Hyperemesis gravidarum

Summary

Hyperemesis gravidarum (MONDO:0006791) is a disease with 3 cohort genes (6 GWAS associations across 11 studies) and 31 clinical trials. Top therapeutic interventions include clonidine, metoclopramide, and mirtazapine.

At a glance

• Cohort genes: 3
• GWAS associations: 6
• Clinical trials: 31

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperemesis gravidarum
Mondo ID	MONDO:0006791
EFO	EFO:1000971
MeSH	D006939
SNOMED CT	14094001
UMLS	C0020450
MedGen	43776
MedDRA	10020614
Is cancer (heuristic)	no

Also known as: hyperemesis gravidarum · hyperemesis gravidarum (disease) · pernicious vomiting of pregnancy · pregnancy pernicious vomiting

Data availability: 6 GWAS associations (11 studies) · 1 HPO phenotype.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › obstetric disorder › pregnancy disorder › hyperemesis gravidarum

Related subtypes (28): funisitis, chorea gravidarum, luteoma of pregnancy, polyhydramnios, impetigo herpetiformis, gestational diabetes, placenta disorder, pemphigoid gestationis, dystocia, pruritic urticarial papules and plaques of pregnancy, familial gestational hyperthyroidism, pseudohyperaldosteronism type 2, aromatase deficiency, acute fatty liver of pregnancy, malignancy diagnosed during pregnancy, postpartum psychosis, peripartum cardiomyopathy, gestational trophoblastic neoplasm, hypertension, pregnancy-induced, chronic intervillositis of unknown etiology, pregnancy disorder with abortive outcome, postpartum amenorrhea-galactorrhea syndrome, pregnancy associated osteoporosis, twin anemia-polycythemia sequence, twin-reversed arterial perfusion sequence, selective intrauterine growth restriction, amniotic fluid embolism, vasa previa

Genetics & variants

GWAS landscape

6 GWAS associations across 11 studies. Top hits map to 3 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs16982345	2e-19	GDF15 - LRRC25	G	1.5
rs749451	6e-18	PGPEP1	?
rs143409503	9e-12	LINC02380 - SRIP1		1.33
rs77775955	1e-10	PGR-AS1 - TRPC6	?
rs74096894	2e-08	PPM1H	?
rs45543339	2e-06	LRRC25	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90624211	Yonezawa Y	2024	17,423	2,092	Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.
GCST90624210	Yonezawa Y	2024	11,424	8,091	Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.
GCST90624209	Yonezawa Y	2024	2,799	16,716	Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.
GCST90624212	Yonezawa Y	2024	2,799	2,092	Genome-wide association study of nausea and vomiting during pregnancy in Japan: the TMM BirThree Cohort Study.
GCST90726838	Kim HI	2026	1,939	42,087	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.
GCST90245826	Changalidis AI	2022	1,594	324,433	Aggregation of Genome-Wide Association Data from FinnGen and UK Biobank Replicates Multiple Risk Loci for Pregnancy Complications.
GCST005930	Fejzo MS	2018	1,306	15,756	Placenta and appetite genes GDF15 and IGFBP7 are associated with hyperemesis gravidarum.
GCST90436546	Zhou W	2018	230	408,731	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90651545	Liu TY	2025	173	129,451	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90436547	Zhou W	2018	153	408,731	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	1
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intergenic_variant	2
intron_variant	2
regulatory_region_variant	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs16982345	19	18389912	G>A	0.27	regulatory_region_variant	GDF15 - LRRC25	2e-19	Tier 3: regulatory
rs749451	19	18368837	T>A,C	0.05	3_prime_UTR_variant	PGPEP1	6e-18	Tier 2: splice/UTR
rs143409503	4	57484899	TAGC>T,TAGCAGCAGCAGAGC,TAGCAGC	0.05	intergenic_variant	LINC02380 - SRIP1	9e-12	Tier 4: intronic/intergenic
rs77775955	11	101376983	G>A,C	0.05	intergenic_variant	PGR-AS1 - TRPC6	1e-10	Tier 4: intronic/intergenic
rs74096894	12	62681588	A>G	0.05	intron_variant	PPM1H	2e-08	Tier 4: intronic/intergenic
rs45543339	19	18392384	C>G,T	0.05	intron_variant	LRRC25	2e-06	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IGFBP7	Orphanet:284247	Familial retinal arterial macroaneurysm

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
LRRC25	HGNC:29806	ENSG00000175489	Q8N386	Leucine-rich repeat-containing protein 25	gwas
GDF15	HGNC:30142	ENSG00000130513	Q99988	Growth/differentiation factor 15	gwas
IGFBP7	HGNC:5476	ENSG00000163453	Q16270	Insulin-like growth factor-binding protein 7	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
LRRC25	Leucine-rich repeat-containing protein 25	Plays a role in the inhibition of RLR-mediated type I interferon signaling pathway by targeting RIGI for autophagic degradation.
GDF15	Growth/differentiation factor 15	Hormone produced in response to various stresses to confer information about those stresses to the brain, and trigger an aversive response, characterized by nausea, vomiting, and/or loss of appetite.
IGFBP7	Insulin-like growth factor-binding protein 7	Binds IGF1 and IGF2 with a relatively low affinity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
LRRC25	Other/Unknown	no		LRR_dom_sf, LRRC25
GDF15	Other/Unknown	no		TGF-b_C, TGF-beta-like, Cystine-knot_cytokine
IGFBP7	Antibody/Immunoglobulin	yes		IGFBP-like, Kazal_dom, Ig_sub

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
monocyte	1
metanephros cortex	1
placenta	1
type B pancreatic cell	1
blood vessel layer	1
renal medulla	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
LRRC25	156	broad	marker	monocyte, leukocyte, granulocyte
GDF15	208	ubiquitous	marker	metanephros cortex, placenta, type B pancreatic cell
IGFBP7	294	ubiquitous	marker	renal medulla, vena cava, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
IGFBP7	1,825
LRRC25	1,533
GDF15	153

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDF15	Q99988	4
IGFBP7	Q16270	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRC25	Q8N386	70.48

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Post-translational protein phosphorylation	1	100.2×	0.012	IGFBP7
Senescence-Associated Secretory Phenotype (SASP)	1	99.3×	0.012	IGFBP7
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	IGFBP7

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to metformin	1	2808.7×	0.004	GDF15
GDF15-GFRAL signaling pathway	1	2106.5×	0.004	GDF15
negative regulation of growth hormone receptor signaling pathway	1	1685.2×	0.004	GDF15
cellular response to chemical stress	1	1404.3×	0.004	GDF15
positive regulation of fatty acid oxidation	1	1203.7×	0.004	GDF15
reduction of food intake in response to dietary excess	1	842.6×	0.004	GDF15
negative regulation of leukocyte migration	1	842.6×	0.004	GDF15
response to cortisol	1	842.6×	0.004	IGFBP7
negative regulation of appetite	1	766.0×	0.004	GDF15
regulation of steroid biosynthetic process	1	766.0×	0.004	IGFBP7
negative regulation of multicellular organism growth	1	561.7×	0.004	GDF15
positive regulation of myoblast fusion	1	526.6×	0.004	GDF15
cellular response to prostaglandin E stimulus	1	421.3×	0.005	IGFBP7
cell surface receptor protein serine/threonine kinase signaling pathway	1	366.4×	0.005	GDF15
negative regulation of SMAD protein signal transduction	1	300.9×	0.006	GDF15
response to retinoic acid	1	191.5×	0.009	IGFBP7
embryo implantation	1	175.5×	0.009	IGFBP7
regulation of signal transduction	1	133.8×	0.012	IGFBP7
regulation of cell growth	1	110.9×	0.013	IGFBP7
negative regulation of transforming growth factor beta receptor signaling pathway	1	86.9×	0.016	GDF15
transforming growth factor beta receptor signaling pathway	1	79.5×	0.017	GDF15
positive regulation of MAPK cascade	1	40.3×	0.031	GDF15
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	39.2×	0.031	GDF15
cell-cell signaling	1	34.8×	0.033	GDF15
angiogenesis	1	31.2×	0.036	IGFBP7
negative regulation of cell population proliferation	1	21.1×	0.051	IGFBP7
cell adhesion	1	18.7×	0.055	IGFBP7
signal transduction	1	8.0×	0.121	GDF15

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

4 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Clonidine	Phase 3
Promethazine	Phase 3
Gabapentin	Phase 2
Metoclopramide	Phase 2

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LRRC25	0	0
GDF15	0	0
IGFBP7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GDF15	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	IGFBP7
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LRRC25, GDF15

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
LRRC25	0	—
GDF15	2	—
IGFBP7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 31.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	22
PHASE2	4
PHASE3	3
PHASE4	1
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02300155	PHASE4	COMPLETED	Improving Multivitamin Supplementation to Pregnant Women
NCT00293644	PHASE3	COMPLETED	Pre-emptive Treatment of Severe Nausea and Vomiting of Pregnancy
NCT00861523	PHASE3	TERMINATED	Does Thiamine Help Vomiting and Nausea in Pregnancy?
NCT01559012	PHASE3	COMPLETED	Transdermal Clonidine in the Treatment of Severe Hyperemesis Gravidarum
NCT07129473	PHASE2	NOT_YET_RECRUITING	Hyperemesis Gravidarum Risk Reduction With Metformin
NCT02163434	PHASE2	COMPLETED	Comparison of Gabapentin and Metoclopramide for Treating Hyperemesis Gravidarum
NCT03785691	PHASE2	TERMINATED	Validating the Effect og Ondansetron and Mirtazapine in Treating Hyperemesis Gravidarum
NCT05098067	PHASE2	COMPLETED	Capsaicin Cream as an Adjunctive Therapy for Nausea and Vomiting of Pregnancy
NCT05452174	PHASE1/PHASE2	WITHDRAWN	Endeavor to Stop Nausea/Vomiting Associated With Pregnancy (E-SNAP)
NCT06442813	Not specified	NOT_YET_RECRUITING	Effects Of Emotional Freedom Technique and Hypermesis Gravidarum
NCT06615843	Not specified	RECRUITING	Randomized Study of a Dematerialized Management for Post-Emergency Gynecological Follow-Up
NCT06772974	Not specified	NOT_YET_RECRUITING	Tablet Ginger Versus Tablet Doxylamine Succinate in Control of Nausea and Vomiting in Pregnancy
NCT00795561	Not specified	COMPLETED	Management of Nausea and Vomiting of Pregnancy
NCT01836835	Not specified	COMPLETED	Pregnancy Specific Nausea Questionnaire (PUQE) Translated and Tested in Norwegian
NCT02541682	Not specified	COMPLETED	Assessment of the Relationship Between Affective Temperament and the Severity of Nausea and Vomiting in Early Pregnancy
NCT02619188	Not specified	UNKNOWN	Nutritional Markers in Normal and Hyperemesis Pregnancies
NCT02830321	Not specified	COMPLETED	The Association of Helicobacter Pylori in the Pathogenesis of Hyperemesis Gravidarum in Pregnant Women
NCT02862496	Not specified	UNKNOWN	Bone Health in Hyperemesis Gravidarum
NCT03127293	Not specified	COMPLETED	Hyperemesis Gravidarum and Osteoporosis
NCT03950167	Not specified	COMPLETED	Gallbladder Functions & Serum Cholecystokinin Levels in Women Diagnosed With Hyperemesis Gravidarum
NCT04284696	Not specified	COMPLETED	Chewing Gum Containing Vitamin-c to Treat Emesis Gravidarum
NCT04719286	Not specified	COMPLETED	MinSafeStart - Decision Aid Tool for Better Treatment of Nausea and Vomiting During Pregnancy
NCT04785911	Not specified	COMPLETED	Use of the Modified PUQE Score on Admitted Cases of Hyperemesis Gravidarum (HG) to Guide Response to Treatment
NCT04828967	Not specified	COMPLETED	Use of Hypnosis in Hyperemesis Gravidarum
NCT05175079	Not specified	COMPLETED	Acupressure in Hyperemesis Gravidarum
NCT05446025	Not specified	COMPLETED	The Levels of the Orexin, Galanin and aMSH and CART in Patients With Hyperemesis Gravidarum
NCT05829473	Not specified	UNKNOWN	The Effect of Guided Imagery and Diaphragmatic Breathing Exercise in Pregnant Women With Hyperemesis Gravidarum
NCT06245811	Not specified	COMPLETED	Inflammation Markers in Hyperemesis Gravidarum
NCT06266819	Not specified	UNKNOWN	The Effect of Mint Flavored Chewing Gum on Hyperemesis Gravidarum Nausea Vomiting Severity, Coping With Stress and Anxiety Level in Pregnants With Hyperemesis Gravidarum
NCT06581796	Not specified	COMPLETED	Pepsinogen-1 Serum Levels in Hyperemesis Gravidarum
NCT07613814	Not specified	COMPLETED	Development of a Management Model for Hyperemesis in Pregnant Women Through the Vibratory Emesis Massage

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLONIDINE	4	2
METOCLOPRAMIDE	4	2
MIRTAZAPINE	4	2
THIAMINE ION	4	2
CAPSAICIN	4	1
PROMETHAZINE	4	1
GINGER	3	1
ZUCAPSAICIN	3	1