Severity and duration of nausea and vomiting symptoms in pregnancy and spontaneous abortion.
ABSTRACT Earlier studies have shown an inverse association between the presence of nausea and vomiting in pregnancy (NVP) and spontaneous abortion (SAB), but no study to date has examined the effects of symptom duration on the risk of SAB.
We examined NVP symptom severity and duration in relation to the occurrence of SAB. Data were collected from 2407 pregnant women in three US cities between 2000 and 2004 through interviews, ultrasound assessments and medical records abstractions. Discrete-time continuation ratio logistic survival models were used to examine the association between NVP and pregnancy loss.
Lack of NVP symptoms was associated with increased risk for SAB [adjusted odds ratio (OR) = 3.2, 95% confidence interval (CI): (2.4, 4.3)], compared with having any symptoms. Reduced risks for SAB were found across most maternal age groups for those with NVP for at least half of their pregnancy, but the effects were much stronger in the oldest maternal age group [OR = 0.2, 95% CI: (0.1, 0.8)].
The absence of NVP symptoms is associated with an increased risk of early pregnancy loss. As symptom duration decreases, the likelihood of early loss increases, especially among women in the oldest maternal age group.
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ABSTRACT: Studies have suggested that nausea and vomiting of pregnancy (NVP) may confer favorable pregnancy outcome, when compared to women not experiencing NVP. However, this was never examined systematically.Reproductive Toxicology 05/2014; · 2.77 Impact Factor
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ABSTRACT: Pregnancy sickness is widespread in human mothers but its etiology, somewhat surprisingly, remains unclear. Human chorionic gonadotropin (hCG) has long been considered a prime hormonal suspect, but the correlation between pregnancy sickness and hCG levels is imperfect resulting in uncertainty about its causal role. As others have noted part of this uncertainty likely stems from the structural and functional diversity of hCG. One enigmatic role of hCG is its action as a thyroid stimulator during early gestation. Native hCG is weakly thyrotropic but is produced in prodigious quantities and suppresses the production of thyroid stimulating hormone (TSH) but not curiously when TSH levels are in the higher deciles. Higher levels of hCG induce higher maternal production of thyroxine (T4). hCG thus appears to augment and sometimes even supplant TSH in the regulation of thyroid hormone in early gestation. This has lead to the suggestion that hCG serves as a backup system, albeit incomplete, for the production of essential thyroid hormone during pregnancy. Another interpretation, however, is that hCG, produced by the embryo, serves as a second control circuit for the thyroid during pregnancy. If so, it serves embryonic interests that are at odds with maternal interests (maternal-embryo conflict) under conditions of iodine deficiency. Iodine is an essential micronutrient for neurodevelopment and thyroid function, and has been in short supply for most humans over most of our evolutionary history. Iodine deficiency during gestation has severe impacts on embryo neuromotor development, but also induces thyroid disease in mothers, impairing her future reproductive prospects. Under this view, embryos use hCG to push mothers to release more thyroid hormone. hCG, however, is produced outside the normal maternal thyroid control circuit and thus is not subject to a normal negative feedback. hCG also serves multiple functions simultaneously therefore its production is likely not fine-tuned for thyroid function per se. hCG levels may remain high even when thyroid hormone production is more than sufficient to meet the needs of mother and embryo. Instead, the system appears to be regulated at the back end by clearing surplus hormone using placental Type II (D2) and Type III (D3) deiodinases. As maternal thyroid hormone levels rise, placental D3 is upregulated, shunting more T4 and T3 into a deactivating pathway. The metabolites that result, particularly the inert metabolite of T4, reverse T3, are correlates of surplus thyroid hormone production and thus are strong candidates for the proximate triggers of pregnancy sickness. Nausea and vomiting of early pregnancy thus arises as a by-product of an antagonistic pleiotropy between mother and embryo over the allocation of iodine: when dietary iodine is scarce, a benefit accrues to the embryo at a cost to mother; when iodine is plentiful, pregnancy sickness ranging from frequently mild to occasionally severe, is a sequelae of undiminished embryonic demands. If pregnancy sickness serves as a marker of thyroid function, an absence of first trimester nausea and vomiting sickness may indicate a higher priority for testing of thyroid function to avert the inimical effects of hypothyroidism during gestation.Journal of Theoretical Biology 01/2014; 355:61–67. · 2.30 Impact Factor
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ABSTRACT: Background/aims: Nausea and vomiting of pregnancy (NVP) impact in the pregnant woman´s quality of life, especially when are persistent or severe. The objective is to estimate the prevalence and factors associated with the persistence of NVP in each trimester of pregnancy.Methods: We studied a cohort of 263 pregnant women with gestational age < 12 weeks. Data were collected using the Gastro- Esophageal Reflux Questionnaire validated for use in the Spanish population. Data were collected through telephone interviews at the end of each trimester of pregnancy. The main variable was the presence of NVP in each trimester and their persistence along the pregnancy.Results: The prevalence of nausea in the each trimester was 63.5 %, 33.8 %, 26.2 %, and vomiting was 29.3 %, 22.1 %, 14.1 %, respectively. Factors associated with nausea in the first trimester were Latin-American origin (OR: 3.60, 95 %IC 1.61- 80.5) and primary education (OR: 0.31; 0.13-0.73); vomiting was associated with Latin-American origin (OR: 13.80, 1.82-104.4) and was inversely associated with weight gain (OR: 0.58, 0.35-0.97). Persistence of NVP were only associated with suffering the symptom in the previous trimester (p < 0.01), and did not find other predictor factors.Conclusions: NVP´s prevalence declines along pregnancy, is associated with race and inversely with weight gain, and its persistence over time cannot be predicted.Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva 05/2014; 106(5):318-324. · 1.32 Impact Factor
ORIGINAL ARTICLE Reproductive epidemiology
Severity and duration of nausea and
vomiting symptoms in pregnancy and
Ronna L. Chan1,2,*, Andrew F. Olshan2,3, David A. Savitz4,5,
Amy H. Herring3,6, Julie L. Daniels1,2, Herbert B. Peterson1,7,
and Sandra L. Martin1
1Department of Maternal and Child Health, School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599,
USA2Department of Epidemiology, School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
3Carolina Population Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA4Department of Preventive
Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA5Present address: Department of Community Health, Department of
Obsterics and Gynecology, Brown University, Providence, RI 02912, USA6Department of Biostatistics, School of Public Health, The
University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA7Department of Obstetrics and Gynecology, School of Medicine,
The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
*Correspondence address. Department of Epidemiology, Gillings School of Global Public Health, The University of North Carolina at Chapel
Hill, CB# 7435, McGavran-Greenberg Hall, Chapel Hill, NC 27599-7435, USA. Tel: +1-919-843-0441; E-mail: firstname.lastname@example.org
Submitted on January 5, 2010; resubmitted on August 6, 2010; accepted on August 27, 2010
background: Earlier studies have shown an inverse association between the presence of nausea and vomiting in pregnancy (NVP) and
spontaneous abortion (SAB), but no study to date has examined the effects of symptom duration on the risk of SAB.
methods: We examined NVP symptom severity and duration in relation to the occurrence of SAB. Data were collected from 2407
pregnant women in three US cities between 2000 and 2004 through interviews, ultrasound assessments and medical records abstractions.
Discrete-time continuation ratio logistic survival models were used to examine the association between NVP and pregnancy loss.
results: Lack of NVP symptoms was associated with increased risk for SAB [adjusted odds ratio (OR) ¼ 3.2, 95% confidence interval
(CI): (2.4, 4.3)], compared with having any symptoms. Reduced risks for SAB were found across most maternal age groups for those with
NVP for at least half of their pregnancy, but the effects were much stronger in the oldest maternal age group [OR ¼ 0.2, 95% CI: (0.1, 0.8)].
conclusions: The absence of NVP symptoms is associated with an increased risk of early pregnancy loss. As symptom duration
decreases, the likelihood of early loss increases, especially among women in the oldest maternal age group.
Key words: spontaneous abortion / miscarriage / nausea and vomiting / pregnancy
Nausea and vomiting in early pregnancy (NVP) affects 50–90% of
women (Klebanoff et al., 1985; Klebanoff and Mills, 1986; Tierson
et al., 1986; Lacroix et al., 2000; Chan et al., 2009) and is commonly
the earliest symptom of pregnancy. Severity of symptoms, timing of
symptom onset and duration vary both among women and across
multiple pregnancies of a woman. Symptoms can begin as early as
2–4 weeks’ gestation (Gadsby et al., 1993; Lacroix et al., 2000) and
commonly resolve by 20 weeks’ gestation (Gadsby et al., 1993; Brous-
sard and Richter, 1998), but may continue to affect up to 20% of
women beyond 20 weeks’ gestation (Broussard and Richter, 1998).
The pathogenesis of NVP is poorly understood, but has been attrib-
uted to rises in the serum levels of human chorionic gonadotrophin
(hCG) and estrogen (Jarnfelt-Samsioe et al., 1983; Cunningham
et al., 2005). A number of maternal characteristics, including primipar-
ity (Bashiri et al., 1995), younger maternal age (Klebanoff et al., 1985;
Bashiri et al., 1995) and lower education (Klebanoff et al., 1985) have
been associated with NVP, and higher maternal BMI has been ident-
ified as a risk factor for vomiting (Klebanoff et al., 1985).
Spontaneous abortion (SAB) is defined as a pregnancy loss before
20 completed weeks’ gestation. While ?10–14% of all clinically
recognized pregnancies result in SAB (Wilcox et al., 1985; Wilcox,
2010), the actual rate of pregnancy loss, as shown with the use of bio-
chemical assays, is actually two to five times higher (Ellish et al., 1996;
Forbes, 1997; Wilcox et al., 1999). Current knowledge on causes of
early pregnancy loss is limited, but two consistent risk factors are
older maternal age and history of previous pregnancy loss (Andersen
& The Author 2010. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved.
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Human Reproduction, Vol.25, No.11 pp. 2907–2912, 2010
Advanced Access publication on September 22, 2010 doi:10.1093/humrep/deq260
et al., 2000; de La Rochebrochard and Thonneau, 2002; George et al.,
2006). Many earlier studies that examined the association between
NVP and SAB (Jarnfelt-Samsioe et al., 1983; Klebanoff et al., 1985;
Tierson et al., 1986; Weigel and Weigel, 1989a,b; Weigel et al.,
2006) have methodological limitations. These include aspects of par-
ticipant selection criteria, sample size, ascertainment of NVP infor-
mation and classification of NVP symptoms and analytical approach.
These differences in study design and analysis make comparison and
interpretation of results difficult. Most importantly, no earlier study
has examined the association between symptom duration and SAB.
We recruited a large cohort of women early in gestation or before
they conceived so early clinically detectable pregnancy losses could be
identified. We were able to collect detailed prospective data on the
pregnancy, characteristics and timing of nausea symptoms and vomit-
ing episodes, behavioral factors and other maternal characteristics.
Using these data, we examined the association between severity
and duration of NVP and SAB.
Materials and Methods
Some of our methods have been described elsewhere (Promislow et al.,
2004; Savitz et al., 2005, 2006; Chan et al., 2009). We identified and
recruited women who were newly pregnant and women who were
trying to conceive from Raleigh, NC; Memphis, TN and Galveston, TX.
Women were recruited from prenatal clinics and community locations
(e.g. grocery stores, libraries, coffee shops, churches) between 2000 and
2004 for a prospective cohort epidemiological study (right from the
start) that examined the relationship between drinking water disinfection
by-products and early pregnancy loss. Women were eligible to be in the
study if they were at least 18 years old and pregnant at ,12 weeks ges-
tation or had been attempting pregnancy for fewer than 6 months. The
recruitment process has been described in detail elsewhere (Promislow
et al., 2004; Savitz et al., 2005, 2006). All women completed a screening
interview to determine eligibility.
An early pregnancy endovaginal ultrasound was sought around 9 weeks’
gestation (median gestational age at ultrasound ¼ 9.3 weeks) to confirm
pregnancy viability and to ascertain the gestational age of the fetus. We
found that self-reported last menstrual period (LMP) in this cohort was
highly reliable based on the comparison of self-reported LMP and ultra-
sound dating (Savitz et al., 2005, 2006); therefore, self-reported LMP
was primarily used to calculate gestational age. Ultrasound dates were
used (18%) only when they differed from self-reported dates by more
than 7 days or when LMP was not known.
Detailed interviews took place at baseline (shortly after enrollment but
at no later than 16 weeks’ gestation) and at follow-up (between 20 and 25
weeks’ gestation) to collect more detailed information on health beha-
viors, medical and reproductive history, and current pregnancy history
and symptoms such as NVP. All women provided this information regard-
less of their pregnancy outcome; women who experienced an SAB before
a scheduled interview were contacted for an interview as soon as possible,
and the language in the interview was amended to take into consideration
the pregnancy loss.
Timings of onset (start of NVP symptoms) and ending dates were col-
lected separately via self-report for symptoms of nausea and vomiting epi-
sodes, noting the month, day and year. For those who were unable to
recall the exact day of onset, we collected timing information with
respect to ‘week in the month’ and we imputed the day as the mid-point
of the week. We assigned symptom ending date at 20 weeks for women
whose symptoms had not subsided at the time of the interview (26%
nausea only; 13% both nausea and vomiting).
Absence or presence of NVP symptoms, whether nausea alone or with
the addition of vomiting episodes, was used to characterize symptom
severity into: (1) no symptoms, (2) nausea only and (3) nausea symptoms
with vomiting episodes. Because symptom start and ending dates and the
time period in which each individual was considered to be at risk for NVP
varied, duration was a time-varying covariate for each individual and was
categorized as: (1) no symptoms by week j, (2) having NVP for ,half of
pregnancy at gestational week j and (3) having NVP for ≥half of pregnancy
at gestational week j. Pregnancy outcome data were ascertained via par-
ticipant self-report, with confirmation through medical record abstraction
and/or with the presence or absence of corresponding vital records for
the pregnancy. We defined SAB as a loss of a pregnancy before 20 com-
pleted weeks’ gestation from LMP.
We used a discrete-time continuation ratio logistic survival model (Cole
and Ananth, 2001; Singer and Willett, 2003; Rodriguez, 2008) to examine
pregnancy loss in relation to symptoms of NVP. Adjusted odds ratios
(ORs) and 95% confidence intervals (CIs) were generated for the con-
ditional probability of having a pregnancy loss in a given gestational
week, conditional on a woman’s pregnancy having survived to the begin-
ning of that gestational week. Pregnancies were followed from the time
of enrollment into the study and contributed to the risk set until 20
weeks’ gestation, time of SAB or last point of study contact for those
loss-to-follow-up, whichever came first.
Two distinct discrete-time survival models were used to estimate the
sub-classes (one model for severity and another for duration) of symp-
toms of NVP in relation to early pregnancy loss. The covariates that we
considered were identified using a directed acyclic graph; these were
known to be predictors of pregnancy loss, including maternal age (Ander-
sen et al., 2000; de La Rochebrochard and Thonneau, 2002), race and eth-
nicity (Wen et al., 2001), maternal education, marital status, smoking
(Parazzini et al., 1997), alcohol use (Henderson et al., 2007), BMI
(Lashen et al., 2004; Metwally et al., 2008), age at menarche (Parazzini
et al., 1997), parity (Wen et al., 2001) and pregnancy loss history
(George et al., 2006). Effect measure modifiers were evaluated by com-
paring stratum-specific estimates of each covariate of interest along with
examination of the likelihood ratio test using a criterion of P , 0.15. Cov-
ariates that were deemed not to be modifiers were then examined next as
potential confounders. Covariates were retained as confounders in the
final models if they changed the effect estimates for the exposure of inter-
est by .10% when removed from the model. In each model, maternal
race and ethnicity, maternal education, marital status, alcohol use, age at
menarche, parity and pregnancy loss history were evaluated as potential
confounders; maternal age was included as an effect measure modifier.
All statistical analyses were conducted using SAS (SAS Institute Inc.,
Cary, NC, USA). This study was reviewed and approved by The
UNC-Chapel Hill Public Health Institutional Review Board (study
A total of 2766 women were enrolled into the study, with ?10% (n ¼
252) pre-enrolled into the study before becoming pregnant. Of these,
32 women withdrew from the study. We excluded 227 women for
ineligibility due to being .12 weeks’ gestation at the time of enroll-
ment, being lost to follow-up (unreachable by study staff for .7
weeks) or relocating outside the study areas. We further excluded
69 women with second or third study pregnancies, 8 with invalid
key data elements for pregnancy dating and 23 with multiple gestation
pregnancies. These exclusions resulted in a total of 2407 women in
the final analysis (Chan et al., 2009).
Chan et al.
The majority of the study participants (82.5%) were recruited
from the Raleigh or Memphis study areas. Mean age at enrollment
was 27.8 years (SD ¼ 5.5) and mean gestational age at enrollment
was 54.8 days (SD ¼ 14.0). Although non-Hispanic White women
made up over 50% of the cohort, a substantial proportion (31.7%)
was non-Hispanic Blacks. Very few women reported being smokers
or consumers of alcohol during pregnancy (Chan et al., 2009).
Approximately 45% were considered overweight or obese prior to
pregnancy based on the World Health Organization cutpoints
(World Health Organization). Almost half were nulliparious and 21%
reported having had a prior pregnancy loss (Table I). There were
258 (10.7%) SABs in this study population, and percent SAB did not
vary by study site.
As stated in an earlier report (Chan et al., 2009), 89% of the
women in this cohort experienced some form of NVP, and more
than half (53.0%) report experiencing symptoms of nausea with vomit-
ing episodes (Table I). Further, onset for NVP was most likely to begin
in early pregnancy, with 99% of initial nausea symptoms and 95.3% of
initial vomiting episodes taking place in the first trimester (Chan et al.,
2009). When vomiting was at its worst, 51% reported vomiting once a
day and 13% reported having more than three vomiting episodes daily.
On average, women with both nausea and vomiting reported having
vomiting episodes 3.3 days each week when symptoms were con-
sidered ‘the worst’ by the women. The median onset time for
nausea symptoms was 5.7 weeks and that for vomiting episodes
was 7.0 weeks from LMP (data not shown) (Chan et al., 2009). The
overall mean symptom duration was eight gestational weeks.
Week-specific conditional probability of SAB by NVP status and
symptom duration is shown in Fig. 1. There was a 3- to 10-fold increase
in risk of first trimester pregnancy loss for women without NVP symp-
toms, compared with women who experienced some NVP symptoms;
however, the riskof SAB for women without NVP symptomsrevertsto
the baseline risk after the first trimester. Riskof SAB by week in the first
trimesterdid not differgreatlyfor womenwith ashorterduration(NVP
,half pregnancy at given week j) than those with a longer duration; no
difference in risk was seen between groups beyond the first trimester
based on duration of NVP symptoms.
Overall, women with no symptoms had three times the odds of
having an SAB [OR ¼ 3.2, 95% CI: (2.4, 4.3)] compared with
women with any form of NVP symptoms. Table II shows the results
,25 years old
25–29 years old
30–34 years old
≥35 years old
≥12 to ,16 years
$40 001–$80 000/year
Prepregnancy BMI (kg/m2)a
Normal weight (18.5–24.9)
Age at menarche
≤11 years old
12–13 years old
≥14 years old
Table I Sociodemographic characteristics, selected
maternal behavior, and reproductive histories of
women in analysis: Right from the Start (2000–2004),
n 5 2407.
Pregnancy loss history
No prior loss
≥1 pregnancy with no loss
≥1 pregnancy with ≥1 loss
Nausea symptoms only
Nausea and vomiting
Table I Continued
aBMI, body mass index, based on World Health Organization classifications.
bNVP, nausea and vomiting during pregnancy.
Nausea and vomiting and risk of spontaneous abortion
of modeling the week-specific odds of a woman having an early preg-
nancy loss for the different characteristics of NVP symptoms, stratified
by maternal age. Adjustment for the potentially confounding factors
did not materially alter the OR estimates. Compared with women
with nausea and vomiting, the OR for no NVP symptom and SAB
increased with increasing maternal age, from an OR of 4.0 [95% CI:
(2.1, 7.6)] for women ,25 years old to an OR of 11.7 [95% CI:
(4.5, 26.7)] for women 35 years and older (likelihood ratio test P ,
0.0001). An unvarying and more moderate pattern of association
was found across maternal age groups for having nausea symptoms
only, compared with nausea and vomiting. Maternal age also modified
the association between duration and SAB. Compared with no symp-
toms, longer duration (NVP ≥half pregnancy) was found to have a
much reduced odds for SAB among the oldest maternal age group
[OR ¼ 0.2, 95% CI: (0.1, 0.8) for ≥35 years old]. However, this
pattern of association was not observed in the younger age groups.
Fixed effects by study site did not alter the magnitude of association.
In a prospective cohort study, we examined the associations between
the subgroups of NVP and SAB in a population of women recruited
early in their pregnancy or women who were planning a pregnancy.
The prevalence of NVP (35.4% for nausea symptoms only, 53.0% for
both symptoms) was within the range for nausea symptoms only (20–
50%) and for both symptoms (48–80%) reported by previous cohort
studies (Kallen et al., 2003; Lagiou et al., 2003; Weigel et al., 2006);
the prevalences for nausea only and both nausea symptoms and
Figure 1 Week-specific conditional probability of pregnancy loss by NVP status and symptom duration, Right from the Start (2000–2004).
<25 years old25–29 years old
No symptoms5.7 (4.0, 8.0) 5.1 (3.6, 7.3)4.0 (2.1, 7.6)
Nausea only 2.4 (1.8, 3.3)2.5 (1.8, 3.4) 2.0 (1.5, 2.8)
NVP ,half pregnancy0.5 (0.4, 0.6) 0.5 (0.4, 0.6)1.0 (0.2, 1.7)
NVP ≥half pregnancy
Table II Unadjusted and adjusted OR on the association between NVPasymptom severity and duration and risk of
pregnancy loss and adjusted ORs stratified by maternal age: Right from the Start (2000–2004), n 5 2407.
NVP characteristicsMain effects modelModels with an interaction term (maternal age)
30–34 years old
≥ ≥35 years old
3.9 (1.9, 8.0)
2.0 (1.4, 2.9)
6.5 (3.2, 13.2)
2.5 (1.8, 3.6)
11.7 (4.5, 26.7)
3.4 (2.2, 5.4)
1.1 (0.6, 2.2)
1.3 (0.4, 4.6)
0.7 (0.4, 1.4)
0.5 (0.1, 2.1)
0.4 (0.2, 0.9)
0.2 (0.1, 0.8)0.2 (0.2, 0.3) 0.3 (0.2, 0.4) 1.0 (0.3, 3.4)
aNVP, nausea and vomiting during pregnancy.
bOR, odds ratio.
cCI, confidence interval.
dCompared with symptoms of both nausea and vomiting; models stratified by maternal age and adjusted for maternal race and ethnicity, education, marital status, alcohol use, age at
menarche, parity and pregnancy loss history.
eCompared with no symptoms; models stratified by maternal age and adjusted for maternal race and ethnicity, education, marital status, alcohol use, age at menarche, parity and
pregnancy loss history.
Chan et al.
in which recruitment took place exclusively in prenatal clinics (Gadsby
et al., 1993; Weigel et al., 2006). Symptom duration was found to be
within the range for mean duration (8–12 gestational weeks) as seen
portion of our cohort reported their symptoms lasting for 6 weeks or
less. This may be linked to our study design that collected symptom
data early in pregnancy, increasing the completeness of reporting and
thus may have included more short-duration symptom reports. We
observed an increase in risk for SAB that was limited to mid-first trime-
ster among women without NVP, and no observable difference in risk
was seen after the first trimester in this group compared with women
with NVP (regardless of duration). The gestational weeks during
which heightened weekly probability of SAB was seen, corresponded
to a critical window in embryonic and early fetal development for
In addition to confirming earlier findings that absence of NVP symp-
toms is associated with pregnancy loss, we also were able to provide
evidence that longer duration of symptoms reduced risk of pregnancy
loss. The mechanisms by which NVP predicts favorable pregnancy
outcome are not known; nevertheless, several different mechanisms
have been postulated to explain the reported feto-protective effect
of NVP. These include the role of NVP in reducing fetal exposure
to potential teratogens present in the maternal diet (Weigel and
Weigel, 1989a), improving the quality of maternal diets to favor the
consumption of certain nutrients, increasing energy expenditure that
alters hormonal balance in favor of maternal and fetal tissue growth
(Weigel and Weigel, 1989a; Coad et al., 2002), along with other
dietary pathways. Alternatively, one theory suggests NVP simply is a
reflection of maternal sensitivity to hormones (e.g. hCG) that them-
selves are related to pregnancy outcome (Stein and Susser, 1991;
Our findings also provided insights into the contribution of maternal
were found tobedifferentacrossmaternalagegroups. Therisk forSAB
related to no NVP symptoms increased with increasing maternal age.
Shorter symptom duration was associated with decreasing risk for
SAB as maternal age increases; the same pattern was seen in longer
symptom duration but the decrease in SAB in older women was
more marked compared with younger women. Some of the ORs
ation is warranted. It is known that the rate of pregnancy loss begins to
increase for women betweenages 30and 35,resultingfrom chromoso-
each having a different underlying biological process. While losses from
chromosomal abnormalities are related to the quality of the ovum and
the viability of the conceptus, chromosomally normal losses are likely
related to anatomical or physiological changes that occur with age.
women without NVP. The extent to which this explains the effect of
NVP on age-specific outcome is not known. The use of assisted repro-
duction techniques registries suggested strongly that the effect of
increasing age on early pregnancy loss is related to decreases in
oocyte and embryo quality (Schieve et al., 2003).
The strengths of this study include our ability to enroll from the
community (37%) and prospectively collect data from newly pregnant
women early in pregnancy, thus allowing for a more complete assess-
ment and minimizing misclassification from recall bias. Moreover,
studies of early pregnancy loss are subject to left truncation because
a proportion of the source population is excluded due to pregnancy
losses prior to recruitment (Hertz-Picciotto et al., 1989; Howards
et al., 2007); our analytical methods account for left truncation in mini-
mizing biased effect estimates due to participation differential by
Our analysis builds upon past research on the association between
NVP symptoms and SAB; nevertheless, limitations still exist in our
study regarding the information collected on NVP symptoms. First,
misclassification of exposure reporting and of the timing of NVP
from self-reported data could have occurred; however, because
NVP assessment took place prior to recognition of 71% of pregnancy
losses (the remaining 29% interviewed after loss), the potential for
recall error would be limited. Second, we imputed symptom ending
dates for 18% of women with any NVP symptoms who reported
that their symptoms had not subsided at the time of the interview;
even if symptom duration for them was calculated from an actual
ending date, the effect estimates would have been impacted minimally
because all women were censored by week 20, an end-point in the
gestational period that was reflective of a time when most symptoms
are expected to subside (Lacroix et al., 2000). Third, we did not
collect information daily on NVP symptoms; hence, we made assump-
tions that a woman’s symptom was always “nausea only” or always
“nausea and vomiting”. The variability in patterns of the NVP cycle
and the direct influences from such characteristics on SAB cannot
be directly addressed. Lastly, although we utilized community recruit-
ment and targeted recruitment at women who were early in their ges-
tation period or those who were not yet pregnant, we still could have
missed capturing women with subclinical pregnancy losses and a frac-
tion of clinically recognized losses because of missed enrollment,
potentially producing more imprecise estimates and underestimating
the magnitude of the associations.
In conclusion, we found, as have others, the presence of NVP
decreases the risk of SAB, with this decrease higher in women 30
years and older. We also found that the effect of symptom duration
is greatest among that group. With a more complete assessment of
the timing and occurrence of NVP and the use of biochemical
assays, we may achieve a better understanding of the biological and
physiological mechanisms of NVP and in turn, elucidate the possible
interplay between this common pregnancy phenomenon and modifi-
able risk factors (e.g. smoking, alcohol, environmental toxicants) as
well as non-modifiable risk factors (e.g. age, chromosomal karyotype)
associated with pregnancy loss.
The authors gratefully acknowledge Dr J. Chris Slaughter for useful
This study was supported jointly by the American Water Works
Association Research Foundation (AwwaRF) and the US Environ-
mental Protection Agency (USEPA) under Cooperative Agreement
Nos CR825625-01, CR827268-01 and CR828216-01.
Nausea and vomiting and risk of spontaneous abortion