Pregnancy and neonatal outcomes in women receiving calcineurin inhibitors: A systematic review and meta-analysis

British Journal of Clinical Pharmacology. 2022;88(9):3950-3961


AIMS: Calcineurin inhibitors (CNIs) are often used for solid organ transplantation recipients or patients with immune-mediated diseases. This systematic review and meta-analysis aims to understand how CNIs affect pregnancy and neonatal outcomes. METHODS Electronic databases were searched for observational studies assessing pregnancy and neonatal outcomes in CNI-treated patients. The pooled rate of each outcome was determined. Metaregression was conducted to identify contributing factors to the outcomes. RESULTS We analysed 98 studies with a total of 5355 pregnancies in 4450 CNI-treated patients. The pooled rates of live birth and spontaneous abortion were 82.1% (95% confidence interval [CI] 76.7-86.4%) and 11.7% (95% CI 8.7-15.5%), respectively. The rates of preterm delivery (33.2%, 95% CI 29.2-37.5%), low birth weight (35.8%, 95% CI 27.7-44.8%) and preeclampsia (13.5%, 95% CI 9.4-19.2%) were 3-4 times higher than the rates of general population. Nearly half of the CNI-treated patients required caesarean delivery (43.5%, 95% CI 36.9-50.3%). The rates of stillbirth, neonatal and maternal death were 4.2% (95% CI 2.8-6.2%), 2.9% (95% CI 1.8-4.8%) and 2.3% (95% CI 1.3-4.1%), respectively. Metaregression showed that preeclampsia was significantly associated with the risks of preterm delivery and low birth weight. Older maternal age, prepregnancy hypertension and cyclosporine use increased the risk of preeclampsia. CONCLUSION Given the higher mortalities in CNI-treated patients and their children than the general averages, their pregnancy is considered high risk. The risks of preterm delivery and low birth weight were primarily attributed to preeclampsia. Since prepregnancy hypertension increased its risk, an appropriate preconception blood pressure management may improve their outcomes.

CET Conclusion

Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This was a well-conducted systematic review that searched multiple databases and was registered with the PROSPERO system (CRD42021291249). Two independent authors screened studies for inclusion. A large number of studies were included (98) and all were observational in design, including 5,355 pregnancies in 4,450 patients. Study quality was assessed using the Newcastle-Ottawa Scale, but it is not clear if this was completed in duplicate. Studies were subdivided into immune-mediated inflammatory diseases and organ transplant recipients, further subdivided by organ type. Multiple pregnancy outcomes are investigated with pooled estimates and metaregression analysis to identify contributory factors. The pooled rates of pre-term delivery, low birth rate and pre-eclampsia were 3-4 times higher for patients on CNI than the general population. However, rates of induced and spontaneous abortion were lower, and there was no increase in gestational diabetes or major congenital malformations. Cyclosporin use was significantly associated with gestational hypertension and pre-eclampsia, itself related to higher rates of pre-term delivery. Heterogeneity was statistically assessed as moderate to severe. The study also found significant publication bias for most pregnancy and neonatal outcomes, but this issue is not addressed in any way. Altogether the study suggests that CNI-treated patients must be considered as a higher risk group. Unfortunately, there is not clear information on CNI dosing regimens or emergency versus elective caesarean section. Despite the weaknesses, the paper does have a large population and clearly presents summary rates from multiple studies for pregnancy and neonatal outcomes, particularly for organ transplant recipients.

Study details

Aims : This study aimed to evaluate the effect of calcineurin inhibitors (CNIs) on pregnancy and neonatal outcomes.
Interventions : Electronic databases including PubMed/MEDLINE and EMBASE were searched. Studies were screened by two independent reviewers. The quality of the included studies was assessed using the Newcastle–Ottawa Scale.
Participants : 98 studies were included in the review.
Outcomes : The main outcomes of interest were pregnancy outcomes (rates of induced abortion, spontaneous abortion, preeclampsia, gestational hypertension, gestational diabetes, C-section and maternal death during pregnancy) and neonatal outcomes (rates of live birth, preterm delivery, low birth weight, major congenital malformations, stillbirth and neonatal death).
Follow up : N/A


Funding : No funding was received for this study
Publication type : Systematic Review
Review registration : PROSPERO - CRD42021291249
Organ : Various ; Liver ; Kidney
Language : English
Author email :