Preconception Paternal Health Can Affect Neonatal Health
-Fathers’ comorbidities may increase risk of stillbirth, miscarriage, and ectopic pregnancy
by Kate Kneisel, Contributing Writer, MedPage Today 2021-01-13
Study Authors: Alex M. Kasman, Chiyuan A. Zhang, et al.
Target Audience and Goal Statement: Endocrinologists, nephrologists, obstetrician-gynecologists, primary care physicians
The goal of this study was to determine the associations between preconception paternal health and pregnancy loss.
- Was preconception paternal health associated with pregnancy loss?
Study Synopsis and Perspective:
Although fetal development and prenatal health are influenced by both maternal and paternal health, preconception counseling has traditionally focused on the mother, since the health impacts of a mother on the developing fetus are well established.
However, recent studies have linked adverse fetal outcomes with paternal factors, including advanced age, which has been found to increase risk of premature birth, low birth weight, and low Apgar scores, as well as comorbidities.
- Poor paternal health before conception was associated with a higher risk of pregnancy loss, independent of maternal age and health, according to a retrospective cohort study of U.S. insurance claims data.
- Understand that while the health impacts of a mother on a developing fetus are well established, this study suggests that paternal health is also an important factor in healthy pregnancies.
A previous small cohort study found that pregnancies fathered by men 50 or older had almost twice the risk of ending in a fetal loss compared with pregnancies with younger fathers (hazard ratio 1.88, 95% CI 0.93-3.82), after adjustment for maternal age, reproductive history, and maternal lifestyle during pregnancy.
According to a recent analysis of insurance records, pregnancy loss was more common when the father had medical comorbidities.
Specifically, the risks of ectopic pregnancy, miscarriage, and stillbirth were at least 10% greater when fathers had claims related to medical conditions, such as obesity, diabetes, or high blood pressure, in the year before conception, reported Michael Eisenberg, MD, of Stanford University in California, and colleagues.
A dose-response effect was also noted, with pregnancy loss becoming more likely as the number of paternal comorbidities increased, the researchers noted in Human Reproduction.
Eisenberg and team obtained U.S. insurance claims data from 2009 to 2016, identifying couples linked to the same primary insurance. Both women and men had to be enrolled in the same insurance plan for 1 year before the estimated date of conception. The analysis was limited to women ages 20 to 45.
The study included 956,804 pregnancies, about a quarter of which resulted in a loss. Mothers were an average age of 33 years and fathers were an average age of 35 years; 4.6% of men were over age 45. About 23% of the fathers in the study had at least one component of metabolic syndrome before conception. The average observation period for men prior to conception was 3.9 years versus 3.7 years for women.
Pregnancy outcomes including live birth, stillbirth, ectopic pregnancy, and spontaneous abortion were analyzed, as was parental health in the year before conception, based on metabolic syndrome diagnosis (hypertension, hyperlipidemia, obesity, diabetes), the Charlson Comorbidity Index, and individual chronic illnesses like chronic obstructive pulmonary disease, cancer, or heart disease.
Analyses were adjusted for year, region, maternal hypertension, maternal diabetes, maternal obesity, and maternal and paternal age and smoking, and sensitivity analyses were also conducted to assess how families with multiple pregnancies or losses might influence the results.
The risk of pregnancy loss increased with a higher number of paternal components of metabolic disease. Compared with fathers who had no components of metabolic syndrome, there was a 10% increased risk of pregnancy loss among fathers who had one component (relative risk [RR] 1.10, 95% CI 1.09-1.12). This risk increased to 15% when fathers had two components (RR 1.15, 95% CI 1.13-1.17), and 20% when fathers had three or more components (RR 1.19, 95% CI 1.14-1.24).
Similar risks were observed with Charlson Comorbidity Index and individual chronic illnesses, and less healthy fathers had a higher risk within each type of pregnancy loss, including stillbirth, ectopic pregnancy, and spontaneous abortion.
Study limitations acknowledged by Eisenberg and co-authors included the possibility of uncontrolled confounding, as well as misclassification due to coding errors in the retrospective data. Additionally, the analysis included only pregnancies covered by employer-based insurance, and several socioeconomic and demographic factors could have further affected pregnancy loss rates.
Source Reference: Human Reproduction 2020; DOI: 10.1093/humrep/deaa332
Study Highlights and Explanation of Findings:
Approximately 30% of conceptions have a pregnancy trajectory that ends prior to live birth, the researchers noted in discussing their findings, and while some pregnancy losses may be related to embryonic aneuploidy, many remain unexplained after chromosomal abnormalities and maternal risk factors have been ruled out.
While paternal advanced age has been linked with adverse fetal outcomes, poor paternal health transcends the age effect, according to Eisenberg and team, who observed adverse pregnancy outcomes across all unhealthy paternal age groups.
Paternal exposures to smoking and alcohol consumption prior to conception may also potentially increase the risk of both restricted growth and spontaneous miscarriage. In addition, decreased folate levels appeared to influence neonatal health, such that a 400 μg/day increase in preconception paternal folate intake was associated with a 2.6-day longer gestation after adjustments for potential confounders, including maternal folate intake.
Similarly, another study found that paternal diabetes as measured by insulin resistance, as well as smoking, were associated with worse fetal outcomes, such that men who fathered pregnancies affected by otherwise unexplained fetal growth restriction had an odds ratio of 7.68 (95% CI 2.63-22.40, P<0.0001) for having a 1-unit higher log HOMA-IR value and an odds ratio of 3.39 (95% CI 1.26-9.16, P=0.016) for being a smoker compared with fathers of normal grown offspring.
Likewise, lower birth weight has been noted for infants born to fathers with diabetes and with higher levels of fast food consumption (P<0.05).
While the etiologies for the link between fathers’ health and pregnancy loss are unknown, Eisenberg and colleagues noted that they may involve epigenetic changes in the sperm — i.e., heritable changes in gene expression that occur without modifications at the DNA sequence level, which may be transmitted from fathers to offspring via spermatozoa.
In addition, alterations to chromosomal proteins, DNA, or RNA in sperm that are caused by paternal illnesses may result in disruptions of fetal development and possible outcomes such as miscarriage or stillbirth. Abnormal sperm DNA fragmentation has also been linked with an increased risk of recurrent spontaneous abortion.
Notably, the prevalence of obesity and type 2 diabetes is expected to steadily increase in the next decades. It is becoming increasingly clear that the sperm epigenome is sensitive to environmental factors, including diet, according to a review of potential epigenetic mechanisms for transferring paternal environmental information to offspring.
Specifically, acquired metabolic disorders and diet have the potential to affect male reproduction and induce signatures in gametes that may compromise the health of offspring. Furthermore, it is possible that these disorders may affect more people of reproductive age and for longer periods, who in turn transmit this genetic information to future generations, creating a vicious cycle with a huge societal impact.
Brian Nguyen, MD, of the University of Southern California’s Keck School of Medicine, who was not involved in this research, said the study encourages gender equity in reproductive healthcare.
« We have not allowed ourselves to look at fathers being a potential source of pregnancy loss or pregnancy morbidity, » Nguyen said in an interview. « I think now we are beginning to open ourselves up to this idea, and are finding a whole lot more. »
While this research does not show causality, Nguyen said the link between paternal health and pregnancy outcomes, albeit small, « is no longer deniable. »
Eisenberg said that this study should encourage providers to have conversations with their patients about paternal health before conception.
« This gives more evidence that the father is important, » he noted. « It’s certainly not bad advice to tell a man to be healthy, to have a good diet and exercise. It’s good for the health of a man, but it also can help a pregnancy as well. »
Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College