OBGYN providers’ lack of knowledge and management of genetic risks due to advanced paternal age underscore the need for updated practice guidance

Abstract

The objective of this pilot study was to characterize healthcare professionals’ knowledge of advanced paternal age (APA), the associated risks, as well as current clinical practices regarding APA. Our study utilized an online survey that questioned providers who see children with genetic conditions and patients who are or may become pregnant regarding demographic information, APA knowledge, APA guideline familiarity, and their clinical practices. A total of 67 providers responded to the survey. We had responses from 54 physician participants in the specialties of medical genetics (GEN), maternal fetal medicine (MFM), and obstetrics and gynecology (OBGYN). OBGYN, but not MFM, reported significantly lower agreement that current data supports an association between APA and certain genetic diseases compared to GEN. Furthermore, OBGYN were less likely to identify established risks associated with APA and more likely to incorrectly identify unestablished risks compared to GEN and MFM. Regardless of specialty, the majority of physicians were unfamiliar with the most recently published APA guidelines. This study revealed a desire for more information regarding APA risks and management among our participants. Our data suggest that GEN, MFM, and OBGYN would benefit from updated and more visible guidelines regarding APA. Additionally, OBGYN consistently showed knowledge gaps and misconceptions regarding the risks of APA. Targeted educational or guidance materials regarding APA may also be beneficial for OBGYNs.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12687-022-00595-y.

Introduction

Advanced paternal age (APA) is associated with several adverse outcomes. Among the most robust associations are increased risk for a child with de novo dominant Mendelian conditions, autism spectrum disorder (ASD) and neuropsychiatric conditions (Simard et al. 2019) Meta-analyses over the past decade have summarized the risks for several adverse outcomes including ASD (Hultman et al. 2011) and schizophrenia(Miller et al. 2011). Of the known risks associated with APA, de novo dominant Mendelian conditions have been a major focus of APA-related research. De novo dominant Mendelian conditions are those in which a heterozygous pathogenic variant, which is not inherited from either parent, leads to a disease phenotype. The relative risk associated with APA for de novo pathogenic variants is about 10 times that of the general population, though it is still less than 1% (Yatsenko and Turek 2018). Specifically, APA has been associated with achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta, Apert syndrome, Crouzon syndrome, Marfan syndrome, and neurofibromatosis (Nybo Andersen and Urhoj 2017). Infertility and risk for miscarriage have also been associated with APA; however, the exact magnitude of these risks is unclear (Brandt et al. 2019). It has also been suggested that APA may be associated with an increased risk for birth defects such as cleft palate, diaphragmatic hernia, and other anomalies (Brandt et al. 2019; McIntosh et al. 1995). A recent meta-analysis found that APA is a risk factor for congenital heart disease, but the magnitude of this risk may be too small for targeted screening (Joinau-Zoulovits et al. 2020).

In contrast with advanced maternal age (AMA), there remains ambiguity around APA in both its medical definition and the guidelines set forth for its management. The American College of Obstetricians and Gynecologists (ACOG) first released a practice advisory regarding genetic counseling for APA in 1997 (ACOG Committee Opinion 1997). The age for APA was not defined in this statement but it was recommended that couples undergo genetic counseling to address their specific concerns and did not provide guidance for all potentially at-risk pregnancies (ACOG Committee Opinion 1997). The American College of Medical Genetics (ACMG) published the most recent guidelines regarding APA in 2008 and defined APA as > 40 years of age (Toriello and Meck 2008). The guidelines are largely similar despite a difference of over a decade in their publication. The 2008 guidelines recommended pregnancies with a father of APA be approached as any other pregnancy being treated for potential prenatal diagnosis (Toriello and Meck 2008). A detailed anatomic survey at 18–20 weeks is recommended to evaluate the fetus for potential defects that can be isolated or related to a genetic condition associated with APA. They also acknowledge that many of the potential conditions these fetuses are at risk for would not be identified through ultrasound and tailored genetic counseling is recommended (Toriello and Meck 2008). At the time of their publication, no screening tools, other than ultrasound, were available to assess risk for APA-related genetic conditions. Advances in cell-free non-invasive prenatal screening have demonstrated the feasibility of screening for single-gene genetic conditions, some of which are associated with APA (Tsao et al. 2019; Zhang et al. 2019). This type of non-invasive prenatal screening may provide an inroad to screen at-risk pregnancies due to APA, despite not currently being recommended as a standard of care (ACOG Practice Advisory 2020).

In a time where the age of fatherhood is progressively increasing (Khandwala et al. 2017), it is important to ensure that we are providing patients the most current knowledge and management practices to empower their medical decision-making. While prior studies have shown that genetic counselors are aware that APA is associated with known risks during pregnancy (Quirin et al. 2020), the majority of genetic counselors were unfamiliar with the ACMG guidelines (Toriello and Meck 2008). There are no studies to date describing physicians who are typically the first medical contact for patients whose pregnancy is at risk due to APA. This pilot study aims to investigate the current knowledge and practices of Medical Geneticists (GEN), Maternal-Fetal Medicine specialists (MFM), and Obstetricians and Gynecologists (OBGYN) regarding APA.

Materials and methods

This study was approved and deemed exempt by the Institutional Review Board (IRB) at Indiana University. The 28 question survey was adapted from a published survey used to measure the attitudes and practices of genetic counselors regarding APA (Quirin et al. 2020). Survey data were collected and managed using the Research Electronic Data Capture (REDCap) software (Harris et al. 2019; Harris et al. 2009) hosted at Indiana University. Physicians and non-physician healthcare providers who see children with genetic conditions or people who are pregnant or thinking of becoming pregnant were considered eligible participants. Recruitment took place over 4 months from June 2020 to October 2020. Eligible participants were recruited via publication of the survey link on private, provider social media pages, and email. The survey link was emailed to the 232 members of the Central Association of Obstetricians & Gynecologists with two reminder emails. The majority of OBGYN and MFM participants were recruited via CAOG membership email. Most GEN participants were recruited via social media pages for Medical Geneticists. The survey included questions regarding demographic data, knowledge of APA, attitudes and risk perception of APA, awareness of guidelines, and current practices. Questions were a mixture of Likert-scale responses, agree/disagree, and multiple choice. An optional second survey was available to those who completed the APA survey to enter a random drawing to receive one of five gift cards for their participation, purchased by the Medical and Molecular Genetics Department at Indiana University. The full survey is available in the Supplemental Material. Based on the low number of responses from non-physician providers, only the data from physician responders were analyzed.

Statistical analysis

Three categories of providers were defined based on specialty of the participant. GEN refers to participants who identified as medical geneticists, MFM refers to those who identified as maternal-fetal medicine, and OBGYN refers to participants who identified gynecology, obstetrics, or both as their specialty. Descriptive statistics of the respondent demographics and categorical variables are reported as numbers (n) and percentages (%). Pearson’s Chi-squared test was used to determine overall association between dichotomous outcomes. Logistic regression was employed to test if multiple variables predicted dichotomous outcomes and analysis of variance (ANOVA) was used for quantitative outcomes. Post-hoc pairwise comparisons (Tukey’s HSD) were utilized to determine the direction and magnitude of association. Age was included in the models to account for variability in the outcome variables. Length of practice was not included in the model due to its correlation with age (r = 0.95, p < 0.001). Correlations between continuous variables were estimated using Pearson’s correlation coefficient. To maintain adequate numbers in individual categories, responses to the APA cutoff age were binned into two categories: > 40 (APA guideline age) and all other categories (> 35, > 45, > 50, > 55, > 60, and those who did not know) for analyses. All statistical analyses were performed in R version 4.0.3 (Team 2014) and figures were produced using the package ggplot2 (Wickham 2009).

Results

Demographics

A total of 67 survey responses were collected, yielding a 29% response rate. Two responses were omitted based on eligibility or a failure to complete most survey questions. Demographics of all respondents are summarized in Supplemental Table 1. The majority (90.8%) of respondents identified as a physician. Due to the low number of non-physician participants (n = 6), analyses focused solely on physician responses. The sample sizes for the three categories were GEN: n = 21, MFM: n = 16, and OBGYN: n = 17. Five individuals did not fit into any category, and their responses were excluded from all analyses. Table 1 summarizes demographic, APA knowledge, and APA practices information for each of the three categories GEN, MFM, and OBGYN.

Table 1.

Summary of GEN^a, MFM^b, and OBGYN^c physician demographics, knowledge, and practices regarding advanced paternal age (APA)

	GEN n = 21	MFM n = 16	OBGYN n = 17
Demographic variables	Mean (SD)	Mean (SD)	Mean (SD)
Age (p = 0.003)	43.0 (8.6)	55.4 (15.4)	54.6 (11.5)
Length of practice (years)	10.1 (8.0)	22.9 (13.7)	23.8 (12.6)
Average patients per week (p < 0.0001)	21.7 (21.5)	86.2 (57.9)	67.1 (24.5)
% pregnant in practice	20.1 (21.6)	99.9 (0.25)	59.6 (25.0)
APA Knowledge	n (%)	n (%)	n (%)
APA age cutoff
> 35	4 (19.0)	0	0
> 40	11 (52.4)	5 (31.3)	4 (23.5)
> 45	5 (23.8)	5 (31.3)	3 (17.6)
> 50	1 (4.8)	3 (18.8)	5 (29.4)
> 55	0	2 (12.5)	1 (5.9)
> 60	0	1 (6.3)	0
I don’t know/ unaware	0	0	4 (23.5)
Familiar with guidelines
Yes (p = 0.16)	9 (42.9)	9 (56.3)	4 (23.5)
No	12 (57.1)	7 (43.7)	13 (76.5)
Risks associated with APA
ASDd	17 (81.0)	9 (56.3)	9 (52.9)
De novo dominant Mendelian conditions	20 (95.2)	14 (87.5)	4 (23.5)
Psychiatric conditions	8 (38.1)	5 (31.3)	5 (29.4)
Chromosomal conditions	1 (4.8)	4 (25)	10 (58.8)
I don’t know/ unaware	0	0	3 (17.6)
Desire more information
Yes	17 (81.0)	9 (56.3)	14 (82.4)
No	4 (19.0)	7 (43.7)	3 (17.6)
APA Practices	n (%)	n (%)	n (%)
Likelihood of discussing APA
Very Likely	4 (19.0)	5 (31.3)	0
Likely	11 (52.4)	6 (37.5)	6 (35.3)
Unlikely	6 (28.6)	5 (31.3)	7 (41.2)
Very Unlikely	0	0	4 (19.0)
Offered testing/ screening for APA
Yes	7 (33.3)	11 (68.8)	3 (17.6)
No	14 (66.7)	5 (31.3)	14 (82.4)
Optimal test or screen for APA
Extensive ultrasound	5 (25.0)	3 (18.8)	2 (13.3)
NIPT/NIPSe	1 (5.0)	1 (6.3)	5 (33.3)
NIPT/NIPSe for de novo pathogenic variants	5 (25.0)	5 (31.3)	2 (13.3)
Amniocentesis	1 (5.0)	3 (18.8)	0
CVSf	0 (5.0)	1 (6.3)	0
Other	2 (10.0)	1 (6.3)	1 (6.7)
None of the above	6 (30)	2 (12.5)	5 (33.3)
Made a referral for APA
Yes	3 (14.3)	5 (31.3)	5 (33.3)
No	18 (85.7)	11 (68.7)	12 (66.7)
Consulted a genetics professional for APA
Yes	5 (23.8)	9 (56.3)	6 (35.3)
No	16 (76.2)	7 (43.7)	11 (64.7)

^aMedical geneticists (GEN)

^bMaternal-fetal medicine (MFM)

^cObstetricians and gynecologists (OBGYN)

^dAutism spectrum disorder (ASD)

^eNon-invasive prenatal screening/testing (NIPS/NIPT)

^fChorionic villus sampling (CVS)

Age was significantly different between specialties (F = 6.6, df = 2, p = 0.003) and those who identified as GEN were younger than both MFM (p = 0.008) and OBGYN (p = 0.011) physicians. Age and length of practice were significantly correlated among specialties (r = 0.95, p < 0.001). The number of patients seen per week varied significantly between specialties (F = 8.7, df = 2, p < 0.001). Compared to both MFM (p = 0.004) and OBGYN (p = 0.002), GEN reported seeing significantly fewer patients per week. The average reported percent of pregnant patients in their practice was 20.1 for GEN, 59.6 for OBGYN, and 99.9 for MFM.

APA knowledge

The largest proportion of respondents identified > 40 years (20/54; 37.0%) or > 45 years (24%; 13/54) of age as the cutoff for APA. There was no association between specialty and the binary APA cutoff age (X² = 3.68, df = 2, p = 0.16). Most respondents (32/54; 59.3%) were not familiar with the most recent guidelines regarding APA. Specialty was not associated with APA guideline familiarity (X² = 3.72, df = 2, p = 0.16). However, people who were more familiar with the APA guidelines identified the cutoff age (> 40) that is stated in the guidelines (X² = 6.23, df = 1, p = 0.013). Respondents who were unfamiliar with the APA guidelines were more likely to respond that they wanted more information regarding the guidelines (X² = 5.76, df = 1, p = 0.016).

Respondents were asked to read the following statement: “The body of currently published evidence establishes a correlation between advanced paternal age and certain genetic disorders” and rank their agreement on a scale of 1–10, with 10 expressing the highest level of agreement. Figure 1 is a boxplot representation of respondents’ agreement with the above statement between specialties. Two responses were excluded from analysis because the participant selected “I don’t know/ I am unaware.” There was a significant association between agreement and type of physician (F = 4.30, df = 2, p = 0.019) (Fig. 1). Pairwise comparisons revealed that OBGYN agreement (mean = 7.62; SD = 2.03) was significantly lower than GEN (mean = 9.10, SD = 1.18; p = 0.020) but not MFM (mean = 8.88, SD = 1.54; p = 0.075). There was no difference between MFM and GEN mean agreement (p = 0.91).

Fig. 1.

Box plot representation of agreement with the statement that advanced paternal age is associated with certain genetic conditions. The mean agreement is represented by a gray circle. Mean agreement is significantly higher between GEN and OBGYN (p < .05). GEN refers to medical geneticists, MFM refers to maternal-fetal medicine, and OBGYN refers to obstetricians and gynecologists

Specific risks associated with APA are summarized in Table 1 and pair-wise comparisons were made between specialties. GEN were 49 times more likely to identify de novo dominant Mendelian conditions as a risk associated with APA compared to OBGYNs (OR = 49.0, p = 0.001). MFM were 22.8 times more likely, compared to OBGYN (OR = 22.8 p = 0.001). On the other hand, OBGYN were 24.1 times more likely to incorrectly identify chromosome abnormalities as a risk associated with APA compared to GEN (OR = 24.1, p = 0.007), whereas GEN and MFM were equally likely (p = 0.168).

APA practices

Overall, most respondents (32/54; 59.3%) indicated that they were “likely” or “very likely” to discuss APA with a patient. GEN were 4.6 times more likely to discuss APA with a patient compared to OBGYN (OR = 4.6, p = 0.030), whereas MFM were marginally more likely compared to OBGYN (OR = 4.0, p = 0.060). There was no association between age (t(52) = 0.16, p = 0.87) or length of practice (t(52) = − 0.015, p = 0.99) and discussing APA with a patient. Most respondents (33/54; 61.1%) had not offered screening or testing options to their patients for APA. However, MFM were 10.3 times more likely to offer screening or testing compared to OBGYN (OR = 10.27, p = 0.005). GEN and OBGYN were equally likely to offer screening or testing (p = 0.28). The proportion of OBGYN who reported consulting a genetic counselor or genetics professional based on APA was 35.3% (6/17) and 56.3% (9/16) for MFM.

Physician responses regarding varied practices related to APA are summarized in Table 1. There was no consensus on the optimal test or screen for risks related to APA among specialties. The most common response to the optimal screen or test for APA was non-invasive prenatal testing/screening (NIPT/NIPS) for heterozygous pathogenic variants among MFM (5/16; 31.3%). GEN most commonly identified extensive ultrasound and NIPT/NIPS for heterozygous pathogenic variants as the optimal test or screen for APA (5/21; 25%). In comparison, OBGYN most commonly identified standard NIPT/NIPS as the optimal test or screen for APA (5/17; 33.3%). Three individuals did not respond to the question regarding the optimal screen or test for APA. Familiarity with the guidelines was not associated with offering screening or testing for APA (X² = 2.80, df = 1, p = 0.094) or discussing APA with a patient (X² = 0.68, df = 1, p = 0.41).

Discussion

This is one of the first studies to provide insights into the current knowledge and management practices regarding APA among genetics and prenatal care physicians. Most importantly, the majority of respondents were interested in learning more information about APA guidelines. This is suggestive of a desire within the genetics and prenatal communities for updated or more visible guidelines. The most recent guidelines for APA management were published in 2008 (Toriello and Meck 2008) and identified APA as > 40 years old. Familiarity with the guidelines was associated with identifying > 40 as the APA age cutoff. Nonetheless, we observed responses in each of the other age cutoff answer choices (> 35, > 45, > 50, > 55, > 60, and those who did not know) indicating a lack of consensus or clear guidance. For individuals seeking to learn more about APA, there are not modern guidelines that account for the significant advances that have occurred in prenatal screening creating unique options that were not addressed, such as NIPT. Despite outdated guidelines, most physicians indicated they were likely to discuss APA, though OBGYN were less likely to discuss APA than GEN and marginally less likely than MFM. It is possible that OBGYN, and MFM to a lesser degree, do not have the time to stay current on the APA literature due to seeing a significantly higher number of patients weekly. A unifying, visible, and up-to-date guideline may alleviate this constraint.

Independent of age disparities between specialties, GEN, but not MFM, had higher agreement that APA is linked to certain genetic conditions compared to OBGYN (Fig. 1). Further, MFM and GEN were far more likely to identify de novo dominant Mendelian conditions as a risk associated with APA than OBGYN. Of note, OBGYN were more likely to incorrectly identify chromosome abnormalities as a risk associated with APA when compared with GEN but not MFM. Chromosome abnormalities have a recognized association with advanced maternal age (AMA) (Hook 1981; Hook et al. 1983), and there are clear guidelines regarding how to care for at-risk pregnancies due to AMA (ACOG Committee Opinion 2014). There is no well-established relationship between APA and chromosomal abnormalities, but these studies are often complicated by the presence of both AMA and APA. A recent study of the chromosomal composition of IVF embryos from young donor mothers did not find an association between paternal age and the rate of aneuploidy but did find a higher rate of segmental aberrations (ex. chromosome 1p deletion) among men aged > 50 (Dviri et al. 2020). It is possible that OBGYN confuse risks associated with AMA and those associated with APA because the risks are better characterized and of greater magnitude. This is further supported by the fact that OBGYN most commonly identified standard NIPT/NIPS, used to screen for chromosomal aneuploidies (Dondorp et al. 2015), as the optimal test or screen for APA. By comparison, GEN and MFM more often identified NIPT/NIPS for de novo heterozygous pathogenic variants, suggesting a better understanding of the increased risk for de novo dominant Mendelian conditions with APA.

In contrast to what was observed among the practices of genetic counselors regarding APA (Quirin et al. 2020), age and length of practice were not correlated with discussing APA. However, it is important to point out that while GEN was significantly younger than both MFM and OBGYN respondents, they were more likely to discuss APA. Surprisingly, only MFM had greater odds of offering screening or testing on the basis of APA. This correlation is likely the result of the high proportion of pregnant patients in the MFM practice compared to GEN and OBGYN. While guideline familiarity among specialties was associated with recognizing > 40 as the APA cutoff age, it was not associated with offering testing or screening options, like a detailed anatomic survey, or discussing APA as would be recommended by the limited 2008 guidance (Toriello and Meck 2008). This could be explained by OBGYN participants consulting with a genetic professional; however, the majority of OBGYN reported that they have not consulted a genetics professional on the basis of APA. In fact, MFM reported a higher proportion of individuals who have consulted a genetics professional based on APA. Moreover, the most frequently identified optimal test or screen for APA was NIPT/NIPS for de novo pathogenic variants, which the American College of Obstetricians and Gynecologists (ACOG) currently recommends against in a practice advisory statement (ACOG Practice Advisory 2020). As the clinical and predictive value of this technology becomes clearer, NIPT/NIPS screening for novel pathogenic variants may become an effective screening tool for pregnancies at-risk due to APA. Currently, with careful pre- and post-test counseling, this screening may be useful for some individuals and future guidance should address this innovation in non-invasive prenatal genetic screening. In contrast, the 2008 guidelines only recommend extensive ultrasound as a screening tool for APA (Toriello and Meck 2008) which was the second most frequently identified optimal test in our study. This is understandable as additional screening options, such as NIPT/NIPS, were not available at the time of publication of the guidelines, further reflecting the need for updated guidance.

Limitations

Although this study was able to compare the knowledge and discussion of APA between three types of specialties, it was limited by the low number of responses from eligible participants. Thus, we were only capable of detecting associations with large effect sizes. Additionally, we were unable to include responses of non-physician providers such as mid-wives, due to a small number of responses.

Conclusion

Patients see a variety of prenatal healthcare professionals as they plan their pregnancy as well as during their pregnancy, and optimal care among providers to manage the risk of these pregnancies is essential. This pilot study identified that focused education regarding APA should be targeted toward OBGYN who consistently showed gaps and misconceptions in their responses regarding APA. Updated guidelines which reflect the most current risks and advances in prenatal genetic screening for APA are overdue, especially for non-genetics providers.

Author contribution

All authors contributed to the study conception and design. Material preparation and data collection was performed by Joseph Biddle. Data analyses were performed by Joseph Biddle and Leah Wetherill. The first draft of the manuscript was written by Joseph Biddle, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

Gift cards were purchased by the Department of Medical and Molecular Genetics, Indiana University School of Medicine.

Data availability

The data that support the findings of this study are available from the corresponding author (LW, leahweth@iu.edu) upon reasonable request.

Code availability

Not applicable.

Declarations

Ethics approval and consent to participate

All procedures followed were in accordance with the ethical standards of Indiana University and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all respondents for being included in the study.

Conflict of interest

The authors declare no conflict of interest.