Journal of Obstetrics and Gynaecology

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Biotin deficiency in hyperemesis gravidarum

Ayse Busra Onder, Suleyman Guven, Selim Demir, Ahmet Mentese & Emine
Seda Guvendag Guven

To cite this article: Ayse Busra Onder, Suleyman Guven, Selim Demir, Ahmet Mentese & Emine
Seda Guvendag Guven (2019): Biotin deficiency in hyperemesis gravidarum, Journal of Obstetrics
and Gynaecology, DOI: 10.1080/01443615.2019.1604640

To link to this article: https://doi.org/10.1080/01443615.2019.1604640

Published online: 23 Jul 2019.

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JOURNAL OF OBSTETRICS AND GYNAECOLOGY
https://doi.org/10.1080/01443615.2019.1604640

ORIGINAL ARTICLE

Biotin deficiency in hyperemesis gravidarum

Ayse Busra Ondera, Suleyman Guvena, Selim Demirb , Ahmet Mentesec and Emine Seda Guvendag Guvena
a
Departments of Obstetric and Gynecology, Faculty of Medicine, Trabzon, Turkey; bDepartment of Nutrition and Dietetics, Faculty of Health
Sciences, Trabzon, Turkey; cMedical Laboratory Techniques, Vocational School of Health Sciences, Karadeniz Technical University,
Trabzon, Turkey

ABSTRACT KEYWORDS
The aim of this study was to determine the serum biotin levels in patients with hyperemesis gravida- Biotin; hyperemesis
rum (HG). Ninety pregnant women with HG (mild (n ¼ 30), moderate (n ¼ 30) and severe (n ¼ 30)), and gravidarum; modified
80 pregnant women without HG were included for this study. In both groups, serum biotin levels were PUQE; pregnancy
measured. There were no statistically significant differences in demographic and clinical characteristics
between the HG groups and the control group except for PUQE scores. Serum biotin levels in all
hyperemesis gravidarum groups were statistically significantly lower than control group. Negative stat-
istically significant correlation between hyperemesis gravidarum severity and serum biotin levels was
noted. This is the first study that shows low serum biotin levels in women with hypereme-
sis gravidarum.

IMPACT STATEMENT
 What is already known on this subject? Almost 80% of pregnant women have nausea and vomit-
ing. If nausea and vomiting became severe and the symptoms combined with weight loss and
ketonuria; the diagnosis should be hyperemesis gravidarum (HG). The etiopathogenetic factors of
this unwanted condition have not been exactly known. Biotin is an essential water-soluble vitamin.
Biotin catabolism increases in pregnancy. Marginal biotin deficiency occurs in approximately 50%
of the gestations despite the “normal” biotin intake on the diet.
 What do the results of this study add? Current study results elucidated that serum biotin levels
were lower in HG cases compared to non HG cases. This study is the first study that reports the
association between low serum level of biotin and HG.
 What are the implications of these findings for clinical practice and/or further research?
Further research is needed to show the importance of biotin supplementation in women with
hyperemesis gravidarum.

Introduction Biotin is an essential water-soluble vitamin that acts as

The main symptoms of pregnancy are nausea and vomiting
(Tierson et al. 1986). Initially, nausea and vomiting starts
two–four weeks following fertilisation, the degree of the
symptoms reaches at the top at 9–16 weeks’ of gestation,
and resolves at 22 weeks’ of pregnancy. If these symptoms
became severe and combined with weight loss and keto-
nuria, the diagnosis should be hyperemesis gravidarum (HG)
(Zur 2013). Nowadays, HG is classified in three groups (mild,
moderate and severe) (Lacasse et al. 2008).
The reported prevalence of HG is up to 2.0% (Lee and
Saha 2011), and patients with electrolyte/water imbalance,
dehydration, ketonuria and weight loss should be hospital-
ised (Gazmararian et al. 2002).
The etiopathogenetic factors of this unwanted condition
have not exactly been known. Currently, it has been believed
that HG is derived from multifactors (such as organic, genetic,
endocrine, infectious, psychological, metabolic, placental fac-
tors) (Verberg et al. 2005).
cofactor for 5 carboxylase enzymes in mammals. These
enzymes have important role in the metabolism of protein,
lipids and carbohydrates. In response to biotin deficiency,
carboxylase activities are reduced proportionally (Tong 2013).
Enzyme deficiencies usually give serious clinical symptoms
below the level of 10-50% (Baur et al. 2002; Pacheco-Alvarez
et al. 2002; Stanley et al. 2002). Although the adequate intake
during pregnancy was reported as 30 lg/day, there are stud-
ies reporting various values in the literature between
30–200 lg/day (Mock et al. 1985, 1997).
Biotin catabolism increases in pregnancy. Mock et al. had
shown that marginal biotin deficiency occurred in about 50%
of the gestations despite the ‘normal’ biotin intake on the
diet (Mock et al. 2002). Because of severe nausea and vomit-
ing, these women cannot take adequate biotin with diet. The
serum biotin levels in women with HG have not been
reported previously.
The aim of this study was to determine the serum biotin
levels in patients with hyperemesis gravidarum.

CONTACT Suleyman Guven drsuleymanguven@yahoo.com KTU Tip Fakultesi, Farabi Hastanesi, Kadin Hastaliklari ve Dogum ABD, Trabzon 61080, Turkey
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
2 A. B. ONDER ET AL.
Methods
A total of 170 pregnant women (with HG (study group,
n ¼ 90), and without HG (control group, n ¼ 80)) between the
ages of 18–35 years who did not complete the 22nd gesta-
tional week at Department of Obstetrics and Gynaecology of
Karadeniz Technical University were included for this study.
Institutional ethic board approval was obtained for this pro-
spective age-matched case control study (Date: 9 March
2016, registration number: 2016/25). Signed inform consent
was obtained from all cases.
The diagnosis of HG cases was done based on following
criteria: (a) vomiting period 3 times/day, (b) weight loss
compared to pre-pregnancy 3 kg or 5%, and (c) ketonuria.
All women in the study group had all three criteria (Golberg
et al. 2007).
All cases answered and scored Modified PUQE questions
(Pregnancy-Unique Quantification of Emesis and Nausea,
Table 1) (Lacasse et al. 2008). HG cases were grouped in
three, according to the Classification of PUQE. Thirty preg-
nant patients with mild HG disease (total score <7 according
to PUQE Index), 30 pregnant patients with moderate HG dis-
ease (7–12 points according to PUQE Index), and 30 patients
with severe HG disease (total score 13–15 according to PUQE
Index) were included as study groups.
All cases received 400 mg of folic acid supplementation
from the preconception period until the 12th gestational
week and multivitamin supplementation after 12 weeks.
There was 200 mg of d-Biotin in commercially available
multivitamin tablets.
The exclusion criteria were: (1) not signing the informed
consent form, (2) multiple and molar pregnancy, (3) history
of the present illness (hypertension, diabetes, thyroid, cardio-
vascular diseases, liver and kidney failure, asthma,
Helicobacter pylori infection, etc.), (4) having abnormal thyroid
function test results, (5) the presence of other frequent
causes of nausea and vomiting such as urinary tract infection,
respiratory tract infection, etc, (6) regular drug use other than
vitamins and folic acid.
After an overnight fast of 8 h, serum samples were taken
from all cases between 08:00 and 09:00 h. Blood was collected
from the antecubital vein, 5 mL of maternal blood into a non-
heparinized tube, allowed to clot, centrifuged at 3000 g for
10 min, serum aspirated and stored at 20  C until analysis.
In both groups, serum biotin levels were measured spec-
trophotometrically using commercially available ELISA
(Enzyme-Linked ImmunoSorbent Assay, Catalogue number
K8140, Immun diagnostik, Germany) kits in the direction of
Table 1. Modified PUQE (Pregnancy-Unique Quantification of Emesis/Nausea) Index.
1. On an average day, for how long do you feel nauseated or sick to your stomach?
>6 h 4–6 h
(5 pts) (4 pts)
2. On an average day how many times do you vomit or throw up?
7 or more 5–6
(5 pts) (4 pts)
3. On an average day how many times do you have retching or dry heaves without bringing anything up?
7 or more 5–6
(5 pts) (4 pts)
Total score is sum of replies to each of the three questions. HG classification: Mild (total score 6), Moderate (total score in between 7 and 12),
Severe (total score 13) (Lacasse et al. 2008).
the manufacturer’s instructions. The serum level of biotin was
expressed in ng/L. Intra and inter-assay variability of test was
1.5% and 4.9%, respectively. All data were coded in the SPSS
13.0 package programme. For statistical analysis, One-way
Variance Analysis (ANOVA) and Pearson Correlation Analysis
Tests were used. p value < .05 was considered as statistically
significant.
Results
The mean age (29.50 ± 4.80 in mild, 27.97 ± 4.57 in moderate,
26.67 ± 5.33 in severe HG and 28.68 ± 4.44 in control groups,
p > .05, One-Way ANOVA), mean gestational age (8.36 ± 3.66
in mild, 8.77 ± 3.29 in moderate, 9.30 ± 3.13 in severe HG and
8.15 ± 2.03 in control groups, p > .05, One-Way ANOVA),
mean gravida (2.43 ± 1.48 in mild, 2.07 ± 1.23 in moderate,
2.27 ± 1.28 in severe HG and 2.31 ± 1.40 in control groups,
p > .05, One-Way ANOVA), mean parity (0.93 ± 1.20 in mild,
0.73 ± 0.83 in moderate, 0.87 ± 0.97 in severe HG and
0.86 ± 0.90 in control groups, p > .05, One-Way ANOVA), and
mean BMI (24.02 ± 3.44 in mild, 24.48 ± 3.93 in moderate,
23.48 ± 4.26 in severe HG and 24.21 ± 4.15 in control groups,
p > .05, One-Way ANOVA) were comparable in HG and con-
trol groups (Table 2).
The comparison of mean modified PUQE scores in HG
(5.67 ± 0.48 in mild, 8.43 ± 1.16 in moderate, 13.37 ± 0.67 in
severe) and control (3.48 ± 0.50) groups were statistically sig-
nificant (p < .05, One-Way ANOVA, Table 2).
The comparison of serum biotin levels in the study (mild
HG, moderate HG, and severe HG) and the control groups is
given in Table 3. Serum biotin levels in all HG groups were
statistically significantly lower than the control group
(p ¼ .014 for mild HG versus control, p < .001 for moderate
HG versus control. p < .001 for severe HG versus control). As
the severity of HG increased, the mean serum biotin lev-
els decreased.
Considering the study group, there was a negative correl-
ation between Modified PUQE response score to Question 1
(r ¼0.510, p < .001, Pearson correlation test), Question 2
(r ¼0.413, p < .001, Pearson correlation test) and Question 3
(r ¼0.542, p < .001, Pearson correlation test) and serum bio-
tin levels.
Discussion
Nausea and vomiting in pregnancy usually begins at 5th
weeks’ of pregnancy; reaching the summit at 8–12th weeks’
2–3 h 1 h Not at all
(3 pts) (2 pts) (1 pts)
3–4 1–2 None
(3 pts) (2 pts) (1 pts)
3–4 1–2 None
(3 pts) (2 pts) (1 pts)
 JOURNAL OF OBSTETRICS AND GYNAECOLOGY 3

Table 2. Comparison of demographic and clinical features of mild, moderate and severe HG, and control groups.
Groups Mild HG (n ¼ 30) Moderate HG (n ¼ 30) Severe HG (n ¼ 30) Control (n ¼ 80) p
Mean age (years) 29.50 ± 4.80 27.97 ± 4.57 26.67 ± 5.33 28.68 ± 4.44 0.104
Mean gestational week 8.36 ± 3.66 8.77 ± 3.29 9.30 ± 3.13 8.15 ± 2.03 0.264
Mean gravida 2.43 ± 1.48 2.07 ± 1.23 2.27 ± 1.28 2.31 ± 1.40 0.764
Mean parity 0.93 ± 1.20 0.73 ± 0.83 0.87 ± 0.97 0.86 ± 0.90 0.875
Mean BMI 24.02 ± 3.44 24.48 ± 3.93 23.48 ± 4.26 24.21 ± 4.15 0.790
Mean PUQE score 5.67 ± 0.48 8.43 ± 1.16 13.37 ± 0.67 3.48 ± 0.50 0.000
One-Way ANOVA test was used for statistical analysis. The means are given as ± standard deviation.
Bold p values present the statistical significance.

Table 3. Comparison of serum biotin levels of the study (mild, moderate and severe HG) and control groups.
Group Mild HG (n ¼ 30) Moderate HG (n ¼ 30) Severe HG (n ¼ 30) Control (n ¼ 80) p
Serum biotin (ng/L) 89.31 ± 39.55 74.75 ± 22.60 53.79 ± 13.98 115.17 ± 48.69 p 5 .014 (Mild HG vs. Control)
p 5 .000 (Moderate HG vs. Control)
p 5 .000 (Severe HG vs. Control)
p ¼ .903 (Mild HG vs. Moderate HG)
p 5 .003 (Mild HG vs. Severe HG)
p ¼ .235 (Moderate HG vs. Severe HG)
One-Way ANOVA test was used for statistical analysis.
Bold p values present the statistical significance.

of pregnancy, and then spontaneously declining until the
16th weeks’ of pregnancy. However, in 10% of the cases, the
symptoms last for the whole pregnancy (Gadsby et al. 1993).
In this study, similar to the literature findings, the mean ges-
tational week was 8.36 ± 3.66 in the mild; 8.77 ± 3.29 in the
moderate and 9.30 ± 3.13 in the severe HG groups.
In this study, serum biotin levels in all HG groups were
statistically significantly lower than control group. Serum bio-
tin levels were also negatively correlated with HG clinical
grade (mild, moderate and severe). While there is an associ-
ation between low biotin levels and severity of HG, we are
still cautious about claiming a causative link because of limi-
tations of the study.
In many countries women take prenatal vitamins (includ-
ing biotin) during pregnancy. The main symptoms of HG are
nausea and vomiting (Klebanoff et al. 1985). These women
cannot take adequate biotin with dietary and often have to
stop taking vitamins due to the severe nausea/vomiting and
thus deficiency may occur.
In one previous study marginal biotin deficiency during
pregnancy has been reported and this deficiency was attrib-
uted to the increase in catabolism of this vitamin in preg-
nancy (Mock et al. 2002). It has been shown that biotin
deficiency can cause nausea and vomiting.(Sweetman et al.
1981; Levenson 1983). In one reported case, parenteral biotin
therapy improved the developed symptoms of depression,
nausea and vomiting in hyperalimented patient for several
months (Levenson 1983). Since only one measurement was
made in this study; it may be arguable that whether biotin
deficiency may be secondary to vomiting, or biotin deficiency
may exacerbate nausea and vomiting.
The main limitations of this study were low sample size
and not having the data of serum pre-pregnancy levels
of biotin.
Primigravidity, young age, obesity, having a previous HG
pregnancy, having a sister with HG (17-fold increased risk),
and having predisposing genetic variants for GDF15
(p ¼ 2.4  10–41) or IGFBP7 (p ¼ 9.2  10–24) are the reported
possible risk factors of HG (Fejzo et al. 2018). In our study,
women with HG did not have any such risk factors.
In conclusion, current study results elucidated that serum
biotin levels were lower in HG cases compared to non HG
cases. This is the first study that reports the association
between low serum biotin levels and HG. HG may be associ-
ated with maternal and foetal morbidity. Further research is
needed to investigate the importance of biotin supplementa-
tion in women with HG.
Disclosure statement
No potential conflict of interest was reported by the authors.
ORCID
Selim Demir http://orcid.org/0000-0002-1863-6280
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