The potential association between psychiatric symptoms and the use of levonorgestrel intrauterine devices (LNG-IUDs): A systematic review

Figures & data

Figure 1. PRISMA flow diagram that depicts the search process and the number of retrieved articles for inclusion in this review.

Table 1. Summary of the included studies.

Study	Design	Country	Population	Association of LNG with depression
a) Studies associated with increased or reported depressive symptoms:
Langlade et al. 2019	Retrospective	France	3324 Reports of adverse effects related to LNG-IUD	Psychiatric disorders including depression symptoms were reported in the population.
Horibe et al. 2018	Retrospective	Multi country	253 Reports of postpartum depression received from FAERS † database	LNG-IUD was associated with higher risk of postpartum depression
Skovlund et al. 2018	Prospective	Denmark	Half a million women followed through The National Health Register of Denmark	LNG-IUD use was associated with higher risk of suicide and suicide attempts compared to non-users of hormonal contraceptives
Daud and Ewies 2008	Cross-sectional	UK	145 Women with LNG-IUD use between 1998 and 2003	Depression was reported as a side effect of LNG-IUD use
Robinson et al. 2008	Retrospective	UK	1056 Women using LNG-IUD were surveyed	Depression was reported as a side effect in 60 (6%) of women
Elovainio et al. 2007	Cohort study	Finland	119 Women undergoing treatment for menorrhagia	Depression was stated as a reason for discontinuation of LNG-IUS use, however whether the depressive symptoms was caused by the intrauterine device is unclear
Backman et al. 2000	Retrospective	Finland	17914 Women using LNG-IUD were surveyed	Premature removal of LNG-IUS was associated with higher risk of depression
Andersson et al. 1994	Randomised trial	Sweden	1821 Women using LNG-IUD and 937 women using Nova T	Cumulative termination rate due to depression was higher in the LNG-IUD group
Cox et al. 2000	Phase-III multicenter study	UK	40 Women	3 Complaints of depression were reported to be associated with LNG-IUD use
Nilsson et al. 1982	Randomised trial	Finland	Women between 18 and 38 years were enrolled	Increase of depression symptoms was reported in the first year following LNG-IUS use
b) Studies associated with decreased depressive symptoms:
Roberts and Hansen 2017	Retrospective	US	75,528 Records of postpartum women	LNG-IUD was associated with lower risk of depression diagnosis
Keyes et al. 2013	Prospective	USA	Data of 6654 women were assessed from the National Longitudinal Study of Adolescent Health	Hormonal contraceptives were associated with lower risk of depression and suicide attempts.
c) Studies with no association of depressive symptoms:
Tazegül Pekin et al. 2014	Prospective	Turkey	120 Premenopausal women	Depression scores were assessed before insertion of LNG-IUS and 6 months after. No significant change in depression scores were seen after the follow up, indicating no effect of LNG-IUD on depression.
Enzlin et al. 2012	Cross-sectional	Belgium	353 Women using LNG-IUS and 49 women using Cu-IUD ††††	No significant difference regarding depression symptoms was found between both groups.
Toffol et al. 2012	Retrospective	Finland	Data of 8586 women were obtained from the national FINRISK Study Surveys and analysed †††††	No association of depression and LNG-IUD use was found.
Toffol et al. 2011	Retrospective	Finland	Data of 3223 women were obtained from the Finnish-population-based Health 2000 study	No association between current use of LNG-IUD and depression scores were found
d) Studies associated with increased risk of anxiety:
Slattery et al. 2018	Prospective	UK	Reports retrieved from THIN †† database of UK general practice	Positive association of LNG-IUD with depression, anxiety and sleep problems was found in users compared to non-users
e) Studies associated with increased risk of suicide:
Skovlund et al. 2016	Prospective	Denmark	Data from National Prescription Register and the Psychiatric Central Research Register in Denmark	Risk of first-use antidepressant and depression diagnosis was higher in women using the LNG-IUD
f) Studies with unclear association of depressive symptoms:
Aleknaviciute et al. 2017	Cross-sectional	Netherlands	55 Women divided into 3 groups of LNG-UD only, EE30/LNG ††† and no contraception	LNG potentiates the autonomic response of heart rate during psychosocial stress
Eisenberg et al. 2015	Partially randomised trial	USA	1600 Women under 35 years and 151 women between 35-45	Depression occurred in 91 (5.4%) of women in a 3-year follow up period
Heikinheimo et al. 2014	Prospective	Sweden	170 Women currently using a LNG-IUD presenting to replace it with a second device	Discontinuation of LNG-IUD was reported in 2 women due to depression. However whether the depression was related to the LNG-IUD is not clear
Sivin and Stern 1994	Randomised trial	USA	Parous women aged 18 to 38 years randomised to LNG-IUD or copper IUD	First occurrence of depression was described in some women with LNG-IUS however this was not statistically significant compared to copper IUD

†FAERS: Food and Drug Administration Adverse Event Reporting System

††THIN: The Health Improvement Network

†††EE30/LNG: oral ethinylestradiol/levonorgestrel (0.03mg/0.15mg).

††††Cu-IUD: Copper IUD

†††††FINRISK: Finland Risk factor survey.

Table 2. Characteristics of the included study (Part 1).

Study	Age	Controls	follow up	Country	Sample size	Setting	Precise design
Langlade et al. 2019	37 Years, IQR: 32–42	No controls	–	France	3224 Case reports	Case reports of adverse events of Mirena in France	Case reports involving Mirena in the French national pharmacovigilance database. A comparison was made before and after the media coverage of the adverse effects of LNG IUD.
Horibe et al. 2018	–	No controls	–	Japan	7,561,254 Reports	FAERS dataset was downloaded from the FDA website	The dataset was screened for postpartum depression being assessed in women taking different contraceptives
Skovlund et al. 2018	21, SD4	Never users and former users	8.3years, 4.7sd	Denmark	475802 Women, 3,920,818 person–years	The Danish Sex Hormone Register	National cohort study that includes all women living in Denmark starting from age 15 and followed up for adverse effects of contraceptive use
Slattery et al. 2018	36.9 Years LNG and 33.1 years non LNG	Non–medicated IUD users	4.2 LNG and 4.4 years non LNG	UK	10,872 LNG and 6871 non LNG users	Data from UK general practice electronic medical records	Comparison between LNG IUD and non-LNG IUDs over a follow up period of 5 years. The time to first manifestation of the disease following the insertion of IUD was analysed and compared with the control group.
Aleknaviciute et al. 2017	18–45 Years	Copper IUD	–	The Netherlands	210 Women	Medical centres	Analysis of three studies where women with LNG-IUS were compared to oral levonorgestrel and Copper IUD regarding stress reactivity
Roberts and Hansen 2017	28.5 SD 5.2	Women who were not exposed to hormonal contraception during the postpartum period	8.9m (SD 4.0)	USA	75528 Postpartum women	US military medical system	A secondary analysis of insurance records postpartum women enrolled in the US military medical system assessing the association between hormonal contraceptives and depressive symptoms
Skovlund et al. 2016	24.4 Range 15–34	Non users of hormonal contraceptives	Followed from entry till event or January 2013	Denmark	1,061,997 Women	Data from the National Prescription Register and the Psychiatric Central Research Register in Denmark	A nationwide prospective cohort study in Denmark studying the association between hormonal contraceptive and first diagnosis of depression or prescription of anti-depressants
Eisenberg et al. 2015	16–45 Years range	–	3 Years follow up	USA	1751 Women	Clinical sites in the USA, with in-person or phone follow up	Open-label, partially randomised trial, comparing LNG efficacy in different age groups
Heikinheimo et al. 2014	38.7 4.5sd	No controls	5 Years, yearly follow up	Sweden	170 Women	Multicenter study	Prospective multicenter study assessing data in second consecutive LNG IUD
Tazegül Pekin et al. 2014	36.5 18–50 Range	–	6 Months	Turkey	120 Menopausal women	Women attending clinics	Women referred for menorrhagia were recruited into the study and followed up for 6 months
Enzlin et al. 2012	17–55	IUD	None	Belgium	402	Multicenter, gynecological follow-up	Analysis of national survey data testing the associations of hormonal contraceptives and depressive symptoms
Toffol et al. 2012	25–64, Mean age 39.8 years, SD 8.6	Hormonal contraception	None	Finland	8586	National FINRISK Study Survey, a cross-sectional population-based health survey carried out in Finland every 5 years since 1972.	Analysis of national survey data testing the associations of hormonal contraceptives and depressive symptoms
Toffol et al. 2011	18–29 Years vs 30–54 years	Young vs. older groups	None	Finland	3223	National FINRISK Study Survey, a cross-sectional population-based health survey carried out in Finland every 5 years since 1972.	Analysis of national survey data testing the associations of hormonal contraceptives and depressive symptoms
Daud and Ewies 2008	43 (6.8), Mean (SD)	None	None	UK	145	Women with IUS for DUB at The Ipswich Hospital NHS Trust	Analysis of cross-sectional survey assessing the associations of hormonal contraceptives and depressive symptoms
Robinson et al. 2008	43.74 Years (range 20–81 years)	None	None	UK	1056	Women with IUS in Queens’ Medical Centre, Nottingham, England.	Analysis of cross-sectional survey assessing the associations of hormonal contraceptives and depressive symptoms
Elovainio et al. 2007	35–49	Hysterectomy	6m, 12m, 5y	Finland	236	Women treated for menorrhagia with IUS or hysterectomy	Non-blinded RCT comparing LNG-IUS to hysterectomy
Backman et al. 2000	36 (Mean)	None	None	Finland	17914	Women with IUS in Finland	Cross-sectional
Cox et al. 2000	18–45	None	12m	UK	689	Family planning clinics	Ongoing, open, single group, multicenter phase III study in out-patients.
Andersson et al. 1994	30.3 (SD 4.9)	Copper IUD	3m, 12m and 5 y	Sweden	2758	Women attending clinics	Open randomised comparative multicenter trial of two parallel groups, LNG IUS and Copper IUD users
Nilsson et al. 1982	18–38	IUD	3m, 6m, 12m	Finland	483	Women attending clinics	Open randomised comparative multicenter trial between LNG-IUS and copper IUD

LNG: Levonorgestrel; IUD: intrauterine device; IUS: intrauterine device; FAERS: FDA Adverse Event Reporting System; FDA: U.S. Food and Drug Administration; FINRISK: Finnish population survey on risk factors on chronic; noncommunicable diseases; DUB: dysfunctional uterine bleeding; MEDDRA: medical dictionary for regulatory activities; WHO: World Health Organisation; ROR: reporting odds ratio; OR: odds ratio; HR: hazard ratio; ICD: International Classification of Diseases; BDI: Beck's Depression Inventory; GHQ: General Health Questionnaire; DASS: Depression Anxiety Stress Scales; SSFS: Short Sexual Functioning Scale; QSF: Questionnaire on Sexual Functioning; VAS: Visual Analogue Scale; EQ-5D-3 L: descriptive system comprises the following five dimensions: mobility; self-care; usual activities; pain/discomfort and anxiety/depression; Cu-IUD: copper intrauterine device; TSST: Trier Social Stress Test; HMB: heavy menstrual bleeding; RCT: randomised controlled trial.

Table 3. Characteristics of the included study (Part 2).

Study	Definition of exposure	Definition and measurement of outcome	Inclusion criteria	Exclusion criteria	Summary of results
Langlade et al. 2019	Mirena IUD usage	Description of the AEs coded according to the MedDRA classification	All case reports involving Mirena® recorded in the database according to the accountability (WHO) criteria.	Non mentioned	Depressive disorders were reported more frequently following the media coverage in France
Horibe et al. 2018	LNG-IUS use	Coded according to the Medical Dictionary for Regulatory Activities	Only the drug code of primary suspected drugs was included	Duplicate reports of the same patient from different reporting sources from the analysis and extracted reports	LNG-IUS was associated with higher risk of postpartum depression (ROR: 12.5, 95%CI 8.7–18)
Skovlund et al. 2018	Comparison between never users and current users of hormonal contraceptives were made.	Diagnosis of suicide attempt or a contact with a somatic or psychiatric hospital defined as ‘suicide attempt’	Woman who turned 15 with no prior contraceptive use	Women with prior suicide attempts, antidepressant use, psychiatric diagnoses, cancer diagnoses, or venous thrombosis diagnoses	Risk of first attempt of suicide was higher in LNG-IUS users compared to never users (HR 2.86, 95%CI 2.06–3.97), however this was true for other hormonal contraceptives as well
Slattery et al. 2018	Seven codes for LNG-IUDs and 31 for non-hormonal IUDs in the THIN product dictionary	The first Read Code or prescribed treatment for panic attacks, anxiety, sleep disorders or restlessness after prescription of the study IUD	Incident prescription for LNG-IUDs and non-LNG-releasing IUDs in women with at least 1 year of follow-up after registration	Women with a history of previous IUD insertion were excluded	LNG-IUD was associated with higher risk of first-time development of depressive symptoms (HR 1.17, 95%CI 1.08–1.26), however no significant effect on persons with past history of depression (HR 1.08, 95%CI 0.97–1.21)
Aleknaviciute et al. 2017	LNG-IUS and, Trier Social Stress Test, ACTH stimulation test	Heart rate, salivary cortisol, Hair cortisol as response to stress	–	Psychiatric disorders, pregnancy or lactation, use of medications other than contraceptives, thyroid disorders, gynaecologic or pelvic diseases	Women using LNG IUD had exaggerated salivary cortisol response to TSST compared to oral LNG and normal controls, potentiated heart rate was recorded during the test
Roberts and Hansen 2017	Medicare Severity-Diagnosis Related Group codes	ICD-9 Codes were used for the definition of depressive symptoms during 12 months following delivery	–	Women diagnosed with depression or used antidepressants in 24 months prior to the study	Women with LNG-IUD showed lower risk of healthcare visit related to depression (HR 0.65, 95% CI 0.52–0.82), however no significant effect on start of antidepressant use (HR 1.01 95%CI 0.87–1.18). Women in younger ages had a higher risk of using antidepressants in the first postpartum year (HR: 1.64, 95% CI 1.28–2.09)
Skovlund et al. 2016	A first redeemed prescription of hormonal contraception	Depressive symptoms were defined as: first prescription of an anti-depressants or according to ICD-10 codes F32 to F33.9	Females aged 15–34 years using hormonal contraceptives with no prior diagnosis of depression or any major psychiatric disorders	Previous diagnosis of depression or antidepressant use, previous psychiatric disorders, previous cancer diagnosis and women with contraindications to hormonal contraceptives were excluded	Compared to non-users of hormonal contraceptives, users of LNG IUD experienced a rate ratio of 1.4 (95%CI, 1.31–1.42) for first use of antidepressants and 1.4 (1.22–1.50) for first diagnosis of depression. Higher age was associated with lower risk of first use of antidepressants
Eisenberg et al. 2015	Levonorgestrel IUS placement	Adverse events were organised into standardised terms using the MedDRA (Medical Dictionary for Regulatory Activities)	Healthy, non-pregnant, sexually active women aged 16–45 years with regular menstrual cycles were recruited	Pregnancy, pelvic inflammatory disease, malignancy, previous psychiatric disorders, and drug allergies	Depression or depressive symptoms was reported in 5.4% of LNG IUS users over 3 years
Heikinheimo et al. 2014	Second consecutive LNG IUS	Not mentioned	Women using LNG-IUS for contraception or treatment of HMB and planning to replace it with new one	Menopausal symptoms impairing the subject’s quality of life or current oestrogen therapy for menopausal symptoms were exclusion criteria	The authors reported 2 discontinuations of the LNG-IUD due to depression, however whether the IUD was the cause of depression is not clear
Tazegül Pekin et al. 2014	LNG IUD for 6 months	13-item Beck’s Depression Inventory	Pre-menopausal women aged 18–50 years	Patients who desired removal of LNG-IUS before 6 months period, pelvic inflammatory disease, malignancy, previous psychiatric disorders, and drug allergies.	No significant difference in depressive symptoms scores from baseline and after 6 months follow up
Enzlin et al. 2012	LNG-IUS	BDI-II, DAS, WHO well-being scale, SSFS, QSF	Over 18 years, in a stable heterosexual relationship for > 1 year, using Cu-IUD for at least 6 months.	–	Non-significant difference was observed between LNG-IUD and Cu-IUD users regarding depressive symptoms (Beck depression inventory score) and sexual dysfunction
Toffol et al. 2012	Hormonal contraception	BDI-21, BDI-13	–	–	A negative association between the current use of OCs and Beck Depression Inventory-13 (BDI-13) score was found
Toffol et al. 2011	Hormonal contraception	BDI-21, GHQ-12, CIDI	–	–	The current use of the LNG-IUS was inversely associated with ‘earlier waking’ (BDI) and with ‘impaired concentration’ (GHQ), while the length of LNG-IUS use was inversely associated with ‘strain’ (GHQ)
Daud and Ewies 2008	LNG-IUS	VAS, adverse events, satisfaction	LNG-IUS inserted for DUB regardless of whether it was also needed as a contraceptive	–	Some women reported discontinuation of the LNG-IUS dure to progestogenic adverse effects which included depression among other causes
Robinson et al. 2008	LNG-IUS	Adverse events, satisfaction	All women who had been fitted with a LNG-IUS in the Menstrual Disorders Clinic at the Queen’s Medical Centre	–	Depressive symptoms were reported in 60 out of 772 women, however it was not clear whether it was the cause or not
Elovainio et al. 2007	LNG-IUS	Pain relief, BDI-13,	Women between 35 and 49 years who were menstruating, who had completed their family size, eligible for a hysterectomy according to commonly used criteria	Previous malignancies, endometrial and ovarian pathologies, urinary or bowel diseases	Depressive symptoms were related to discontinuation of LNG-IUS use (OR: 3.7, 95%CI 1.55–8.82) during a 5 year follow up. The result remained significant after adjusting for other confounders
Backman et al. 2000)	LNG-IUS	Subjective report of depressive symptoms	All women in Finland who had a LNG IUS inserted below age 48	Planning pregnancy or age over 48	Premature removal of IUS was associated with 45% increase in depressive symptoms, (HR:1.45, 95%CI 1.32–1.60). The result remained significant after adjusting for other factors
Cox et al. 2000	LNG-IUS	Subjective reports of mood swings or depression	According to the doctor’s own clinical judgement	–	3 Out of 689 women reported that the cause for LNG-IUS removal was mood swings or depression
Andersson et al. 1994	Insertion and follow up of LNG-IUS	Subjective reports of depression	Between 18 and 38 years with at least one prior pregnancy	History of ectopic pregnancy, currently breast-feeding, steroid hormones contraceptives 12 months before the study	Subjective reports of depressive symptoms were more in women with LNG-IUS compared to copper IUD
Nilsson et al. 1982	Insertion and follow up of LNG-IUS	Subjective reports of depression	Between 18 and 38 years with one prior pregnancy	Pregnancy or breast feeding, history of pregnancy, pelvic inflammatory disease, no long-acting hormonal contraceptives since last pregnancy	Nervousness and depression were reported in 23.8–22.4% and 11.2–14.4% in IUS, respectively. However, it was not clear whether the LNG-IUS was the main cause for the depressive symptoms

LNG: Levonorgestrel; IUD: intrauterine device; IUS: intrauterine device; FAERS: FDA Adverse Event Reporting System; FDA: U.S. Food and Drug Administration; FINRISK: Finnish population survey on risk factors on chronic; noncommunicable diseases; DUB: dysfunctional uterine bleeding; MEDDRA: medical dictionary for regulatory activities; WHO: World Health Organisation; ROR: reporting odds ratio; OR: odds ratio; HR: hazard ratio; ICD: International Classification of Diseases; BDI: Beck's Depression Inventory; GHQ: General Health Questionnaire; DASS: Depression Anxiety Stress Scales; SSFS: Short Sexual Functioning Scale; QSF: Questionnaire on Sexual Functioning; VAS: Visual analogue scale; EQ-5D-3 L: descriptive system comprises the following five dimensions: mobility; self-care; usual activities; pain/discomfort and anxiety/depression; Cu-IUD: copper intrauterine device; TSST: Trier Social Stress Test; HMB: heavy menstrual bleeding; RCT: randomised controlled trial.

Table 4. Cochrane ROB2 tool for assessment of randomised trials.

Study	Risk of bias arising from the randomisation process	Allocation concealment	Blinding of participants and personnel	Blinding of outcome assessment	Incomplete outcome data	Selective reporting	Other bias
Eisenberg et al. 2015	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk
Andersson et al. 1994	Low risk	Low risk	Some concerns	Some concerns	Low risk	Low risk	Low risk
Sivin and Stern 1994	Low risk	Low risk	Low risk	Some concerns	Low risk	Low risk	Low risk
Nilsson et al. 1982	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk	Low risk

Table 5: NIH prospective studies with no control group.

Study	1: Clear research question	2: Clear definition of study population	3. Representative population	4. Enrolment of all eligible subjects according to predefined criteria	5. Large enough sample size	6. Clear definition of intervention	7. Clear definition of outcome measures	8. Assessors blinded to exposure	9. 20% or less loss to follow-Up	10. Analysis of change in outcome measures (Before and after)	11. Outcome measures examined multiple times	12. Analysis co nducted at a group level?	Score
Heikinheimo et al. 2014	Y	Y	Y	N	Y	Y	Y	CD	N	Y	Y	NA	9
Elovainio et al. 2007	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	Y	NA	10
Cox et al. 2000	Y	Y	Y	N	Y	Y	Y	N	N	Y	Y	NA	8

Y: yes; N: no; CD: cannot determine; NA: non-applicable.

Table 6. New castle Ottawa scale for non-randomised studies.

Study ID	Newcastle–Ottawa Scale
	Selection (maximum:★★★★)				Comparability (maximum:★★)	Exposure (maximum:★★★)			Total score (out of 9)
	Is the case definition adequate? (maximum:★)	Representativeness of the cases (maximum:★)	Selection of controls (maximum:★)	Definition of controls (maximum:★)	Comparability of cases and controls on the basis of the design or analysis	Ascertainment of exposure (maximum:★)	Same method of ascertainment for cases and controls (maximum:★)	Non-Response rate (maximum:★)
Slattery et al. 2018	★	★	★	★	★★	★	★	–	8
Aleknaviciute et al. 2017	★	–	★	★	★	★	★	–	6
Enzlin et al. 2012	★	–	★		★	★	★	–	5

Note: The stars represent points for each study.

Table 7. NIH for observational and cross-sectional studies.

Study	1: Clear research question	2: Clear definition of study population	3: 50% eligible participation rate	4: All subjects recruited from similar populations and time period	5: Sample size and power justification	6: Exposure measured before outcome	7: Adequate timeframe for association between exposure and outcome	8. Different levels of exposure were examined	9: Same exposure for all participants	10: Exposure assessed multiple times	11: Outcome measure was clear	12: Outcome assessors blinded to exposure	13: Loss to follow-up 20% or more	14: Adjustment for confounding factors	Overall score
Langlade et al. 2019	Y	Y	Y	Y	N	Y	Y	NA	Y	N	N	Y	NA	Y	10
Horibe et al. 2018	Y	Y	NA	Y	N	Y	Y	NA	Y	N	Y	Y	NA	N	8
Skovlund et al. 2018	Y	Y	Y	Y	NA	Y	Y	Y	Y	Y	Y	Y	Y	Y	12
Roberts and Hansen 2017	Y	Y	NA	Y	NA	Y	Y	N	Y	Y	Y	Y	NA	Y	9
Skovlund et al. 2016	Y	Y	NA	Y	NA	Y	Y	Y	Y	Y	Y	Y	NA	Y	11
Tazegül Pekin et al. 2014	Y	Y	NA	Y	N	Y	Y	NA	Y	Y	Y	Y	Y	Y	12
Keyes et al. 2013	Y	Y	NA	Y	N	Y	Y	Y	Y	N	Y	Y	NA	Y	10
Toffol et al. 2012	Y	Y	NA	Y	N	Y	Y	N	Y	N	Y	Y	NA	Y	9
Toffol et al. 2011	Y	Y	Y	Y	Y	Y	Y	Y	Y	N	Y	Y	NA	Y	11
Daud and Eweis 2008	Y	Y	Y	Y	N	Y	Y	Y	Y	Y	Y	Y	Y	N	11
Robinson et al. 2008	Y	Y	Y	Y	N	Y	Y	NA	Y	Y	Y	Y	NA	Y	11
Backman et al. 2000	Y	Y	Y	Y	NA	Y	Y	N	Y	Y	Y	Y	Y	N	11

Y: yes; N: no; CD: cannot determine; NA: non-applicable.

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Data availability statement

All the data used for the conduction of this study are readily available from the articles included in the analysis. However, the data collected can be obtained by contacting the first author (Dr. Mohmed Elsayed at [email protected]).