Drug tolerability in assisted reproduction techniques: a longitudinal study

Figures & data

Table 1. Main patient characteristics.

General patient variables
Age, years	33.4 ± 4.1
Body mass index (BMI), Kg/m2	26.6 ± 6.0
Nationality
Spanish	55 (90.2)
Other	6 (9.8%)
Work situation
Employed	35 (57.4%)
Unemployed	18 (29.5%)
Not stated	8 (13.1%)
Accompanied by partner
No	39 (63.9%)
Yes	22 (36.1%)
Tobacco
Non-smoker/ Ex-smoker	45 (73.8%)
Smoker	16 (26.2%)
Exercise
No	39 (63.9%)
Yes	22 (36.1%)
Coffee consumption
No/low caffeine	35 (57.4%)
Yes	16 (42.6%)
Hours of sleep	7.8 ± 1.1
Habitual drug consumption previous to fertility treatment
NSAIDs	8 (7.4%)
Antiasthma	1 (1.9%)
Birth control	4 (7.4%)
Anticonvulsants	1 (1.9%)
Antidepressants	1 (1.90%)
Hyperprolactinemia	1 (1.9%)
Hypothyroidism	5 (9.3%)
None	34 (63.0%)
Others	3 (5.6%)
Sterility type
Primary	48 (78.7%)
Secondary	7 (11.5%)
Unknown	6 (9.8%)
Sterility cause
Male	35 (64.8%)
Female	8 (14.8%)
Mixture	8 (14.8%)
Idiopathic	3 (5.6%)
Non stated	7
Female sterility
Low ovary reserves	2 (3.3%)
Endometriosis	6 (9.8%)
Tubaric factor	4 (6.6%)
Polycystic ovary	4 (6.6%)
Disovulation	1 (1.6%)
Other	2 (3.3%)
Hormones
FSH
1–12 mU/mL	54 (96.4%)
>12 mU/mL	2 (3.6%)
Non stated	5
LH
2–10 mU/mL	53 (94.6%)
10 mU/mL	3 (5.4%)
Non stated	5
Estradiol
<50 pg/mL	34 (59.6%)
50–100 pg/mL	23 (40.4%)
Non stated	4
Prolactin
0–20 ng/mL	32 (65.3%)
20 mg/mL	17 (34.7%)
Non stated	12
Sterility duration (years), median (range)	3 (1 to 25)

Table 2. Variables included in multivariate models for different types of adverse reactions.

	ADEs General	ADEs Endocrine-metabolic	ADEs Central nervous system	ADEs Genital-urinary	ADEs Injection site reaction	ADEs gastrointestinal	ADEs neuromuscular
Age
>35 years	1	1	1			1	1
</= 35 years (ref)	0.38 (0.16 to 0.94)	0.28 (0.09-0.88)	0.09 (0.80-1.03)			0.38 (0.16-0.89)	0.27 (0.70-1.01)
Smoking
No (ref)	1	1
Yes	4.61 (1.06-19.96)	9.10 (3.07-27.0)
Low treatment response
No (ref)	1
Yes	0.03 (0.002-0.50)
Treatment
In vitro (ref)	1	1	1	1	1	1	1
Insemination	0.47 (0.21-1.07)	0.39 (0.14-1.12)	0.67 (0.29-1.55)	0.73 (0.22-2.40)	0.60 (0.25-1.42)	0.52 (0.23-1.13)	0.33 (0.09-1.23)
BMI
BMI increase (1 kg/m^2)			3.10 (3.03-3.21)				1.12 (1.01-1.24)
Duration of sterility					0.85 (0.72-1.00)
Increasing one year of sterility
Exercise
Yes (ref)							1
No							5.10 (1.53-16.9)

ADE_s: adverse effects; ref: reference category

Results expressed as Odds Ratios (OR) and 95% Confidence Intervals (95%CI)

Table 3. Incidence of adverse effects.

Type of Adverse Effect	Follitropin Beta		Menotropin		Follitropin alpha		Ganirelix		Cetrorelix		Nafarelin
	M (n = 53)	C (n = 62)	M (n = 15)	C (n = 88)	M (n = 14)	C (n = 39)	M (n = 0)	C (n = 24)	M (n = 0)	C (n = 14)	M (n = 9)	C (n = 7)
ADE General	34 (64.2%)	48 (77.4%)	1 (6.7%)	70 (79.5%)	10 (71.4%)	34 (87.2%)	–	15 (62.5%)	–	13 (92.9%)	5 (55.6%)	5 (71.4%)
ADE Central nervous system	20 (37.7%)	23 (37.1%)	0	34 (38.6%)	8 (57.1%)	16 (41%)	–	5 (20.8%)	–	5 (35.7%)	3 (33.3%)	3 (42.9%)
ADE Cardiovascular	1 (1.9%)	1 (1.6%)	0	1 (1.1%)	0	0	–	0	–	0	0	0
ADE Respiratory	0	3 (4.8%)	0	5 (5.7%)	0	3 (7.7%)	–	1 (4.2%)	–	1 (7.1%)	1 (11.1%)	1 (14.3%)
ADE Genital-urinary	5 (9.4%)	5 (8.1%)	0	6 (6.8%)	2 (14.3%)	3 (7.7%)	–	3 (12.5%)	–	3 (21.4%)	0	0
ADE Neuromuscular	9 (17%)	8 (12.9%)	0	15 (17%)	0	8 (20.5%)	–	2 (8.3%)	–	2 (14.3%)	2 (22.2%)	1 (14.3%)
ADE Endocrine-metabolic	15 (28.3%)	15 (24.2%)	0	26 (29.5%)	1 (7.1%)	15 (38.5%)	–	3 (12.5%)	–	6 (42.9%)	3 (33.3%)	2 (28.6%)
ADE Gastrointestinal	13 (24.5%)	22 (35.5%)	0	37 (42%)	8 (57.1%)	19 (48.7%)	–	5 (20.8%)	–	5 (35.7%)	3 (33.3%)	2 (28.6%)
ADE Injection site reaction	8 (15.1%)	29 (46.8%)	0	39 (44.3%)	6 (42.9%)	17 (43.6%)	–	9 (37.5%)	–	8 (57.1%)	1 (11.1%)	2 (28.6%)

Results expressed as number of adverse effect (ADE); (% patients with ADE)

M: monotherapy; C: combined

Table 4. Associations between drugs and the incidence of each type of adverse effects.

	ADEs General	ADEs Endocrine-metabolic	ADEs Central nervous system	ADEs Genital-urinary	ADEs Injection site reaction	ADEs Gastrointestinal	ADEs Neuromuscular
Follitropin-beta	1.38 (0.61–3.11) p = 0.44	1.06 (0.43–2.61) p = 0.89	0.71 (0.33–0.53) p = 0.38	1.47 (0.46–4.76) p = 0.52	1.26 (0.55–2.88); p = 0.58	0.74 (0.35–1.54) p = 0.42	1.03 (0.33–3.19) p = 0.96
Menotropin	1.62 (0.75–3.50) p = 0.22	1.03 (0.44–2.39) p = 0.95	1.13 (0.54–2.33) p = 0.74	0.42 (0.13–1.38) p = 0.15	0.59 (0.23–1.52) p= 0.28	0.98 (0.47–2.05) p = 0.97	1.02 (0.32–3.31) p = 0.97
Follitropin–alpha	2.71 (0.95–7.72) p = 0.06	1.41 (0.53–3.75) p = 0.49	2.26 (0.93–5.47) p = 0.07	1.25 (0.38–4.16) p = 0.71	2.06 (0.84–5.06) p= 0.11	3.10 (1.37–6.99) p = 0.006	1.31 (0.37–4.62) p = 0.68
Ganirelix	0.67 (0.24–1.91) p = 0.46	0.18 (0.04–0.91) p = 0.037	0.41 (0.12–1.31) p = 0.13	1.45 (0.36–5.81) p = 0.60	0.45 (0.15–1.39) p= 0.17	0.42 (0.16–1.12) p = 0.08	1.49 (0.32–6.96) p = 0.61
Cetrorelix	3.55 (0.56–22.4) p = 0.18	1.42 (0.41–5.00) p = 0.58	0.86 (0.26–2.84) p = 0.80	3.36 (0.81–13.95) p = 0.09	2.91 (0.71–11.93) p = 0.14	0.72 (0.23–2.25) p= 0.57	0.55 (0.08–3.41) p = 0.52
Nafarelin	0.41 (0.14–1.16) p = 0.09	0.71 (0.20–2.50) p = 0.60	0.85 (0.30–2.37) p = 0.75			0.58 (0.18–1.82) p = 0.35	0.79 (0.16–3.89) p = 0.77

ADEs: adverse drug effects; Results expressed as OR (95%CI). Estimates have been adjusted with Generalized Estimated Equation (GEE) multivariate models (Table 2).

Table 5A. Associations between infertility drugs and the incidence of adverse effects according to administration (in monotherapy or in combination) and type of therapy (in vitro fertilization or artificial insemination).

	GENERAL ADEs				CENTRAL NERVOUS SYSTEM ADEs		ENDOCRIN-METABOLIC ADEs
	In vitro	Insemination	Monotherapy	Combination	In vitro	Insemination	In vitro	Insemination
Follitropin B	1.06 (0.36–3.13) P = 0.91	2.97 (0-63–6.87) P = 0.23	2.38 (0.81–6.98)P = 0.12	0.36 (0.09–1.49) P = 0.16	0.66 (0.84–1.82) P = 0.25	0.83 (0.24–2.87) P = 0.77	097 (0.31–3.07) P = 0.96	1.15 (0.23–5.80) P = 0.87
Menotropin	4.36 (0.53–12.4) P = 0.01	0.15 (0.04–0.65) P = 0.01	0.09 (0.007–1.24) P = 0.07	1.06 (0.26–4.29) P = 0.93	1.36 (0.51–3.60) P = 0.54	0.30 (0.71–1.32) P = 0.11	1.15 (0.37–3.57) P = 0.81	0.25 (0.03–2.08) P = 0.20
Follitropin A	2.41 (0.68–8.60) P = 0.18	2.79 (0.48–16.1) P = 0.25	1.68 (0.34–8.29) P = 0.52	2.79 (0.67–11.6) P = 0.16	1.96 (0.67–5.71) P = 0.22	3.19 (0.66–15.34) P = 0.15	1.87 (0.57–6.19) P = 0.30	1.14 (0.19–7.03) P = 0.88
Ganirelix	0.44 (0.12–1.57) P = 0.21	0.68 (0.10–4.61) P = 0.69	–	0.36 (0.12–1.08) P = 0.068	0.41 (0.10–1.61) P = 0.20	0.36 (0.41–3.24) P = 0.37	0.31 (0.06-1.61) P = 0.17	–
Cetrorelix	2.53 (0.30–21.6) P = 0.40	–	–	3.22 (0.41–21.6) P = 0.23	1.12 (0.30–4.21) P = 0.86	0.40 (0.02–6.37) P = 0.52	0.44 (0.08–2.49) P = 0.36	–
Nafarelin	0.28 (0.08–0.97) P = 0.04	–	–	0.45 (0.06–3.16) P = 0.42	0.72 (0.22–2.32) P = 0.58	–	0.53 (0.13–2.10) P = 0.36	–

ADEs: adverse drug reactions. Results expressed as OR (95%CI). Estimates have been adjusted with Generalized Estimated Equation (GEE) multivariate models (Table 2).

Table 5B. Associations between infertility drugs and the incidence of adverse effects according to administration (in monotherapy or in combination) and type of therapy (in vitro fertilization or artificial insemination).

	GENITOURINARY ADEs		SITE INJECTION REACTION ADEs		GASTROINTESTINAL ADEs		NEUROMUSCULAR ADEs
	In vitro	Insemination	In vitro	Insemination	In vitro	Insemination	In vitro	Insem.
Follitropin B	3.77 (0.76–18.66) P = 0.10	0.29 (0.03–2.18) P = 0.23	1.33 (0.46–3.79) P = 0.59	1.32 (0.33–5.30) P = 0.69	0.58 (0.22–1.52) P = 0.27	0.82 (0.26–2.61) P= 0.74	0.47 (0.13–1.74) P = 0.26	–
Menotropin	0.56 (0.15–2.10) P = 0.39	–	1.97 (0.55–7.08) P= 0.23	0.56 (0.003–0.94) P = 0.05	1.95 (0.74–5.06) P= 0.17	0.32 (0.07–1.41) P = 0.13	0.78 (0.21–2.88) P = 0.71	–
Follitropin A	0.51 (0.10–2.54) P = 0.41	7.17 (0.72–71.21) P = 0.09	1.30 (0.41–4.18) P = 0.65	4.18 (0.90–19.36) P = 0.07	3.85 (1.27–11.70)P = 0.02	4.35 (1.11–17.04) P = 0.03	3.38 (0.77–14.89) P = 0.10	–
Ganirelix	0.26 (0.24–6.45) P = 0.78	1.96 (0.13–28.58) P = 0.62	0.41 (0.12–1.44) P = 0.17	0.84 (0.08–8.10) P= 0.88	0.25 (0.08–0.83) P = 0.02	2.06 (0.38–11.04) P = 0.40	0.69 (0.10–4.75) P = 0.71	–
Cetrorelix	2.96 (0.53–16.40) P = 0.21	3.59 (0.23–55.37) P = 0.36	1.94 (0.41–9.12) P = 0.40	52.78 (0.02–1323284) P = 0.32	0.47 (0.12–1.89) P = 0.28	1.53 (1.18–12.67) P = 0.70	0.90 (0.15–5.57) P = 0.91	–
Nafarelin	–	–	–	–	0.56 (0.17–1.85) P = 0.34		0.74 (0.14–3.76) P = 0.71	–

ADEs: adverse drug reactions. Results expressed as OR (95%CI). Estimates have been adjusted with Generalized Estimated Equation (GEE) multivariate models (Table 2).

Figure 1. Association between infertility medication and general adverse drug effects stratified by assisted reproduction technique and type of administration (combination versus monotherapy) . Data shown as Odds Ratio (95% Confidence Interval) and estimated by multivariate Generalized Estimated Equation (GEE) models.

Figure 2. Association between infertility medication and site injection reaction adverse drug effects stratified by assisted reproduction technique. Data showed as Odds Ratio (95% Confidence Interval) and estimated by multivariate Generalized Estimated Equation (GEE) models.

Figure 3. Association between infertility medication and gastrointestinal adverse drug effects stratified by assisted reproduction technique. Data showed as Odds Ratio (95% Confidence Interval) and estimated by multivariate Generalized Estimated Equation (GEE) models.