Forty-three patients were studied (age at diagnosis 27 ± 6.0 years and age at pregnancy 32.4 ± 5.4 years) for a total of 58 pregnancies (31 patients underwent one pregnancy; two pregnancies were recorded in nine patients, and three were recorded in three patients). Among the 43 women studied, 10 (23.3%) had macroadenomas, and 33 (76.7%) had microadenomas. At diagnosis, the median tumor diameter was 6 mm (IQR 5–9 mm), and the median PRL was 112.3 ng/ml (IQR 50–149.7 ng/ml). None of the patients underwent pituitary neurosurgery (NS) or radiotherapy (RT) before pregnancy, while a single patient underwent NS during the postpregnancy follow-up (six years later). By the time of conception, 18 patients were receiving BRM therapy (dose 6.16 ± 6.6 mg/day; IQR 2.5–20 mg/day), and 40 were receiving CAB (dose 1.6 ± 3.3 mg/week, IQR 0.25–17.5 mg/week). The two populations analysed were comparable in terms of age at diagnosis, age at pregnancy, prevalence of macro/microadenoma, adenoma size at diagnosis and PRL levels at diagnosis (Table 1). The estimated cumulative dose of BRM taken during pregnancy was 274.8 ± 399 mg (IQR 2.5–1260 mg), the median foetal exposure time was 35 days (IQR 28–35 days), and the estimated cumulative dose of CAB was 4.6 ± 4.3 mg (IQR 1–18 mg), with a median foetal exposure time of 28 days (IQR 28–35 mg) (Table 1). Although all patients were instructed to interrupt DA therapy once pregnancy was confirmed, in two cases, the patients continued BRM therapy throughout the course of gestation (in one there was no medical indication; in the other, there was severe headache). The patients were followed up for at least 10 years, with a mean of 16.4 ± 8.4 years (CAB 12.7 ± 6.3 vs BRM 24.7 ± 6.3; p < 0.01).

Thirty-three of 43 patients (76.7%) achieved normalization of PRL levels before pregnancy (nadir vs pretreatment: 9.5 ng/ml, IQR 4.3–20.5 ng/ml vs 112.3 ng/ml, IQR 50–149.7 ng/ml; p = 0.0003; Fig. 1A); of these, 15 patients had inhibited PRL levels (< 4.8 ng/ml). There was no significant difference between CAB and BRM in terms of treatment duration to achieve PRL normalization, although patients treated with CAB tended to normalize PRL levels earlier (4.3 ± 1.7 months vs 9.4 ± 12.3 months; p = 0.08). In 11/43 patients (25.6%), the pituitary lesion exhibited a significant (> 20%) diameter reduction (4.9 ± 3.0 mm vs 8 ± 5.45 mm; p = 0.01; Fig. 1B), and in three patients, the lesion completely disappeared before pregnancy. In all the other patients, the lesion did not undergo volumetric variations. The diameter of the tumor before pregnancy was significantly lower in the CAB group (p = 0.023) (Table 1).

A: Prolactin levels (ng/ml) at diagnosis and before pregnancy. B: adenoma maximum diameter (mm) at diagnosis and before pregnancy

Forty-eight pregnancies (82.7%) came to term (38th–42nd week), eight ended in a preterm delivery (two in the CAB group and six in the BRM group), and two ended in a spontaneous abortion (both at the 10th week, one in the CAB group and one in the BRM group) (Table 1). No congenital malformations, gestational trophoblastic disease or extrauterine implantation was found in any of the pregnancies. Sixteen of the 56 (28.6%) deliveries occurred by caesarean section (six cases for breech presentation, one case for macrosomia in gestational diabetes, one case due to absence of valid contractions, one case for wrapping of the umbilical cord around the neck, three cases due to the advanced age of the mother, two cases for foetal distress and two for preeclampsia; supplemental material: Table 1S), 38/56 pregnancies (67.8%) resulted in spontaneous deliveries, and two were pharmacologically induced. The median new-born weight at birth was 3400 g (IQR 3240–3750 g), and the median APGAR score was 9 (IQR 9–9). In the population of women receiving BRM, two children were born underweight (weight < 2500 g) (11.2%), 14 had a normal weight (77.8%) and one had macrosomia (5.5%); on the other hand, in the population of women treated with CAB, three children were found to have a weight at birth < 2500 g (7.5%), 32 had a normal weight (80%), and four had a macrosomal weight (10%). However, no significant difference was found in child weight between the CAB and BRM treatment groups (Table 1).

The following complications occurred during pregnancy or delivery: two cases of preeclampsia, two cases of gestational diabetes, one case of placenta previa and a new diagnosis of uterine fibroma. Foetal distress problems occurred in seven patients who presented with acute respiratory distress syndrome (ARDS) (Table 1, Table 1S).

Two of the patients studied continued to take BRM for the entire duration of gestation: the first gave birth preterm by caesarean section but had no complications in terms of foetal outcome; the other patient delivered spontaneously at full term without any complications during child development.

Thirty-six of the 56 infants (64.3%) were breastfed for a mean duration of 15.56 ± 20.32 weeks (range 2–96 weeks). The duration of breastfeeding in CAB patients was significantly longer (p = 0.04) (Table 1).

The two groups showed a slight difference in terms of child complications during follow-up; these complications were more frequent (p = 0.046) in the CAB group (22.5% of CAB pregnancies, 15.5% of all pregnancies). To reduce bias resulting from including siblings, we performed a subanalysis solely on the first pregnancies and no statistical difference was confirmed, although a trend of significance persists (supplemental material: Table 2S).

In women treated with CAB at conception, speech disorders (transient) were found in six children, walking delay in one case and atopic dermatitis during childhood in two cases. None of these were found in the BRM women (Table 1).

According to the descriptive statistics, no significant differences were found in terms of obstetric (complications during pregnancy, characteristics of delivery, spontaneous/caesarean delivery, or full/preterm birth) or neonatal (APGAR, weight at birth, malformations) outcomes between the CAB and BRM groups (Table 1).

Given that developmental disorders (speech and walking delay) were the most common alterations observed in children, we investigated any predictors of these disorders by assessing both maternal and foetal factors. Univariate regression analyses revealed that maternal age at pregnancy, weight at birth, APGAR score, breastfeeding duration, days of DA exposure, and pregnancy/delivery complications did not interfere with developmental problems (Table 2). Analysing these data considering first pregnancy only (data available for 41 patients) no significant differences emerged (supplemental material: Table 3S).

After the last pregnancy, in 21/43 women (48.8%), remission of hyperprolactinemia, defined as normalization of PRL levels, was documented in the absence of therapy, while disease persistence was found in 22/43 (51.2%). Unexpectedly, in our series, a greater number of pregnancies per patient seemed to be associated with the persistence of the disease (p = 0.04).

To assess the impact of pregnancy on the pituitary lesions, we exclusively considered the first pregnancy of each patient (data available for 42 pregnancies). This approach was employed to eliminate the potential influence of restarting DA therapy between successive pregnancies. After the first pregnancy, 42.9% of patients achieved biochemical remission, while 57.1% exhibited persistent disease. Specifically, among those who achieved remission, 11/28 patients (39%) were treated with CAB, while 7/14 (50%) with BRM. However, no statistically significant difference was observed (p = 0.740).

The two populations were similar in terms of age at diagnosis (p = 0.336), age at pregnancy (p = 0.354), prevalence of macro/microadenoma (p = 0.875), size of the adenoma at diagnosis (p = 0.574), breastfeeding (p = 0.920), and duration of breastfeeding (p = 0.633). PRL levels at diagnosis were similar between the two populations (p = 0.405), while the prepregnancy PRL nadir was significantly lower in patients who achieved biochemical remission (4.6 ng/ml, IQR 2.8–10.6 ng/ml vs 12.4 ng/ml, IQR 4.8–27.0 ng/ml; p = 0.023).

Among the patients who did not achieve remission, 17 restarted CAB, four restarted BRM, and three did not receive DA therapy. At the last follow-up, adenoma data were available for 22 of these patients. In the CAB group, four patients maintained lesion stability, nine experienced a reduction, and two experienced complete shrinkage. In the BRM group, two patients had stable lesions, one had a reduction, one had an increase, and none had total shrinkage. Nevertheless, these differences were not statistically significant (p = 0.134).