Pentaerythritol tetranitrate prevents preterm birth in pregnancies with compromised placental function

Germany: A study published in the American Journal of Obstetrics and Gynecology has mentioned that pentaerythritol tetranitrate (PETN) does not affect the fetal growth restriction (FGR) and perinatal death in high-risk pregnancies. However, it reduces preterm birth, thereby prolonging pregnancy and maternal blood pressure.

FGR is a pathologic restriction of intrauterine supply and is a significant cause of perinatal mortality and morbidity. The fetus fails to achieve its genetic growth potential, and intrauterine malnutrition leads to developmental disturbances. Nitric oxide (NO) donors such as PETN reduce the impedance in the uteroplacental vessels and possess protective effects on the endothelium.

A PETN pilot study evaluated that PETN intervention compared to placebo causes 38% relative risk (RR) reduction of FGR or perinatal death with adjusted RR, and preterm birth (before 32 weeks of gestation) reduces by 70 %( adjusted RR of 0.436).

Based on the above data, Dr. Tanja Groten from the Department of Obstetrics of Jena University Hospital, with the team of researchers, hypothesized that "PETN could prevent FGR in women with impaired placental perfusion at mid -gestation."

The main aim and objective of the researchers team were to evaluate the effectiveness of PETN on the development of FGR and perinatal death in placentation failure at mid-gestation. FGR is abnormal uterine Doppler flow and a birthweight <10th centile (per the population growth charts).

Women with a history of hypertension, diabetes, FGR, stillbirth, premature placental abruption, HELLP syndrome, or preeclampsia were "high-risk." PETN and placebo tablets were identical in size, shape, taste, and color and were indistinguishable from participants, nurses, and clinicians

The critical points of the study are:

• The study assessed the efficacy and safety of 50 mg PETN twice a day.

• The trial was conducted at 14 tertiary-care hospitals.

• The study enrolled 317 women.

• 125 of 317 randomized women (39.4 %) were at high-risk.

• The PETN/placebo was taken orally twice until 36 + 6 weeks of gestation/ the day of delivery.

• Maternal and fetal status and condition assessment was done every four weeks.

• The data was recorded via an encrypted data link (HTTPS) using data entry masks.

• The primary outcome was Perinatal death and/or development of FGR (composite outcome).

• The secondary outcomes were birthweight, FGR requiring delivery before 30, 34, and 37 weeks gestation, preterm birth, and rate of neonatal intensive care unit (NICU) admission complications.

• Maternal secondary outcome measures were pregnancy-induced hypertension.

• The cumulative incidence of the primary outcome in the PETN and placebo group was 41.1% (62/155 infants) and 45.5% (71/161 infants).

• The difference between the two groups was statistically insignificant, with an adjusted RR of 0.90.

• Five perinatal deaths constituting 3.3%, were reported in the PETN group, while 7 cases (4.5 %) in the placebo group (RR,0.74).

• The cumulative incidence of the combined endpoint of birthweight below the third centile, intrauterine or neonatal death, and placental abruption in the PETN group and the placebo group was 25.2% (38/155 infants) and 26.3% (41/161 infants), respectively. The adjusted RR was 0.90.

• The birthweight of 61 infants (40.7%) in the PETN group and 69 infants (44.2%) in the placebo group was <10th percentile.

• In 138 cases, 57 in PETM and 81 in placebo, preterm birth before 37 weeks of gestation occurred.

• The risk reduction for preterm birth had an estimated RR was 0.73.

• Severe neonatal morbidity in the PETN and placebo group occurred in 30.1 % and 35.8%, respectively.

• The cumulative incidence of PIH in the PETN and the placebo was 23.9% and 36.6% respectively, adjusted RR, 0.65.

The researchers explained that women with a history of high BP, diabetes, antiphospholipid, etc., have a higher risk of FGR. One-third of pregnant women with impaired perfusion of the uterine arteries at midgestation are related to FGR.

The researcher concluded, in our study, FGR occurred in 110 of 307 (35.8%) cases. The risk reduction for preeclampsia was 20% vs. 29.2% (RR, 0.7) between the treatment groups, indicating PETN related to a reduced rate of PIH. Preterm birth before 37 weeks' gestation could be reduced by 30%.

They wrote, "We used a dosage of 50 mg because PETN is now only available in Pentalong 50-mg tablets (PUREN Pharma GmbH & Co KG, München, Germany), which might have decreased the effect."

The researchers finally wrote, "We failed to demonstrate the designated impact of PETN on the development of FGR and perinatal mortality and morbidity. However, it reduces prematurity and might improve maternal outcomes."

Further reading:

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation—a randomized trial - American Journal of Obstetrics & Gynecology