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DOI: 10.1055/a-2641-7664
Management of Prenatally Diagnosed Malformations of the Central Nervous System: Factors Influencing Decision-making and the Time of Termination of Pregnancy
Article in several languages: English | deutschAuthors
Abstract
Introduction
CNS malformations are among the most common malformations diagnosed prenatally and one of the main reasons for late terminations of pregnancy. Making the correct diagnosis and prognostic counseling a33re complex. The aim of this study was to analyze pregnancy outcomes with regard to specific malformations, the factors which affect decision-making, and the time between diagnosis and termination as well as the causes of late diagnosis and late termination.
Patients and Method
A retrospective examination was carried out of all pregnancies with fetal CNS malformations treated at a perinatal center between 2003 and 2014. Termination rates, type of malformation, and gestational age at initial diagnosis and at termination were recorded. The factors influencing decision-making and the time between diagnosis and termination were analyzed statistically. A case-by-case analysis was carried out of any terminations performed after week 26+0 of gestation.
Results
In 139 of 251 cases (55.44%), the pregnancy was terminated between week 13+1 and week 38+2 of gestation (median: 22+4 GW). The median time from the initial diagnosis to the start of termination (Δtermination) was 10 days (range: 1 to 94 days). Relevant factors influencing the decision to terminate the pregnancy were the type of malformation compared to isolated ventriculomegaly (non-isolated ACC [aOR 17.5; p < 0.001], holoprosencephaly [aOR 24.4; p < 0.001], spina bifida [aOR 7.24; p < 0.001], other neural tube defects [aOR 62.5; p < 0.001]) and the presence of additional genetic anomalies (aOR 6.38; p = 0.014). The decision to terminate the pregnancy occurred less often when the diagnosis was made at or after week 22+0 of gestation (aOR 0.24; p < 0.001). Significant factors which affected the time between diagnosis and the start of termination (Δtermination) were: having a fetal MRI (HR 0.41; p = 0.003) and maternal age (HR 0.95 per additional year; p = 0.034). The interval between diagnosis and termination was significantly shorter if a destructive abnormality (HR 10.5; p = 0.004) or a (non-spina bifida) neural tube defect (HR 3.86; p = 0.002) was present. A known chromosomal aberration (p = 0.87), non-CNS anomalies (p = 0.58), or a diagnosis ≥ 22+0 GW (p = 0.74) affected the time between diagnosis and termination. The analysis of particularly late terminations from week 26+0 of gestation onwards found that avoidable delays in making the diagnosis or terminating the pregnancy only occurred in a few individual cases.
Conclusion
The diagnostic and prognostic complexity of cerebral malformations means that delayed diagnosis and prolonged decision-making are common, even under optimal conditions of care. Early introduction of standardized prenatal diagnostic examinations is needed for to ensure that the pregnant woman receives open-ended, informed counseling as soon as possible. But late termination of pregnancy is not necessarily negative as, in most cases, this is due to the need for a differentiated prenatal diagnostic evaluation – for example, a fetal MRI – and the ethical requirement of sufficient time to provide informed, well-considered decision-making.
Introduction
The prevalence of malformations of the central nervous system is assumed to be around 1 per 100 live births, making these malformations some of the most common fetal anomalies diagnosed prenatally [1]. The spectrum of malformations is wide and ranges from findings expected to have no or only a very limited impact on the child’s subsequent development to malformations resulting in the severe impairment of all motor, sensory and cognitive functions and even, in certain cases, of vegetative functions as well. Diagnosing CNS malformations, prenatal counseling, and assessment of the prognosis are very challenging. Depending on the type and severity of the prenatally diagnosed or suspected malformation, a certain percentage of parents decide to carry the pregnancy to term. Malformations of the central nervous system are typically only diagnosed very late and the pregnancy can only be terminated at a late stage of pregnancy, often only after the 22nd GW, meaning that feticide is necessary in many cases [2] [3] [4]. The correct diagnosis is often only made late in pregnancy because many CNS malformations are only clearly identifiable at an advanced stage of pregnancy, as brain maturation processes occur comparatively late in pregnancy.
The aim of this retrospective study was to determine the direct outcomes of ongoing pregnancies: which percentage of pregnant women receiving treatment in a level I perinatal center opted for a termination of pregnancy for various CNS malformations, what type of termination was carried out, and in which week of gestation the pregnancy was terminated. The study also investigated the time of the initial diagnosis in relationship to the time of termination of pregnancy, the possible causes of delays in the diagnosis or termination and whether the diagnosis was confirmed postnatally. An analysis was carried out in cases where the diagnosis was not confirmed to see whether knowledge of the correct (postnatal) diagnosis would have had an impact on the parental choice.
Patients and Method
This study is a retrospective analysis of all pregnancies and births of infants treated in a level I perinatal center between 2003 and 2014 diagnosed prenatally with CNS malformations. Identification of cases was done using the standard data collected in the birth registers. Data on prenatal and postnatal findings, mode of delivery, and follow-up care was obtained from the hospital’s internal systems (ViewPoint, SAP).
The initial diagnosis of CNS malformation was based on sonographic findings. An MRI was additionally carried out prenatally in individual cases to confirm and particularize the findings. Postnatal diagnostic confirmation was done with MRI or ultrasound in live-born infants and by neuropathological examination following termination of pregnancy if the parents agreed. Primary recorded outcomes were whether the pregnancy was terminated prematurely (abortion/termination) or was carried to term. The analysis classified the completed pregnancies, differentiating them into “live-born” and “died peripartum” as well as “diagnosis confirmed postnatally” and “different diagnosis.” Twin pregnancies and pregnancies terminated due to spontaneous intrauterine fetal death were excluded from the analysis.
The time of initial diagnosis was determined as the time of the first recorded diagnosis, which in most cases was the time of the first examination by an experienced medical specialist with advanced qualifications (DEGUM II or III). Not all previous (suspected) diagnoses, e.g., made in the context of standard prenatal care or delay until presentation to a medical specialist, were recorded. In all cases of termination of pregnancy, the time between the initial diagnosis and the start of termination, i.e., the time of feticide or of the first administration of the drug was calculated using the information in VIEWpoint, and references to possible causes of the delay in diagnosis or termination were documented. A case-by-case analysis into the possible causes for late diagnosis or late termination was carried out in all cases terminated in or after week of 26+0 gestation.
In accordance with our in-hospital standards, all patients were offered the services of a neuropediatric council as well as – depending on the suspected diagnosis – of a pediatric and/or neonatal council. These counseling sessions were usually held after performing fetal MRI, if such an MRI was carried out. Depending on the indication, patients were additionally offered diagnostic puncture (e.g., amniocentesis). Patients also received genetic counseling in the context of this diagnostic procedure.
The first regression analysis investigated which factors were independently associated with the decision to have an abortion. Variables which were integrated into the multivariable logistic regression model were chosen based on their clinical plausibility and included the type of CNS anomaly, the presence of other non-CNS malformations, known chromosomal aberrations, diagnosis after week 22+0 of gestation and maternal age.
A second regression analysis was carried out to analyze the subgroup of pregnant women who chose to have a termination. Cox regression analysis was used to investigate which variables were associated with the time between diagnosis of a CNS anomaly and the termination (defined as the start of the medical intervention). The following parameters were integrated into the Cox regression model: type of CNS anomaly, presence of non-CNS malformations, known chromosomal aberrations, fetal MRI carried out, diagnosis after week 22+0 of gestation, and maternal age.
The results of both regression analyses were presented as adjusted odds ratio or hazard ratio, confidence intervals, and a p value for every variable.
As is standard practice in our institution, written consent to the scientific use of anonymized data was obtained from all patients. All procedures met the ethical standards of the relevant committee for human experiments (institutional and national) and the current version of the Declaration of Helsinki (1975).
Results
A total of 259 pregnancies with fetal CNS anomalies were investigated between 2003 and 2014. Eight pregnancies were excluded from the analysis: six because they were twin pregnancies and two because of spontaneous intrauterine fetal death. 44.6% (112) of parents opted to carry the pregnancy to term and 55.4% (139) opted for a termination. The terminations of pregnancy (start of induction of medical abortion or feticide) were carried out between 13+1 and 38+2 weeks of gestation (median: 22+4 GW). Postpartum, the postnatal diagnosis differed from the prenatal diagnosis in 19 cases. In 218 cases (86.9%) information was available about the time of initial diagnosis; the median gestational age at initial diagnosis was 20+3 GW (min 12+1; max 38+6). The clinical characteristics of the study population are summarized in [Table 1].
Diagnosed Malformations and Pregnancy Outcomes
The gestational age at diagnosis, the rate of terminations of pregnancy, the gestational age at the time of termination and the time between diagnosis and medical abortion or feticide differed depending on the respective diagnostic group ([Table 2]). The highest rate of terminations was observed in the group with neural tube defects without spina bifida (95.5%), while the lowest rate was recorded in the group with isolated ventriculomegaly (21.6%). The termination rate of some small subgroups, for example the group with arachnoid cysts, was 0%. The decision to terminate the pregnancy in the groups with different malformations varied, depending on the presence of additional genetic anomalies, further extracerebral malformations, and the severity of the diagnosed anomaly. Because of the limited case numbers in the various subgroups, it was not possible to evaluate the statistical significance of the differences between groups. For example, the termination rate for fetuses with severe or moderate ventriculomegaly was 28.6% and 22.2% respectively, while all pregnancies with mild ventriculomegaly were continued.
Factors influencing decision-making and the timing of termination of pregnancy
For 139 terminations, the median gestational age at the time of termination of pregnancy was 22+4 GW (range: 13+1 to 38+2 GW). The median time from the initial diagnosis to the start of the termination (Δtermination) was 10 days (range: 1 to 94 days).
A comparison of gestational ages at termination showed that the median time (Δtermination) between diagnosis and termination was 6 days (range: 1–17 days) for terminations carried out up to and including week 21+6 of gestation and was therefore significantly shorter than for the group of terminations carried out after week 22+0 of gestation where the median time between diagnosis and termination was 15 days (range: 4–92 days) (p < 0.001). The time of first diagnosis also differed significantly between the two groups: in the group of earlier terminations, the median gestational age when the diagnosis was obtained was 19+4 GW (range: 12+0–21+0), whereas the median time of diagnosis for the group with later terminations was 21+6 GW (range: 15+1–36+4) (p < 0.001), see [Table 3]. However, Cox regression did not confirm the time of diagnosis as a significant factor influencing Δtermination (see below).
Multivariable regression analysis showed that a known chromosomal aberration was associated with the decision to terminate the pregnancy (aOR 6.38; p = 0.014). Conversely, pregnancy terminations were carried out significantly less often if the CNS anomaly was diagnosed in week 22+0 of gestation or later (aOR 0.24; p < 0.001). Importantly, it must be noted that this effect was independent of the type of CNS anomaly. Compared to isolated ventriculomegaly (reference diagnosis), there were significantly more decisions to terminate the pregnancy if non-isolated ACC (aOR 17.5; p < 0.001), holoprosencephaly (aOR 24.4; p < 0.001) or spina bifida (aOR 7.24; p < 0.001) or other neural tube defects (aOR 62.5; p < 0.001) were present. Other CNS anomalies, maternal age (p = 0.39) and the presence of additional malformations outside the CNS (p = 0.14) were associated with the decision to terminate the pregnancy (see [Table 4]).
In the subgroup of pregnant women who decided to terminate their pregnancy, the time between diagnosis and the start of termination of pregnancy (feticide or induction of abortion) was significantly longer if a fetal MRI was carried out (HR 0.41; p = 0.003) or the maternal age was higher (HR 0.95 per additional year; p = 0.034). However, the time between diagnosis and the start of termination was significantly shorter if a destructive abnormality (HR 10.5; p = 0.004) or a (non-spina bifida) neural tube defect was identified (HR 3.86; p = 0.002). A known chromosomal aberration (p = 0.87), non-CNS anomalies (p = 0.58) or a diagnosis in ≥ 22+0 GW (p = 0.74) did not have a significant impact on the time to termination ([Table 5]).
A case-by-case analysis was additionally carried out to identify potential reasons for particularly late terminations of pregnancy. A total of 29 cases terminated after week 26+0 of gestation were investigated. Possible causative factors for the delay were:
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late detection of pregnancy and/or late precise diagnosis (n = 7)
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the wait for fetal MRI findings (n = 6)
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the wait for genetic diagnostic findings (n = 6)
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diagnosis only emerged over the course of pregnancy (n = 5)
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delayed/complex establishment of diagnosis in cases with unclear findings (n = 5)
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malformations which may have been missed at previous examinations (n = 2)
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delayed referral to specialist ultrasound/perinatal center (n = 2)
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pregnant woman needed a long time to make the decision (n = 3)
(→ see Table S1, additional material, available online)
A statistical analysis of these case-by-case factors was not carried out because of the limited numbers of cases.
Terminations with and without feticide
63 (45.3%) of the 139 terminations of pregnancy were feticides and were carried out at a median gestational age of 24+1 GW (range: 20+2 to 38+2 GW). 41 feticides (65.1%) were carried out after 24+0 GW. Except for one case of termination by sectio parva for complete placenta previa, all the pregnant women delivered the fetus vaginally after feticide.
Spina bifida was the most common indication for feticide (n = 19), with a median time from diagnosis to termination (Δtermination) of 14 days (range: 6–50 days). In two cases (11%) Δtermination was more than 4 weeks; the delay was due to late detection of pregnancy and a long delay in making the decision, respectively.
Other common diagnoses for feticide were:
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agenesis of the corpus callosum (n = 9), Δtermination: 14 days (range: 7–92)
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ventriculomegaly (VM) (n = 7), Δtermination: 33 days (range: 9–41)
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posterior fossa malformations (n = 6), Δtermination: 16 days (range: 12–23)
The time from diagnosis to termination was particularly long in cases with ventriculomegaly: Δtermination in 5 of 10 cases (50%) was more than 4 weeks. A lengthy decision-making process was also recorded for cases with isolated agenesis of the corpus callosum (ACC) with Δtermination > 4 weeks in 2 of 9 cases (22%) and > 3 weeks in 4 of 9 cases (44%).
A total of 76 terminations of pregnancy (54.6%) without feticide were medically induced; the gestational age at termination ranged from 13+1 to 31+6 GW (median: 20+3 GW). 15 terminations were induced between 22+0 and 23+6 GW and 4 terminations after 24+0 GW. Medical terminations without feticide after the 24th week of gestation were carried out for non-viable fetal malformations such as trisomy 18 or anencephaly.
Fetal MRI
77 patients had a fetal MRI and 23 of them subsequently had a termination of pregnancy (21 cases ≥ 22+0 GW); 54 cases delivered a live-born infant, 4 of whom died postpartum.
Postpartum or postmortem confirmation of diagnosis
Deviating diagnoses were found postpartum or postmortem for 19/251 infants (7.6%). Postnatal confirmation of the original diagnosis in 112 live-born infants was obtained by MRI in 71 cases (63.4%), while sonographic confirmation or exclusion of the diagnosis was considered sufficient in 37 other cases (33.0%). Four infants died immediately postpartum prior to MRI/ultrasound examination. In one infant with very mild ventriculomegaly, the original diagnosis was not followed up postpartum. A total of 16 of the 41 infants who did not have a postnatal MRI had already had a prenatal MRI. Postnatal confirmation of diagnosis in these infants was obtained with ultrasound; one of the infants died immediately postpartum. A comprehensive neuropathological examination was carried out in 73 of the 139 (52.5%) cases of termination of pregnancy. In 11 fetuses (7.9%), autolytic changes in the brain meant that a neuropathological examination was not possible. 30 parents (21.6%) refused an autopsy and in an additional 29 cases (20.8%), no information about the reason for the lack of a neuropathological examination was provided. However, even in cases without neuropathological examination, information on whether the diagnosis was confirmed or not was available: external pathological assessment of 19 children confirmed open spina bifida (n = 18) and one case with anencephaly (n = 1). Clinical examination of one infant with severe ventriculomegaly confirmed severe CNS abnormality (gaping cranial sutures). A genetic disorder (triple X, L1CAM, two cases with triploidy, trisomy 21, two cases with trisomy 18, one balanced translocation 13,17 with multiple malformations, trisomy 13 and Turner syndrome, cri du chat syndrome) was confirmed in a further 11 cases. Nine fetuses without a confirmed genetic abnormality presented with multiple malformations outside the CNS. An MRI was carried out postmortem in 13 cases to confirm the diagnosis, meaning that the diagnosis could be confirmed in four more cases of inconclusive or missing neuropathological examinations.
Discussion
Malformations of the central nervous system (CNS) are anomalies which may result in extremely severe developmental impairment. Because of their complexity and because brain maturation occurs relatively late in pregnancy, such anomalies are often only diagnosed late in pregnancy and prognostic predictions are challenging. This makes comprehensive multidisciplinary counseling of affected parents essential [2] [3] [4] [5] [6].
Counseling must present all options – carrying the pregnancy to term, palliative care of the infant after the birth or termination of pregnancy – equally in an open, unbiased way. However, because of the severity of the expected developmental limitations, a significant percentage of parents take the decision to terminate the pregnancy at a relatively late stage. In these cases, feticide according to the definition (medical indication) in Sec. 218a para. 2 of the StGB [= Strafgesetzbuch, German Criminal Code] is often necessary.
CNS anomalies are among the most common causes of late terminations of pregnancy with an incidence of 20–30% [3] [4] [5] [6] [7]. The time of diagnosis varies globally as do the frequency and time of termination. The differences depend on the different statutory regulations and prenatal screening standards in the respective countries.
Determination of CNS anomalies based on requirements in the German Maternity Guidelines and quality of the ultrasound examinations in the 2nd (and 3rd) trimester of pregnancy
In Germany, prenatal screening of the fetal CNS is very much determined by the wish of the pregnant woman and the qualifications of the examining medical professionals. Until 2012, the German Maternity Guidelines only required documentation of a single image of the head, abdomen, and extremities; targeted examinations between week 18+6 and week 21+6 of gestation were only routinely offered after extended organ screening was introduced. Nevertheless, the quality of ultrasound examinations remains inconsistent as screening is provided by examiners with varying levels of training and very different ultrasound units. A comprehensive examination of the CNS is not generally carried out and the costs of such examinations are only borne by health insurance companies if medically indicated. This must be set against the expected, often very serious consequences of CNS malformations on child development [4]. The German Society for Ultrasound in Medicine (DEGUM) has therefore proposed integrating a standardized CNS diagnostic workup in accordance with the international guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) into basic prenatal screening in Germany [8].
Factors influencing decision-making: type of malformation, additional genetic or extracranial findings and time of diagnosis
The rates of medically indicated terminations of pregnancy in the investigated cohort differed considerably according to the type of CNS malformation. Similar findings have also been reported in comparable studies [4] [9] [10] [11]. Previous studies also found an association between identification of genetic abnormalities and the decision to terminate the pregnancy [9] [10]. In contrast, the presence of extracerebral malformations was not found to be a significant predictor in our study. A possible explanation for this could be the low number of cases overall and the wide heterogeneity of extracerebral malformations which ranged from prognostically less severe abnormalities such as ventricular septal defect or a stomach could not be clearly imaged to complex malformation syndromes with a very unfavorable prognosis. The importance of extracranial malformations for terminating pregnancies might be different in larger and more homogenous cohorts. There are no comparable studies on this issue in the literature.
Another relevant factor was the time when the diagnosis was obtained. This has also been described in another study as an important factor [12]. The lower numbers of terminations of pregnancy following late diagnosis could be due to an increasing emotional attachment to the fetus with advancing gestational age, making the decision to terminate the pregnancy more difficult psychologically. Alternatively, it is also important to know that severe malformations with high rates of terminations, for example anencephaly or spina bifida, are often definitively diagnosed in earlier stages of pregnancy.
Maternal age was not found to be a significant factor influencing decision-making. This suggests that there was no significant difference between younger and older pregnant women in their general attitudes toward continuing the pregnancy. There are no comparable data on the impact of maternal age on the decision whether to terminate the pregnancy in the current literature.
Spina bifida and other neural tube defects: the most common form of CNS malformations and its impact on decision-making in pregnancy
Neural tube defects are the biggest group of CNS malformations. According to a systematic review, the termination rate is 85% (59–100%) for anencephaly and 63% (31–97%) for spina bifida. Factors influencing the decision to terminate the pregnancy in cases with spina bifida include regional differences (Europe 66% vs. North America 50%), additional abnormalities (66% with vs. 56% without), and the subtype (open 60% vs. closed 33%). Moreover, the termination rate before week 24 of gestation was higher (86% vs. 27% after the 24th GW). There are also country-specific differences; in the Netherlands, for example, the overall termination rate is lower but the rate after early diagnosis is comparable [13].
In our study, the termination rate for spina bifida without additional abnormalities was 50.9%, which is slightly lower than in the above-referenced review article. The termination rate for fetuses with additional genetic or extracranial abnormalities and fetuses with anencephaly was 100%, which is higher than the rates in comparable studies [11] [13]. But in contrast to these studies, our study only included prenatally diagnosed cases with spina bifida or anencephaly. Depending on the local situation, international studies report significantly lower termination rates for anencephaly even though this type of malformation is incompatible with survival. The reported termination rates are 57% in Brazil [14], 61.4% in Canada [15] and 79% in the Netherlands [16]. The striking differences compared to the high rates of termination found in our study could be ascribed to the structure of the health care system, the availability of ultrasound screening, ethical reasons, and legal regulations governing the termination of pregnancy.
Factors influencing the time to termination of pregnancy
The median time from first diagnosis to termination of pregnancy was comparable to those reported in other retrospective cohort studies [4] [11] [17]. Differences were apparent based on the type of malformation and gestational age. The median time to termination of pregnancy for spina bifida (not significant) and for other neural tube defects (significant) was relatively short, which could be due to the comparatively clear prognosis and good visibility of the defects. Very long times between diagnosis and termination (> 4 weeks) were rare and were due to late detection of pregnancy or a long decision-making process on the part of the pregnant woman.
The relatively long time between diagnosis and termination for VM and ACC could be a reflection of the greater complexity of the predicted prognosis. It is almost impossible to properly estimate the extent of impairment based on sonographic morphology alone. Fetal MRI, which is often only carried out around week 28 of gestation, prolongs the diagnostic process but also provides additional important prognostic information. Carrying out an MRI at an earlier stage of pregnancy was not considered useful because of the physiological course of fetal brain development. In our patient cohort, all nine terminations for ACC (without additional CNS anomalies) were carried out after 24+0 GW, whereas only 68.4% of terminations in a comparative German cohort were carried out after 24+0 GW [4]. However, a French study also reported 100% of terminations were carried out after 24 weeks [17]. Isolated ventriculomegaly and (partial or complete) agenesis of the corpus callosum were a particular challenge for prenatal counseling. It is almost impossible to reliably estimate the severity of later cognitive developmental impairment based on morphological findings alone. In accordance with other studies we found that the termination rate when additional genetic disorder or further intracranial or extracranial anomalies were present was significantly higher than for isolated malformations [9] [10].
For all malformations, fetal MRI prolongs the time between (suspected) diagnosis and the possible start of termination, but this should not be viewed negatively. It reflects the fact that certain diagnoses, especially cerebral dysgenesis, can only be definitively made following more detailed imaging with MRI. It is also important to be aware that because of the ongoing brain development, many CNS malformations assessed with MRI can only be reliably diagnosed in the later stages of pregnancy. This is why there is a very good reason to only recommend fetal MRI from week 28 of gestation at the earliest, as this is the preferable time when a differentiated assessment of cerebral structures is possible.
Although the median time between diagnosis and termination of 10 days appears to be appropriate given the complexity of diagnosis and counseling described above, the following results were questioned and reviewed to see whether there might be signs of unnecessary delays in diagnosis or termination:
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32.2% of terminations were carried out after week 24+0 of gestation.
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In at least 16 cases (11.2%), the time between diagnosis and termination was > 4 weeks.
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In at least 17 cases (11.9%), the diagnosis was only made after 24+0 GW.
The question is whether these very late terminations could have been at least partially avoided or whether the time was reasonable, given the complexity of the diagnosis, the necessary diagnostic examinations using MRI and/or genetic testing and the need to allow parents sufficient time to make a decision. Parents must not be put under pressure when they are making a decision but must instead be able to freely decide whether they wish to have further diagnostic investigations, whether they wish to have a termination, and if so, when.
A case-by-case analysis (Supplement, Table S1) showed that an earlier diagnosis or decision might only have been possible in specific cases: two cases with malformations (lumbosacral spina bifida) not detected at 2nd trimester screening, and two other cases where the time between detection of anomalies during screening and presentation to a perinatal center was inexplicably long (> 5 weeks). In all other cases, the late termination was justified, either because a definitive diagnosis could not be obtained any earlier or because the pregnancy was detected late, the diagnosis was complex and required a long diagnostic pathway, or parental decision-making required more time to weigh up the options.
Overall, 86.7% of malformations were identified before 24+0 GW. However, the rate for neural tube defects was 93% and therefore significantly higher than for other malformations (80%). It was also higher than the 51% of malformations identified before 24+0 GW reported for a comparable cohort in Germany [4]. The reasons for this are ultimately not clear; the difference could be due to regional differences in health care structures. There are currently no data available on the number of pregnant women who undergo expanded screening and/or precise diagnostic examinations in accordance with the DEGUM standards in the different regions of Germany.
In 50% of cases, terminations for CNS malformations (except for neural tube defects) were carried out after the 24th week of gestation, which is similar to the 61% reported in a comparable study [4]. It is not possible to state how many cases could have been diagnosed earlier as information about examinations carried out prior to the referral to a medical specialist is lacking. It is therefore impossible to say how often an earlier diagnosis could have been obtained.
Different postnatal or postmortem diagnosis
We identified two main situations where the prenatal diagnosis was not confirmed postnatally or postmortem:
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Mild anomalies: In several cases, for example cases with isolated VM or ACC, the postnatal examination did not confirm the prenatal findings, and the infant was unremarkable. As these malformations had already been classified prenatally as comparatively mild, all these pregnancies were carried to term. It is therefore unlikely that misdiagnosis affected the primary outcome of pregnancy.
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Severe malformations: In some particularly severe cases, the postnatal diagnosis differed from the prenatal diagnosis, for example, when severe ventriculomegaly diagnosed prenatally turned out to be holoprosencephaly or when additional life-limiting factors such as chromosomal disorders were identified postpartum. Here too, the effect of this misdiagnosis on the management of the pregnancy was very limited.
Overall, the study confirms the high quality of prenatal diagnostic examinations and, at least in the investigated cohort, there were no indications that misdiagnosis had a significant effect on primary pregnancy outcomes (carrying the pregnancy to term or termination). One limitation of the study is that fetal autopsies were not carried out in all cases of termination of pregnancy. Detailed neuropathological examinations of the CNS were also not always possible because of the time span between feticide, delivery, and autopsy, which means that the ability to assess whether a prenatal diagnosis was confirmed after termination of pregnancy was limited. The sensitivity of ultrasound examinations was not analyzed as this study did not record CNS malformations diagnosed postpartum in infants who were reported as unremarkable prenatally.
Conclusion
This analysis underscores the importance of specialized ultrasound examinations in the 2nd trimester of pregnancy, especially for a detailed examination of the fetal CNS. Although the conditions of care were good, CNS anomalies were often only recognized late, in many cases because of their diagnostic complexity. In several cases, the definitive diagnosis was only obtained after carrying out a lengthy diagnostic investigation in a prenatal center. The prenatal diagnostic ultrasound examinations carried out in our cohort were very precise, and postnatal or postmortem diagnoses which differed from the prenatal diagnoses did not significantly affect management of the pregnancy. As many CNS malformations (e.g., gyration disorders) can only be identified at a later stage of pregnancy because of the physiological fetal brain development, carrying out an additional standardized CNS ultrasound in the 3rd trimester of pregnancy would be useful.
Standardized early diagnostic screening could ensure that pregnant women can have extensive open-ended counseling which takes account of the complexity of the CNS malformation as early as possible. In many cases, the relatively long time from the first diagnosis to termination of pregnancy should not be construed negatively, especially in cases with complex malformations which make the prognosis difficult to predict. It is important to give parents sufficient time for comprehensive counseling and decision-making, which may also necessitate repeated consultations and examinations. But it is also very important to avoid “unnecessary” delay factors, for example, late non-specific diagnostic examinations. Open, non-judgmental decision-making weighs up both the protection of life and the support given to pregnant women who decide to continue the pregnancy. But pregnant women must have the opportunity to freely decide and avoid being traumatized by a late diagnosis, very late termination or being barred internationally from terminating the pregnancy after a specific week of pregnancy.
Limitations and Outlook
The data presented here were collected retrospectively and not all details, for example the time of first diagnosis, were recorded in full. After pregnancies were terminated, the rate of postpartum diagnoses which differed from the original diagnosis could not be assessed in their entirety, as meaningful neuropathological examinations were only carried out in half of the cases. This study also did not include fetuses with CNS anomalies caused by infections such as CMV, which can be attributed to the fact that these fetuses were recorded in the register of births as infections and not as CNS anomalies. Most of the pregnancies with CNS anomalies and spina bifida analyzed in this study occurred prior to the inclusion of comprehensive ultrasound screening in the German Maternity Guidelines (2013). A relevant question in this context would be whether these legal changes have improved the rates of early recognition of malformations. After standardized ultrasound screening was introduced, a Dutch study reported a significant increase in the rates of spina bifida detected before week 24th of gestation, with detection rates rising from 43% to 88% [18].
Supplementary Material
Table S1: Terminations of pregnancy from week 26+0 of gestation.
Conflict of Interest
The authors declare that they have no conflict of interest.
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- 8 Kähler C, Schramm T, Bald R. et al. Aktualisierte Qualitätsanforderungen an die Ultraschall- Screeninguntersuchung in der pränatalen Basisdiagnostik (=DEGUM-Stufe I) im Zeitraum 18 + 0 bis 21 + 6 Schwangerschaftswochen. Ultraschall Med 2020; 41: 499-503
- 9 Davutoglu EA, Arica G, Sahin NE. et al. Clinical characteristics and perinatal outcome of fetuses with ventriculomegaly. Arch Gynecol Obstet 2024; 310: 2065-2071
- 10 De Keersmaecker B, Jansen K, Aertsen M. et al. Outcome of partial agenesis of corpus callosum. Am J Obstet Gynecol 2024; 230: 456.e1-456.e9
- 11 Domröse CM, Bremer S, Buczek C. et al. Termination of pregnancy after prenatal diagnosis of spina bifida: a German perspective. Arch Gynecol Obstet 2016; 294: 731-737
- 12 Bolluk G, Bakirci IT, Cok M. et al. Evaluating pregnancy termination decisions for fetal anomalies: a retrospective study in a tertiary referral center. Rev Assoc Med Bras (1992) 2024; 70: e20231118
- 13 Johnson CY, Honein MA, Dana Flanders W. et al. Pregnancy termination following prenatal diagnosis of anencephaly or spina bifida: a systematic review of the literature. Birth Defects Res A Clin Mol Teratol 2012; 94: 857-863
- 14 Machado IN, Martinez SD, Barini R. Anencephaly: do the pregnancy and maternal characteristics impact the pregnancy outcome?. ISRN Obstet Gynecol 2012; 2012: 127490
- 15 Tairou F, de Wals P, Bastide A. Validity of death and stillbirth certificates and hospital discharge summaries for the identification of neural tube defects in Quebec City. Chronic Dis Can 2006; 27: 120-124
- 16 van Adama Scheltema PN, Nagel HTC, Brouwer OF. et al. Outcome of children with prenatally diagnosed central nervous system malformations. Ultrasound Obstet Gynecol 2003; 21: 41-47
- 17 Rouleau C, Gasner A, Bigi N. et al. Prevalence and timing of pregnancy termination for brain malformations. Arch Dis Child Fetal Neonatal Ed 2011; 96: F360-F364
- 18 Fleurke-Rozema JH, Vogel TA, Voskamp BJ. et al. Impact of introduction of mid-trimester scan on pregnancy outcome of open spina bifida in The Netherlands. Ultrasound Obstet Gynecol 2014; 43: 553-556
Correspondence
Publication History
Received: 14 February 2025
Accepted after revision: 22 June 2025
Article published online:
02 September 2025
© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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References/Literatur
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- 9 Davutoglu EA, Arica G, Sahin NE. et al. Clinical characteristics and perinatal outcome of fetuses with ventriculomegaly. Arch Gynecol Obstet 2024; 310: 2065-2071
- 10 De Keersmaecker B, Jansen K, Aertsen M. et al. Outcome of partial agenesis of corpus callosum. Am J Obstet Gynecol 2024; 230: 456.e1-456.e9
- 11 Domröse CM, Bremer S, Buczek C. et al. Termination of pregnancy after prenatal diagnosis of spina bifida: a German perspective. Arch Gynecol Obstet 2016; 294: 731-737
- 12 Bolluk G, Bakirci IT, Cok M. et al. Evaluating pregnancy termination decisions for fetal anomalies: a retrospective study in a tertiary referral center. Rev Assoc Med Bras (1992) 2024; 70: e20231118
- 13 Johnson CY, Honein MA, Dana Flanders W. et al. Pregnancy termination following prenatal diagnosis of anencephaly or spina bifida: a systematic review of the literature. Birth Defects Res A Clin Mol Teratol 2012; 94: 857-863
- 14 Machado IN, Martinez SD, Barini R. Anencephaly: do the pregnancy and maternal characteristics impact the pregnancy outcome?. ISRN Obstet Gynecol 2012; 2012: 127490
- 15 Tairou F, de Wals P, Bastide A. Validity of death and stillbirth certificates and hospital discharge summaries for the identification of neural tube defects in Quebec City. Chronic Dis Can 2006; 27: 120-124
- 16 van Adama Scheltema PN, Nagel HTC, Brouwer OF. et al. Outcome of children with prenatally diagnosed central nervous system malformations. Ultrasound Obstet Gynecol 2003; 21: 41-47
- 17 Rouleau C, Gasner A, Bigi N. et al. Prevalence and timing of pregnancy termination for brain malformations. Arch Dis Child Fetal Neonatal Ed 2011; 96: F360-F364
- 18 Fleurke-Rozema JH, Vogel TA, Voskamp BJ. et al. Impact of introduction of mid-trimester scan on pregnancy outcome of open spina bifida in The Netherlands. Ultrasound Obstet Gynecol 2014; 43: 553-556