus. In some instances the infection may be debilitating to the mother and indirectly result in pregnancy loss. Cytomegalovirus (CMV) Fetal cytomegalovirus infection presents an increased risk for abortion but it does not appear that maternal genital infection increases the risk of abortion. Fetal infection occurs in about 20% of maternal infections. Intrauterine growth retardation: risk of brain damage is moderate after fetal infection early in pregnancy; characteristic parenchymal calci cation.

Quality of available information: good to excellent.

CMV damages organs principally by

cellular necrosis.

Herpes simplex virus

Generalized organ infections, microcephaly, hepatitis, eye defects, vesicular rash. Maternal infection

Quality of available information: good.

can be transmitted in utero or perinatally. Herpes simplex 2 is one of the few infections where it is

Fetal

anomalies associated with herpes

agreed that the risk of abortion is increased.

simplex virus infection appear to be due

Human immunode ciency virus (HIV)

The overall risk of vertical transmission of HIV is 25 e 40%. Fetal HIV infection and asymptomatic maternal HIV infection are not associated with adverse effect on fetal growth or development. Symptomatic maternal HIV infection, other sexually transmitted diseases and opportunistic

to disruption rather than malformation. Quality of available information: fair to good. Prophylactic treatment with zidovudine

infections may increase the risk of low birth weight or perinatal morbidity.

does

not appear to cause permanent

Parvovirus B19

Infection can result in erythema infectiosum in children but in the fetus can result in hydrops fetalis and fetal death; congenital anomalies are likely to be very rare. The risk for stillbirth with hydrops

Greater than 80% incidence of embryonic infection with exposure in rst 12 weeks, 54% at 13 e 14

adverse effects in the fetus. Quality of available information: fair to good.

has been clearly substantiated. An increased risk for abortion has been suggested, but is more

Fetal

infection is not frequent. Infection

Rubella virus

dif cult to substantiate.

of red blood cell precursors causes severe anemia. Quality of available information:

weeks, 25% at end of second trimester, and 100% at term. Defects include mental retardation, deafness, cardiovascular malformations, cataracts, glaucoma, microphthalmia. Diabetes mellitus or rubella panencephalitis may develop later in life. The abortigenic risk of maternal rubella is

excellent. Rubella has an af nity for speci c tissues. Damage is caused by mitotic

uncertain.

inhibition, cell death and interference

 

with

histogenesis by repair processes,

resulting in calci cation and scarring.

Syphilis

Defects in 50% of offspring after early exposure to primary or secondary syphilis and 10% after late

Quality of available information: good.

exposures. Defects include maculopapular rash, hepatosplenomegaly, deformed nails,

Fetal

pathology is associated with

Toxoplasmosis

osteochondritis at joints of extremities, congenital neurosyphilis, abnormal epiphyses, chorioretinitis. Syphilis can increase the incidence of abortion. Hydrocephaly, microphthalmia, chorioretinitis. Risk is predominantly associated with pregnancies

maturation of the fetal immune system at about the 20th week. Quality of available information: good

Varicella-zoster

in which the mother acquires toxoplasmosis. Epidemiological studies do not indicate that toxoplasmosis increases the incidence of early abortion, but congenital toxoplasmosis may be responsible for the stillbirth of severely affected fetuses. Skin and muscle defects; intrauterine growth retardation; limb reduction defects. No measurable increased risk of early teratogenic effects. Incidence of maternal varicella during pregnancy is low

to excellent. Toxoplasmosis is unlikely to contribute to the risk of repeated abortion. Quality of available information: fair to good.

but risk of severe neonatal infection is high if maternal infection occurs in last week of pregnancy.

Virus

infection of fetal tissues can cause

Venezuelan equine

There does not appear to be an increased risk of rst trimester abortion. Hydroencephaly; microphthalmia; central nervous system destructive lesions; luxation of hip.

cellular necrosis. Quality of available information: poor

encephalitis

There are not enough data to determine whether infection presents an increased risk of abortion.

to fair.

Infection can cause cellular necrosis in

fetal tissues but fetal infection is rare.

144

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139e152

Table 1 ( continued )

Developmental

Reported effects or associations and estimated risks

Comments a

toxicant

Lead

There is no indication that serum lead levels < 50 mg% result in congenital malformations in exposed embryos and fetuses but the developing central nervous system in the fetus and child may be susceptible to lead toxicity, resulting in decreased IQ and behavioral effects. Lead levels > 50 mg% result in anemia, and encephalopathy can have serious effects on central nervous system development. Lead levels < 50 mg% do not increase the risk of abortion.

Quality of available information: good. Whereas there are human studies indicating small de ciencies in IQ in patients with lead levels > 10 mg%, there could be other explanations for these IQ differences. Furthermore, pathological ndings have not been described in the brain at these levels. Quality of available information: fair to good. Antidepressant; mechanism has not been de ned.

Lithium carbonate

Although animal studies have demonstrated a clear teratogenic risk, the effect in humans is uncertain. Early reports indicated an increased incidence of Ebstein s anomaly, other heart and great vessel defects, but as more studies are reported the strength of this association has diminished. Lithium levels within the therapeutic range ( < 1.2 mg%) do not increase the risk of abortion.

Maternal conditions Diabetes Caudal hypoplasia or caudal regression syndrome; congenital heart disease; anencephaly. Vascular lesions in long-standing diabetics may produce placental dysfunction and result in fetal growth retardation. Documented signi cant increased risk of abortion. The risk is greatest in untreated diabetics or in patients who are poorly controlled; insulin therapy protects the fetus.

Quality of available information: good. Results of in-vitro studies suggest that diabetic embryopathy has a multifactorial etiology. Adverse fetal

Quality of available information: fair to

Endocrinopathy

If condition is compatible with pregnancy, effects are similar to those following administration of

effects have not been demonstrated with gestational diabetes. Quality of available information: good.

Nutritional deprivation

high or low doses of the hormone. Hypo- and hyperthyroidism may increase the risk of abortion. Cushing s disease, pituitary tumors, hypothalamic tumors and androgen-producing tumors do not appear to increase the risk of abortion, but may contribute to infertility. Central nervous system anomalies; intrauterine growth restriction; increased morbidity. In some instances of teratogenesis, abnormal nutrition may be the nal common mechanism. Severe malnutrition can contribute to pregnancy loss at any stage of pregnancy.

Receptor-mediated exposures to high levels of hormone.

good. The high mitotic rate of the fetus in general and the central nervous system in particular is very sensitive to severe alterations in nutrient supply.

Phenylketonuria

Mental retardation; microcephaly; intrauterine growth retardation. Documented signi cant increased risk of abortion. The risk is greatest in pregnant women who were not treated for their phenylketonuria.

Quality of available information: good. Very high levels of phenylalanine interfere with embryonic cell metabolism.

Mechanical problems

Birth defects such as club feet, limb reduction defects, aplasia cutis, cranial asymmetry, external ear malformations, midline closure defects, cleft palate and muscle aplasia. Submucosal and intramural myomata, amniotic bands, multiple implantations, bi d uterus or infantile uterus which contribute to mechanical problems do not result in early abortions.

Quality of available information: good. Physical constraint can result in distortion and a reduction in blood supply and is more frequent in pregnancies with multiple conceptuses, abnormal uterus, amniotic abnormalities, certain placental abnormalities and oligohydramnios.

Methyl mercury

Minamata disease: cerebral palsy, microcephaly, mental retardation, blindness, cerebellar hypoplasia. Does not appear to decrease fertility unless the mother becomes clinically ill from methyl mercury poisoning. At low exposures the teratogenic effect predominates and there are few human data to indicate the risk of abortion.

Quality of available information: good. Organic mercurials accumulate in lipid tissue causing cell death due to inhibition of cellular enzymes,

Methylene blue Hemolytic anemia and jaundice in neonatal period after exposure late in pregnancy. There may be a small risk for intestinal atresia but this is not yet clear. No indication of increased risk of abortion.

especially sulfhydryl enzymes. Since most cases result from accidental environmental exposure, risk estimation is usually retrospective. Quality of available information: poor to fair. Used to mark amniotic cavity during amniocentesis.

Misoprostol

Misoprostol is a synthetic prostaglandin analog that has been used by millions of women for illegal abortion. A low incidence of vascular disruptive phenomenon, such as limb reduction defects and Moebius syndrome, has been reported.

Quality of available information: fair. Classical animal teratology studies would not be helpful in discovering

Mycophenolate mofetil

these effects, because vascular disruptive effects occur after the period of early organogenesis. Quality of the data: fair.

Oxazolidine-2,4-diones

This drug is a highly ef cient immunosuppressant used to prevent organ rejection after organ transplantation. The agent, which blocks purine synthesis in lymphocytes, raised de nite concern when congenital defects were reported to the National Transplantation Pregnancy Registry: three infants all exposed through the rst trimster exhibited congenital malformations, two with cleft lip with cleft palate, and all three with microtia; one of the infants had a diaphragmatic defect, a malformation seen in rats and rabbits treated with mycophenolate mofetil. Fetal trimethadione syndrome: V-shaped eye brows, low-set ears with anteriorly folded helix, high-

Investigators raise concerns regarding teratogenicity.

(trimethadione,

arched palate, irregular teeth, CNS anomalies, severe developmental delay. Wide variation in

Quality of available information: good to excellent.

paramethadione)

reported risk. Characteristic facial features are documented only with chronic exposure. The abortifacient potential has not been adequately studied, but appears to be minimal.

Anticonvulsants; affects cell membrane permeability. Actual mechanism of action has not been determined.

D-Penicillamine

Cutis laxa, hyper exibility of joints. Condition appears to be reversible and the risk is low. There are no human data on the risk of abortion.

Quality of available information: fair to good. Copper chelating agent; produces

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139 e152

Table 1 ( continued )

145

Developmental

toxicant

Reported effects or associations and estimated risks

Comments a

Polychlorinated

biphenyls

Cola-colored babies: pigmentation of gums, nails and groin; hypoplastic deformed nails;

intrauterine growth retardation; abnormal skull calci cation. Although abortion can be induced at high exposures, most human exposures from environmental contamination are unlikely to increase the risk of abortion.

Progestins Masculinization of female embryo exposed to high doses of some testosterone-derived progestins and may interact with progesterone receptors in the liver and brain later in gestation. The dose of progestins present in modern oral contraceptives presents no masculinization or feminization risks. All progestins present no risk for non-genital malformations. Many synthetic progestins and natural progesterone have been used to treat luteal phase de ciency, embryos implanted via in-vitro fertilization, threatened abortion or bleeding in pregnancy with variable results. Conversely, synthetic progestins that interfere with progesterone function may cause early pregnancy loss; RU- 486 (mifepristone) is presently used speci cally for this purpose.

copper de ciency inhibiting collagen synthesis and maturation. Quality of available information: good. Environmental contaminants; polychlorinated biphenyls and frequently occurring contaminants are cytotoxic. Body residues in exposed women can affect pigmentation in offspring for up to 4 years after exposure. Quality of available information: good. Stimulates or interferes with sex steroid receptor-containing tissue.

Radioactive isotopes

Tissue- and organ-speci c damage is dependent on the radioisotope element and distribution, i.e.

Quality of available information: good

Radiation

131 I administered to a pregnant woman can cause fetal thyroid hypoplasia after the 8th week of development. Radioisotopes used for diagnosis present no risk for inducing abortion because the dose to the embryo and implantation site is too low. There may be unusual circumstances wherein isotopes are introduced into the abdominal cavity in a pregnant woman for the treatment of malignancy. If the resulting dose to the embryo or fetus is substantial, the risk for abortion is increased. Microcephaly; mental retardation; eye anomalies; intrauterine growth retardation; visceral

to excellent. Higher doses of radioisotopes can produce cell death and mitotic delay. Effect is dependent on dose, distribution, metabolism, and speci city of localization. Quality of available information: good

(external irradiation)

malformations. Teratogenic risk depends on dose and stage of exposure. Exposures from diagnostic

to excellent.

Retinoids, systemic

procedures present no increased risk of abortion, growth retardation or malformation. No measurable risk with exposures for 5 rad ( 5 mGy) of X-rays at any stage of pregnancy. In contrast, exposure of the pregnant uterus to therapeutic doses of ionizing radiation signi cantly increases the risk of aborting the embryo; the fetus is more resistant. Increased risk of central nervous system, cardio-aortic, ear and clefting defects. Microtia, anotia,

Diagnostic and therapeutic agents; produce cell death and mitotic delay.

(isotretinoin,

thymic aplasia and other branchial arch, aortic arch abnormalities and certain congenital heart

Quality of available information: fair. Used in treatment of chronic

etrentinate)

malformations. Exposed embryos are at greater risk for abortion. This is plausible since many of the

dermatoses. Retinoids can cause direct

Retinoids, topical

malformations, such as neural tube defects, are associated with an increased risk of abortion.

cytotoxicity and alter programmed cell death; affect many cell types but neural crest cells are particularly sensitive. Quality of available information: poor.

(tretinoin)

Epidemiological studies, animal studies and absorption studies in humans do not suggest a teratogenic risk. Regardless of the risks associated with systemically administered retinoids, topical retinoids present little or no risk for intrauterine growth retardation, teratogenesis or abortion because they are minimally absorbed and only a small percentage of skin is exposed.

Topical administration of tretinoin in animals in therapeutic doses is not teratogenic, although massive exposures can produce maternal toxicity and reproductive effects. More importantly, topical administration in humans results in non-measurable blood levels.

Smoking and nicotine

Placental lesions; intrauterine growth retardation; increased postnatal morbidity and mortality. While there have been some studies reporting increases in anatomical malformations, most studies do not report an association. There is no syndrome associated with maternal smoking. Maternal or placental complications can result in fetal death. Exposures to nicotine and tobacco smoke are a signi cant risk for pregnancy loss in the rst and second trimester.

Quality of available information: good to excellent. While tobacco smoke contains many components, nicotine can result in vascular spasm vasculitis which has

Sonography

No con rmed detrimental effects resulting from medical sonography. The levels and types of

resulted in a higher incidence of placental pathology. Quality of available information: good

(ultrasound)

medical sonography that have been used in the past have no measurable risks. The present clinical use of diagnostic ultrasound presents no increased risk of abortion.

to excellent. It appears that if the embryonic temperature never exceeds 39 C, there is no measurable risk.

Streptomycin

Streptomycin and a group of ototoxic drugs can affect the eighth nerve and interfere with hearing; it is a relatively low risk phenomenon. There are not enough data to estimate the abortigenic potential of streptomycin. Because the deleterious effect of streptomycin is limited to the eighth nerve, it is unlikely to affect the incidence of abortion.

Quality of available information: fair to good. Long-duration maternal therapy during pregnancy is associated with hearing de ciency in offspring.

Tetracycline

Bone staining and tooth staining can occur with therapeutic doses. Persistent high doses can cause hypoplastic tooth enamel. No other congenital malformations are at increased risk. The usual therapeutic doses present no increased risk of abortion to the embryo or fetus.

Quality of available information: good. Antibiotic; effects seen only if exposure is late in the rst or during second or third trimester, since tetracyclines have to interact with calci ed tissue.

Thalidomide

Limb reduction defects (preaxial preferential effects, phocomelia), facial hemangioma, esophageal or duodenal atresia, anomalies of external ears, eyes, kidneys, and heart, increased incidence of neonatal and infant mortality. The thalidomide syndrome, although characteristic and recognizable, can be mimicked by some genetic diseases. Although there are fewer data pertaining to its abortigenic potential, there appears to be an increased risk of abortion.

Quality of available information: good to excellent. Sedative e hypnotic agent. The etiology of thalidomide teratogenesis has not been de nitively determined.

146

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139e152

Table 1 ( continued )

Developmental

Reported effects or associations and estimated risks

Comments a

toxicant

Thyroid: iodides, radioiodine, antithyroid drugs (propylthiouracil), iodine de ciency

Fetal hypothyroidism or goiter with variable neurologic and aural damage. Maternal hypothyroidism is associated with an increase in infertility and abortion. Maternal intake of 12 mg of iodide per day increases the risk of fetal goiter.

Quality of available information: good. Fetopathic effect of endemic iodine de ciency occurs early in development. Fetopathic effect of iodides, antithyroid drugs and radio iodine involves metabolic block, decreased thyroid hormone synthesis and gland development. Quality of available information: poor to fair. Neurotoxicity is produced in adults who abuse toluene; a similar effect may occur in the fetus. Quality of available information: good. Anticonvulsant; little is known about the teratogenic action of valproic acid.

Toluene Intrauterine growth retardation; craniofacial anomalies; microcephaly. It is likely that high exposures from abuse or intoxication increase the risk of teratogenesis and abortion. Occupational exposures should present no increase in the teratogenic or abortigenic risk. The magnitude of the increased risk for teratogenesis and abortion in abusers is not known because the exposure in abusers is too variable.

Valproic acid Malformations are primarily neural tube defects and facial dysmorphology. The facial characteristics associated with this drug are not diagnostic. Small head size and developmental delay have been reported with high doses. The risk for spina bi da is about 1% but the risk for facial dysmorphology may be greater. Because therapeutic exposures increase the incidence of neural tube defects, one would expect a slight increase in the incidence of abortion.

Vitamin A

The same malformations that have been reported with the retinoids have been reported with very high doses of vitamin A (retinol). Exposures < 10 000 IU present no risk to the fetus. Vitamin A in its recommended dose presents no increased risk for abortion.

Quality of available information: good. High concentrations of retinoic acid are cytotoxic; it may interact with DNA to delay differentiation and/or inhibit protein synthesis. Quality of available information: poor. Mechanism is likely to involve a disruption of cell calcium regulation with excessive doses.

Vitamin D

Large doses given in vitamin D prophylaxis are possibly involved in the etiology of supravalvular aortic stenosis, el n faces, and mental retardation. There are no data on the abortigenic effect of vitamin D.

a Quality of available information is modi ed from TERIS [22] .

them on the options available, but not on which option to select. On the contrary, in one survey, up to 6% of all physicians would recommend medical termination of pregnancy for women who had undergone a single CT at 6 weeks of gestation and 27% of all phy- sicians surveyed were uncertain if they would recommend a medical termination of pregnancy ( Box 2 ) [29] . In case of a toxi- cological exposure, the counselor should attempt to establish a good understanding of the exposure in question and its timing. A list of information required to provide high quality counseling to those exposed is listed in Boxes 1 and 3 . The pervasive problem is that many physicians and counselors tell the patient or family what to do. In many instances the counselor (i) has no expertise con- cerning the risks of an exposure, or (ii) the counselor knows the risks, but he/she does not take the time to educate the patient about the risks.

6. Counseling: What are the reproductive or developmental concerns of pregnant women and/or family members concerning the risk of alleged or suspected toxicological exposures during pregnancy or before pregnancy? Role of the counselor

These concerns include (i) birth defects (congenital malforma- tions), (ii) pregnancy loss (miscarriage or spontaneous abortion), (iii) growth retardation, (iv) prematurity, (v) neurobehavioral ef- fects (decreased IQ, small head size, convulsive disorders, autism, attention de cit hyperactivity disorder) and cancer. All of these effects except for cancer and mutations in the F 1 generation are deterministic effects (threshold effects, tissue reaction effects) ( Table 5 ). The term tissue reaction effects is a new term adopted because it conveys the concept that these effects involve exposure to tissues indicating that many cells have to be affected, which explains why there is a threshold below which there is no increased risk ( Table 5 ). Mutagens have the potential to induce cancer or genetic effects by altering one cell, and therefore theoretically do not have a threshold [20 e 44] . Recent discussions of the universal application

of the linear-no-threshold hypothesis (LNTH) indicate that there is disagreement as to whether the LNTH is applicable at very low exposures to environmental toxicants and with protracted toxicant exposures ( Table 5 ) [35e 37] .

7. The role of the counselor

The classical approach for the evaluation of risks from in-utero environmental exposures is to review the available epidemiolog- ical studies and appropriate animal models, and to evaluate these data from the standpoint of biologic plausibility or biologic common sense ( Box 4 ) [26] . In order to perform an analysis outlined in Box 4 , the drug, chemical or physical agent has to have been distributed or sold for a period of years so that epidemiological data, animal toxi- cology data and in-vitro studies are available for analysis.

7.1. Evaluating the allegation of teratogenicity

When confronted with the question of the teratogenicity of certain environmental agents, the question can be posed from various vantage points:

1. Evaluating the risk of reproductive toxicity of an environmental agent.

2. Evaluating the suggestion that an environmental agent was responsible for an individual child s birth defect or other

reproductive effects.

3. Evaluating the cause of congenital malformations in a particular child or a group of children.

4. Determining whether to publish a case report of a patient or a cluster of patients with a particular congenital malformation or

a constellation of congenital malformations that may be asso- ciated with an environmental agent [38] .

If one wishes to answer the generic question, Is a particular

environmental drug, chemical or physical agent a reproductive toxicant? , then a formal approach is recommended that includes a

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139 e152

147

Box 2 Responsibilities of the counselor.

1.

Questions submitted by patients or contacts regarding environmental toxicant exposures should never be described as silly, dumb or unnecessary. Every response should attempt to dignify the question as appropriate. However, the counselor should provide scientific expla- nations as to why the contact’s concerns are or are not substantiated by the available facts. The counselor is an educator.

2.

It is difficult for many counselors to comprehend the anguish, heartache, fear and concern in the hearts and minds of the contacts when they are concerned about the health of their fetus from exposures to environmental

toxicants. The degree of fear is related to the mental state of the contact as well as the type and magnitude of the exposure to the environmental toxicant.

3.

Many counselors do not understand that their profes- sional goal should be to educate the contact about the reproductive or developmental risks that may result from

a

particular environmental exposure, not to advise them

what decision they should select.

4.

Many novice counselors do not realize that it is their re-

sponsibility to provide the contacts with the background risk that they face, even when there are no increased risks from the exposure. The contacts are requested to keep the counselor informed. Do they have any more ques- tions? Please keep in touch, send a picture. The consul- tation is signed with ‘Warm regards’. It should be made clear to the contact that the counselor has functioned as an educator. The counselor does not advise contacts on what decision to select, only the options that are avail- able. Yet, many contacts thank the counselor for telling them what to do, even though they have not been advised on which available option to select.

5.

It

is important to permanently save a written record of the

statements of the contact and the counselor.

6.

Each consultation that definitively determined that their reproductive or developmental risks are not increased

ends with this statement:

‘Your risk for birth defects or miscarriage is not increased above the background risks that all healthy pregnant women face. The background risks for preg- nant women with no personal or family history of reproductive or developmental problems is 3% for birth defects and 15% for miscarriage. All pregnant women face these risks, many of which we cannot yet prevent.’ We wish them good luck with their pregnancy and to keep in touch. If the contact asks about the risks of mental retardation, cancer or other effects, these background risks are discussed also. The answers are directed specifically to their questions. If the contact is concerned about cancer in her offspring from either preconception or postconception exposures, it is most important to educate the contact regarding the high background incidence of cancer in the population. Potentially lethal cancers occur in 23% of the population, which dwarfs the incidence of envi- ronmentally induced cancer. It is important to point out that the spontaneous occurrence of cancer, which in- creases with age due to mutation that occurs in the dividing somatic cells, is the most important etiology of human cancer.

Box 3 Minimum information required to provide adequate counseling to women or couples regarding concerns about the risks of environmental toxicant exposures before or during the pregnancy. a

1. Is the contact pregnant, possibly pregnant or planning to become pregnant?

2. If the contact is pregnant, does she know the date she became pregnant? Does she know the date of the first day of her last menstrual period?

3. Does she know the date of conception from other sour- ces: an ultrasound that timed the pregnancy or a date when intercourse took place that is consistent with other information about timing?

4. Are there historical pregnancy risks (birth defects, miscarriage, etc.) for the mother or the family e for example, a history of miscarriages, birth defects, infer- tility or serious illnesses in the contact, spouse, or par- ents or siblings?

5. Does the contact know the name of the environmental toxicant to which she or her spouse was exposed? Is it a drug, chemical or physical agent (such as radiation or heat)? What was the amount and length of the exposure before or during pregnancy? Provide the dates and amount (dose) of the exposure. The Environmental Pro- tection Agency (EPA) has prepared toxicological evalu- ations of chemicals using animal studies and now high- throughput in-vitro studies. The EPA may even have estimated a reference dose exposure, which is an expo- sure that has no deterministic reproductive effects.

6. Has the woman or couple sought advice from another counselor about the developmental risks of this expo- sure? Please provide details of the response.

7. The needs of the person seeking counseling are the only operative issues to be considered.

a Adapted from Brent [23] .

ve-part evaluation as described in Box 4 [26] . This formal approach is utilized only when a drug or chemical has been utilized and sold for a period of many years and, during that time, studies on epidemiology, animals and pharmacokinetics have been performed [30 e 37] . If, on the other hand, one is concerned about the reproductive effects of an environmental agent in an individual patient, the question may sometimes be answered without the bene t of epidemiological studies, dosimetry or animal studies, utilizing the basic principles of teratology, reproductive toxicology and genetics. Key factors in such an evaluation are having an experienced clini- cian who is knowledgeable about the genocopies that can mimic environmental teratogens, who is aware of the importance of dose or exposure and who is aware of the basic principles of develop- mental biology and teratology. A clinician trained and experienced in these elds may have a decisive role in utilizing the principles of teratology ( Box 1 ) and biological plausibility in evaluating the allegation that a particular environmental agent was responsible for a child s congenital malformations [10,28,38 e 40,42,44,45,52] .

7.2. Counselors must have knowledge of known or possible reproductive toxins

Reproductive and developmental counselors should have been educated and prepared to discuss background risks of birth defects and the broad subject of the etiology of developmental birth defects

148

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139e152

Table 2 Etiology of human congenital malformations. a

Box 4 Evaluation of potential for developmental toxicity in the human:

evidence of a possible causal relationship. a

Suspected cause

Percent of total

 

65

15 e 25

10

4

3

Unknown Polygenic Multifactorial (gene e environment interactions) Spontaneous errors of development Synergistic interactions of teratogens Genetic Autosomal and sex-linked inherited genetic disease Cytogenetic (chromosomal abnormalities) New mutations Environmental (total) Maternal conditions: alcoholism; diabetes; endocrinopathies; phenylketonuria; smoking and nicotine; starvation; nutritional de cits Infectious agents: rubella, toxoplasmosis, syphilis, herpes simplex, cytomegalovirus, varicella-zoster, Venezuelan equine encephalitis, parvovirus B19 Mechanical problems (deformations): amniotic band constrictions; umbilical cord constraint; disparity in uterine size and uterine contents Chemicals, prescription drugs, high-dose ionizing radiation, hyperthermia

1 e 2

Epidemiological studies

Controlled epidemiological studies consistently demon- strate an increased incidence of a particular spectrum of embryonic and/or fetal effects in exposed human populations.

Secular trend data

Secular trends demonstrate a positive relationship between the changing exposures to a common environmental agent in human populations and the incidence of a particular

embryonic and/or fetal effect.

An animal model can be developed which mimics the hu- man developmental effect at clinically comparable expo- sures. Since mimicry may not occur in all animal species, animal models are more likely to be developed once there is good evidence for the embryotoxic effects reported in the human. Developmental toxicity studies in animals are indicative of a potential hazard in general rather than the potential for a specific adverse effect on the fetus when there are no human data on which to base the animal experiments.

Dose e response relationship

Developmental toxicity in humans increases with dose (exposure) and the developmental toxicity in animals oc- curs at a dose that is pharmacokinetically (quantitatively) equivalent to the human exposure.

Biological plausibility

The mechanisms of developmental toxicity are understood and the effects are biologically plausible.

a Modified from Brent et al. [25] , Brent [26,27], and Shepard [28] .

is concerned about the etiology of the child s birth defects. Another frequently asked question pertains as to whether a cluster of similar birth defects in a small geographic area is due to an environmental toxicant. (1) Preconception exposure: The father or the mother in the family may have been exposed to a toxicological exposure before the pregnancy has occurred. One of the future parents could have been treated with radiation therapy or chemotherapy for cancer that they survived; or one of the parents had multiple diagnostic X- rays as a child or adolescent. The family is concerned about the genetic effects of prior alleged toxicological mutagenic exposures at home or at work. Of the thousands of consultations we have received, about 20% are from future parents concerned about pre- conception toxicological exposures. Some of the exposures have occurred many years before they contemplated having a family. Genetic studies of the offspring of patients exposed to muta- genic agents are largely negative. However, we know that muta- tions have been produced, but the risk of viable offspring with an

2 Animal developmental toxicity studies

a Source: Brent [9] .

and reproductive problems ( Tables 2 and 3 ). Counselors must have knowledge of known or possible reproductive toxins and be familiar with how the medial literature dealing with teratogens can be accessed [22,46 e 55] . Table 1 provides a list of known or alleged reproductive toxin or teratogenic agents. The TERIS and OTIS websites are more up-to-date, as is the genetic website of the National Library of Medicine (OMIM). Each counselor may have many consultations in their les; however, it is not the purpose of this publication to provide numerous examples. On the Health Physics website, Ask the Expert (ATE), there are more than 60 prototype questions. NCRP 174, published in 2013 [52] , has an appendix with scores of consultation questions and answers that pertain to the preconception and postconception risks of ionizing radiation, ultrasound, non-ionizing electromagnetic elds, CT scans and magnetic resonance imaging. A few examples of responses to contacts exposed to environ- mental toxicants are presented below. A preconception and post- conception toxicant exposure is discussed, as well as a contact who

Table 3 Reproductive risks per million recognized pregnancies. a

Reproductive risks

Frequency

Immunologically and clinically diagnosed spontaneous abortions per million conceptions ( < 20% has lethal malformations or chromosome abnormalities that cause abortion before the rst month of gestation). Clinically recognized spontaneous abortions per million clinically recognized pregnancies. Spontaneous abortion after the rst missed menstrual period. Genetic diseases per million births Multifactoral or polygenic genetic environmental interactions) Dominantly inherited disease Autosomal and sex-linked genetic disease Cytogenetic (chromosomal abnormalities) New mutations in the developing ova or sperm prior to conception Major malformations (genetic, unknown, environmental) Prematurity (Ireland: 55 000; USA: 124 000) Fetal growth restriction Stillbirths ( > 20 weeks; wide range in prevalence because of variables contributed by cultures, socio-economic factors, race, prenatal medical care) Infertility

350

000

150

000

110 000

90 000

10 000

1200

5000

3000

30 000

69 000

30 000

4000

e 20 900

7% of couples

a Source: Brent [9] .

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139 e152

149

Table 4 Survey of obstetricians and family physicians from Ontario, Canada, on medical termination of pregnancy in women who underwent radiography or computed to- mography (CT) during early pregnancy. a

 

Percentage of respondents

 

Medical termination of pregnancy recommended

Family physicians ( n ¼ 208)

Obstetricians ( n ¼ 65)

Radiography

CT

Radiography

CT

Y e s Not sure No

1

6

0

5

25

39

6

25

74

55

94

70

a Source: Ratnapalan et al. [29] .

increased incidence of new mutations or cancer is so low that you would need very large populations of exposed individuals to demonstrate the increased risk. There is no convincing direct evidence of germline mutation seen as heritable disease in the offspring of humans and attributable to ionizing radiation and mutagenic chemicals and drugs, yet these mutagens clearly induce mutations in microbes and somatic cells of rodents and humans, and in offspring of exposed mice. It would be unwise to ignore the possibility of human germ-cell mutations, especially since progress in human genetics may be able to address these issues in the future. Preconception exposure of the ovaries or testes to toxicological agents or low exposure to mutagenic drugs or chemicals is a very low risk phenomenon, especially for exposures from diagnostic radiological procedures. There is no risk for sterility. Since the vulnerable irradiated ova will have been ovulated in two menstrual cycles (2 months) and the irradiated sperm replaced in two spermatogenesis cycles (4 months), it is best that the family wait that period of time before attempting conception. If pregnancy oc- curs during these windows of time, the environmental toxicant mutagenic risks are miniscule ( Box 3 ) compared with spontaneous risk of germ cell mutations. There are numerous published studies on the offspring of parents who have been exposed to high dose radiation, chemotherapy and other toxicological agents that are proven mutagens; if the exposure is high enough, infertility may result. However, if fertility is intact, the offspring do not manifest an increase in cancer or hereditary diseases [31,34,56 e 77] . One addi- tional consideration is that many deleterious mutations (sponta- neous or as a result of preconception toxicity exposure) would not be expressed as effects in the offspring because they are lethal to the developing ova or sperm or to the very young developing embryo because of defective ova or sperm, a result that has been described as biological ltration [9,42] . Down syndrome has been extensively studied as a possible consequence of diagnostic X-ray procedures but an association has not been established [83] . Some medical studies have been plagued by differential recall bias between mothers of affected and normal

children, as well as publication bias in not reporting negative ndings [84] . Studies of cancer survivors are particularly important because they are numerous and, most importantly, because the timing and dose of their exposure to radiation (and potentially mutagenic chemicals) is accurately documented. The rates of genetic defects in offspring of survivors and of sibling controls were not statistically signi cant [34,56,59 e 69,72 e 82] . In a population of Danish children born after their parent s treatment with radiation, the risk of congenital malformation was increased but was not statistically signi cant [risk ratio: 1.2 (95% con dence interval: 0.9 e1.8; n ¼ 36)] [85] and there was no evidence of a correlation between birth defects and gonadal dose, reconstructed on individual patient treatment records (mean doses were 1.3 Gy to ovaries and 0.5 Gy to testes) [34,79] . These data suggest that the agents and doses to which these individuals have been exposed do not induce trans- missible mutations in human spermatogonial stem cells and resting oocytes at a frequency high enough to be detected over the background of spontaneous mutations ( Table 3 ). (2) The spouse is pregnant or considering pregnancy and is concerned about medications that she has been prescribed or is taking, chemicals in the workplace, whether she should have an X- ray suggested by her physician, concern about the power lines near her home, the microwave oven in her kitchen, or numerous frightening messages on the Internet. The most common concern is whether their child may be born with birth defects. Miscarriage and mental retardation are next on their list, or whether their future child is at increased risk for developing cancer. If the family is concerned about medications prescribed for the pregnant spouse or other environmental exposures that have been extensively studied, the counselor may be able to determine whether there extensive toxicological data have been published and are available to the counselor. Table 1 lists about 60 environ- mental toxicants that have been studied to determine their ability to affect the developing embryo/fetus or that are alleged to have affected the developing embryo/fetus. If the concern is about a chemical exposure, the family may not know the name of the chemical or the exposure, which makes it dif cult or impossible to provide an adequate risk assessment. Several websites may be of assistance (CDC, OMIM, TERIS; see Box 5 ). After obtaining the toxicological information, the following process should be initiated as suggested in Boxes 2 and 3 . (3) Since the risk of birth defects is 3% and miscarriage occurs in 15% of pregnancies in women after the rst missed menstrual period, the family may contact the counselor to explain the etiology of the developmental or reproductive problem in their child ( Box 3 , Table 2 ). Determining the etiology of birth defects or miscarriage in an individual infant or pregnancy can be a dif cult task, especially if the description of the malformation is provided to the counselor by the parent or the family physician. Second, this task could be very

Table 5 Stochastic and threshold dose e response relationships of diseases produced by environmental agents.

Phenomenon

Pathology

Site

Diseases

Risk

De nition

Stochastic (LNTH a )

Damage to a single cell may result in disease

DNA (genes and chromosomes)

Cancer, germ cell mutation

Some risk exists at all dosages; at low doses, risk may be less than spontaneous risk

The incidence of the disease increases but the severity and nature of the disease remain the same Both the severity and incidence of the disease increases with dose

Threshold (deterministic effect) (tissue reaction effect)

Multicellular injury

Multiple, variable etiology, affecting many cell and organ processes

Malformation, growth retardation, death, toxicity, etc.

No increased risk below the threshold dose

LNTH, linear no-threshold hypothesis.

a Modi ed from Brent [9] .

150

R.L. Brent / Seminars in Fetal & Neonatal Medicine 19 (2014) 139e152

Box 5

Websites.

CDC e Centers for Disease Control

OMIM e Online Mendelian Inheritance of Man

Human Genome Project

TERIS e Teratogen Information System

(you need an ID and password, which can be obtained from your university library or hospital if they have a subscrip- tion). Shepard TH. Catalogue of teratogenic agents . 8th ed. Baltimore: Johns Hopkins University Press; 1995 (now on the TERIS website).

Health Physics Society

OTIS e Organization of Teratology Information Specialists

time consuming for an individual counselor. It is probably more appropriate to refer the family to a good genetic or dysmorphology clinic. (4) Determining whether to publish a case report of a patient or

a cluster of patients with a particular congenital malformation or a

constellation of congenital malformations that may be associated with an exposure to an environmental agent [38] . Clinical evaluation of a child with congenital malformations by an experienced and well-trained physician who is familiar with the elds of developmental biology, teratology, epidemiology, and ge- netics may be a simple or complex task. Too often, the entire emphasis is placed on epidemiological data that may be meager or insuf cient for a rational conclusion when clinical ndings that are readily available can provide de nitive answers with regard to the etiology of a child s malformations or the merits of an environ- mental etiology. Robert W. Miller [10] coined the term the alert physician because he observed that discoveries of toxic environ- mental situations or agents were made by observant clinicians. A review article by Brent [36] indicated that most new teratogens were discovered by alert counselors, physicians or scientists, not by epidemiological investigations. Epidemiological investigations could be initiated in order to con rm the alert scientist s pre- sumptive ndings. Shepard emphasized that, if the teratogenic syndrome observed in a group of toxicant-exposed patients was rare and unique, the nding was worth pursuing because the toxicant may be a new teratogen [28] . The editor of the American Journal of Medical Genetics requested

a teratologist to determine whether a submitted article should be published since several pregnant women had been exposed to misoprostol and the offspring had malformations that could be produced by a vascular disruptive agent. The reviewer recom- mended that the article should be published in order to stimulate further research concerning this drug s potential teratogenicity and to alert health care workers about the fact that misoprostol might be a new teratogen [38] . A clinician trained and experienced in these elds can have a decisive role in utilizing the principles of teratology ( Box 4 ) and biological plausibility in evaluating the allegation that a particular environmental agent was responsible for a child s congenital malformations [9,28,38 e 40,42,44,45] . Two

excellent publications that discuss the utilization of teratology principles and biologic plausibility have been published by Graham et al. [45] and Carey et al. [44] .

8. Conclusion

During the past century and especially since the end of World War II, there have been many advances and discoveries in the elds of teratology, developmental biology, genetics, radiology, obstet- rics, reproductive toxicology and many other elds, improving the care and diagnosis of children with birth defects. In the early years of the twentieth century, medical education improved in the USA through the efforts of the Carnegie Foundation and Abraham Flexner. However, there were no educational programs for training professionals on how to deal with environmental toxicants and their risks or on dealing with patients or families who were con- cerned about these risks. It was George Engle who introduced the biopsychosocial model of health care, which taught that one should not ignore the patient s environmental and social defenses because these determine how the patient will respond to the care program. If the patient or contact does not sense that the counselor is compassionate or empathetic, the care program will falter. Engle and Rogers legitimized counseling. Rogers put the nal stamp on this philosophy by indicating that the counselor s task was to convince the contact that the contact s best interests were the counselor s highest priority (unconditional positive regard) [4] . The Teratology Society was chartered in 1961 and was the rst group of clinicians and scientists who were interested in birth de- fects. An offspring of the Teratology Society, OTIS, was more inter- ested in counseling but never developed a program that certi ed counselors. Genetics became a board-certi ed specialty that did certify counselors. Similar birth defect organizations were formed in Europe, Japan and Australia. The review includes a summary of the drugs, chemicals and physical agents that have been documented to result in congenital malformations and reproductive effects when pregnant women are exposed during pregnancy. The principles of teratology were also summarized and emphasize that: (i) no teratogenic agent can be described qualitatively as a teratogen, since a teratogenic exposure must include not only the agent, but also the dose and the time in pregnancy when the exposure occurs; (ii) even agents that have been demonstrated to result in malformations cannot produce every type of malformation; (iii) known teratogens can be pre- sumptively identi ed by the spectrum of malformations they pro- duce; (iv) it is easier to exclude an agent as a cause of birth defects than to de nitively conclude that it was responsible for birth de- fects; (v) when evaluating the risk of exposures, the dose is a crucial component in determining the risk; (vi) teratogenic agents follow a toxicological dose e response curve e this means that each teratogen has a threshold dose, below which there is no risk of teratogenesis, no matter when in pregnancy the exposure occurred; (vii) the evaluation of a child with congenital malfor- mations cannot be adequately performed unless it is approached with the same scholarship and detail as is any other complicated medical problem; (viii) each physician must recognize the conse- quences of providing erroneous reproductive risks to pregnant women exposed to drugs and chemicals during pregnancy or alleging that a child s malformations are due to an environmental agent without performing a complete and scholarly evaluation. When a counselor responds to a parent s inquiry ( What caused my child s birth defect? ), the physician should respond in the same scholarly manner that would be utilized in performing a differential diagnosis for any clinical problem. Physicians have a protocol for evaluating complex clinical problems. If a mother of a malformed infant had some type of exposure during pregnancy, such as a

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diagnostic radiological examination or medication during preg- nancy, the consulting physician should not support or suggest the possibility of a causal relationship before performing a complete evaluation. Likewise, if a pregnant woman who had not yet deliv- ered had some type of exposure during pregnancy, the consulting physician should not support or suggest the possibility that the fetus is at increased risk before performing a complete evaluation. Only a small percentage of birth defects are due to prescribed drugs, chemicals and physical agents.

Con ict of interest statement

None declared.

Funding sources

None.

References

[1] Flexner A. Medical education in the United States and Canada. Bulletin No. Four (The Flexner Report). Carnegie Foundation for The Advancement of Teaching; 1910 . [2] Engle G. The need for a new medical model: a challenge for biomedicine. Science 1977;196(4286):129 e 36 . [3] Rogers C. Counseling and psychotherapy: newer concepts in practice. Boston, MA: Houghton/Mif in; 1942 . [4] Rogers C. Client-centered therapy: its current practice, implications and the- ory. London: Constable; 1951 . [5] Rogers C. A theory of therapy, personality and interpersonal relationships as developed in the client-centered framework. In: Koch S, editor. Psychology: a study of a science. Formulations of the person and the social context, vol. 3. New York: McGraw-Hill; 1959 . [6] Brent RL. Medicolegal aspects of teratology. J Pediatr 1967;71:288 e 98 . [7] Brent RL. The irresponsible expert witness: a failure of biomedical graduate education and professional accountability. Pediatrics 1982;70:754 e 62 . [8] Brent RL. Litigation-produced pain, disease and suffering: an experience with congenital malformation lawsuits. Teratology 1977;16:1 e 14 . [9] Brent RL. Reproductive and teratologic effects of low frequency electromag- netic elds: a review of in vivo and in vitro studies using animal models. Paper presented at the Thirty-third Annual Meeting of the National Council on Ra- diation Protection and Measurements. The effects of pre- and postconception exposure to radiation, 2 e 3 April, 1997, Arlington, Virginia. Teratology 1999;59:261 e 86 . [10] Miller RW. How environmental hazards in childhood have been discovered:

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risks from exposure to low levels of ionizing radiation. Committee to Access Health Risks from Exposure to Low Levels of Ionizing Radiation Board on Radiation Effects Research, Division. Washington, DC: National Academies Press; 2005, http://www.nap.edu . [38] Brent RL. Congenital malformation case reports: the editor s and reviewer s dilemma. Am J Med Genet 1993;47:872 e 4 . [39] Wilson JG, Brent RL. Are female sex hormones teratogenic? Am J Obstet Gynecol 1981;141:567 e 80 . [40] Brent RL, Christian M, Diener RM. Teratogen update: evaluation of the reproductive and developmental risks of caffeine. Birth Defects Res B Dev Reprod Toxicol 2011;92:152 e 87 . [42] Holmes LB, editor. Common malformations. New York: Oxford University Press; 2012. p. 470 . [44] Carey JC, Martinez L, Balken E, Leen-Mitchell M, Robertson J. Determination of human teratogenicity by the astute clinician method: review of illustrative agents and a proposal of guidelines. Birth Defects Res A Clin Mol Teratol 2009;85:63 e 8 . [45] Graham Jr JM, Jones KL, Brent RL. Contribution of clinical teratologist and ge- neticists to the evaluation of the etiology of congenital malformations alleged to be caused by environmental agents, ionizing radiation, electromagnetic elds, microwaves, radionuclides, and ultrasound. Teratology 1999;59:307 e 13 . [46] Jones KL, editor. Smith s recognizable patterns of human malformation. 6th ed. Philadelphia: Elsevier/Saunders; 2006 . [47] Scialli AR, Lione A, Boyle-Padgett GK, editors. Reproductive effects of chemi- cal, physical, and biologic agents reprotox. Baltimore: Johns Hopkins Uni- versity Press; 1995 . [48] McKusick VA, editor. Mendelian inheritance in man. 6th ed. Baltimore: Johns Hopkins University Press; 1983 . [49] Schardein JL, editor. Chemical induced birth defects. 3rd ed. New York: Marcel Dekker; 2000. p. 1109. revised and expanded . [50] Brent RL. Ionizing radiation. In: Queenan JT, Hobbins JC, Spong CY, editors. Pro- tocols for high risk pregnancies. 5th ed. Oxford:Wileye Blackwell; 2010. p. 21 e 32. [51] Brent RL. Counseling patients exposed to ionizing radiation during pregnancy. Pan Am J Public Health 2006;20(2/3):198 e 204 . [52] Brent RL, Bushberg JT, Linet M, Ziskin MC, Frush DP, Harms RW, et al. NCRP Report No. 174. Preconception and prenatal radiation exposure: health effects and protective guidance. Bethesda, MD: Recommendations of the National Council on Radiation Protection and Measurements; 24 May 2013. p. 351 . [53] American Academy of Pediatrics, Center for Child Health Research and the Environmental Protection Agency. The vulnerability, sensitivity, and resiliency

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[25]

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1335 e 9 .

379 e 83 .

[75]

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Further reading

in Fetal & Neonatal Medicine 19 (2014) 153 e 160 Contents lists available at ScienceDirect Seminars

Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

journal homepage: www.el sevier.com/l ocate/siny

Medicine journal homepage: www.el sevier.com/l ocate/siny Review Urgent global opportunities to prevent birth defects

Review

Urgent global opportunities to prevent birth defects

Vijaya Kancherla a , Godfrey P. Oakley Jr. a , * , Robert L. Brent b

a Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA b Alfred I. DuPont Hospital for Children, Jefferson Medical College, Wilmington, DE, USA

for Children, Jefferson Medical College, Wilmington, DE, USA summary Keywords: Birth defects Congenital abnormalities

summary

Keywords:

Birth defects

Congenital abnormalities

Population surveillance

Prevalence

Prevention

Birth defects are an urgent global health priority. They affect millions of births worldwide. But their prevalence and impact are largely under-ascertained, particularly in middle- and low-income countries. Fortunately, a large proportion of birth defects can be prevented. This review examines the global prevalence and primary prevention methods for major preventable birth defects: congenital rubella syndrome, folic acid-preventable spina bi da and anencephaly, fetal alcohol syndrome, Down syndrome, rhesus hemolytic disease of the fetus and the newborn; and those associated with maternal diabetes, and maternal exposure to valproic acid or iodine de ciency during pregnancy. Challenges to prevention ef- forts are reviewed. The aim of this review is to bring to the forefront the urgency of birth defects pre- vention, surveillance, and prenatal screening and counseling; and to help public health practitioners develop population-based birth defects surveillance and prevention programs, and policy-makers to develop and implement science-based public health policies.

2013 Published by Elsevier Ltd.

1. Introduction

Birth defects are one of the leading causes of infant mortality in the world, contributing to more than 3 million deaths among children aged < 5 years [1] . Their impact is immeasurable, having life-long health and economic implications for the affected indi- vidual, the family, and society. Middle- and low-income countries have twice the prevalence and mortality associated with birth de- fects compared with developed countries [1] . When addressing mortality among people aged < 50 years, birth defects are among top contributors. A recent report on the global burden of disease ranked birth defects as the 17th most common cause of disability-adjusted life- years (DALYs), amounting to 39 million DALYs. This came as an improvement since 1990, when birth defects ranked 13th among the leading causes of DALYs and contributed to a total of 54 million DALYs [2] . These statistics indicate that birth defects prevention efforts in the last two decades were bene cial, and there is a need to further intensify their surveillance and prevention. Only then can we achieve maximum reduction in birth defects-associated DALYs in a global context. Also, there is an increasing consensus on shifting focus to non-communicable diseases worldwide, which are now leading the burden of disease and rising in prevalence.

* Corresponding author. Address: Department of Epidemiology, Rollins School of Public Health, Emory University, 1518 Clifton Rd NE, Room 4007, Atlanta, GA 30322, USA. Tel.: þ 1 678 613 6918; fax: þ 1 404 325 6918. E-mail address: gpoakley@mindspring.com (G.P. Oakley).

1744-165X/$ e see front matter 2013 Published by Elsevier Ltd.

Lack of population-based surveillance and prenatal care pro- grams contributes to gaps in our knowledge of birth defects in the developing world. Even though they appear to be rare, birth defects are a major public health priority at a population level. As with polio and smallpox, many birth defects are preventable and can be completely eliminated by timely primary prevention. We have reviewed current literature on a group of major birth defects that are highly preventable. These birth defects include congenital rubella syndrome, folic acid-preventable spina bida and anencephaly, fetal alcohol syndrome, Down syndrome, and rhesus hemolytic disease of the fetus and newborn. We have also reviewed birth defects associated with maternal diabetes, those with in-utero exposures to valproic acid, and maternal iodine deciency. Our aim is to identify their prevalence in the populations and challenges to primary prevention strategies. We hope that this review will serve as a resource to address modiable risk factors for preventable birth defects and provide an update on current research in the eld. Public health practitioners and epidemiologists can use this review as an update on population-based birth defects surveillance and preven- tion programs. Our review may be helpful to policy-makers to implement science-based policies such as mandatory food fortica- tion, and universal prenatal screenings and vaccinations.

2. Congenital rubella syndrome

Congenital rubella syndrome is a group of birth defects that result from maternal infection to rubella virus during pregnancy. Affected infants suffer with cataracts, hearing loss, congenital heart defects,

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and both physical and mental retardation. Severity of these defects depends on the time at which the fetus is exposed to the infection in utero, with the highest risk during the rst trimester. Congenital rubella syndrome also poses a high risk of transmission from the affected infant during the rst year after their birth, contributing to the spread of infection to those in their household or close contact. First identied in 1941, congenital rubella syndrome has been associated with a high infant mortality worldwide [3]. Introduction of rubella vaccination during the early 1970s and effective implementation of mass vaccination programs in several World Health Organization (WHO) member countries in recent years has led to about 80% reduction in rubella cases, and consequently congenital rubella syn- drome [4]. However, its prevention has not been complete due to challenges associated with birth and transmission rates in different countries [5]. Congenital rubella syndrome has been completely eliminated in the USA as of December 2011 [6], and an ongoing sur- veillance monitors the success of this program [7], whereas middle- and low-income countries in Africa, the Western Pacic, and South East Asia, where the vaccination rates are below 70%, have signi- cantly high rates of rubella infections among women of childbearing age [8]. Because of these gaps in primary prevention, about 120 000 rubella cases still occur each year in the world [4]. China, Bangladesh, Poland, Bosnia and Herzegovina, and Ukraine document the highest proportion of congenital rubella cases, with an estimated total of 100 000 births affected each year [9]. Some of the challenges to total prevention of congenital rubella syndrome are variability in vaccina- tion coveragewithin and between countries. Countrieswith high birth rate require more than 80% vaccine coverage among women of childbearing age, thus requiring additional vaccination campaigns. Also, population isolation in low-income countries hinders vaccina- tion programs [5]. The WHO has strongly urged countries that are lacking rubella immunization programs to accelerate their efforts to prevent rubella and congenital rubella syndrome [10]. Complement- ing currentimmunization programs with selective rubella vaccination among girls and young women is recommended [3].

3. Folic acid-preventable spina bi da and anencephaly

Folic acid-preventable spina bi da and anencephaly (FAPSBA) are common birth defects affecting the central nervous system. In spite of unequivocal evidence from controlled trials in 1991 con- rming the effectiveness of folic acid in prevention of spina bi da and anencephaly [11] , each year about 246 000 cases of FAPSBA occur globally [1] . Countries that have implemented mandatory folic acid forti cation of food have seen a signi cant reduction in the prevalence of FAPSBA [12 e14] . But not all countries implement mandatory forti cation policies that promote adequate folic acid by women of reproductive age [15] . Bell and Oakley [16] have estimated the proportion of FAPSBA cases that can be prevented worldwide, suggesting that 75% of all neural tube defects can be prevented through folic acid forti cation, and when there is a good coverage of populationwith access to the country-speci c forti cation program. Accordingly, less than one-quarter of total preventable cases of FAPSBA were prevented worldwide. The number of cases of FAPSBA prevented have increased from 9% in 2006 [16] to 15% in 2012 [17] ; however, more needs to be done to prevent remaining cases, which amount to 200 000 cases each year globally. There is an urgent need for those countries with the majority of these cases, such as India [18] and China [19,20] , to implement mandatory folic acid forti - cation policies and to promote consumption among women of reproductive age. Some countries opt to offer folic acid supplements to adolescent girls and women, instead of fortifying centrally pro- cessed food. Such a prevention strategy based on folic acid supple- ment intake is shown to be effective in only 50% of women who adhere to the program [21] . It has also been shown that supplement

programs for high-risk women with a history of neural tube defect- affected pregnancy, even if successful, prevent only a small fraction (2 e 5%) of FAPSBA [21] . Thus, optimal prevention of FAPSBA is achievable only through mandatory forti cation of centrally pro- cessed food. There are many challenges for mandatory forti cation programs in low- and middle-income countries: forti cation pro- grams are known to be dynamic and in uenced by industry and consumption patterns, lack of political will to implement mandatory forti cation, resistance from the milling industry to purchase and disseminate folic acid premix in the our, isolation and individual dietary practices of communities that limit intake of centrally pro- cessed our, and concerns about safety, cost-effectiveness, and impact on consumer choice. In countries that implement forti ca- tion, compliance and uptake have to be monitored periodically. Overall, assessment of serum folate concentrations among women of reproductive age can serve as an easy and cost-effective way to identify risk for FAPSBA and implement primary prevention Figure 1.

4. Fetal alcohol syndrome

Fetal alcohol syndrome is a structural and neurodevelopmental group of disorders in individuals with prenatal exposure to alcohol. Those affected suffer lifelong disability, with no cure. There is a wide variation in the prevalence of fetal alcohol syndrome worldwide, and numbers of cases have steadily increased in the last decade [22]. In the USA, the estimated prevalence is 2 e7 cases per 1000 live births [23]. Studies from Europe [24], Africa [25e 27], Israel [28], Australia [29,30], and Russia [31] show a much higher prevalence. The highest preva- lence to date has been reported from high-alcohol-consuming regions of South Africa (90 per 1000 births) [32]. The WHO has recently convened to study the burden of fetal alcohol syndrome in developing countries using in-school screeners. Worldwide, 5 e10% of all preg- nancies are at risk for alcohol-related birth defects [33,34]. Recent studies in the USA show that almost 50% of reproductive-aged women used alcohol, which included about 8% of pregnant women; while binge drinking is prevalent in 15% of non-pregnant women and 1.4% of pregnant women [35]. Drinking during pregnancy is also a major concern in low- and middle-income countries [36e 38]. As maternal alcohol use during pregnancy is frequently under-ascertained during the prenatal period, this estimate may be much higher in reality [39]. Behavioral modication among reproductive-aged women should be the central theme in the prevention of fetal alcohol syndrome [40]. Some challenges to prevention of fetal alcohol syndrome include cultural and societal attitudes concerning alcohol use, women with high-risk behaviors entering prenatal care late in pregnancy, and lack of, or inaccessible, preventive and counseling services in several countries. Addressing barriers such as guilt and embarrassment among women regarding their alcohol use will also be an important challenge in assessing the burden [41]. It has been shown that a ma- jority of health care providers fail to address the effects of alcohol abuse or to diagnose fetal alcohol syndrome due to lack of training and knowledge [42,43]. Assessment of maternal alcohol use during pregnancy should become a standard and routine measure to aid in risk assessment for the fetus and for counseling and treatment of alcohol use. Finally, an integrated approach should be developed to provide health, social, and referral services in a culturally adopted setting to those affected with alcohol-related birth defects.

5. Maternal age and Down syndrome

Down syndrome is the most common chromosomal abnormality in newborns. Affected individuals have high rates of intellectual disability and several birth defects. Down syndrome was rst char- acterized in the mid-1800s, and advanced maternal age was deter- mined as the most signicant risk factor in the early 1930s [44]. Non-

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V. Kancherla et al. / Seminars in Fetal & Neonatal Medicine 19 (2014) 153e160

Figure 1. The status of global prevention of folic acid-preventable spina bi da and anencephaly, 2012 [17].

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disjunction errors in chromosomes and/or biological aging of oocytes in mothers of advanced age are suggested as probable causes for Down syndrome [45]. Despite improved knowledge and screening, about 5400 births in the USA are affected with Down syndrome each year [45] . The prevalence of Down syndrome has increased in the last two decades, with an increasing trend in delaying childbirth globally [46]. Middle- and low-income countries record a large proportion of births to women of advanced age, while reporting twice as many cases of Down syndrome as developed countries [1,47]. On the con- trary, countries where family planning is well-promoted show early and better-spaced pregnancies, and have lower births to women of advanced maternal age. European countries that have national screening policies for Down syndrome (within the rst trimester) identify a large number of prenatally diagnosed Down syndrome cases, as compared to countries without such policies [48]. A large majority of prenatally diagnosed Down syndrome cases (w 90%) are medically terminated. Socio-economic and technological disparities hinder the success of prenatal screening programs in both developed and developing countries. Both individual and societal changes that encourage lowering the age of conception among women will serve as the single most cost-efcient and effective intervention to prevent Down syndrome in future births. Implementation of universal screening and counseling (both pre and post conception) is urgently required in middle- and low-income countries. Improving organi- zational and cultural factors to reduce variation in prenatal screening will better contribute towards Down syndrome prevention in several countries [48].

6. Rhesus hemolytic disease of the fetus and newborn

Several red-cell antigens have been identied in association with the hemolytic disease of the fetus and the newborn (HDFN). Among these, antigen RhD is one of the most common. Incompatibility be- tween RhD-negative mother and RhD-positive fetus during preg- nancy will result in production of antibodies to the fetal RhD antigens (also termed as alloimmunization) [49]. Pregnancies complicated by alloimmunization have a high risk of fetal and neonatal morbidity and mortality in future pregnancies, and in the absence of timely pro- phylaxis can lead to fetal jaundice, hydrops (requiring intrauterine transfusions), fetal anemia, and stillbirths in about 2.4 per 1000 live births [50]. The mortality rate associated with HDFN in a developed country such as the UK is about 6 per 100 000 live births or 50 deaths per year [51], and is expected to be much higher among developing countries. The alloimmunization is completely treatable by early identication and administering anti-D immune globulin to the expectant mother. Anti-D immune globulin has been in use since the 1960s and has resulted in marked reduction in the alloimmunization to RhD antigen in pregnant women [52]. Lacking prophylaxis, it is estimated that at least one in every six RhD-negative women deliv- ering an RhD-positive baby would be at risk [53]. To understand the racial distribution of this burden, w15% of Caucasians, 3e 5% of African-Americans, 8% Asian-Indians, and < 1% of Asians have RhD- negative blood groups [50,54,55]. The prevalence of RhD-negative blood group in Europeans is relatively high, and varies between 11% and 21%. For example, inwestern countries, asin England andWales,it is estimated that w 17% of the pregnantwomen are RhD-negative, and, among these, 59% are at risk for alloimmunization [56]. Non-invasive methods have gained prominence and have aided signicantly in the reduction of the affected cases. However, several limitations exist. Improper screening for RhD-negative status, limited prenatal care facilities, and failure of identication and treatment with immune globulin among high-risk pregnancies has contributed to persistence of the problem around the world. Developed countries have imple- mented successful screening programs to identify RhD-negative women early in pregnancy and administer the immune globulins to

prevent HDFN; however, there is a wide variation in both screening methods and clinical management policies among different countries [57]. On the other hand, most developing countries lack screening. According to the March of Dimes, 100% of cases with HDFN can be prevented by immune prophylaxis [1]. In sub-Saharan Africa the fre- quency of RhD-negative women is: Nigeria 4.4%, Guinea 4.1%, Kenya 3.9%, western Uganda 3.6%, and Cameroon 2.4%; yet there is limited prophylaxis available due to several challenges including poor research, limited access, affordability of anti-D immune globulin, high prevalence of illegal abortions, and poor documentation of medical histories on previous pregnancies, all of which are associated with high rates of HDFN-relatedmorbidity andmortality in the region [58e 63]. In order to achieve reduction in the deaths associated with HDFN, there is an urgent need for prenatal screening for RhD antigens, uni- versal access of immune prophylaxis to all women who test RhD negative, better documentation of reproductive histories, and pro- motion of post-partum prophylaxis to mothers at risk.

7. Maternal diabetes associated birth defects

Maternal insulin-dependent diabetes and adverse glycemic control in pregnancy has been consistently associated with a high risk of birth defects in the offspring both in developed and devel- oping countries [1] . A three-fold increased risk has been noted for major cardiovascular, renal, and gastrointestinal defects in infants born to diabetic mothers compared with their counterparts [64 e 66] . Overweight and obesity are signi cant predisposing factors that lead to diabetes, and both children and adults are at risk worldwide [67] . Despite advances in medical management, birth defects associated with maternal diabetes are a common occur- rence. In the USA w 100 000 babies are born to diabetic mothers. The prevalence estimates for diabetes-associated birth defects range between 2 and 6 per 1000 births in high-income countries, and are expected to be several times greater in low- and middle- income countries [1] . Pregnant mothers with higher levels of HbA1c at conception have a greater risk of delivering a baby with birth defects as compared to pregnant mothers with normal levels. Better glycemic control before pregnancy is shown to reduce the risk signi cantly [68] . Unfortunately, more than one-third of women of reproductive age with diabetes are unaware of their condition [69] ; this proportion may be incrementally more in developing countries [70] . However, prevention of diabetes- associated birth defects is possible [71] . Selectively monitoring women with juvenile diabetes can be part of the solution. Also, screening women for high Gamma-hydroxybutyrate (GHb) con- centration will help identify high-risk pregnancies, and prevention efforts can be focused accordingly [72] . Both public- and patient- oriented approaches in lifestyle modi cation are needed. Aware- ness of diabetes and its pregnancy-related risk must be improved among women of reproductive age worldwide. Population-based screening for women with undiagnosed diabetes is also an urgent need. Challenges exist in terms of feasibility and funding for uni- versal screening. Africa and South East Asia, which face the highest burden of diabetes, have a dearth of primary health centers that can provide oral hypoglycemic agents to pregnant diabetic women [73] . Other challenges include failure to adhere to, or respond to, treat- ment among those who are on diabetes medications [74] . A multi- pronged approach with increased awareness among health care professionals, periodic screening, and management, has been shown to have a positive impact on prevention [75,76] . As a pri- mordial prevention, governments should devise health policies that promote both education and healthy lifestyles. Political will, advocacy by health care professionals, and involvement from the community are important next steps to boost prevention of diabetes-associated birth defects [74] .

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8. Valproic acid

A positive association between valproic acid (an anti-epileptic drug) taken in early pregnancy and having offspring with spina bi da was rst shown in the year 1982. This association was highly signi cant, with a 20-fold increase in risk of spina bi da to babies born to mothers who were exposed to valproic acid in the rst trimester compared with those born to mothers who were unex- posed [77] . Several subsequent studies further con rmed this as- sociation, along with new ndings of valproic acid teratogenicity in association with other major birth defects, including cardiac, uri- nary, and oro-facial defects in the fetus [77 e 84] . Following these studies, many countries have revised their prescription guidelines for women with epilepsy and have recommended judicious use of valproic acid during pregnancy for epilepsy disorders, advising less teratogenic forms of anti-epileptic drugs to women of childbearing age [85 e 88] . However, other uses of valproic acid, such as for pain, migraine, and bipolar disorder make them highly likely to stay in the market, and be prescribed to women of childbearing age without an epilepsy indication [89] . There is a high risk of off-label use of this drug in developing countries. The US Food and Drug Administration has made valproic acid a class X drug for migraines, where the risks involved in using valproic acid in pregnant women clearly outweigh potential bene ts. Within the USA, it was estimated that w 40 cases of spina bi da have occurred due to valproic acid use [90] , and about 4 per 1000 prescriptions are still written for valproic acid for non- epilepsy conditions [89] . The March of Dimes Global report on birth defects (2006) indicated that the risk of such exposure is even higher in developing countries where valproic acid use may be uncon- trolled and more common compared with more expensive and less teratogenic anticonvulsive drugs [1,91] . Thus, it becomes an urgent necessity to educate not only neurologists, but psychiatrists and other practitioners to eliminate valproic acid prescriptions among women of childbearing age, and that its use is seldom justi ed, for both epilepsy and non-epilepsy indications. Additionally, awareness needs to be brought both among the medical community and among the population about the teratogenic effects of this drug, so women in developing countries are not exposed to valproic acid.

9. Iodine de ciency

Iodine de ciency affects w 2 billion people globally and is a large concern for women of childbearing age. Each year, about 50 million children are born to iodine-decient mothers, and about 40% of these children suffer signicant intellectual disability [92]. In 2007, the WHO reported a high prevalence of iodine deciency in both devel- oped and developing regions of the world, and not just con ned to remote andmountainous regions, as previously thought [93]. National nutritional surveys from the USA estimate that w 35% of pregnant women have at least mild iodine deciency [94]. To address this problem, the American Thyroid Association recommends 150 mg per day of iodine intake for pregnant and lactating women, starting early at preconception [95,96]. Pregnancy confers an increased need for iodine, [97] and its insufciency has been associated with cretinism, intellectual delays, birth defects, and other suboptimal outcomes in theinfant [95,98]. Iodine deciencyis also themostimportant cause of preventable intellectual disability in infants worldwide [96]. Dietary intake is the only source of iodine; however, prenatal vitamins and supplements also contain iodine and should be recommended to women of childbearing age. Use of iodized salt has been implemented in several countries to reduce iodine deciency. But only 70% of households worldwide have access to iodized salt, and there is a need to promote it extensively to achieve optimal intake [99]. Known challenges to successfuliodization include use of cheaper non-iodized salt, limitation in quality control during salt production, compliance

failures, personal preferences, lack of awareness by households about benets of iodized salt, market uctuations, and poor enforcement of regulations mandating iodization [92]. Political commitment and salt iodization legislation are also important to move ahead. There is a need to identify optimal indicators for iodine de ciency, improved screening of women of childbearing age, and monitoring iodine con- tent in salt. Asmost people are limiting their salt intake to reduce their risk of hypertension, other vehicles have to be explored to deliver needed iodine to populations worldwide [92]. Taking these timely steps, we may be able to prevent a majority of babies from the ill outcomes associated with iodine deciency.

10. Other opportunities for prevention

A recent review summarized a list of preventable birth defects ( Box 1 ) [100] . This prevention can be achieved by screening for chromosome abnormalities and genetic disease, vaccinations, screening for teratogenic infectious diseases such as human im- munode ciency virus and gonorrhea, and limiting or eliminating the use of all known teratogenic drugs (e.g. anticoagulants, reti- noids, and thalidomide). We should also be vigilant of new te- ratogens. Parents should be informed of preconception diagnostic choices including amniocentesis, chorionic villous sampling, maternal serum monitoring, and ultrasound monitoring to di- agnose identi able genetic diseases and serious birth defects.

Box 1 Prevention of congenital malformation and reproductive effect [100] .

1.

Rubella vaccination.

2.

Folic acid and vitamin B 12 supplementation: 400 mg and 6 mg per day.

3.

Supplementation of iodide to deficient patients and populations.

4.

Meticulous diabetic control.

5.

Competent diagnosis and management of maternal hypothyroidism.

6.

Screening for chromosome abnormalities and genetic disease.

7.

Hepatitis B vaccination for at-risk women.

8.

Human immunodeficiency virus screening and treatment.

9.

Screening for Neisseria gonorrhoea , Chlamydia tra- chomatis , group B streptococcus.

10.

Vaccination of patients with group B streptococcus.

11.

Maternal phenylalanine management for maternal phenylketonurics.

12.

Management or discontinuation of oral use of antico- agulants, anticonvulsants, retinoids, thalidomide and all known teratogens.

13.

Recognize that new teratogens can be represented in the next new drug or chemical exposure: angiotensin- converting enzyme inhibitors, angiotensin II receptor blockers, mycophenolate, tumor necrosis factor blockers.

14.

Amniocentesis, chorionic villus sampling, maternal serum monitoring, ultrasound monitoring to diagnose identifiable genetic diseases and serious birth defects in order for the parents to be informed about their options.

15.

Maternal smoking and alcohol cessation.

16.

Obesity control in itself reduces the risk of birth defects and decreases the risk of developing diabetes.

17.

Immunization against known teratogenic infections. Botulina toxin vaccine for the pregnant mother to pre- vent infant botulism.

18.

Malaria vaccine to prevent malaria in pregnancy which increases the risk of miscarriage.

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Timely counseling on high-risk behavioral and lifestyle choices such as maternal smoking, alcohol, caffeine, recreational drugs, and obesity and overweight is needed in relation to their adverse effects on pregnancy. While there are many prevention strategies to reduce the incidence of birth defects worldwide, there is not enough space allotted in this article for such extensive review.

the incidence of birth defects worldwide, there is not enough space allotted in this article for
the incidence of birth defects worldwide, there is not enough space allotted in this article for

Con ict of interest statement

None declared.

Funding sources

11. Conclusion

Opportunities to prevent birth defects are abundant, but there are also many challenges in the process. Pediatricians, researchers, and public health practitioners in the eld of birth defects should intensify prevention efforts, and undertake comprehensive and in- tegrated efforts to accelerate the pace of prevention at a global scale for preventable birth defects. Help and commitment from govern- mental and non-governmental organizations, in a complementary manner, is crucial to developing affordable and feasible prevention programs. Only then can we achieve our goal of bringing current rates of major preventable birth defects close to nil. We have witnessed the global eradication of polio, which is almost of the same magnitude as the current number of cases of folic acid-preventable spina bi da. Similarly, an integrated approach from the government and non-governmental agencies has resulted in global eradication of smallpox. Lessons from suc- cessful programs can be shared. Birth defects prevention is achievable by combating socio-economic inequities and disparities in health care for women of reproductive age. Need-driven and impact-oriented approaches with improved education, prophy- laxis, and prenatal care are needed. There exists an urgent need to translate research ndings to policy. Now that developed countries are on their path towards success, priority should now be placed on middle- and low-income coun- tries. Funding for birth defects surveillance is urgently required to plan and develop a functional primary prevention infrastructure for future births. Over time, the health and economic returns, both at micro and macro levels, would be signi cant. Political will and commitment by communities are an absolute necessity to initiate and sustain birth defects prevention on a global scale.

Practice points

Global programs to prevent birth defects are an urgent global health priority. Congenital rubella syndrome and folic acid-preventable spina bifida and anencephaly could be eliminated from all countries by implementing prevention programs already shown to eliminate these birth defects in a few countries. Effective intervention programs must be developed and implemented to prevent the three-fold increase in major malformations among women with insulin-dependent diabetes mellitus, as well as birth defects and develop- mental disorders from in-utero exposure to alcohol. Valproic acid should be limited to persons with epilepsy who have been shown not to have control with at least one other anticonvulsant, and should never be the first-line treatment for epilepsy for women of reproductive age. Active, effective intervention programs promoting optimal maternal birth age are needed to reduce the current Down syndrome epidemic in developed countries and to prevent the epidemic in countries that have yet to experience it. There is a need to further intensify birth defects surveil- lance and prevention programs in developing countries. Political will and commitment by communities are inte- gral for birth defects prevention on a global scale.

None.

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Contents lists available at ScienceDirect

Seminars in Fetal & Neonatal Medicine

journal homepage: www.el sevier.com/l ocate/siny

Medicine journal homepage: www.el sevier.com/l ocate/siny Review Vaccines and pregnancy: Past, present, and future

Review

Vaccines and pregnancy: Past, present, and future

Sonja A. Rasmussen a , * , Amelia K. Watson b , Erin D. Kennedy c , Karen R. Broder d , Denise J. Jamieson e

a In uenza Coordination Unit, Of ce of Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

b University of Georgia, Athens, GA, USA

c Immunization Services Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

d Immunization Safety Of ce, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA

e Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, USA

Centers for Disease Control and Prevention, Atlanta, GA, USA summary Keywords: Newborns Pregnant women Safety Vaccine

summary

Keywords:

Newborns

Pregnant women

Safety

Vaccine

Vaccination during pregnancy with certain vaccines can prevent morbidity and mortality in pregnant women and their infants. However, previous recommendations often focused on the potential risks of vaccines to the fetus when used during pregnancy. In recent years, additional data have become available on the absence of increased risks for adverse events associated with vaccines when administered during pregnancy and on their bene ts to mothers and infants. Currently two vaccines e (i) inactivated in u- enza, and (ii) tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) e are recom- mended for use by all pregnant women by the United States Advisory Committee on Immunization Practices. Here we review the history of vaccination during pregnancy, the current status of recom- mendations for vaccination during pregnancy in the USA, and the potential for future advances in this area, including key barriers that must be overcome to accommodate these advances. Published by Elsevier Ltd.

1. Introduction

Vaccinations have had a substantial impact on decreasing morbidity and mortality in the USA and the world, and because of this impact, vaccinations are considered one of the top ten public health achievements in the twentieth century [1] . Vaccination during pregnancy has the potential to protect not only the mother, who may be at increased risk of morbidity and mortality from in- fectious disease, but also her infant through maternal antibodies that are transferred across the placenta during the second half of pregnancy. In addition, mothers vaccinated during pregnancy are less likely to transmit an infection to their infant after birth. Because of their immature immune systems, young infants are often particularly vulnerable to infectious diseases, and their ability to mount an immune response to vaccinations is often inadequate [2] . Past discussions regarding the use of vaccines during pregnancy often focused on potential risks to the infant, rather than on their bene ts. In recent years, data have accumulated on the bene ts of

* Corresponding author. Address: 1600 Clifton Road, MS A-28, CDC, Atlanta, GA 30333, USA. Tel.: þ 1 404 639 2297. E-mail address: skr9@cdc.gov (S.A. Rasmussen).

1744-165X/$ e see front matter Published by Elsevier Ltd.

certain vaccines to infants when given to their mothers during pregnancy and on the absence of increased risks for adverse events associated with administration of vaccines during pregnancy. Here we review the history of the use of vaccines during pregnancy, what is known about the risks and bene ts of vaccines during pregnancy on the mother and her infant, and the increasing emphasis in recent years on the bene ts of certain vaccines when given during pregnancy. We also discuss future advances in the area of vaccines and pregnancy with the potential to improve maternal and infant health.

2. Past

The concept that vaccination during pregnancy could protect a newborn infant is not a new one. As early as 1879, it was recognized that newborn infants born to mothers who received Jennerian vaccination (smallpox vaccination) during pregnancy were pro- tected from vaccinia virus early in life [3] . The protective effect of maternally transferred antibodies on offspring was shown in 1892 using a mouse model [4] . In humans, it was recognized early in the twentieth century that many infants were resistant to some com- mon infectious diseases during the rst few months of life, espe- cially if the mother was known to have had the disease [5] , and this

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protection was correlated with the presence of maternal antibodies that were passed transplacentally from mother to the fetus [6] . Vaccination with tetanus toxoid during pregnancy has been used for many years to protect infants born to women in developing countries from neonatal tetanus. Observational studies in the 1960s provided evidence that neonatal tetanus could be prevented with tetanus toxoid vaccination during pregnancy, and a double-blind controlled trial subsequently provided con rmation: the neonatal tetanus death rate was 7.8 deaths per 100 births among infants born to mothers in the control arm, compared to no deaths among infants born to mothers who received two or three injections with tetanus toxoid more than 6 weeks apart [7] . These results subse- quently led to the World Health Organization s Maternal and Neonatal Tetanus Elimination Initiative, a program focused on tetanus toxoid vaccination of pregnant and childbearing age women and promotion of hygienic deliveries. This initiative has resulted in a 93% reduction in neonatal deaths due to tetanus [8] . Much of the previous guidance on vaccinations during preg- nancy emphasized concerns that vaccine exposure could place the fetus or infant at risk or could be perceived as doing so; however, as additional data on bene ts of vaccines during pregnancy and on the absence of increased risks for adverse events after maternal vaccination have accumulated, that emphasis has changed. The history of recommendations by the Advisory Committee on Im- munization Practices (ACIP), a group of experts that develops rec- ommendations on use of vaccines in the USA [9] , related to in uenza vaccination during pregnancy is illustrative. Inactivated in uenza vaccination of pregnant women and other groups at increased risk for in uenza-associated complications was rst recommended by the Surgeon General in 1960 [10] , but many subsequent recommendations were less supportive. In 1990, the ACIP noted that an increased risk of in uenza-associated compli- cations in pregnant women had not been documented, except during pandemics. Thus, only pregnant women with underlying conditions were recommended to receive in uenza vaccination, and waiting to vaccinate until after the rst trimester was a reasonable precaution to minimize any concern over the theoretical risk of teratogenicity [11] . In 1995, based on case reports and other studies, the ACIP recommendation was extended to women without underlying conditions, but only during the third trimester of pregnancy [12] . In 1997, after a study had shown an increased risk of in uenza-associated hospitalizations among pregnant women during interpandemic periods, especially during the sec- ond and third trimesters [13] , ACIP recommended second and third trimester vaccination [14] . The 1997 recommendations noted that many experts considered in uenza vaccination to be safe in all trimesters of pregnancy, but that delaying vaccination until after the rst trimester would avoid coincidental association of the vaccine with rst trimester spontaneous abortions