Clinical data and pregnancy outcomes after inadvertent exposure to GnRH-a soon after conception
Among 26,002 IVF cycles conducted with GnRH-a long protocol in our centre over the past 17 years, 146 (0.56%) cycles resulted in clinical pregnancy during the administration of GnRH-a. The number of annual GnRH-a long protocol-associated IVF cycles and the corresponding spontaneous conception cases involving exposure to GnRH-a are summarised in Fig. S1. Follow-up surveys were available for 114 (78.08%) mothers. Clinical data of the initial 146 couples, the 114 couples with follow-up available, and the 32 couples lost to follow-up are presented in Table S1.
Among the 114 women with inadvertent pregnancy, 65 (57.02%) gave birth to 66 children (including one twin pregnancy). Another three (2.63%) individuals remain pregnant at the time of writing. The remaining mothers (40.35%) had to terminate their pregnancies due to ectopic pregnancies (15.79%) or suffered spontaneous abortion (24.55%) (Fig. 1a).
Tubal damage, male factors, and RSA accounted for the initial infertility in 47 (41.23%), 27 (23.68%), and 14 (12.28%) cases, respectively, and other causes were responsible for infertility in 26 (22.81%) cases (Fig. 1b). In addition, the composition of subfertile cases with distinct aetiology based on the classification of pregnancy outcome is summarised in Fig. 1c. There were no significant differences between the live birth group and the non-live birth group in terms of the baseline characteristics, such as couples’ age, duration of infertility, body mass index, basal sex hormone levels, number of antral follicles, and the sperm parameters (Table 1).
Table 1
Clinical characteristics of the couples inadvertently exposed to GnRH-a soon after conception
Clinical parameters | Couples with unexpected pregnancies associated with GnRH-a (n = 114) | p value |
Women with live birth (n = 65) | Women without live birth (n = 49) |
Female general characteristics | | | |
Age (y) | 29.02 ± 3.42 | 30.06 ± 3.82 | 0.127 |
Duration of infertility (y) | 3.13 ± 1.90 | 3.00 ± 2.49 | 0.749 |
Primary infertility cases (%) | 30 (46.15) | 26 (53.06) | 0.465 |
BMI (kg/m2) | 21.97 ± 3.20 | 21.04 ± 2.38 | 0.090 |
Basal serum sex hormone levels | | | |
FSH (pmol/L) | 6.94 ± 2.11 | 7.08 ± 1.75 | 0.711 |
LH (pmol/L) | 5.30 ± 3.15 | 4.84 ± 2.26 | 0.726 |
E2 (pmol/L) | 165.71 ± 133.16 | 173.99 ± 112.68 | 0.171 |
T (pmol/L) | 1.41 ± 1.34 | 1.19 ± 0.46 | 0.380 |
PRL (pmol/L) | 16.18 ± 11.53 | 19.31 ± 12.58 | 0.260 |
Number of antral follicles | | | |
Right ovary | 5.80 ± 2.29 | 5.33 ± 2.57 | 0.320 |
Left ovary | 5.46 ± 2.46 | 5.78 ± 2.31 | 0.490 |
Male characteristics | | | |
Age (y) | 30.85 ± 4.68 | 31.69 ± 4.21 | 0.320 |
Sperm volume (ml) | 3.52 ± 1.57 | 3.70 ± 1.59 | 0.542 |
Sperm concentration (106/ml) | 91.17 ± 81.43 | 70.15 ± 50.38 | 0.115 |
Progress motility (%) | 44.43 ± 17.57 | 42.34 ± 15.08 | 0.247 |
Sperm abnormality rate (%) | 90.33 ± 43.40 | 90.78 ± 43.85 | 0.433 |
Annotation: BMI, body mass index; FSH, follicle stimulating hormone; LH, luteinizing hormone; E2, estradiol; T, testosterone; PRL: prolactin. |
Maternal complications of women who gave live birth after inadvertent exposure to GnRH-a
The occurrences of preterm delivery, gestational hypertension, and gestational diabetes among the assessed 65 women who gave live birth after spontaneously conceiving with exposure to GnRH-a were 18.46%, 4.62%, and 4.62%, respectively. There were no cases associated with placenta previa or postpartum haemorrhage. Notably, the incidence of these complications in this cohort was comparable to that of the age-matched mothers who had conceived naturally or following IVF (Table S2).
Neonatal characteristics and long-term neurodevelopmental outcomes of children born after exposure to GnRH-a
Neonatal health parameters, such as birth weight, body measurements, and Apgar score, of the 66 children who were born after exposure to GnRH-a were all in the normal range. Furthermore, except for one case of ventricular septal defect (VSD) and one case of cleft lip (CL), no other significant malformations occurred (Table S3). The VSD had closed naturally about 6 months after birth, and the CL had been surgically repaired by the age of 2 years.
Of the 66 children, only 31 (46.97%) children aged 2 to 8 years (5.03 ± 1.80) were available for investigation of neurodevelopment (Table 2). There was no evidence of any family history that might be associated with mental disorders in this cohort. Only one child was diagnosed as having ASD. The general cognitive status was within the normal range in the other children, and their average FSIQ score was 105.77 ± 8.58.
Table 2
Neonatal characteristics and long-term neurodevelopment outcomes of the 31 children born following exposure to GnRH-a
Clinical data | Children born following exposure to GnRH-a (n = 31) | Children born following IVF (n = 45) | Children born following spontaneous convince (n = 45) | P value |
Mode of delivery | | | | |
Caesarean section % * | 40.0 (12/30) | 64.44(29/45) | 37.78(17/45) | 0.023 |
Neonatal health outcomes | | | | |
Gestational weeks | 37.97 ± 1.89 | 37.80 ± 2.37 | 38.60 ± 1.84 | 0.093 |
Singleton birth | 29 | 33 | 45 | - |
Twins | 1 | 6 | 0 | - |
Birth weight (g) | 3175.81 ± 477.82 | 3160.00 ± 405.45 | 3308.89 ± 373.15 | 0.111 |
Body measurements (cm) | 50.16 ± 2.53 | 49.73 ± 1.79 | 50.11 ± 1.19 | 0.449 |
Apgar score | 9.97 ± 0.18 | 9.87 ± 0.34 | 9.93 ± 0.25 | 0.239 |
Birth defects | 1 (Cleft lip) | 1 (ASD) | 0 | - |
Neurodevelopmental outcomes | | | | |
Children age (year) | 5.03 ± 1.80 | 5.22 ± 1.99 | 5.16 ± 1.15 | 0.860 |
FSIQa | 105.77 ± 8.58 | 105.98 ± 10.61 | 104.60 ± 11.26 | 0.865 |
ADHD | 0 | 2 | 1 | - |
ASDs | 1 | 0 | 0 | - |
Annotation: *, GnRH-a group vs IVF group (p = 0.037); a, the child with ASDs was not evaluated; IVF, in vitro fertilisation; ASD, atrial septal defect; FSIQ, full-scale intelligence quotient; ADHD, attention-deficit hyperactivity disorder; ASDs, autism spectrum disorders. |
In addition, the neonatal health and long-term neurodevelopmental outcomes of the 31 children with GnRH-a exposure were compared with those of 45 IVF-related children and 45 naturally conceived children. One child in the IVF group was diagnosed with an atrial septal defect. The caesarean section rate of the study group was significantly lower than that of the IVF group (p = 0.037). There were no other statistically significant differences between the study group and the two control groups in terms of gestational weeks, birth weight, body measurements, and Apgar scores. In terms of neurodevelopmental outcomes, two subjects in the IVF group and one subject in the spontaneous conception group had ADHD features. The average FSIQ scores of the study group were comparable to those of the control groups.
Repregnancy outcomes of the 62 women with discrepant results of the GnRH-a-exposed spontaneous pregnancies
Repregnancy outcomes of the 62 (55.86%) women who wanted an additional child or desired to become pregnant again after a spontaneous abortion or an ectopic pregnancy are summarised in Fig. 2. The individuals were subdivided into three subgroups based on outcomes of the previous GnRH-a-related spontaneous pregnancy. For the 65 women who had given birth successfully, 17 (26.15%) individuals desired to have a second child, and 12 spontaneous pregnancies culminated in 11 live births and 1 ectopic pregnancy. All 28 women with previous spontaneous abortions desired to fall pregnant again, and 16 succeeded in becoming pregnant: eight conceived naturally and gave birth to children, while the other eight became pregnant after IVF, and gave live birth (five) or suffered spontaneous abortion (three). The remaining 17 (94.44%) women who had experienced ectopic pregnancies chose IVF to attempt reproduction. Ultimately, nine of them gave live birth and two individuals suffered spontaneous abortion.