Motherisk Rounds: Neural Tube Defects and Dydrogesterone

Motherisk Int J 2020;1:17

 

Gideon Koren MD FRCPC FACMT
Ariel University and Motherisk Israel, Shamir Medical Center

 

Question:

We have a case of cervical insufficiency resulting in two miscarriages of otherwise normal fetuses. In the subsequent two pregnancies the woman received dydrogesterone (DYD). In both cases the fetuses were diagnosed with encephalocele and the pregnancies were terminated. Prior to both pregnancies the mother received folic acid. Relevant MTHFR mutations were ruled out. Can these neural tube defects (NTD) be due to DYD?

Answer:

In a large cohort study of 7700 pregnancies exposed to DYD and compared to 770,000 unexposed controls, the odds ratio for NTD was significantly higher than among the unexposed [RR= 2.29 (95% CI 1.32-3.97)]. There was also an increased risk for hydrocephalus (Motherisk Int J 2020;1:11). In this family, there was no NTD  in the two previous pregnancies without DYD, ruling out a genetic risk due to polymorphism in MTHFR.

 

Case*:

A healthy couple experienced two successive miscarriages due to cervical insufficiency. The fetuses were examined and appeared normal. The healthy 60 kg ,30 y.o. mother and 36 y.o. 70 kg father, both non-smoking, were subsequently advised to use DYD at 30mg/d. Conception was uneventful, but in both cases ultrasound revealed encephalocele and the pregnancies were terminated. Karyotype examinations of the fetuses were normal. The mother was homozygous for MTHFR A1298C. The mother received folic acid 400mcg/d in the first 3 pregnancies and 800mcg methylfolate and folinic acid in the fourth pregnancy.

What is the likelihood that DYD caused or contributed to the NTD in this family?

Discussion:

Around 70% of cases of neural tube defects (NTD) are believed to be folic acid- dependent, and can be prevented by adequate fortification with folic acid pre conceptually (1). Several mutations in maternal methylenetetrahydrofolate reductase (MTHFR), the enzyme that breaks down folic acid to folate, have been associated with increased risk for NTD. Specifically, a recent meta- analysis of 47 studies have shown that MTHFR C677T is associated with 23% increased risk of NTD [OR 1.23 (95% CI 1.07-1.42)]. In contrast, MTHFR A1298C (for which the woman in our case was homogenous) does not appear to be associated with increased NTD risk, based on 22 studies (2).

A large study addressing the odds for specific malformations following exposure to DYD in the first trimester reported on 7742 babies exposed in utero to DYD and 777,422 unexposed controls. This study detected an estimated risk for both NTD as well as hydrocephalus (3), as presented in the table.

Table: Odds ratios for specific malformations associated with first trimester exposure to DYD

Significant results bolded.

 

OR CI
Min Max
Hypospadias 1.28 1.06 1.55
Undescended testis/ cryptorchidism 1.0 0.85 1.19
Cong. Dislocation of Hip 0.9 0.78 1.04
Fallot Tetralogy 1.1 0.72 1.33
VSD* 1.02 0.91 1.32
Renal Dysplasia 1.04 0.85 1.33
Cong. Pylorus Stenosis 1.04 0.84 1.18
PDA* 1.27 0.96 1.67
Cong. Aortic Insufficiency 1.65 1.008 2.71
Pulm. Stenosis 0.95 0.81 1.48
Cong. Catarct 1.52 0.84 2.76
Spina Bifida 2.29 1.32 3.97
Cong. Hydocephalus 1.75 1.03 1.96
TGA* 2.03 0.75 5.4
Overall cardiovascular malformations    1.18 1.06 1.33

 

VSD: Ventricular septal defect

PDA: Patent ductus arteriosus

TGA: Transposition of great arteries

 

While it is impossible to prove causation based on a case series, there are several points in this series  that support a causative role of DYD in causing or contributing to neural NTD):

In the first two pregnancies, without DYD exposure, there were no NTD, whereas the two subsequent pregnancies with DYD- resulted in NTD. The mother received appropriate preventative doses of folic acid. Maternal mutations for MTFHR were examined, and although homogenous for MTHFR A1298C, this genotype has not been associated with increased risk for NTD.

In summary, this case series suggests a possible role to DYD in causing NTD in this family. More studies will help to further clarify this association. However, it must be considered by fertility experts prescribing DYD, especially that other congenital malformations, such as cardiovascular, have also been shown to exhibit increased teratogenic risk.

*The family consented to the publication of their case.

 

References:

  1. Berry RJ, Li Z, Erickson JD, Li S, Moore CA et al. Prevention of neural tube defects with folic acid in China. N Engl J Med 1999;341:1485-1490
  2. Zhang T, Lou J, Zhong R, et al. Genetic variants in the folate pathway and the risk of neural tube defects: A meta analysis of the published literature PLOS One 2013;8:4 e59570
  3. Koren G, Gilboa D: Dydrogesterone exposure in the first trimester of pregnancy and fetal malformations. Motherisk Int J 2020;1;11