Association of the Common Cold in the First Trimester of Pregnancy With Birth Defects

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Association

of the

Common

Cold

in the

First

Trimester

of Pregnancy

With

PEDIATRICS Vol. 92 No. 4 October 1993 559

Birth

Defects

Jun Zhang, MB*, and Wen-wei Cai, MD

ABSTRACT. Objective. To examine the association

be-tween the common cold with or without fever in the first

3 months of pregnancy and birth defects in offspring.

Design. A case-control study.

Setting. Data are from the Shanghai Birth Defects

Monitoring Program, conducted in 29 hospitals in

Shang-hai, China from October 1, 1986 to September 30, 1987.

Subjects. A total of 986 birth defects cases, 990

fre-quency-matched live birth controls, and 159 stillbirth

controls.

Results. Modestly elevated risk of birth defects was

identified among women who reported having a cold

with or without fever in the first trimester of pregnancy.

Notably increased relative risks were observed for

anen-cephalus (odds ratio IORI = 3.9, 95% confidence interval

[CII = 2.0 to 7.7), spina bifida (OR = 4.1, 95% CI = 1.7 to

9.7), hydrocephalus (OR = 2.3, 95 %CI = 1.1 to 5.1), cleft

lip (OR = 2.2, 95 %CI = 1.4 to 3.4), and undescended

testicle (OR = 1.8, 95 %CI = 1.0 to 3.0). Our study further

found that the overall relative risks were consistent by

using two different control groups, suggesting that this

association was unlikely to be due to recall or report bias.

Conclusion. Common cold in the first trimester of

pregnancy may be associated with an increased risk of

birth defects in offspring. However, these findings

should be interpreted cautiously. Pediatrics 1993;

92:559-563; birth defect, cold, fever, pregnancy

Many epidemiologic investigations have been

per-formed to examine the association between maternal

hyperthermia in early pregnancy and congenital

malformations in offspring. Previous studies in

which hyperthermia was associated with an illness

did not take the underlying diseases into account,1

leaving a question open as to whether the illness or

the attendant fever causes the defects. Common cold

is a major cause of maternal fever in early pregnancy.

In a case-control study, Kurppa and colleagues5

showed that cold in the first trimester of pregnancy

was associated with the increased occurrence of

an-encephaly (adjusted odds ratio [OR] = 4.5, 95%

con-fidence interval [CI] - 2.2 to 9.1). However,

knowl-edge about cold in relation to birth defects is still

very limited. More studies are warranted.

This report examines the association between cold

with or without fever in the first trimester of

gesta-From the *Carolina Population Center and Department of EpidemioIog

University of North Carolina at Chapel Hill, North Carolina, and the IDe-partment of Maternal and Child Health, Shanghai Medical University, Shanghai, Public Republic of China

Received for publication Sep 16, 1992; accepted Apr 8, 1993.

Reprint requests to (J. Z.) Carolina Population Center, CB# 8120, 207 Uni-versity Square East, Chapel Hill, NC 27516-3997.

Acad-emy of Pediatrics.

tion and birth defects by using data from the

Shang-hai Birth Defects Monitoring Program. To detect

p0-tential recall or report bias, internal and external

comparisons were made. It should be noted that

common cold is a clinical syndrome, loosely defined

and caused by a variety of respiratory viruses.6 It

also has different connotations in different cultures

and countries. In Shanghai, both cold-like illnesses

and influenza-like illnesses are usually diagnosed as

an upper respiratory tract infection without serologic

tests. Influenza may be diagnosed during an

epi-demic. For lay people, it is more difficult to

distin-guish between a cold and influenza, and they

gener-ally call both of them “cold.” Therefore, some

patients and controls who reported having a cold

might have had influenza or other illnesses.

MATERIAL AND METHODS

Data used here are from the Shanghai Birth Defects Monitoring

Program, conducted in Shanghai, China from October 1, 1986 to

September 30, 1987. A stratified random sample of 29 of 72

hos-pitals was selected from Shanghai Municipality based on birth

distribution by hospital levels (municipal, district/county) and

location (urban and rural). During the active surveillance

moni-toring period, every live birth with a defect and birth weight of 1000 g was registered and matched with a live birth free of

defects delivering in the same room just before or after the study

patient. Every stillbirth with birth weight of 1000 g and early

neonatal death (died within 7 days after birth) was also recorded and matched with a control in the same manner. If a control died

within 7 days after birth, it became a study patient, and a new

eligible control was added. Only newborns whose mothers were

residents of Shanghai were eligible to be enrolled as cases or controls. A normal live birth immediately before the index case was preferred to serve as a control. However, if this newborn was ineligible or discharged from hospital, the normal live birth after

the index case was selected as the control. Autopsies were

per-formed on 80% of the perinatal deaths (stillbirths + early neonatal

deaths). Most of the remaining 20% had a clinically diagnosed cause of death unrelated to congenital anomalies. Perinatal deaths with pathologically verified anomalies were included in the group

of birth defects. The classification of congenital anomalies was

based on the International Classification of Diseases, Ninth

Revi-sion (ICD-9 code 740-759, including major and minor anomalies.

Newborns with bilateral anomalies were coded as having one defect. Up to 12 malformations for each case were recorded. Before

8 days after birth, birth defects were ascertained by pediatricians

or pathologists who had no knowledge of maternal cold history.

During the monitoring period, 75 756 births with weights of

1000 g or greater whose mothers were residents of Shanghai were recorded. Among them, 1013 live births and perinatal deaths with defects were identified, and an equal number of controls were

selected. All the mothers of cases and controls were interviewed in

the hospitals by specially trained interviewers soon after delivery. A pretested uniform questionnaire was used. Although interview-em were not blinded to case-control status, most of the maternal and infant information was recorded from prenatal care cards and clinical records, such as the occurrence of severe vomiting in early

pregnancy and threatened abortion (<28 weeks of gestation).

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TABLE 1. Characteristics of the Cases and Controls*

Parity 0

77 81 79

18 17-t 17

5 2 4

Paternal smoking, cigarettes/d

0 1-9 10-19 20

Women were asked if and when they had a cold during

preg-nancy (first, second, or third trimester); if there was any fever with

the cold; whether they had febrile illness without a cold; and when

the febrile illness occurred (first, second, or third trimester).

How-ever, no information was sought on the degree of temperature

elevation or on the duration of the cold or fever. The cold was not

rigorously defined by any symptoms or signs but based on

wom-en’s self-judgment. Women were asked whether and when they

had infection with rubella, herpes, cytomegalovirus, and hepatitis.

In addition, women were asked how many cigarettes they and

their husbands smoked per day and how often they drank alcohol

(occasionally, often, or daily). Because women smoking and

drink-ing are rare in Shanghai7 and only two study mothers smoked and

one of them drank during pregnancy, maternal smoking and

drinking were not considered as confounders. Also information

about maternal exposure to radiation, various chemicals, and

pes-ticides during pregnancy was collected (1.2%, 7.1%, 0.4% among

cases and 0.7%, 2.0%, 0.2% among controls, respectively).8

How-ever, excluding those exposed women from analysis did not

change the results (not shown), indicating that those exposures

did not confound the relationship of interest.

To examine potential for recall or reporting bias, in which

women with adverse outcomes are more inclined to report colds,

we compared the cases with the controls regarding frequency of

self-reported colds in the first trimester and in the second and

third trimesters. Further, we employed another group of selected

stillbirths as the second control group. Included were antepartum and intrapartum fetal deaths from umbilical cord complications,

eg, knot of the cord, cord around neck,or prolapse of the cord.

These stillbirths were associated with neither cold or fever nor

birth defects but certainly were perceived by the mother as an

adverse outcome.

Starting with 1013 birth defects cases, 1013 frequency-matched normal live birth controls, and 166 stillbirth controls, we excluded

those who reported having rubella or herpes simplex infections

during pregnancy (7 cases, 2 controls, and 1 stillbirth). No one

reported cytomegalovirus infection. Because hepatitis viruses

have not been implicated as teratogenic agents, we included

women having hepatitis during pregnancy. We further excluded

those who had thyroid diseases (hypo- or hyperthyroidism) (3

cases and 2 live birth controls). No preexisting diabetes was

re-ported in our study population. Further eliminated were those

who reported having fever without cold (13 cases, 11 controls, and

3 stillbirths) and having cold and/or fever but not recalling the

timing of the event (4 cases, 8 controls, and 3 stillbirths). These exclusions left 986 cases, 990 live birth controls, and 159 stillbirth controls for analysis.

RESULTS

The maternal age of case patients tended to be

older than that of controls (see Table 1). Slightly more

cases than live birth controls were parous and had a

threatened abortion. Stillbirth controls had lower

in-cidence of severe vomiting in early pregnancy.

Al-though more case patients reported cold/fever in the

first trimester than the live birth controls, the

differ-ence in frequency diminished in the second and third

trimesters (see Table 2).

In comparison with live birth controls, women

who reported having a cold in the first trimester

without a fever had a modestly increased risk of birth

defects in offspring (crude OR = I .38, 95% CI = I .03

to I .85) (Table 3). A similar OR was identified for

women who had a cold with fever (crude OR 1.43,

95% CI = I .01 to 2.01). Overall, women who were

exposed to a cold in the first trimester had a 40%

increased risk of birth defects. These results are

gen-erally consistent with those when stillbirths served as

the controls. Adjustment for maternal age, parity,

Se-vere vomiting in early pregnancy, threatened

abor-tion, and paternal smoking had no impact on the

results.

Maternal age, y

20-29

30-34

35

Case Live Birth Stillbirth

n = 986 Control Control

(%) n=990

(%)

n=159

(%)

92 951: 88

1+ 8 5 12

Severe vomiting

No 87 88 92

Yes 13 12 8

Threatened abortion

No 91 94t 94

Yes 9 6 6

37 41 39

22 20 25

25 24 16

16 15 20

*

x2

test was done between case and live birth control and between

case and stillbirth control.

tP < .01.

P < .05.

When we examined the birth defects grouped by

organ systems, we found that colds with or without

fever were most strongly related to defects in the

central nervous system and facial anomalies (Table

4). Interestingly, the ORs in the group having a cold

without fever were generally the same as those in the

corresponding group having a cold with fever,

al-though the latter tended to be slightly higher.

Table 5 presents the association between cold with

or without fever (combined) and specific birth

de-fects which had a sufficient number of exposed cases

(5). Women who had a cold in the first trimester

had four times increased risk of anencephalus and

spina bifida (OR = 3.9, 95% CI 2.0 to 7.7; OR = 4.1,

95% CI = 1.7 to 9.7, respectively). Elevated ORs were

also observed for hydrocephalus (OR = 2.3), cleft lip

with or without cleft palate (OR = 2.2), and

unde-scended testicle (OR = I .8), which were statistically

significant.

DISCUSSION

This study suggests that a first trimester cold with

or without a fever is associated with an increased risk

of birth defects. Because one control group was

corn-posed of mothers whose neonates were stillborn,

those mothers would be expected to have a recall or

reporting bias similar to mothers whose babies were

born with birth defects. However, the similar

find-ings by using live born and stillborn controls argues

against recall bias. This argument was further

sup-ported by the similarity in frequency of self-reported

cold and fever in the second and third trirnesters

between the cases and live birth controls (Table 2). In

addition, the substantial difference in odds ratios for

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TABLE 2. Frequency of Self-reported Cold or Fever During Pregnancy

ARTICLES 561

First Trimester* Second/ Third Trimestersf

Case Live Birth Case

(n = 986) Control (n = 986)

(n = 990)

Live birth Control (n = 990)

Cold without fever 118 91 126

Cold with fever 83 62 77

Overall 201 153 203

124 73 197

* Women could have cold or fever in the second and/or third trimesters.

t Women did not have cold or fever in the first trimester.

TABLE 3. Cold and Fever in the First Trimester and Birth Defects

Case, Live Birth Control Stillbirth control

n n OR (95% CI)* OR (95% CI)

No cold or fever 786 837 137

Cold without fever 118 91 1.38 14

(1.03-1 .85)

Cold with fever 83 62 1.43 8

(1.01-2.01)

Overall 201 153 1.40 22

(1.11-1 .76)

Adjusted ORt 1.39

(1.01-1.76)

1.47

(0.83-2.61)

1.81

(0.87-3.76)

1.59 (0.99-2.55)

1.54 (0.95-2.50) * OR, odds ratio; CI, confidence interval.

t Multiple logistic regression adjusted for maternal age, parity, severe vomiting in early pregnancy, threatened abortion, and paternal smoking.

recall or report bias. For example, it is unlikely that

cases with cleft lip would report differently from

cases with cleft palate or anomalies of external ears.

Our findings are also consistent with a previous

study in the magnitude of the increased risk of

an-encephaly (OR = 3.9, 95% CI 2.0 to 7.7 in this study

and OR = 4.5, 95% CI = 2.2 to 9.1 in the previous

one).5

Influenza A virus has been demonstrated to cause

failure of the neural tube to close in chick embryos.9

A study by Johnston et a!10 suggested that influenza

virus infection may act by altering metabolic

path-ways essential for neural tube closure. Coffey and

Jessop found that among 12 552 women, more

moth-ers of children with congenital abnormalities had

in-fluenza during pregnancy than those with normal

offspring (18.4% vs 3.6%).h1 In another prospective

study they found a higher frequency of anencephaly,

spina bifida, meningocele, and encephalocele in

off-spring of women having influenza in the first

trimes-ter.12 One study by Leck also found that the

preva-lence of cleft lip increased significantly after major

influenza epidemics,13 which was consistent with

our findings. However, results from epidemiologic

studies on the association of influenza viral infection

with neural tube defects are inconsistent and by no

means 14l 5

Although several other viruses have been

demon-strated to have teratogenic effects (eg,

cytomegalo-virus, rubella virus, and herpes simplex virus), most

viruses have unknown effects on the embryo.

Differ-ent viruses may cause different types of damage to

the fetus, depending on the types of cells in which a

virus grows.6 Even the same virus might cause

dif-ferent malformations, depending on the timing of

exposure during embryogenesis. Viruses causing

malformations may also cause embryonic mortality,

resulting in spontaneous abortion.1’ Many women

with subclinical infection would have been classified

as “unexposed.” Such misclassification is likely to be

TABLE 4. Colds in the First Trimester a nd Birth Defe cts by Organ Systems

Defects No Cold Cold Without Fever Col d With Fever

(ICD-9 codes)* or Fever,

n

---.

.

n OR (95% CI)

..-n

.-

_

.

OR (95% CI)

Live birth controls 837 91 62

Central nervous system (740-742) 69 17 2.3 (1.3-4.0) 15 2.9 (1.6-5.4)

Facial anomaly (734, 744, 749) 176 36 1.9 (1.2-2.9) 24 1.8 (1.1-3.0)

Heart and circulatory system (745-747) 94 9 0.9 (0.4-1.8) 10 1.4 (0.7-2.9)

Respiratory system (748) 29 7 2.2 (1.0-5.1) 3

-Digestive system (750, 751) 64 10 1.4 (0.7-2.9) 7 1.5 (0.7-3.3)

Urogenital system (752, 753) 150 19 1.2 (0.7-2.0) 15 1.4 (0.8-2.4)

Musculoskeletal and limbs (754-756) 202 28 1 .3 (0.8-2.0) 24 1 .6 (1.0-2.6)

Integument (757) 56 7 1.2 (0.5-2.6) 2

-Other (758, 759) 89 12 1.2 (0.7-2.3) 13 2.0 (1.1-3.7)

* lCD, International Classification of Diseases, 9th Revision.

Note : some fetuses had multiple malformations in different systems.

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Defects Exposed, Nonexposed Odds ratio

n n (95% confidence interval)

Live birth controls 153 837 1.0

Anencephalus 15 21 3.9 (2.0-7.7)

Spina bifida 9 12 4.1 (1.7-9.7)

Hydrocephalus 9 21 2.3 (1.1-5.1)

Anomalies of external ears 7 34 1.1 (0.5-2.5)

Cleft lip ± cleft palate 34 84 2.2 (1.4-3.4)

Cleft palate 6 25 1.3 (0.6-3.2)

Ventricular septal defect 7 21 1.8 (0.8-4.3)

Lung hypoplasia or aplasia 5 18 1.5 (0.6-4.0)

Polydactyly 21 82 1.4 (0.9-2.3)

Varus/valgus deformities of the feet 12 47 1.4 (0.7-2.7)

Undescended testicle 19 59 1.8 (1.0-3.0)

Hypospadias 10 40 1.4 (0.7-2.8)

Down syndrome 11 45 1.3 (0.7-2.6)

TABLE 5. Common Cold With or Without Fever in Early Pregnancy and Selected Birth

similar for cases and controls, which would bias the

results toward the null.18 In addition, inasmuch as

our monitoring was restricted to birth weights of at

least 1000 g, several congenital anomalies were not

identified. It is well established that the vast majority

of embryos with chromosomal anomalies abort

sub-clinically early in the pregnancy, and many fetuses

with major congenital malformations spontaneously

abort before the third trimester. Therefore, if colds

cause birth defects, the ORs in our study may have

been underestimated. Further, because our

monitor-ing ended by the seventh day after birth, some

mal-formations would not have been detected.

Rather than the cold being directly responsible, it

is possible that medications taken for colds are the

cause of malformations. Data from the Collaborative

Perinatal Project suggest that drugs taken to alleviate

symptoms of upper respiratory tract infection may

be teratogenic.19 For instance, elevated relative risks

of birth defects were identified in women who took

analgesic and cold capsules and oxytetracycline in

the first trimester of pregnancy. Based on large

num-bers of exposure, minor malformations were

associ-ated with ingestion of sympathomimetic amine,

phenylpropanolamine, and parasympatholytic

drugs. These agents are common ingredients of

“cold” tablets, nose drops, and inhalants. In addition,

Chinese herbal tablets and powders for oral solutions

are often prescribed for cold in Shanghai. Although

the study collected information on drugs used

dur-ing pregnancy in general, we do not know which

specific drugs were used for the cold and when they

were taken. Further, the components of Chinese

herbal medicines are often unknown, precluding our

evaluation.

Because colds are often accompanied by fever, the

association between colds and birth defects might be

influenced by fever. Maternal hyperthermia in early

pregnancy has been consistently demonstrated to

have teratogenic effects, especially on neural tube

defects, in several animal species.2#{176} Epidemiologic

studies have also reported the association between

hyperthermia in the first trimester and neural tube

defects, facial defects, limb defects, and abdominal

wall defects in offspring. A recent prospective

fol-low-up study showed that exposure to heat in the

form of hot tub, sauna, or fever in the first trimester

of pregnancy was associated with an increased risk

for neural tube defects (relative risk = 2.2, 95% CI =

1.2 to 4.1).21 However, two other prospective

inves-tigations failed to confirm this association?-’23

Eco-logic findings from Finland and Sweden, where

sauna bathing is common, did not support it either,

because these two countries have the lowest reliable

prevalence of anencephaly in the world.24

Because of the very small number of women

hay-ing fever without cold, our study was unable to

ex-amine the association between maternal

hyperther-mia and birth defects in isolation from cold. Further,

because the original study did not set a rigorous

definition of maternal fever, the similarity in odds

ratios between cold with and without fever may be

due to misclassification of fever. Such

misclassifica-tions, however, were likely for low fever (less

terato-genic) but not for high fever (more teratogenic)

be-cause women reporting a cold were unlikely to forget

a high fever. On the other hand, the similarity in

odds ratios suggests that maternal fever alone might

have less effect on congenital malformation, which

contradicts to the hypothesis by Edwards that

con-genital malformations associated with influenza

in-fection may be due to the fever rather than the virus

or drugs used in therapy.25 Our hypothesis is

sup-ported by a previous study-i in which women who

had a common cold without fever bore a risk of

an-encephaly in offspring similar to those who had a

cold with fever. The authors, therefore, excluded the

possibility that the association between colds and

anencephaly was due to hyperthermia.5 Further

studies with a sufficient number of subjects are

needed to confirm or refute our hypothesis.

Although animal studies demonstrate that

mater-nal hyperthermia can cause congenital anomalies,

they cannot always be extrapolated to human

stud-ies.2#{176}First, laboratory animals are usually raised in

very stable and strictly controlled micro- and

macro-environments.26 The optimum temperature range for

rats, for instance, is 20#{176}Cto 26#{176}C.Rats exposed to

29.2#{176}Chave increased evaporative water loss,

in-creased body water turnover, elevated plasma

corti-costerone, and decreased food intake.27 The upper

critical temperature for rats is 32.0#{176}C.For inbreeding

animals, physical adaptation to acute exposure is

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ARTICLES 563

observe that pregnant mice exposed to 42#{176}Cor

higher in early pregnancy have higher risk of birth

defects in offspring. Second, exposing laboratory

ani-mals to hot water will not only increase their body

temperature, but also cause emotional reactions such

as anxiety and restlessness, which in turn disturb

their hormonal balance.27 Third, most of the animal

studies used 42#{176}Cor higher exposure,28 whereas in

adult humans, fever higher than 40#{176}Cis not

corn-mon. For small animals, direct conduction of heat

from hot water may play an important role in raising

core temperature. In a human study, Harvey et al

demonstrated that the usual use of hot tubs and

sauna is unlikely to raise a woman’s body

tempera-ture (measured by vaginal temperature near cervix)

to potentially teratogenic levels (38.9#{176}C).29 Therefore,

the pathogenesis of congenital malformation due to

heat exposure in humans, if true, might be beyond

the simple conduction of heat.

In summary, this case-control study suggests an

association between colds in the first trimester of

pregnancy and birth defects in offspring, especially

anencephalus, spina bifida, hydrocephalus, cleft lip,

and undescended testicles. However, these findings

should be interpreted cautiously. Although season of

exposure was controlled by time matching, other

po-tential confounders might bias the results.

ACKNOWLEDGMENT

The authors gratefully acknowledge Dr. David Savitz for his

careful review on the previous version of this paper.

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2. Pleet HB, Graham JM, Smith DW. Central nervous system and facial defects associated with maternal hyperthermia at four to fourteen weeks gestation. Pediatrics. 1981 ;67:785-793

3. Smith DW, Clarren 5K, Harvey MAS. Hyperthermia as a possible

tera-togenic agent. JPediatr. 1978;92:877-883

4. Little BB, Ghali FE, Snell LM, Knoll KA, Johnston W, Gilstrap LC. Is

hyperthermia teratogenic in the human? Am IPerinatol. 1991;8:185-189

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21. Milunsky A, Ulcickas M, Rothman KJ, Willett W, Jick SS, Jick H.

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22. Clarren 5K, Smith DW, Harvey MAS, Ward RH, Myrianthopoules NC.

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in man. IPediatr. 197995:81-83

23. KleinbrechtJ, Michaelis H, MichaelisJ, Koller S. Fever in pregnancy and congenital defects. Lancet. 1979;i:1403

24. Hyperthermia and the neural tube. Lancet. 1978;ii:560-561. Editorial 25. Edwards MJ. Influenza, hyperthermia and congenital malformations.

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26. Inglis JK. Introduction to Laboratory Animal Science and Technology. Ox-ford: Pergamon Press; 1980

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29. Harvey MAS, McRorie MM, Smith DW. Suggested limits to the use

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1981 ;125:50-53

A SCIENTIFIC TRAP

The National Waste Policy Act sets up a scientific trap in which the public is

encouraged to demand or expect what is close to certainty (from virtually “flawless

science”), and in which scientists and engineers are encouraged to believe or

pretend that they can supply it.

Reaven SJ. How sure is sure enough: How and why stakeholders differ on repository scientific issues.

(Manuscript)

Submitted by Student

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1993;92;559

Pediatrics

Jun Zhang and Wen-wei Cai

Defects