Maternal Diabetes Mellitus and Persistent Pulmonary Hypertension of the Newborn: Accumulated Evidence From Observational Studies

Abstract

Key MessagesWe demonstrate the relationship between maternal diabetes and persistent pulmonary hypertension of newborns in a systematic review. The original studies were retrospective cohort or case-control studies, in which selection bias might exist. Variables (e.g. obesity, macrosomia, antidiabetic agents, antihypertensive agents, lifestyle changes) were often missing, which may influence outcomes.Keywords: diabetes mellitus persistent pulmonary hypertension of the newborn systematic review a b s t r a c t Objectives: Maternal diabetes mellitus (including pre-existing and gestational diabetes mellitus) is linked with adverse infant outcomes. However, the question of whether maternal diabetes increases the risk of persistent pulmonary hypertension of the newborn (PPHN) is unclear. Herein, we conducted a systematic review and meta-analysis to summarize clinical evidence to determine the association between maternal diabetes mellitus and PPHN. Methods: In this systematic review and meta-analysis, we systematically searched PubMed, Embase, Cochrane Library, Web of Science and Google Scholar to identify relevant studies according to predefined criteria. Data from selected studies were extracted, and meta-analysis was performed using fixed effects modelling. Results: In all, we included 7 unique studies with aggregated data on 2 million individuals and >5,000 cases of PPHN. Maternal diabetes was significantly associated with a higher risk of PPHN (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.23 to 1.51). Both case-control and cohort studies exhibited that the presence of maternal diabetes increased the risk of PPHN (case-control: RR, 1.91; 95% CI, 1.02 to 2.79; cohort: RR, 1.36; 95% CI, 1.22 to 1.50). By omitting 1 study at a time, sensitivity analysis made sure that no individual study was entirely responsible for the combined results. Conclusions: Maternal diabetes was associated with increased risk of PPHN. For babies with refractory hypoxemia, with mothers with diabetes, PPHN should be taken into consideration in clinical practice. Ó 2019 The Author(s). Published on behalf of the Canadian Diabetes Association. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Mots clés: diabète sucré hypertension pulmonaire persistante du nouveau-né revue systématique r é s u m é Objectifs : Le diabète sucré maternel (notamment le diabète sucré préexistant et le diabète sucré gestationnel) est lié à des issues défavorables chez le nourrisson. Toutefois, on ignore si le diabète maternel

Factors associated with development of early and late pulmonary hypertension in preterm infants with bronchopulmonary dysplasia

“…The diagnosis of tracheitis is ill-defined in preterm infants, and while authors used their institutional criteria for the diagnosis of tracheitis, many of these clinical criteria are nonspecific.Additionally, the incidence of tracheitis in the study cohort appears relatively high at 40%. Adherence to stringent clinical parameters to diagnose may be necessary.Existing literature describes maternal diabetes as being associated with EPH and pulmonary vascular malformation6 ; thus, this is not a novel factor as stated by the authors.Further research is needed to show if PH has a difference in association between pre-existing maternal diabetes vs gestational diabetes, which could strengthen their statement. Interestingly, this study did not show PH was associated with many other factors including antenatal corticosteroids, oligohydramnios, prolonged rupture of membranes, resuscitation and respiratory support in the delivery room, multiple gestations and low Apgar score <5 at 1 and 5 minutes.…”

“…Existing literature describes maternal diabetes as being associated with EPH and pulmonary vascular malformation 6 ; thus, this is not a novel factor as stated by the authors. Further research is needed to show if PH has a difference in association between pre‐existing maternal diabetes vs gestational diabetes, which could strengthen their statement.…”

AMPK deficiency in smooth muscles causes persistent pulmonary hypertension after birth and premature death

“…Indeed, amelioration by metformin of PPHN [23][24][25] and pulmonary hypertension in the adult 5,27,91,92 has been noted 26 , which may be mediated, at least in part, through AMPK activation as opposed to reduced e ciency of redox and electron transfer at mitochondrial complex I per se 30 or inhibition of fructose-1,6 bisphosphatase 31 . Given that metformin is highly e cacious against type 2 diabetes, it is also interesting to note that AMPK de ciency 93 , PPHN [94][95][96] and pulmonary hypertension of the adult 97,98 are associated with obesity and type 2 diabetes (maternal with PPHN), not least because similar signs and symptoms are present even where no such comorbidity is evident [99][100][101] . Further studies are therefore warranted and required, in order to identify the critical determining pathways by which AMPK de ciency confers such selective cardiopulmonary dysfunction after birth.…”

AMPK deficiency in smooth muscles causes persistent pulmonary hypertension after birth and premature death

“…Indeed, amelioration by metformin of PPHN 23-25 and pulmonary hypertension in the adult 5,27,91,92 has been noted 26 , which may be mediated, at least in part, through AMPK activation as opposed to reduced efficiency of redox and electron transfer at mitochondrial complex I per se 30 or inhibition of fructose-1,6 bisphosphatase 31 . Given that metformin is highly efficacious against type 2 diabetes, it is also interesting to note that AMPK deficiency 93 , PPHN 94-96 and pulmonary hypertension of the adult 97,98 are associated with obesity and type 2 diabetes (maternal with PPHN), not least because similar signs and symptoms are present even where no such comorbidity is evident 99-101 . Further studies are therefore warranted and required, in order to identify the critical determining pathways by which AMPK deficiency confers such selective cardiopulmonary dysfunction after birth.…”