Eur. J. Obstet. Gynecol. Reprod. Biol.

, 26 (1987) 291-302 291

Elsevier

ET0 00545

Hyperemesis during pregnancy and delivery

outcome: a registry study

Bengt K%lltn
Department of Embvology, University of Lund Lund Sweden
Accepted for publication 6 July 1987

Delivery outcome was studied in 3068 pregnancies with the diagnosis of hyper-
emesis in the Swedish Medical Birth Registry for the years 1973-1981. This
diagnosis was present in a little over 3 per thousand deliveries in the registry but its
prevalence varied enormously between different hospitals, from over 1% to practi-
cally nil. The diagnosis was over-represented at low maternal age and first parity
and when the infant was a girl. Twinning occurred at a significantly increased rate.
Gestational length was somewhat shorter and birthweight was lower than expected
but this had no effect on perinatal survival. Congenital malformations were present
slightly more often than expected and this was due to three diagnoses: undescended
testicles, hip dysplasia, and Down syndrome. Possible explanations for this excess
are discussed.

Hyperemesis; Epidemiology; Registry; Malformation

Introduction

Morning sickness is a common complaint during pregnancy and shows varying

degrees up to the state of hyperemesis gravidarum, often necessitating hospitaliza-
tion. Some interest has been paid to the possible adverse effect of this condition on
embryonic or fetal development and the origin of birth defects. This is of special
interest because antiemetic drugs (mainly antihistamines) are often used to relieve
the symptoms, and many studies have been published suggesting a statistical
association between the use of such drugs and the birth of malformed infants, but

Correspondence: Professor Bengt KU&, Department of Embryology, Biskopsgaten 7, S-223 62 Lund,

Sweden.

0028-2243/87/$03.50 0 1987 Elsevier Science Publishers B.V. (Biomedical Division)

292

such reports have also been contradicted [l]. The possible teratogenicity of such
drugs can be confounded by a direct effect of the underlying condition.
Fairly few studies have been published investigating the effect of morning
sickness or hyperemesis on pregnancy outcome. Many studies (e.g. Refs. 2-5) point
out the lower rate of morning sickness and antiemetics use in women whose
pregnancies lead to spontaneous abortion than in women who give birth. There is
more uncertainty about a possible relationship between vomiting and malforma-
tions. Dijring and Hossfeld [6] reported that 4% of infants of 649 women with
hyperemesis gravidarum were malformed while the control group without hyper-
emesis (8422 women) showed only a 1.5% malformation rate. Other studies [7]
found no evidence for such an association, but some [4] using prospectively
collected information did. This was nearly exclusively due to an association between
congenital hip dysplasia, morning sickness, and antiemetic use. No association
between morning sickness and facial clefts has been found [8,9]. Using prospective
data collected in the Collaborative Perinatal Project, an odds ratio of 1.4 was found
for major malformations when women who vomited were compared with women
who did not, but the risk increase was not statistically significant [lo].
Information on morning sickness has usually been retrieved prospectively or
retrospectively by questionnaires or interviews. In the prospectively collected data
no major information bias will exist, but this may be the case in retrospectively
collected information. The rate of morning sickness recorded in the different studies
varies considerably and obviously depends on the definition used. Some examples:
in retrospective data [8], moderate nausea occurred in 15-18% of cases and
controls; in a prospective study morning sickness was registered in 72%, severe
enough to justify the use of antiemetics in 14% [4]. A small prospective study from
the years 1973-74 showed the same rate of morning sickness (71%) but less than
10% used antiemetics [ll]. Other prospective data recorded vomiting in 56% of the
women and 15% received antiemetics [5,10]. All these data were collected in the
1960s when antiemetic use was more prevalent than nowadays.
When a very common complaint such as morning sickness is studied, it is
unlikely that anything but very weak associations can be found. The use of
antiemetic drugs may signify a more severe condition, but its definition is still
uncertain and in studies on fetal effects the possible teratogenicity of the drugs will
complicate the interpretation. The definition of hyperemesis, a condition severe
enough to necessitate hospitalization, is somewhat more distinct, but it is also
relatively rare. A drop in the prevalence of hyperemesis from 2.4% to 0.6% was
noticed in the period 1936 to 1960, ascribed at least in part to the use of anti-nausea
drugs [12]. In the prospective Collaborative Perinatal Project [5], 188 women were
classified as having hyperemesis among 9098 women who had their first pregnancy
in the project and were enlisted before week 14. As hyperemesis may favour early
enlisting, the rate of more than 2% may be an overestimate; as these women were
drawn from a total population of some 56000 women, the rate may be anything
down to 3 per 1000.
A registry study is presented here on the delivery outcome in women who had the
diagnosis of hyperemesis during pregnancy, using the Swedish Medical Birth
Registry, 1973-1981.
 293

Material and methods

The Medical Birth Registry consists of a computerization of the summaries of

standard medical records used in Sweden for maternity health care, delivery and the
examination of the newborn infant. The summaries are prepared for information
exchange between various medical units but a copy is sent to the National Board of
Health and Social Welfare in Stockholm, and the Medical Birth Registry is built
from these copies. They contain among other things diagnoses given during preg-
nancy coded according to the International Classification of Diseases, Injury, and
Death, 8th Edition. Hyperemesis gravidarum has the code 638. From nearly one
million births, all women who had that diagnosis were selected; a total of 3068
pregnancies, which represents a prevalence of about 3 per 1000.
In order to evaluate the variability of the diagnosis, its distribution between
hospitals was studied. The following variables were studied and compared with the
total population: maternal age, parity, twinning rate, infant sex, birthweight distri-
bution, pregnancy length distribution, infant survival, incidence of congenital
malformations.
The observed numbers were compared with expected numbers from the total
registry, sometimes after standardization for other variables.

Results

1. Variability in the diagnosis of hyperemesis

Fig. 1 shows the inter-hospital variability in the diagnosis of hyperemesis. The

variability is immense, with some large hospitals giving this diagnosis to more than
1% of the women, other large hospitals to practically none. This variability and the
variability in malformation registration makes it necessary to standardize for
delivery unit in the analysis. Fig. 2 shows the changes with the year of birth during
the period studied after standardization for hospital participation. An increasing
rate of the diagnosis is seen during the years 1973-76 and after that the rate is fairly
constant. As some variables to be studied vary with year of delivery (e.g., birth-
weight, maternal age), standardization for year of delivery will also be done.

2. Maternal age and parity

Fig. 3A, B shows the maternal age and parity distributions, respectively, among
the women with a diagnosis of hyperemesis and the total registry population. A shift
towards younger maternal age and parity 1 is seen. As these two variables co-vary,
the effect of each one after standardization for the other (and year of birth and
infant sex) was calculated (Fig. 4A, B). Both variables show a significant although
not strong effect, with an approx. 1.3 relative risk in teenage pregnancies and a
slight (1.07) risk at parity 1.
294

Number of hyparemes is
350

.
300

250
.
200

100

50

0
0 5 10 15 20 25 30
Number of births, thousands

Fig. 1. Diagram showing the number of births and the number of women with the diagnosis of
hyperemesis in different hospitals in Sweden, 1973-1981. Each cross represents a hospital with a total
birth number exceeding 1OCQ The whole line represents the average rate, and its approximate 95%
confidence limits are given with dotted lines.

Ratto
1.5
1
L

.s 1

73 74 75 ?6 77 70 79 00 81
Year of delivery

Fig. 2. Ratio between observed and expected numbers of women with the diagnosis of hyperemesis each
year, 1973-1981, standardized for delivery unit. Approximate 95% confidence limits are given.
 295

Per cent
50
1

I-iyperemes is ,, Total

20 25 30 35 40 45 50
Maternal age

Per cent
60

Hyperemes i s
50

40
Total

30

20
;-:

10

0
1 2 3 4 5+
Parfty _

Fig. 3. Maternal age distribution (5-year intervals, 15-19 etc.) (A) and parity distribution (B) for the
cohort with the diagnosis of hypermesis and for the total population.

3. Twinning rate

The increased risk of emesis at twinning is well known. In the present data set
there were 116 twins in 57 complete pairs and two single twins, that is, twins
296

Ratio
1.5-

.5
15 20 25 30 35 40 45
Maternal age

Ratio
1.15 I-

1.1

1.05 /-

.95

.9

.a5

.0

.75

.7
1 2
Parity

Fig. 4. A. Ratio between observed and expected numbers of women in each 5-year maternal age group.
Expected numbers are calculated from the total material after standardization for the year of birth, infant
sex, and parity. B. Ratio between observed and expected numbers of women in each parity group.
Expected numbers are calculated from the total material after standardization for the year of birth, infant
sex, and maternal age.
 297

lacking a co-twin. Among the complete pairs, 46 were like-sexed (24 male-male, 22
female-female), 11 unlike-sexed. The expected number of complete twin pairs from
the population, after standardization for maternal age and parity, is 18.8 like-sexed
pairs and 6.8 unlike-sexed. The 2.2-times risk increase in the hyperemesis group is
thus statistically significant for ah twin pairs (&i-square = 38.9 at 1 d.f., p < 0.001)
and the 2.4-times risk increase for like-sexed pairs is also significant (&i-square =
39.4 at 1 d.f., p -CO.OOl), but for unlike-sexed pairs, the risk increase is somewhat
lower (1.6 times) and not statistically significant (&-square = 2.2 at 1 d.f., p > 0.05).
This difference may, however, be random.
The high rate of like-sexed twin pairs indicating a 61% monozygote rate (accord-
ing to Hardy-Weinbergs law) differs significantly from the rate in the total
population, where the monozygote rate is only 44.9% (&i-square = 6.3, 0.05 > p >
O.Ol), but this is due to the aberrant maternal age/parity distribution. If this is
compensated for, the statistical significance disappears (&i-square = 1.5, N.S.).

4. Infant sex

Among the 3182 infants born, 1486 were males, 1694 were females, and two were
of unknown sex. Thus only 47% of the infants were males, statistically significantly
fewer than expected from the population 51% rate (&i-square = 29.0, p < 0.001). It
can be seen that the sex rate among the twins was normal (0.51) but the difference
in sex rate between singletons and twins may be random (cm-square 0.83, N.S.).

5. Birthweight

Birthweight was studied among singletons after standardization for maternal age,
parity, year of birth, and infant sex. Fig. 5 shows the intensity ratio in each 500 g
birthweight class. It can be seen that there is an excess of infants weighing
2000-2499 g but too few infants weighing between 1000 and 1499 g. Low birth-
weight (< 2500 g) was found in a total of 143 infants; the expected number from the
population is 116.7, &i-square = 5.9, 0.05 > p > 0.01.

6. Length of gestation

Length of gestation was studied in a similar way. Fig. 6 shows the intensity ratio
for each two-week period. A moderate excess is seen for somewhat short preg-
nancies (36-40 weeks) but not for very short pregnancies (below 36). The excess for
< 38 weeks gestations is statistically significant (381 found, 283.9 expected, chi-
square = 11.1 at 1 d.f., p < 0.001).

7. Infant survival

Among all 3182 infants, 15 were stihbom and 12 were livebom but died during
the first week of life. Expected numbers, calculated after standardization for year of
birth, maternity age, parity, and delivery unit, were 17 and 15, respectively. Thus no
298

Ratio

0 1 2 3 4 5
Blrthweight, kg

Fig. 5. Ratio between observed and expected numbers of infants in each 500 g birthweight class (O-499,
SK-999 g etc). Expected numbers are calculated from the total material after standardization for the
year of birth, infant sex, maternal age, and parity.
Ratio
2

1.5

.5

I
0 I

26 20 30 32 34 36 30 40 42 44
Length of gestation, weeks

Fig. 6. Ratio between observed and expected numbers of infants in each two weeks gestational age class
(26-27 weeks etc.) Expected numbers are calculated from the total material after standardization for the
year of birth, infant sex, maternal age, and parity.
 299

excess in perinatal death rate was seen, in spite of the lower birthweight and the
higher twinning rate in the study population.
8. Congenital malformations
One hundred and eighty-six infants (5.8%) had a malformation diagnosis, which
is slightly more than expected (5%); the difference reaches statistical significance
(&i-square = 4.5 at 1 d.f., p -C0.05).

TABLE I

List of malformation diagnoses in 3182 infants born of women with hyperemesis. Diagnoses taken from
Medical Birth Registry, sometimes supplemented with the Registry of Congenital Malformations

Diagnosis Number of infants

Infants with single malformations

preauricular appendix
branchial cyst
ventricular septal defect 2
FalIots tetrad with systemic vein malformation
patent ductus arteriosus 6
unspecified cardiac defects 15
two umbilical vessels 2
nose malformation
pulmonary malformation
bilateral cleft lip and palate
tongue malformation 2
anal atresia
omphalocele or diaphmgmatic hernia 2
unspecified gastrointestinal malformation 2
undescended testicle 21
hypospadias 4
hydrocele testis 11
polycystic kidney 1
hydronephrosis
talipes 12
postaxial polydactyly, hand
syndactyly 3
congenital preluxation of hips 60
craniostenosis 1
unspecified face/skull malformation 1
chondrodystrophy
nevus 8
unspecified skin malformation 1

Infants with complex malformations or syndromes

Down syndrome 9
de Lange syndrome 1
Poland syndrome 1
esophageal atresia and microcephaly 1
cleft lip and palate and unspecified cardiac defect 1
unspecified muitiple malformations, including anal atresia 1
prune belly syndrome 1
asymmetrical face and unspecified facial and gastrointestinal
malformations 1
300

Table I shows the malformation diagnoses registered in the Medical Birth

Registry. For some but not all infants with an unspecified malformation diagnosis
in the registry, further details could be retrieved from the Registry of Congenital
Malformations which has a higher diagnostic accuracy [13].
There were 24 cardiac defects, close to the expected number [22]. One would
expect 5 or 6 hypospadias, and four were found. Twenty-one infants had un-
descended testicles. This figure is high, roughly twice the one expected, but the
diagnosis in the newborn period is uncertain. There were 60 infants with congenital
hip dysplasia. If the expected number is calculated, standardizing for maternal age,
year of birth, and delivery unit, it is found to be 47. The increase just reaches
statistical significance (&i-square = 3.6 at 1 d.f., p = 0.05).
Nine infants with Down syndrome were registered, which is nearly three times
the expected number; when standardized for year of birth, maternal age and parity,
the expected number is 3.2 (0.05 > p > 0.01).

Discussion

The diagnosis of hyperemesis in the Medical Birth Registry is obviously not well
defined, as a large variation in the recorded rate exists between different hospitals.
A variability in the recording of vomiting during pregnancy in different geographi-
cal areas has been described [5]. The average rate of hyperemesis of a little more
than 3 per 1000 in this study is lower than the previous estimate published [12]. It
may be due to different diagnostic criteria, an underestimate in the present study, or
a continued decline in the hyperemesis rate. It is likely that the present material is
somewhat diluted by not very severe cases and the recorded effects are probably
underestimates.
No effects of vomiting during pregnancy or use of antiemetics has been found on
birthweight or gestational length [4,5]. In this study, clear-cut but moderate effects
of hyperemesis were seen on both variables but it should be stressed that this was
not valid for very low birthweight or very short gestational length infants, and no
effect on perinatal mortality was found.
The effects of maternal age and parity resemble those previously described at
pregnancy vomiting (e.g. Ref. 5). Similarly, the increased rate of twinning agrees
well with what has been described for vomiting during pregnancy. This effect is
usually explained by a higher hormone concentration, especially of human chorionic
gonadotropin (hCG), in twin pregnancies, as a relationship between hCG level and
vomiting in pregnancy has been proposed although some authors could not verify it
[14,15]. An increased hCG level during pregnancies with hyperemesis compared to
non-emesis pregnancies has been described, however [16].
The excess of girls among infants born after a pregnancy with hyperemesis fits
with the idea of endocrine effects on the conditions: fetal androgens could counter-
act the described estrogen effect on emesis [17].
It is reasonable to suppose that the high hCG and other hormone levels are due
to a selection of feto-maternal pairs with a strong hormone production from the
placenta. This would fit with the observation that vomiting is less frequent in
women who will miscarry than in other pregnant women.
 301

There are two indications of estrogen effects on the infants born after hypereme-
sis. One is the increased rate of infants with congenital dysplasia of the hip. The
association in this population is not very strong and has a borderline statistical
significance, but agrees with a previous finding [4] of an association between
antiemetic use and the birth of an infant with this condition. The other is the
doubling of the rate of undescended testicles. This observation is in itself not very
important, as the diagnosis cannot be made with certainty in the neonate, but
similar findings have been made on definite cases of undescended testicle (to be
published). Exogenous estrogen may increase the risk of undescended testicle [18],
and the higher estrogen level during pregnancy in nulliparous women compared to
parous women [19] and the increased rate of undescended testicles in first-born
infants has also been taken as evidence for an estrogen effect.
The association between these two conditions and hyperemesis may thus have a
direct explanation from the endocrine mechanisms involved. It is more difficult to
understand the excess of infants with Down syndrome. There are some possible
explanations. One is that it is a random phenomenon: many different types of
malformation have been studied and one of them may randomly show an excess.
Theoretically, the Down placenta may produce more hCG or other hormones
causing hyperemesis than a chromosomally normal placenta does. A third specula-
tive but rather interesting possibility is that the association is the result of a
selection process. We know that a substantial proportion of Down embryos and
fetuses are aborted spontaneously, some estimates say 80% [20]. Perhaps those
variants that have the best functioning placenta with the highest hormone produc-
tion will have an advantage and survive to birth, which could cause a selection of
high hCG producers and an associated hyperemesis. If true, a similar relationship
could exist for other malformations with a high prenatal selection rate, and an
association between the birth of a malformed infant, vomiting, and perhaps use of
antiemetics would occur.
With the exception of the three malformation conditions just discussed, no
association between hyperemesis and malformation is seen in the present material.
This agrees with most studies on the relationship between pregnancy vomiting and
malformations (cf. Ref. lo), but it should be realized that such evaluations are based
on cohort studies where the number of infants with specific types of malformation is
very low. Most severe malformations occur at a rate less than 1 : 1000, and a
possible association with vomiting or hyperemesis can only be demonstrated with
the aid of case-control techniques, and even these must be large. Thus, for instance,
a case-control study on 146 cases of undescended testicle [21] found hyperemesis in
only one case and one control and obviously could not detect an association of the
type we found.

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