Abstract
In the Netherlands, genome-wide non-invasive prenatal testing (NIPT) is offered to all pregnant women as part of the nationwide TRIDENT-2 study. Findings other than trisomy 21, 18, or 13, which are called “additional findings”, are reported only on request of the pregnant woman. This study examined: (1) women’s pre-test perceptions and reasons to opt for additional findings and (2) women’s experiences with- and the psychological impact of being informed about an additional finding. A questionnaire, consisting of the anxiety measure State-Trait Anxiety Inventory (STAI), distress measure Impact of Event Scale (IES) and questions developed specifically for this study, was retrospectively administered to 402 women who received an additional finding. A total of 227 (56.5%) women completed the questionnaire. Most (60.2%) chose to know additional findings because they wanted as much information as possible about the health of their fetus. Almost all (92%) stated that receiving the additional finding was unexpected, a shock, and/or they were in disbelief, for 85% it caused a lot of worry. Post-test, high anxiety (STAI) levels were reported in 15.5% of women, and 7.5% reported severe distress (IES). Women who gave birth to an affected child (n = 10) experienced most psychological impact (STAI and IES). Eighty-six percent of women with a fetal aberration would opt for additional findings again, compared to 49.2% of women whose result was confined to the placenta. Pre-test counseling should focus on explaining the different results NIPT can generate. Post-test counseling should focus on guiding pregnant women through this uncertain and anxious time.
Subject terms: Psychology, Psychology
Introduction
The introduction of the Non-Invasive Prenatal Test (NIPT) has changed the prenatal screening landscape significantly over the last decade [1, 2]. NIPT is primarily used to screen for fetal trisomies 21, 18, and 13, though increasingly other conditions are included [3]. NIPT based on genome-wide sequencing makes it possible to reveal other chromosomal abnormalities, including rare autosomal trisomies and structural chromosomal aberrations, present in the fetus, confined to the placenta, or originating from the pregnant woman [4–7].
The prevalence of findings other than trisomies 21, 18, and 13 when using genome-wide NIPT in the general pregnant population is shown to be approximately 3.5 in 1000, and their disease burden is subject of debate [8–10]. Consequently, pre-test counseling by obstetric caregivers for additional findings, aiming to prepare pregnant women for the different types of results, is challenging [11]. Furthermore, little is known about the potential psychological burden experienced by pregnant women following an additional finding from NIPT [12].
In the Netherlands, prenatal screening is offered as part of a national screening program. In April 2017, a governmental license was granted to offer NIPT to all pregnant women in the TRIDENT-2 study (TRIal by Dutch laboratories for Evaluation of Non-invasive prenatal Testing). Pregnant women were given a choice between no screening, NIPT, or the first-trimester combined test (ftCT) during the study period [13]. Women choosing NIPT could choose to either receive results solely on chromosomes 21, 18, and 13, or also receive additional findings on all other autosomes. Additional findings include rare autosomal trisomies (RATs), structural chromosomal aberrations (SAs), and complex abnormal profiles suggesting a possible acquired chromosomal aberration such as a maternal malignancy.
Sex chromosomes are not analyzed [8]. In the first two years of the study, 149,267 (43.2%) pregnant women opted for NIPT. Of these, 75% chose to have other findings than trisomies 21, 18, and 13 reported. A total of 402 additional findings were detected, of which 22.1% was fetal, 25.1% maternal (13.3% of these maternal findings indicated a maternal malignancy) and 52.8% confined to the placenta [8, 10].
A questionnaire study was designed to investigate women’s experiences in the Netherlands with a prenatally disclosed additional finding from genome-wide NIPT. This study examined (1) women’s pre-test perceptions and reasons to opt for additional findings and (2) women’s experiences with- and the psychological impact of being informed about an additional finding.
Methods
A retrospective questionnaire study was conducted. A questionnaire was administered to all women in the Netherlands who received an additional finding from NIPT between April 2017 and April 2019. The Dutch Ministry of Health, Welfare, and Sport granted approval for the TRIDENT-2 study (license 1017420-153371-PG). The research ethics review committee of Erasmus MC, University Medical Center Rotterdam exempted this questionnaire study (MEC-2018-1685).
Setting
In the Netherlands, in the first trimester of their pregnancy all women are asked about their interest in being informed about prenatal screening tests. At the time of the study, when interested, women engaged in a thirty-minute counseling session by a certified obstetric counselor, mostly a primary care midwife, about the options of first (NIPT or ftCT (available until October 2021)) and second-trimester prenatal screening (fetal anomaly scan around 20 weeks gestation). Information leaflets are provided in different languages, and websites are available to provide further information [8, 14].
Women who wanted to participate in first-trimester screening had a choice between NIPT (€175) and the first-trimester combined test (ftCT) (€168 in 2017). Women that choose NIPT also decide between receiving results only on chromosomes 21, 18, and 13, or also receiving additional findings on all autosomes. Reports on additional findings include rare autosomal trisomies (RATs), structural chromosomal aberrations (SAs), and complex abnormal profiles suggesting a possible acquired chromosomal aberration such as a maternal malignancy [8, 10]. Follow-up invasive prenatal diagnostic testing (i.e. amniocentesis or chorion villi sampling) and/or genetic testing of the pregnant woman and the biological father of the unborn child can further determine if the finding is fetal, (presumably) placental or maternal.
When NIPT detects an additional finding, the pregnant woman is referred to one of the eight regional centers for prenatal diagnostics. In six of the eight centers, the pregnant woman and her primary obstetric caregiver are contacted by telephone by a clinical geneticist. The pregnant woman is given a short description and explanation of the NIPT finding and is invited to the hospital (clinical genetics) for further counseling for diagnostics on short notice. In the other two centers, the clinical geneticist reports the additional finding to the primary obstetric caregiver (in most cases the midwife); the pregnant woman then receives her test-result from her primary obstetric caregiver by telephone, who makes an appointment for the woman with the clinical geneticist.
Inclusion
Peridos, the national digital registration system for prenatal screening, was used to determine which women received an additional finding. All 402 women who received an additional finding from NIPT within the TRIDENT-2 study between April 2017 and April 2019 were considered eligible for participation in the questionnaire study. All women signed informed consent. Women were postnatally invited to complete the questionnaire between 6 and 24 months after receiving their NIPT test-result. Questionnaires, accompanied by a letter explaining the purpose of the study and asking women to participate, were sent to the women’s home address.
Questionnaire
A multidisciplinary team consisting of a clinical geneticist, a psychologist, a social scientist, an obstetrician, a midwife, and a representative of the Dutch Patient Alliance for Rare and Genetic Diseases developed the questionnaire (Supplementary Material 2). Besides questions specifically developed for this study, various validated scales were administered. The questionnaire consisted of open and closed questions, and five-point Likert-scales (completely disagree-completely agree). The main topics addressed were: women’s pre-test perceptions and reasons to opt for additional findings, women’s experiences with being informed of an additional finding, and the psychological impact of receiving an additional finding.
State anxiety was measured by a Dutch version of the six-item short form of the state scale of the Spielberger State-Trait Anxiety Inventory (STAI) [15, 16]. STAI scores between 20 and 37 indicate low anxiety, scores between 38 and 44 moderate anxiety, and scores between 45 and 80 high anxiety [16, 17].
Distress caused by receiving an additional finding from NIPT was measured by a Dutch version of the Impact of Event Scale (IES), consisting of 15 questions [18, 19]. Total scores between 0 and 8 indicate a subclinical reaction, scores between 9 and 25 a mild reaction, scores between 26 and 43 a moderate reaction, and scores between 44 and 75 a severe reaction [20].
Health literacy was measured by a Dutch version of Chew’s set of brief screening questions consisting of three questions. Health literacy was inadequate if an answer other than ‘never’ or ‘occasionally’ was provided on one or more of the items [21, 22].
Tolerance of uncertainty was measured by a Dutch version of the 12-item (IUS-12) version of the Intolerance of Uncertainty Scale [23, 24]. IUS-12 scores between 12 and 36 indicate a high tolerance of uncertainty, scores between 37 and 47 some tolerance of uncertainty, and scores between 48 and 60 low tolerance of uncertainty [24].
Sociodemographic variables included: age, gestational age at the time of NIPT result, time between NIPT result and filling out the questionnaire, ethnicity, level of education, religious affiliation, and method of conceiving. Furthermore, women were asked about their NIPT results, follow-up testing, and decision-making.
Data analysis
Descriptive analyses were used to describe women’s characteristics. Descriptive and frequency analyses were used to display the data. Following other research, the five-point Likert-scales were transformed into three distinctive categories ((Completely) disagree, Neutral, (Completely) agree) [25, 26]. Answers to open-ended questions were content analyzed and categorized by two researchers independently. The outcomes of follow-up diagnostic testing after the NIPT result were assessed and sorted into four categories: results that (1) impact the health of the fetus (fetal (chromosomal) aberrations), (2) are presumably confined to the placenta (placental aberrations), (3) impact (the health of) the pregnant woman (maternal aberrations), and (4) do not fall in a specific category, such as origin of the finding unknown (other). Differences between these groups were evaluated using the Fisher’s Exact Test for proportions or a one-way ANOVA, with Bonferroni post-hoc t-tests, for continuous data. A significance level of p < 0.05 was maintained for all analyses. Analyses were performed using SPSS version 25 for Windows (IBM Statistics for Windows, IBM, NY, USA).
Results
Response and characteristics
In total, 227/402 women completed the questionnaire (56.5% response rate). Characteristics of the respondents are shown in Table 1. Most women (71.8%) were highly educated and the mean age was 34.8 years (SD = 4.54).
Table 1.
Baseline characteristics of the respondents.
| N | 227 |
|---|---|
| Age, mean (range) | 34.8 years (22–49) |
| Gestational age at NIPT result, mean (range) | 14.0 weeks (10–23) |
| Time between having NIPT and receiving NIPT result, mean (SD) | 6.8 weeks (8.6) |
| Time between NIPT result and questionnaire, mean (range) | 18.0 months (6–24) |
| Background, n (%) | |
| Dutch | 206 (90.7) |
| Other – Western | 8 (3.5) |
| Other – Non-Western | 13 (5.7) |
| Education levela, n (%) | |
| Low | 7 (3.1) |
| Intermediate | 57 (25.1) |
| High | 163 (71.8) |
| Active religious affiliation, n (%) | |
| Yes | 17 (7.5) |
| No | 210 (92.5) |
| Conception, n (%) | |
| Spontaneous | 189 (84.1) |
| Assisted reproductive technologyb | 36 (15.9) |
| Health literacy, n (%) | |
| Adequate | 209 (92.1) |
| Inadequate | 18 (7.9) |
| Tolerance of uncertainty (IUS), n (%) | |
| High (score 12–36) | 174 (76.7) |
| Medium (score 37–47) | 48 (21.1) |
| Low (score 48–60) | 4 (1.8) |
| Origin of the additional finding detected by NIPTc | |
| Fetal | 43 (18.9) |
| Placental | 134 (59.0) |
| Maternal | 42 (18.5) |
| Other | 8 (3.5) |
aEducation Level: Low: elementary school, lower level of secondary school, lower vocational training; Medium: high level of secondary school, intermediate vocational training; High: high vocational training, university [27].
bAssisted reproductive technology: ovulation stimulation (n = 11), intrauterine insemination (n = 10), in vitro fertilization (n = 7), intracytoplasmic sperm injection (n = 7), egg cell donation (n = 1).
cBased on confirmation by follow-up testing or confirmation after birth.
NIPT results and follow-up testing
In total, 204/227 women (89.9%) reported they chose follow-up testing (e.g. invasive genetic testing, advanced ultrasound) after receiving their NIPT result and post-test counseling by a clinical geneticist. After follow-up testing or confirmation after birth, 43/227 (18.9%) additional findings were fetal aberrations, 134/227 (59%) were (probably) confined to the placenta, 42/227 (18.5%) were maternal aberrations, for nine of these women the NIPT result indicated a possible acquired chromosomal aberration, and 8/227 (3.5%) did not fit in one of the categories, such as a miscarriage or origin unknown (Table 1 and Fig. 1).
Fig. 1. Overview of the different NIPT results after confirmation by follow-up testing or confirmation after birth.
MC Miscarriage, MM maternal malignancy, RAT Rare Autosomal Trisomy, SA Structural chromosomal aberration, TOP termination of pregnancy, VT vanishing twin. *Unknown whether chromosomal abnormality detected by NIPT was a Rare Autosomal Trisomy (RAT) or Structural chromosomal aberration.
Women’s pre-test perceptions and reasons for choosing to receive additional findings
Almost all women (98.2%) reported having a pre-test counseling session with their obstetric caregiver about prenatal screening (NIPT/ftCT). Nearly half of the women (45.5%) believed the obstetric caregiver paid enough attention to additional findings during this counseling. The data show that women with a result that was (probably) confined to the placenta stated less often that they received sufficient information to make an informed decision about additional findings (55/130, 42.3%) than women with a fetal aberration (30/42, 71.4%, p = 0.001) or a maternal aberration (26/41, 63.4%, p = 0.021). All women’s considerations before participating in NIPT are presented in Table A in Supplementary Material 3.
When asked what their most important reason for choosing additional findings was, most women (60.2%) indicated they chose additional findings because they wanted to know as much as possible about the health of their fetus. For forty-eight women (21.2%) their main reason to choose additional findings was to be able to prevent the birth of a child with aberrations by terminating the pregnancy if a severe finding would be detected in the fetus. For all reasons see Table B in Supplementary Material 3. A slight majority of women (58.5%) did not find it difficult to make a decision about additional findings, 12.5% had a neutral opinion, and 29% did find it difficult to make a decision.
Women’s experiences with being informed of an additional finding
All women received the initial news that an additional NIPT finding was detected via telephone. Most women (64.2%) were directly contacted by the clinical geneticist, whereas 34.8% were first contacted by their primary obstetric caregiver (who was informed by the clinical geneticist). All but three women (98.7%) met with a clinical geneticist in person to discuss their additional finding further. For two women, the NIPT result indicated a known maternal structural chromosomal aberration, so there was no need to meet with the clinical geneticist. For one woman, the reason why she did not meet with a clinical geneticist was unknown. For the vast majority of women (86%), discussing their result with the clinical geneticist helped them understand the meaning of their result. Thirty-eight (16.9%) women had support from a psychologist or medical social worker regarding their NIPT result. Of the 187 women that did not, 40 (21.4%) would have liked such support.
The psychological impact of receiving an additional finding
Women’s experiences with- and psychological impact of their NIPT result are displayed in Table 2. Women with a fetal aberration (30/42, 71.4%) or a maternal aberration (26/41, 63.4%) significantly more often agreed that the NIPT result was valuable for their pregnancy compared to women with a placental aberration (58/132, 43.9%), p = 0.002 and p = 0/033 respectively. For women with a fetal aberration (39/43, 90.7%) or with a placental aberration (119/134, 88.8%), the NIPT result caused them significantly more worry compared to women with a maternal aberration (28/41, 68.3%), p = 0.014 and p = 0.003 respectively.
Table 2.
Women’s experiences with and psychological impact of an additional finding.
| (Completely) agree | ||||
|---|---|---|---|---|
| Fetal N = 43 N (%) | Placental N = 134 N (%) | Maternal N = 42 N (%) | Total N = 226 N (%) | |
| The NIPT result had a negative influence on my feelings about my pregnancy. | 28 (65.1) | 86 (64.2) | 14 (34.1) | 131 (58.0) |
| The NIPT result caused me a lot of worry. | 39 (90.7) | 119 (88.8) | 28 (68.3) | 192 (85.0) |
| The NIPT result made it difficult for me to bond with my fetus. | 18 (41.9) | 37 (27.8) | 5 (12.5) | 62 (27.7) |
| I could go to someone with my worries after receiving the NIPT result. | 33 (76.7) | 86 (67.2) | 30 (76.9) | 154 (70.6) |
| My partner and I usually agreed when it came to decisions about the NIPT result. | 41 (95.3) | 124 (93.9) | 38 (92.7) | 211 (94.2) |
| The NIPT result placed extra pressure on the relationship with my partner. | 7 (16.7) | 25 (19.1) | 7 (17.1) | 39 (17.6) |
| The NIPT result was valuable for my pregnancy. | 30 (71.4) | 58 (43.9) | 26 (63.4) | 117 (52.5) |
For almost all women, receiving the additional finding was unexpected, a shock, and/or they were in disbelief (92%).
Anxiety (STAI) scores are shown in Table 3. Most women had low (76.1%) anxiety scores; 15.5% had high anxiety scores (>45). Women who gave birth to an affected child (n = 10) reported high anxiety scores most often. No significant differences in anxiety were observed between the different groups. Furthermore, t-tests showed that women who had high tolerance of uncertainty (IUS) experienced less anxiety (M = 31.8, SD = 11.3) than women who had medium tolerance of uncertainty (M = 37.5, SD = 12.5) (p = 0.009) or women that had low tolerance of uncertainty (M = 55.1, SD = 6.8) (p < 0.001).
Table 3.
Anxiety (STAI) scores.
| Additional finding/outcome | Total mean anxiety | Low anxiety N (%) | Moderate anxiety N (%) | High anxiety N (%) |
|---|---|---|---|---|
| Fetal, pregnancy terminated, n = 33 | 34.5 | 23 (71.9) | 3 (9.4) | 6 (18.8) |
| Fetal, affected live birth n = 10 | 40.7 | 5 (50.0) | 0 (0.0) | 5 (50.0) |
| Placental n = 134 | 32.1 | 106 (79.1) | 13 (9.7) | 15 (11.2) |
| Maternal structural aberration n = 33 | 34.4 | 26 (78.8) | 1 (3.0) | 6 (18.2) |
| Maternal malignancy n = 9 | 40.4 | 4 (44.4) | 2 (22.2) | 3 (33.3) |
| Total n = 226 | 33.4 | 172 (76.1) | 19 (8.4) | 35 (15.5) |
Spielberger State-Trait Anxiety Inventory (STAI) scores ranged 20–80. Low anxiety = 20–37, moderate anxiety = 38–44, high anxiety = 45–80.
Distress (IES) scores are shown in Table 4. Most women had a subclinical reaction (53.7%); 7.5% had a severe reaction. Women of the different groups showed different mean distress (IES) scores, where women (n = 10) who gave birth to an affected child (M = 23.8, SD = 21.3) experienced significantly more distress from receiving their NIPT result than women (n = 33) who had a structural aberration themselves (M = 6.0, SD = 11.6) (p = .030). On average women had subclinical or mild reactions. Furthermore, ī-tests showed that women who had high tolerance of uncertainty (IUS) experienced less distress (M = 11.8, SD = 15.2) than women who had medium tolerance of uncertainty (M = 21.0, SD = 19.5) (p = 0.002) but did not differ significantly from women that had low tolerance of uncertainty (M = 21.3, SD = 21.2).
Table 4.
Distress (IES) scores.
| Additional finding/outcome | Total mean IES | Subclinical N (%) | Mild N (%) | Moderate N (%) | Severe N (%) |
|---|---|---|---|---|---|
| Fetal, pregnancy terminated n = 33 | 15.9 | 12 (36.4) | 14 (42.4) | 5 (15.2) | 2 (6.1) |
| Fetal, affected live birth n = 10 | 23.8 | 3 (30.0) | 1 (10.0) | 5 (50.0) | 1 (10.0) |
| Placental n = 134 | 14.9 | 70 (52.2) | 29 (21.6) | 23 (17.2) | 12 (9.0) |
| Maternal structural aberration n = 33 | 6.0 | 26 (78.8) | 3 (9.1) | 3 (9.1) | 1 (3.0) |
| Maternal malignancy n = 9 | 14.6 | 5 (55.6) | 2 (22.2) | 1 (11.1) | 1 (11.1) |
| Total n = 227 | 14.0 | 122 (53.7) | 50 (22.0) | 38 (16.7) | 17 (7.5) |
Range Impact of Event Scale (IES) scores 0–75: subclinical = 0–8, mild = 9–25, moderate = 26–43, severe = 44–75.
Women’s reflections on their choice for NIPT with additional findings are shown in Table 5. Most women, irrespective of their NIPT result, would opt for NIPT again in a future pregnancy. However, differences are seen between the groups in choosing for additional findings again. A vast majority (37/43, 86%) of women with a fetal aberration would opt for additional findings again, which is significantly more compared to 65/132, 49.2% of women whose NIPT result was confined to the placenta (p < 0.001), and which does not differ significantly from the 29/42, 69% of women having a maternal aberration (p = 0.072).
Table 5.
Reflections on the choice for NIPT with additional findings.
| (Completely) agree | ||||
|---|---|---|---|---|
| Fetal N = 43 N (%) | Placental N = 134 N (%) | Maternal N = 42 N (%) | Total N = 226 N (%) | |
| If I would opt for first-trimester prenatal screening again, I would opt for NIPT again. | 39 (90.7) | 112 (84.2) | 37 (88.1) | 196 (86.7) |
| If I would opt for first-trimester prenatal screening again, I would opt for NIPT with additional findings again. | 37 (86.0) | 65 (49.2) | 29 (69.0) | 137 (60.9) |
| Choosing for additional findings was the right choice for me in this pregnancy. | 37 (86.0) | 76 (58) | 33 (80.5) | 151 (67.7) |
| In hindsight, I would rather not have had the choice for additional findings. | 3 (7) | 49 (37.1) | 4 (9.5) | 58 (25.8) |
| I regret my choice for additional findings. | 2 (4.7) | 39 (29.5) | 4 (9.5) | 46 (20.4) |
Discussion
The findings demonstrate that overall women were not well prepared for making their decision for additional findings from NIPT, and also not for receiving these findings. For most women receiving the additional finding evoked strong negative emotions. At 6–24 months after receiving the results, a minority still reported high anxiety and distress levels. Overall, most women would opt for NIPT with additional findings again in a future pregnancy; women with a result confined to the placenta would least often opt for additional findings again.
Nearly one third of women found it difficult to make a decision about additional findings. Most women chose NIPT with additional findings because they wanted to know as much as possible about the health of their fetus, which is in line with earlier research [25, 27]. Most women also stated that they did not receive enough information about additional findings in pre-test counseling, and the different origins (fetal/ placental/maternal) NIPT could generate were relatively unknown.
With more information on the different origins of additional findings and their consequences available [10], including the fact that most additional findings from NIPT are confined to the placenta, this could be more addressed in pre-test counseling. Thus, pre-test counseling can be optimized to inform women better about the possible outcomes of NIPT. For example, it has been shown that additional findings confined to the placenta increase the risk of fetal growth restriction and pre-eclampsia, and women may not be adequately prepared for such results [10].
Overall, most women reported low anxiety and distress scores 6–24 months after receiving their NIPT result. The mean anxiety score in our sample is comparable to the anxiety scores of women receiving low risk NIPT results after a high risk ftCT result [28]. However, some women still reported high level of anxiety, especially women who gave birth to an affected child. The women in our study indicated that on average they had to wait 7 weeks until there was more clarity about the meaning of the additional finding detected by NIPT. To manage post-test anxiety and distress levels, it is important to shorten the uncertain and anxious time following an additional finding. Although it cannot be used for all aberrations, one way to shorten the waiting time is by offering chorionic villus sampling instead of waiting to perform an amniocentesis [29]. Another way is by decreasing the turnaround time of diagnostic genetic testing.
Our results show that the impact of receiving an additional finding from NIPT was dependent on women’s ability to tolerate uncertainty. Adequate post-test counseling is important for all pregnant women receiving an additional finding, but for women who have low tolerance for uncertainty it is especially important to properly guide them, for example by means of a specialized psychologist or social worker. Earlier research has shown that low tolerance of uncertainty is associated with more information-seeking behavior and a desire for more information [30, 31]. Post-test counseling could be used to determine which women are more prone to experience a significant impact from receiving an additional finding from NIPT, to ensure these women receive extra support in handling their result and dealing with the uncertainty.
Recent research on additional findings in genetic testing shows that most participants do not regret their decision to receive additional findings [32, 33]. This also accounts for the women in our sample who received either a fetal aberration or maternal aberration as a result from NIPT. Most of these women would opt for NIPT with additional findings again in a future pregnancy. However, women with a placenta confined result would least often opt for additional findings again and most often regret choosing for additional findings. Therefore, informing women about the possibility of placenta confined additional findings in pre-test counseling is especially important to minimize decisional regret. Moreover, women should be informed in post-counseling about the (expected) positive predictive value that the additional finding will be confirmed in the fetus.
The results from this TRIDENT-2 impact study can be used to shape pre- and post-test counseling and offer guidance and support by means of a specialist, preferably a clinical geneticist, trained genetic counselor or specialized midwife, and psychologist/social worker after disclosure of an additional finding.
Pre-test counseling, by means of guiding women through the decision-making process, should inform women about the chance of detecting an additional finding and explain the different origins of additional findings and the follow-up tests needed for confirmation. Pre-test counseling should be supported by means of leaflets, informational websites, online decision aids and informational animations.
Post-test counseling, by means of guidance through emotions, health education and decision-making support, should focus on guiding pregnant women through this anxious and uncertain time [34]. Based on our results we provide recommendations for counseling in Box 1.
Box 1 Recommendations for counseling on additional findings from genome-wide NIPT.
Pre-test counseling
Explain the chance of having an additional finding from NIPT (e.g. 4 in 1000).
Inform women that additional findings need to be confirmed with follow-up tests, and findings can be fetal, placental, or maternal in origin.
Inform women that most additional findings do not affect the health of the fetus but are confined to the placenta. Mention that placenta confined results increase the risk of fetal growth restriction and pre-eclampsia.
Post-test counseling
Provide women with a consultation by a clinical geneticist on short notice to explain the additional finding and follow-up process.
Inform women about the (expected) positive predictive value of the additional finding, i.e. that the finding will be confirmed in the fetus.
Inform women about the post-NIPT confirmation process including the uncertain, sometimes long, waiting time.
Offer all women guidance and support from a specialized psychologist/social worker.
Determine which women need more guidance and support (i.e. have low tolerance of uncertainty).
Strengths and limitations
With our relatively large sample size (N = 227), we were able to report on many aspects of the experiences women had with receiving an additional finding from NIPT. Another strength is that our sample resembles the population of women receiving an additional finding in the first two year of the TRIDENT-2 study with regard to the type of finding detected [10].
A limitation of our study is that it is a retrospective questionnaire study, in which for some women two years had passed since the respondents received their NIPT results; therefore, it is possible that women misremember certain aspects, influencing our results. Furthermore, the wide range in time that passed since women received the NIPT result (6–24 months) makes it difficult to make comparisons. Another limitation is that our study mainly included highly educated women, which could lead to a bias in our results. Furthermore, for the invited women that did not respond to our questionnaire, we do not know their reasons for not participating. Another limitation is that our study did not include the partners of the pregnant women. Future research could include qualitative interviews with pregnant women and their partners about the meaning of the additional finding.
Conclusion
Most women report low/moderate anxiety and distress scores 6–24 months after receiving an additional finding from genome-wide NIPT. Women who gave birth to an affected child reported high anxiety and distress scores most often. Moreover, women with a high tolerance of uncertainty experienced the least anxiety and distress. Overall, most women would opt for NIPT with additional findings again in a future pregnancy; women with a result confined to the placenta would least often opt for additional findings again. Pre-test counseling should focus on explaining the different results NIPT can generate, especially that most results are not fetal aberrations and are confined to the placenta. Post-test counseling should focus on guiding pregnant women through this uncertain and anxious time by shorting of the time necessary for follow-up testing, and by providing adequate psychological support.
Supplementary information
Acknowledgements
The authors would like to thank all participating women for completing the questionnaire. This study was made possible using data from Peridos, the Dutch national digital registration system for prenatal screening. The authors would like to thank all members of the NIPT consortium.
Author contributions
The authors confirm contribution to the paper as follows: Study conception and design: IMB, LH, EHv, MNB & RJHG. Data collection: IMB. Analysis and interpretation of results: IMB, MGP, LH, MNB & RJHG. Draft manuscript preparation: IMB & RJHG. Revised manuscript: LH, EHv, LM, JTG, MGP, MNB & RJHG. All authors reviewed the results and approved the final version of the manuscript.
Funding
This work was partly supported by a grant from the Netherlands Organization for Health Research and Development (ZonMw, No. 543002001).
Data availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Ethical approval
The research ethics review committee of Erasmus MC, University Medical Center Rotterdam exempted this questionnaire study (MEC-2018-1685). All participants signed informed consent.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Contributor Information
Iris M. Bakkeren, Email: i.bakkeren@erasmusmc.nl
Robert-Jan H. Galjaard, Email: r.galjaard@erasmusmc.nl
Supplementary information
The online version contains supplementary material available at 10.1038/s41431-023-01504-8.
References
- 1.Lo YMD, Corbetta N, Chamberlain PF, Rai V, Sargent IL, Redman CWG, et al. Presence of fetal DNA in maternal plasma and serum. Lancet. 1997;350:485–7. doi: 10.1016/S0140-6736(97)02174-0. [DOI] [PubMed] [Google Scholar]
- 2.Warsof SL, Larion S, Abuhamad AZ. Overview of the impact of noninvasive prenatal testing on diagnostic procedures. Prenat Diagn. 2015;35:972–9. doi: 10.1002/pd.4601. [DOI] [PubMed] [Google Scholar]
- 3.Ravitsky V, Roy M-C, Haidar H, Henneman L, Marshall J, Newson AJ, et al. The Emergence and Global Spread of Noninvasive Prenatal Testing. Annu Rev Genom. Hum Genet. 2021;22:309–38. doi: 10.1146/annurev-genom-083118-015053. [DOI] [PubMed] [Google Scholar]
- 4.van Opstal D, Van Maarle MC, Lichtenbelt K, Weiss MM, Schuring-Blom H, Bhola SL, et al. Origin and clinical relevance of chromosomal aberrations other than the common trisomies detected by genome-wide NIPS: results of the TRIDENT study. Genet Med. 2018;20:480–5. doi: 10.1038/gim.2017.132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Fiorentino F, Bono S, Pizzuti F, Duca S, Polverari A, Faieta M, et al. The clinical utility of genome‐wide non invasive prenatal screening. Prenat Diagn. 2017;37:593–601. doi: 10.1002/pd.5053. [DOI] [PubMed] [Google Scholar]
- 6.Pescia G, Guex N, Iseli C, Brennan L, Osteras M, Xenarios I, et al. Cell-free DNA testing of an extended range of chromosomal anomalies: clinical experience with 6,388 consecutive cases. Genet Med. 2017;19:169–75. doi: 10.1038/gim.2016.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Pertile MD, Halks-Miller M, Flowers N, Barbacioru C, Kinnings SL, Vavrek D, et al. Rare autosomal trisomies, revealed by maternal plasma DNA sequencing, suggest increased risk of feto-placental disease. Sci Transl Med. 2017;9:1–11. doi: 10.1126/scitranslmed.aan1240. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.van der Meij KRM, Sistermans EA, Macville MVE, Stevens SJC, Bax CJ, Bekker MN, et al. TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands. Am J Hum Genet. 2019;105:1091–101. doi: 10.1016/j.ajhg.2019.10.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lannoo L, van Straaten K, Breckpot J, Brison N, De Catte L, Dimitriadou E, et al. Rare autosomal trisomies detected by non-invasive prenatal testing: an overview of current knowledge. Eur J Hum Genetics. 2022;30:1323–30. doi: 10.1038/s41431-022-01147-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.van Prooyen Schuurman L, Sistermans EA, Van Opstal D, Henneman L, Bekker MN, Bax CJ, et al. Clinical impact of additional findings detected by genome-wide non-invasive prenatal testing: follow-up results of the TRIDENT-2 study. Am J Hum Genet. 2022;109:1140–52. doi: 10.1016/j.ajhg.2022.04.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Gammon BL, Jaramillo C, Riggan KA, Allyse M. Decisional regret in women receiving high risk or inconclusive prenatal cell-free DNA screening results. J Matern Fetal Neonatal Med. 2018;33:1412–8. doi: 10.1080/14767058.2018.1519541. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Jani JC, Gil MM, Benachi A, Prefumo F, Kagan KO, Tabor A, et al. Genome‐wide cfDNA testing of maternal blood. Ultrasound Obstet Gynecol. 2020;55:13–4. doi: 10.1002/uog.21945. [DOI] [PubMed] [Google Scholar]
- 13.RIVM. Draaiboek prenatale screening downsyndroom en Structureel Echoscopisch Onderzoek. 2018. Available from: https://www.rivm.nl/Documenten_en_publicaties/Professioneel_Praktisch/Draaiboeken/Preventie_Ziekte_Zorg/Draaiboek_prenatale_screening_downsyndroom_en_Structureel_Echoscopisch_Onderzoek
- 14.(RIVM) RvVeM. Screeningen tijdens de zwangerschap: RIVM; 2021. Available from: pns.nl/prenatale-screeningen.
- 15.Marteau TM, Bekker H. The development of a six‐item short‐form of the state scale of the Spielberger State—Trait Anxiety Inventory (STAI) Br J Clin Psychol. 1992;31:301–6. doi: 10.1111/j.2044-8260.1992.tb00997.x. [DOI] [PubMed] [Google Scholar]
- 16.van der Bij AK, de Weerd S, Cikot RJLM, Steegers EAP, Braspenning JCC. Validation of the Dutch short form of the state scale of the Spielberger State-Trait Anxiety Inventory: considerations for usage in screening outcomes. Public Health Genom. 2003;6:84–7. doi: 10.1159/000073003. [DOI] [PubMed] [Google Scholar]
- 17.Tluczek A, Henriques JB, Brown RL. Support for the reliability and validity of a six-item state anxiety scale derived from the State-Trait Anxiety Inventory. J Nurs Meas. 2009;17:19. doi: 10.1891/1061-3749.17.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Horowitz M, Wilner N, Alvarez W. Impact of event scale: a measure of subjective stress. Psychosom Med. 1979;41:209–18. doi: 10.1097/00006842-197905000-00004. [DOI] [PubMed] [Google Scholar]
- 19.van der Ploeg E, Mooren T, Kleber RJ, van der Velden PG, Brom D. Construct validation of the Dutch version of the impact of event scale. Psychol Assess. 2004;16:16. doi: 10.1037/1040-3590.16.1.16. [DOI] [PubMed] [Google Scholar]
- 20.Hutchings ED, G.J. Impact of Event Scale (IES): Clintools. Available from: http://www.clintools.com/victims/resources/assessment/ptsd/ies.html#:~:text=The%20IES%20scale%20consists%20of,a%20total%20subjective%20stress%20score.
- 21.Chew LD, Bradley KA, Boyko EJ. Brief questions to identify patients with inadequate health literacy. Health. 2004;11:12. [PubMed] [Google Scholar]
- 22.Fransen MP, Van Schaik TM, Twickler TB, Essink-Bot ML. Applicability of internationally available health literacy measures in the Netherlands. J Health Commun. 2011;16:134–49. doi: 10.1080/10810730.2011.604383. [DOI] [PubMed] [Google Scholar]
- 23.Carleton RN, Norton MAPJ, Asmundson GJG. Fearing the unknown: a short version of the Intolerance of Uncertainty Scale. J Anxiety Disord. 2007;21:105–17. doi: 10.1016/j.janxdis.2006.03.014. [DOI] [PubMed] [Google Scholar]
- 24.Helsen K, Van den Bussche E, Vlaeyen JWS, Goubert L. Confirmatory factor analysis of the Dutch Intolerance of Uncertainty Scale: comparison of the full and short version. J Behav Ther Exp Psychiatry. 2013;44:21–9. doi: 10.1016/j.jbtep.2012.07.004. [DOI] [PubMed] [Google Scholar]
- 25.van Schendel RV, Dondorp WJ, Timmermans DRM, van Hugte EJH, de Boer A, Pajkrt E, et al. NIPT‐based screening for Down syndrome and beyond: what do pregnant women think? Prenat Diagn. 2015;35:598–604. doi: 10.1002/pd.4579. [DOI] [PubMed] [Google Scholar]
- 26.van der Meij KRM, Njio A, Martin L, Gitsels-van der Wal JT, Bekker MN, van Vliet-Lachotzki EH, et al. Routinization of prenatal screening with the non-invasive prenatal test: pregnant women’s perspectives. Eur J Hum Genet. 2022;30:661–8. doi: 10.1038/s41431-021-00940-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.van der Steen SL, Diderich KEM, Riedijk SR, Verhagen‐Visser J, Govaerts LCP, Joosten M, et al. Pregnant couples at increased risk for common aneuploidies choose maximal information from invasive genetic testing. Clin Genet. 2015;88:25–31. doi: 10.1111/cge.12479. [DOI] [PubMed] [Google Scholar]
- 28.Labonté V, Alsaid D, Lang B, Meerpohl JJ. Psychological and social consequences of non-invasive prenatal testing (NIPT): a scoping review. BMC Pregnancy Childbirth. 2019;19:1–14. doi: 10.1186/s12884-019-2518-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Van Opstal D, Srebniak MI. Cytogenetic confirmation of a positive NIPT result: evidence-based choice between chorionic villus sampling and amniocentesis depending on chromosome aberration. Expert Rev Mol Diagn. 2016;16:513–20. doi: 10.1586/14737159.2016.1152890. [DOI] [PubMed] [Google Scholar]
- 30.Rosen NO, Knäuper B, Sammut J. Do individual differences in intolerance of uncertainty affect health monitoring? Psychol Health. 2007;22:413–30. doi: 10.1080/14768320600941038. [DOI] [Google Scholar]
- 31.Rosen NO, Knäuper B, Di Dio P, Morrison E, Tabing R, Feldstain A, et al. The impact of intolerance of uncertainty on anxiety after receiving an informational intervention about HPV: a randomised controlled study. Psychol Health. 2010;25:651–68. doi: 10.1080/08870440902822913. [DOI] [PubMed] [Google Scholar]
- 32.Nambot S, Sawka C, Bertolone G, Cosset E, Goussot V, Derangère V, et al. Incidental findings in a series of 2500 gene panel tests for a genetic predisposition to cancer: Results and impact on patients. Eur J Med Genet. 2021;64:104196. doi: 10.1016/j.ejmg.2021.104196. [DOI] [PubMed] [Google Scholar]
- 33.Cheung F, Birch P, Friedman JM, Study C, Gen CS, Elliott AM, et al. The long‐term impact of receiving incidental findings on parents undergoing genome‐wide sequencing. J Genet Couns. 2022;31:887–900. doi: 10.1002/jgc4.1558. [DOI] [PubMed] [Google Scholar]
- 34.Bekker M, Henneman L, Macville M, Sistermans E, Galjaard R-J. Benefit vs potential harm of genome-wide prenatal cfDNA testing requires further investigation and should not be dismissed based on current data. Ultrasound Obstet Gynecol. 2020;55:695–6. doi: 10.1002/uog.22030. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.