Eurocat Classification Essay

Department of Maternal and Reproductive Health, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow 226 014, India

Academic Editor: R. L. Deter

Copyright © 2015 Namrata Kashyap et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Early detection of malformation is tremendously improved with improvement in imaging technology. Yet in a developing country like India majority of pregnant women are not privileged to get timely diagnosis. Aims and Objectives. To assess the present status and potential of first trimester ultrasonography in detection of fetal congenital structural malformations. Methodology. This was a retrospective observational study conducted at Sanjay Gandhi Postgraduate Institute of Medical Sciences. All pregnant women had anomaly scan and women with fetal structural malformations were included. Results. Out of 4080 pregnant women undergoing ultrasound, 312 (7.6%) had fetal structural malformation. Out of 139 patients who were diagnosed after 20 weeks, 47 (33.8%) had fetal structural anomalies which could have been diagnosed before 12 weeks and 92 (66.1%) had fetal malformations which could have been diagnosed between 12 and 20 weeks. Conclusion. The first trimester ultrasonography could have identified 50% of major structural defects compared to 1.6% in the present scenario. This focuses on the immense need of the hour to gear up for early diagnosis and timely intervention in the field of prenatal detection of congenital malformation.

1. Introduction

Fetal structural malformations are seen in 3 to 5% of all pregnancies [1]. Detection of malformation is tremendously improved with improvement in imaging technology. In majority of countries worldwide, second trimester scan between 18 and 22 weeks remains the standard of care for fetal anatomical assessment; however, most recent literature shows a significant improvement in detection of fetal abnormalities in first trimester of pregnancy [2]. Besides nuchal abnormalities a wide range of central nervous system, heart, anterior abdominal wall, urinary tract, and skeletal abnormalities can be diagnosed between 11 and 14 weeks of scan. The clear benefits of first trimester ultrasound are early detection and exclusion of major congenital anomalies (not compatible with life or followed by severe handicap), reassurance, and relatively easier pregnancy termination if required.

Currently, the review of recent literature suggests classification of fetal abnormalities as always detectable, potentially detectable, and undetectable till first trimester and anomaly scan. The diagnostic efficacy of first trimester anomaly scan and echocardiography between 11 and 14 weeks has been assessed in medium risk population by Becker and Wegner [3]. The prevalence of major anomalies in their study group was 2.8%. The overall detection rate of fetal anomalies including cardiac defects was 84% and increased with raised nuchal thickness particularly more than 2.5 mm. This highlights the scope of first trimester scan apart from its conventional role in detection of chromosomal abnormality.

First trimester screening is now no more limited to detection of raised nuchal thickness (NT). Becker [4] et al. analysed 6879 cases to assess the prevalence and detection rate of major anomalies by applying first trimester anomaly scan and fetal echocardiography. They concluded that a significant number of fetal anomalies occur with normal NT and more than half of them could be detected in first trimester. Hence, even fetuses with normal NT should be offered first trimester anomaly scan and fetal echocardiography considering the ethical principles of nonmaleficence, justice, and respect for autonomy of pregnant women. Even in this era the benefits of this established technology are not in the reach of all. A vast majority of patients in India are not yet undergoing anomaly scan. We frequently encounter malformations always or potentially detectable during first trimester scan at third trimester or in postnatal period. It depends on both the expertise and resources available along with the awareness and sensitization in general population. This fact of diagnosis is particularly more important in countries like India where medical termination of pregnancy [5] is legally allowed up to 20 weeks of gestation irrespective of malformation being lethal. We see a fair number of patients who are diagnosed with fetal malformation beyond 20 weeks and in that situation they are forced to seek termination services at small substandard centres since they get refusals from all relatively good hospitals due to legal issues associated with termination. Many of such patients get deteriorated due to septic abortion and unnecessary hysterotomy and so forth. Question then arises that where lies the fault, the awareness of the patients or the expertise of the sonologist.

Henceforth, the study was planned to assess the prevalence of fetal malformation in a tertiary care referral centre and to assess the present status of first trimester ultrasonography in the detection of fetal malformations in a tertiary care centre in India.

2. Materials and Methods

This was a retrospective observational study conducted at Sanjay Gandhi Postgraduate Institute of Medical Sciences. All pregnant women attending Department of Maternal and Reproductive Health, OPD, from August 2009 till October 2013 were enrolled in the study. All pregnant women underwent ultrasound (General electrical Voluson S8) and those with fetal structural malformations were evaluated. Malformations were classified according to gestational age of diagnosis, system involved, and type of malformation. Descriptive proportions and frequencies have been used to depict the data.

3. Results

A total number of 4080 pregnant women underwent USG and amongst them 312 (7.6%) patients had fetal structural malformation. The malformations were classified according to gestational age as shown in Table 1. Malformations were classified according to various systems as shown in Table 2.

Table 1: Number of malformations at different gestational age.

Table 2: Classification of malformation according to the system involved.

3.1. Malformations Detected prior to 20 Weeks

Out of total malformed fetuses, 103 (33%) were detected prior to 20 weeks of gestational age and 209 (66.9%) were detected after 20 weeks of gestational age. Out of 103 women who were diagnosed with fetal malformations before 20 weeks, only 5 (1.6%) were detected prior to 12 weeks of gestational age and the remaining 98 (31.4%) were diagnosed between 12 and 20 weeks. Six patients amongst them presented before 12 weeks but malformations were missed and diagnosed later between 12 and 20 weeks. These cases were omphalocele, osteogenesis imperfecta, harlequin ichthyosis, Stickler syndrome, Fraser syndrome, and Dandy-Walker malformation. These conditions, however, are known to present late.

Out of 103 patients diagnosed to have malformation prior to 20 weeks, 80 patients willingly underwent termination of pregnancy in view of malformation being lethal like a fetus with occipital encephalocoele terminated at 20 weeks of gestational age (Figure 1). We had prescribed protocol of oral mifepristone (200 mg) followed by misoprostol induction after 48 hours of mifepristone. Three patients were lost to follow-up. Ten patients had nonlethal malformation and were willing to continue pregnancy. All of them had postpartum neonatal intervention in the Department of Pediatric Surgery, Neonatology and Plastic Surgery, respectively (for posterior urethral valve, extra lobar sequestration, tracheoesophageal fistula, anorectal malformation, congenital diaphragmatic hernia with good LH ratio, meningocele, polycystic kidneys, megacystis, vesicoureteral reflux, and cleft lip palate).

Figure 1: Occipital encephalocoele diagnosed at 20 weeks which was terminated.

Ten patients refused to continue pregnancy despite malformation being lethal. They had obstetrical procedure at their convenient places. Four amongst them had preterm still birth and six babies died in neonatal period. Biggest agony is that two amongst those continuing pregnancies with known lethal malformations had hysterotomy and two had cesarean section for anomalous fetus which could have been avoided.

We found that with the present available technology majority of malformation could be diagnosed before 20 weeks (Box 1).

Box 1: List of common malformations detected before 20 weeks.

First trimester sonography has huge potential of diagnosing fetal anomalies. We found that there are few malformations which could be easily diagnosed before 12 weeks (Box 2).

Box 2: List of common malformations we found usually detectable before 12 weeks.

Five patients were diagnosed prior to 12 weeks for neural tube defect, holoprosencephaly, gastroschisis, cystic hygroma, and anencephaly. All of them had easy termination of pregnancy.

3.2. Malformations Detected after 20 Weeks

Out of 312 pregnant women with malformations, 209 (66.9%) were diagnosed after 20 weeks. 109 had their first USG after 20 weeks and 100 had USG prior to 20 weeks but malformations were missed.

Out of those 100 patients, 6 patients presented to our institute before 20 weeks and malformations were not confirmed until 24 weeks. In 94 women, they went for USG prior to 20 weeks at some other centre and malformation was missed. Amongst those six patients who presented to SGPGI prior to 20 weeks but were missed, there were one case each of Dandy-Walker malformation, autosomal dominant polycystic kidneys, late onset hydrocephalus, and tetralogy of Fallot. All of these tend to be diagnosed late. Two fetuses, one with cleft lip and one with neural tube defect, could have been diagnosed but were missed. There exists a group of malformation which lies in the grey zone of diagnosis before 20 weeks (Box 3).

Box 3: List of malformations we found undetectable before 12 weeks and difficult between 12–20 weeks.

Out of 209 detected cases after 20 weeks, 70 (33.4%) patients had malformations which were detected after 20 weeks and are acceptable because these include conditions which tend to be diagnosed late in gestation like hydrocephalus (Figures 2(a) and 2(b)), agenesis of corpus callosum (Figure 2(c)), congenital cystic adenomatoid malformation (Figure 2(d)), various cardiac structural malformations, cystic kidney diseases, horseshoe kidney, Dandy-Walker malformations and variants, vein of Galen aneurysm, duodenal atresia, fetal goitre, intra-abdominal tumours, gonadal cyst, Hirschsprung disease, and isolated fetal ascites.

Figure 2: (a and b) show late onset hydrocephalus diagnosed at 27 weeks and 32 weeks, noted to occur late as a part of MASA syndrome (patient had history of X-linked hydrocephalus). (c) shows agenesis of corpus callosum which is known to be said with confirmation at later gestation. (d) shows fetal micro cystic congenital cystic adenomatoid malformation (CCAM) which is notorious to be missed early.

3.3. Malformation Missed

Even though missed in first trimester, in 139 (66.5%) patients, fetal malformations could have been diagnosed between 12 and 20 weeks as shown in Box 1. These included malformations like neural tube defect (Figures 3(a) and 3(b)), acrania-exencephaly-anencephaly sequence (Figures 4(a), 4(b), and 4(c)), skeletal dysplasia (Figures 5(a), 5(b), and 5(c)), multicystic dysplastic kidneys (Figure 5(d)), and limb body wall complex (Figures 6(a), 6(b), and 6(c)).

Figure 3: (a and b) show two cases of neural tube defect diagnosed at advanced gestational ages of 22 weeks and 39 weeks.

Figure 4: (a, b, and c) show fetal exencephaly that could be diagnosed at 14 weeks but was missed and diagnosed at 19 weeks and as late as 27 weeks.

Figure 5: (a, b, and c) show skeletal malformation achondrogenesis (3D), thanatophoric dysplasia, and osteogenesis imperfecta. All of them potentially diagnosable before 12 weeks and usually before 20 weeks were missed and were diagnosed late. (d) shows bilateral multicystic dysplastic kidney diagnosed at 31 weeks, with fetus being continued as oligohydramnios.

Figure 6: (a, b, and c) show gross fetal deformity limb body wall complex, diagnosis delayed till 21 weeks in one fetus (Figures 6(a) and 6(b)) and 29 weeks in other fetuses (Figure 6(c)). (d) shows acardiac twin (twin reverse arterial perfusion sequence) diagnosed at 25 weeks when the normal twin had already decompensated making any intervention difficult.

Prenatal interventions in very unique complications of monochorionic twins have become the treatment of choice [6] but diagnosis of acardiac twinning was delayed till 24 weeks (Figure 6(d)). This delayed pick-up of these potentially salvageable conditions leads to high likelihood of adverse pregnancy outcome. The patient had demise of normal cotwin also at 28 weeks.

4. Discussion

The overall prevalence of severe and lethal fetal structural malformation in our study was 7.6% which was higher than that reported in the literature for general population (3–5%), possibly because it was a referral centre for high risk pregnancy and fetal medicine; there is overreporting of cases. Our study calculated that CNS malformations were most common in our study population. As such, preconceptional folic acid is not commonly practiced in our study population. We realize that almost half (52.1%) of our patients had their first USG for anomaly detection after 20 weeks. It reflects the existing darkness of unawareness and vacuum of knowledge in patients and also in basic health care that are first to encounter pregnant women.

We found that, out of the total number of women with diagnosed fetal malformation, 203 (65%) presented before 20 weeks. Hence, equally important is the fact to realize that almost half of these patients who had malformations detected after 20 weeks had their obstetrical sonography before 20 weeks and were missed. This missing out of an anomaly may be because of scarcity of good resolution machines, busy schedules, and lack of expertise as well. For years together, there have been substantial advances in magnification imaging and signal processing which increased the ability to visualize fetal anatomy; there has been great concern on the possibility to diagnose a wide range of fetal anomalies at the time of nuchal translucency scan by transvaginal and transabdominal sonography [7–9].

Almost half of malformations in our study were amenable to be diagnosed in first trimester as reported in current literature. These fetuses were having malformations like neural tube defects, anencephaly, holoprosencephaly, and gastroschisis (Box 2). Castro-Aragon and Levine [10] reported that 60–67% of malformations could have been diagnosed prior to 12 weeks. This is far away from our scenario where we found that only 1.6% (5/312) were diagnosed prior to 12 weeks. This is possibly due to the lack of awareness and lack of expertise as well. Fong et al. [11] in their study scanned 8,537 women between 11 and 14 weeks of gestation (crown rump length, 45–84 mm); there were 175 fetuses with an increased NT. Besides nuchal abnormalities, a wide range of other congenital anomalies can be diagnosed with US at 11–14 weeks of gestation, including defects of the central nervous system, heart, anterior abdominal wall, urinary tract, and skeleton. Oztekin et al. [12] analyzed 1085 pregnancies; 21 (1.93%) fetuses had at least one major structural defect considered detectable by routine ultrasound screening. 14 (1.29%) were identified at early (first trimester) screening and an additional 5 (0.47%) were identified at late (second trimester) USG. They found that majority of fetal structural abnormalities can be detected by sonographic screening at 11–14 weeks, but detailed fetal anatomic survey performed at 18–22 weeks should not be abandoned.

Rossi and Prefumo [13] also laid stress that first trimester ultrasound can detect half of fetal malformations. They included nineteen studies on 78,002 fetuses, with 996 with malformations that were confirmed by postnatal or postmortem examinations. USG at 11 to 14 weeks detected malformation in 472 of the malformed fetuses (51%). Detection rate was highest for neck anomalies (92%) and lowest for limbs, face, and genitourinary anomalies (34% for each). The presence of associated anomalies appears to increase the accuracy of early ultrasonography. Multiple defects were more likely to be identified than isolated malformations (60% versus 44%). Detection rates ranged from 1% to 49% for spina bifida or hydrocephalus, ranged from 50% to 99% for valvular disease and septal defects, were 100% for acrania and anencephaly, and were 0% for corpus callosum agenesis and bladder exstrophy. Combination of transabdominal and transvaginal techniques resulted in a 62% detection rate versus 51% for transabdominal technique only and 34% for transvaginal technique only.

Although first trimester ultrasound can detect about 50% of fetal malformations, it cannot replace second trimester ultrasound because several malformations develop later than the first trimester. Also to be kept in mind is the fact that accuracy of early ultrasonography can be compromised by transient findings like midgut herniation, small septal defects, and hydronephrosis which might get resolved during intrauterine life.

Iliescu et al. [14] did a prospective two-centre 2-year study of 5472 consecutive unselected pregnant women examined at 12 to 13 + 6 gestational weeks. The first trimester scan identified 40.6% of the cases detected overall and 76.3% of major structural defects. Major congenital heart disease (either isolated or associated with extracardiac abnormalities) was 90%. Major central nervous system anomalies were 69.5%. Fetuses with increased nuchal translucency (NT), the first trimester DR for major anomalies, were 96% compared to 66.7% amongst those with normal NT.

There have been several studies seeing application for an extended protocol in which first trimester sonography is supported by a second anomaly scan. The obvious advantage of an extended protocol is that parents are offered the option of earlier and safer termination of pregnancy for the large majority of severe/lethal abnormalities.

Early ultrasound might be more accurate than second trimester ultrasonography for detection of malformations associated with oligohydramnios and anhydramnios which lead to poor visualization at later gestation necessitating amnioinfusion.

We have applied this kind of protocol at our centre particularly in high risk women. First trimester sonography with targeted imaging for fetal malformation appeared particularly more helpful in high risk women with previous history of fetus/neonates with malformations, known risk factors, for example, type 2 diabetes, patients prone for teratogenicity, for example, thromboembolic and valve replacement patients on warfarin, methotrexate intake for connective tissue disorders, and so forth, antiepileptic, chemotherapeutic drugs, and history of infection exposure like rubella. We diagnosed and terminated patients before 16 weeks with rubella exposure and subsequent pulmonary stenosis, severe bony stippling and craniofacial malformation associated with high doses warfarin, VSD associated with type 2 diabetes, neural tube defect with antiepileptic and tetraphocomelia with chemotherapeutic agents, renal agenesis in previous history of Fraser’s syndrome, encephalocoele in previous Meckel-Gruber syndrome, ARPKD and ADPKD, and so forth.

However, a detailed first trimester examination protocol involves supplementary resources: additional examination time and specialized personnel for the abnormal suspected/detected cases. Healthcare systems are yet to determine whether early first trimester diagnosis of most major structural abnormalities is cost-effective. Previous research, albeit using inferior ultrasound technology and a less extended protocol, found that the first trimester anomaly scan was cost-efficient in terms of medical and economic expenses, although they obtained lower detection rates [15, 16].

The present research about the effectiveness of early ultrasonography in the diagnosis of structural defects does have some conflicts, which made it a challenge that to what extent structural congenital abnormalities could be detected by the routine scanning of fetal anatomy combined with nuchal translucency measurement [17]. Few other basic prerequisites associated with early prenatal diagnosis consist of the high experience required and high costs in terms of time and equipment [18]. Even with all these circumstances, the situation in our country is such that a huge number of patients, 209 (66.9%), were diagnosed after 20 weeks which shows the lacunae which need to be filled.

5. Conclusion

In our study we realized that even in a tertiary care centre only 1.6% fetuses with malformation are identified in first trimester. In a way, it throws light on the importance of screening as well as an immense need for early diagnosis and timely intervention in the field of prenatal detection of congenital malformation.

A detailed examination of fetal anatomy during the routine 11–14 weeks of gestation scan provides a comprehensive assessment of fetal anatomy and can detect approximately half of major structural defects in both low-risk and high-risk pregnancies. Detection rate increases markedly beyond 13 weeks of gestation compared with 11 weeks of gestation. We have seen to be better convinced to diagnose holoprosencephaly, achondrogenesis, osteogenesis imperfecta, and spondylocostal dysostosis at 14 weeks compared to 12 weeks. It is also expected that because of the late development of some organ systems and the delayed onset of a significant number of major anomalies in the second and third trimester it is very unlikely that the early scan may replace second trimester ultrasonography.

We need to identify structural malformations before 20 weeks except those conditions which are said to appear further late or reported with confirmation at a later gestational age like few posterior fossa abnormalities, duodenal atresia, and few renal abnormalities. The most important implication is safe termination and avoiding maternal threat to life by forced termination at resourceless and substandard centres. There could be an option of incorporating anomaly scan between 18 and 20 weeks in our health plans and guides at well registered centres with expertise at reasonable cost.

Focus and emphasis should aim at detection of malformation earlier than 12 weeks owing to the very unique and clear facts that first trimester detection leads to easy termination of pregnancy and lessening of women’s mental, physical, and psychological trauma.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Abstract

OBJECTIVE: To compare the incidence of and risk factors for cerebral palsy (CP) in moderately preterm (MP) (32+0–33+6 weeks) and late preterm (LP) (34+0–36+6 weeks) infants with those in very preterm (VP) (<32+0 weeks) and term infants (≥37 weeks).

METHODS: The national register study included all live-born infants in Finland from 1991 to 2008. Infants who died before the age of 1 year, had any major congenital anomaly, or had missing data were excluded. A total of 1 018 302 infants were included in the analysis and they were analyzed in 4 subgroups (VP, MP, LP, and term) and 3 time periods (1991–1995, 1996–2001, and 2002–2008).

RESULTS: By the age of 7 years, 2242 children with CP were diagnosed (0.2%). CP incidence was 8.7% in the VP, 2.4% in the MP, 0.6% in the LP, and 0.1% in the term group. The risk of CP was highest in the study period 1991–1995 in all groups. Factors predictive of an increased CP risk in the MP and LP groups included resuscitation at birth (odds ratio 1.60; 95% CI 1.01–2.53 and 1.78; 1.09–2.90), antibiotic treatment during the first hospitalization (1.63; 1.08–2.45 and 1.67; 1.13–2.44), 1-minute Apgar score <7 (1.70; 1.15–2.52 and 1.80; 1.21–2.67) and intracranial hemorrhage (7.18; 3.60–14.3 and 12.8; 5.58–29.2).

CONCLUSIONS: The incidence of CP is higher in LP and MP infants compared with term infants. There is a nonlinear decrease in incidence over time and with increasing gestational age.

  • Abbreviations:
    CI —
    confidence interval
    CP —
    cerebral palsy
    GA —
    gestational age
    HDR —
    Hospital Discharge Register
    ICD —
    International Classification of Diseases
    LP —
    late preterm
    MBR —
    Medical Birth Register
    MP —
    moderately preterm
    MRI —
    magnetic resonance imaging
    NIHW —
    National Institutes of Health and Welfare
    OR —
    odds ratio
    PROM —
    premature rupture of membranes
    RDS —
    respiratory distress syndrome
    SGA —
    small for gestational age
    VP —
    very preterm
  • The preterm birth rate has increased markedly during the past decades, mainly due to the increase in late preterm (LP) births in a number of countries, especially in the United States.1,2 LP infants are defined as infants born between gestation weeks 34+0 and 36+6; they account for more than 70% of all prematurely born infants in the United States.2,3 This group has commonly been referred to as “near term” infants, but the description has been felt inappropriate in that it underestimates the risks of these preterm infants.3 Moderately preterm (MP) (32+0–33+6 gestation weeks) and LP infants comprise >80% of all preterm births together.4,5 The rate of preterm delivery in Finland has not increased significantly, in contrast to trends in other countries.6

    The brain of the MP and LP infant is more vulnerable to injury than the brain of full-term infants. The weight of the brain at 34 weeks of gestation is only 65% of the term brain and the total brain volume increases linearly with increasing gestational age (GA).7 Morbidity and mortality levels among MP and LP infants are higher compared with term.810 In the United States and the United Kingdom, LP infants have been found to have poorer neurodevelopmental outcomes than term infants,4,1118 but some studies did not find more neurodevelopmental problems among healthy LP children.19 Outcome data may vary due to diverse conditions in different countries and populations. Thus, more data and large prospective studies are needed. No statistics on the long-term outcome of MP and LP infants have been reported from the Nordic countries.

    Cerebral palsy (CP) is defined as a disorder of motor behavior attributable to disturbances in the developing fetal or infant brain.20 According to the standard guideline, the diagnosis of CP is based on medical history, imaging (ultrasound, high-resolution magnetic resonance imaging [MRI]) data, and clinical multidisciplinary evaluations in the pediatric neurology units. The CP incidence has been shown to be dependent on GA in very preterm (VP) infants.21 Also in LP infants, the risk has been almost threefold compared with the term group.22 Risk factors of CP have been identified for term infants,23 but less for MP and LP infants.

    Our aim was to compare the CP incidence among LP and MP infants to that among VP and term infants and to identify risk factors for CP in the Finnish population. The hospitalizations, reimbursements for medicine expenses, and disability allowances due to CP were established to study the burden of CP. Also the effect of time period on the incidence of CP was studied.

    Methods

    This national register study population consisted of all, a total of 1 039 263 infants born in Finland from 1991 to 2008. The baseline characteristic data were collected from the Medical Birth Register (MBR), maintained by the National Institutes of Health and Welfare (NIHW). This register contains information on the mother’s health and interventions during pregnancy and delivery and on the infant’s health and procedures undergone during the first 7 days of life. It collects data on all live births and stillbirths from the GA of 22+0 weeks onward and/or birth weight of at least 500 g.

    Data on deaths were obtained from the Cause-of-Death Register maintained by Statistics Finland and data on major structural anomalies and chromosomal defects24 from the Register of Congenital Malformation, maintained by the NIHW. Infants who died before the age of 1 year (n = 2613), children with at least 1 major congenital anomaly (n =13 007), and cases lacking data on GA were excluded (n = 5520).

    The remaining 1 018 302 infants (98.0% of all) comprised the cohort for analysis. Infants were followed up to 7 years of age or to 2009. The study population was divided into subgroups, the gestation-week categories being VP (≤32+0 weeks, n = 6347), MP (32+0–33+6 weeks, n = 6799), LP (34+0–36+6 weeks, n = 39 932), and term (≥37 weeks, n = 965 224). The GA was based on early pregnancy ultrasound and correction of GA was made if the ultrasound-based estimation had a discrepancy of 5 to 7 days or more compared with menstrual anamnesis.

    Pregnancy- and delivery-related diagnoses of mothers were collected from the Hospital Discharge Register (HDR). This is also maintained by the NIHW and contains information on admission and discharge dates, diagnoses, and surgical procedures. Since 1998, the data also cover hospital outpatient visits. Diagnoses were coded according to the International Classification of Diseases, Ninth Revision (ICD-9) in 1987 to 1995 and according to the 10th Revision (ICD-10) from 1996. Three different time periods were compared: 1991 to 1995, 1996 to 2001, and 2002 to 2008. These periods were chosen because the classification system of disease was changed in 1996 from ICD-9 to ICD-10 and the MBR changed the data collection forms 1.10.1990 and 1.1.1996.

    Preeclampsia was defined as high blood pressure, edemas, and proteinuria by ICD-10 codes O10 to O16 (ICD-9 codes 6420–6429). Premature rupture of membranes (PROM) was sought via ICD-10 codes O42.0 to O42.9 (ICD-9 codes 6581–6583) in the mothers’ diagnoses. Pregnancy-related risk factors were the number of fetuses and their order, timing of birth, in vitro fertilization, and cervical cerclage. Resuscitation at birth included intubation, mechanical ventilation, and/or chest compressions. Phototherapy has been given according to guidelines depending on gestation weeks and some minor variance may exist in guidelines between hospitals. Respiratory distress syndrome (RDS) was diagnosed on the basis of typical changes in chest radiograph, excessive need of oxygen supply, and surfactant therapy. It was traced in the register with ICD-10 code P22.0 (ICD-9 code 769). Small for GA (SGA) infants were defined as those with a birth weight <2 SDs below the mean weight for GA and large for GA infants as those with a birth weight >2 SDs over the mean weight for GA according to the Finnish gender-specific fetal growth curves.25 Umbilical artery pH cutoff <7.05 was used to define fetal acidemia.26,27

    Only variables with good validity in the registers were chosen for the analysis.28,29 Intracranial hemorrhage diagnosis was based on the head ultrasound or MRI findings and classified according to the Papile classification system.30 MP and LP infants do not undergo routine head ultrasounds but infants with asphyxia and/or neurologic symptoms, and/or with need of intensive care are routinely examined with head ultrasound. One-minute Apgar scores were included in the multivariate analysis, but 5-minute scores were excluded because it was found from the register only from 2004 onward. Information on maternal hypertension was available only in combination with preeclampsia. Mother’s diabetes included gestational diabetes, and type 1 and 2 diabetes. Neither data on chorioamnionitis nor antenatal viral infection was possible to define reliably according to registers. Infants were defined to be asphyxiated when they had a 1-minute Apgar score <7 and needed intubation during delivery room resuscitation.

    All inpatient and outpatient visits due to a CP diagnosis in public hospitals were registered according to the HDR. The diagnosis of CP in Finland is based on medical history, ultrasound and MRI data, and multidisciplinary evaluations in the pediatric neurology units of 20 secondary-level central hospitals and 5 tertiary-level university hospitals. CP is usually evident within first 2 years of life and almost always by the age of 3 to 4 years, and the diagnosis is included in the HDR as soon as it has been established. Information on special reimbursements and benefits for disability were collected from the register of the Social Insurance Institution of Finland. All data linkages were done by using unique personal identity codes anonymized by the authorities.

    A case with CP was recorded if the individual was detected in the HDR and/or in the Reimbursement Register of the Social Insurance Institution with ICD-10 codes G80 to G83 in 1996 to 2008 and ICD-9 codes 342 to 344 in 1991 to 1995. Subtypes of CP were defined by topographic involvement (hemiplegia, diplegia, quadriplegia, and other types) and sought from registers with corresponding ICD codes (hemiplegia ICD-10 G80.2/ICD-9 343.1 and 343.4; diplegia G80.1/343.0; quadriplegia G80.0/343.2 and other types including the rest of CP diagnoses according to the baseline ICD code definitions).

    Statistical Analysis

    Characteristics of infants alive at age of 1 year and those of their mothers were described by means with SDs in the case of normal distributed continuous variables, by medians with interquartile range in skew distributed variables, and otherwise if variables were categorical by number of values with percentages. GA groups were compared for each other by Mann-Whitney test, χ2 test, or Fisher's exact test (Tables 1, 2, and 3). Risk factors for CP were sought by logistic regression analysis by using multivariate enter models for each GA group separately (Table 4). In enter model, all variables were entered simultaneously into the model separately for each gestational week class. Association of gestation weeks for CP was studied by adjusting a multivariate model by gestation week classes, term class as reference. Results were shown by odds ratios (ORs) with 95% confidence intervals (95% CIs) in modeling risk factors for CP. A large number of variables were included in the analysis, because in a large population, also less well-known predictors for CP can be detected. Statistical analyses were performed on IBM SPSS Statistics version 20.0.0 (IBM SPSS Statistics, IBM Corporation, Chicago, IL). P < .05 was considered statistically significant.

    TABLE 1

    Characteristics of Infants Alive at Age of 1 Year and Their Mothers, Followed to Age of 7 Years, 1991–2008 (n = 1 018 302; Infants Who Died When Younger Than 1 Year and Infants With Major Congenital Malformations Excluded)

    TABLE 2

    Diagnoses of CP and Data on Reimbursements Due to CP

    TABLE 3

    Diagnoses of CP (n = 2242) and Distribution of CP Subtypes in Gestational Week Categories

    TABLE 4

    Risk Factor Analysis for CP (n = 2242) in 1991–2008 by the Age of 7 Years Using Time From Birth to First Hospital Visit as Following Time Separately for 4 Gestation Week Categories (n = 1 018 302)

    Results

    LP infants accounted for 75% and MP infants for 13% of all prematurely born infants in Finland during this study period. Characteristics of newborns and mothers are shown in Table 1. Proportion of all preterm births was 5.02% from 1991 to 1995, 5.43% from 1996 to 2001, and 5.18% from 2002 to 2008. The proportion of MP and LP infants remained constant; MP infants accounted for 0.63% to 0.69% and LP infants from 3.82% to 4.08% of all births.

    After combining the register data, 2242 CP cases were identified. The incidence of CP was 0.22%, and it decreased nonlinearly with increasing GA, and with time. The decrease by time was greatest in the VP group, and during the latest time period (ie, after 2001) (Table 2, Fig 1). The analysis of CP subtypes showed that the proportion of diplegia cases was greatest in the VP group and of hemiplegia cases in the term group (Table 3).

    FIGURE 1

    Incidences of cerebral palsy (n = 2242) per 100 000 births by age of 7 years by gestational age, birth years 1991–2008 (n = 1 018 302).

    Birth during the earliest period, 1991 to 1995, 1-minute Apgar score <7, and intracranial hemorrhage predicted CP in all GA categories in the logistic regression model (Table 4). Resuscitation at birth was associated with an increased risk in MP and LP groups and in the term group. SGA and antibiotic treatment during the first hospitalization seemed to predict an increased risk of CP in the LP and the term groups. PROM was associated with an increased and antenatal steroid treatment with a decreased risk of CP in the MP group. Antenatal steroid administration was registered from 2004 onward. In the analysis for 2004 to 2008, the OR for CP in the MP group with antenatal steroid was 0.24 (95% CI 0.08–0.76). RDS predicted a decreased risk of CP in the LP group. Independent ORs for CP in premature gestational week groups compared with the full-term group were in the VP group 9.37 (95% CI 7.34–11.96), in the MP group OR 5.12 (95% CI 4.13–6.34), and in the LP group OR 2.35 (95% CI 1.99–2.77).

    Discussion

    In this population the incidence and risk for CP were higher among MP and LP infants compared with those born at term. The burden of CP to the families of the MP and LP children, in terms of medicine expenses, is comparable with term-born babies. Also the need of disability allowance seems to be significantly less common in the MP and LP groups than in the VP cases. Birth at an earlier period, being SGA, and having asphyxia and intracranial hemorrhage emerged as significant predictors for CP, whereas antenatal corticosteroid therapy seemed to reduce the risk. Our results can be used in the counseling of parents and in planning guidelines for follow-up practices of MP and LP newborns.

    The most prominent weakness of register studies is that recording practices may differ significantly among individuals, sites, and regions. The classification system of diseases was changed in 1996. Although diagnoses were converted to be identical, this change might have affected the diagnostic categories. Children born during the last years of the latest study period 2002 to 2008 had shorter follow-up time, which also may have influenced the decrease in CP risk compared with the earlier periods. However, the CP diagnosis was usually made by the age of 1.5 years. Data of 5-minute Apgar score were not available from the register during this study period and we used the 1-minute score, which is a relatively vague marker for outcome. Recording practices for hypoxic-ischemic encephalopathy and multiorgan failure had substantial variance and, thus, could not be included in analysis.

    Strengths of this study are reliable and comprehensive population-based register data and the substantial number of infants. The national health registers in Finland are well-established and validated. The MBR is a high-quality register covering more than 99.9% of all births.29,31 The data quality, completeness, and accuracy of the HDR have been varied from satisfactory to very good in a systematic review.28 Infants were followed to the age of 7 years, by which time the diagnosis of CP is generally made. CP diagnoses can be regarded as reliable, because they are made in public hospitals in specialized units of child neurology. The prevalence of congenital anomalies has been 2.2 times greater in infants born at 32 to 36 weeks of gestation compared with term infants,32 which is a significant confounder when seeking perinatal risk factors. Here, as elsewhere,33 all infants with major congenital anomalies were excluded.

    The CP incidence was in accordance with the literature.34 It was higher in the preterm groups compared with the term group and began to decrease clearly after 28 weeks of gestation. Small rates of CP at 24 and 25 weeks of gestation are probably due to small numbers of cases. In our study, the risk of CP was 5.12 (OR) in the MP compared with the term group. In the United States, the risk of CP has been threefold in LP subjects compared with children born at term,22 whereas the risk in our population was 2.35 (OR) compared with term-born children. In the current study, the risk of CP decreased over time in all subgroups. The drop was greatest in the VP group, probably due to advances in perinatal and neonatal care. The prevalence of CP among MP infants also decreased in the European register study between 1980 and 1998.35 In contrast, according to a recent systematic review and meta-analysis, the overall CP prevalence has remained constant in recent years.36

    SGA predicted the CP risk in the Finnish LP and term infants. In contrast, in a Swedish cohort of 334 cases with CP and 668 controls matched for gestation, gender, and delivery unit, SGA associated with CP in term, but not LP infants.37 In their study, growth status was determined by using customized birth weight percentiles, based on the growth potential calculated for each infant, whereas we used population-based birth weight standards. The different study designs probably explain the conflicting results.

    Resuscitation at birth and low Apgar score were significant risk factors for CP in this study, showing asphyxia at birth to be a major cause of hypoxic ischemic brain injury, and of later motor disability. Efforts to prevent and treat asphyxia seem to be an effective means of preventing CP also in the MP and LP infants. Intracranial hemorrhage increased the risk of CP significantly in all subgroups. It is obvious, and also previously demonstrated, that brain injury visible in brain imaging correlates with the development of CP.38

    An antibiotic treatment appeared to predict a CP risk in groups from moderately preterm to term infants. Premature labor might be predisposed by infection and it is thus common practice to start antibiotic therapy for a premature newborn. Also, most infants who need intensive care are treated with antibiotics in cases of suspected sepsis. Thus, antibiotic treatment is rather a marker of the sickness of the infant than a causative factor for CP. Conversely, true sepsis was not a significant risk factor, possibly because of the small number of cases with a proven sepsis diagnosis. PROM was a predictor for CP in the MP group. PROM can be regarded as a relevant marker of chorioamnionitis in register studies.39,40 Instead, true incidence of chorioamnionitis, a well-known risk factor for CP,41,42 cannot be established in a register study by using the ICD-9 or ICD-10 diagnoses, because histologic or clinical confirmation is rarely available.

    LP infants evince a higher neonatal morbidity compared with term-born infants, this including higher rates of RDS.43 In the current study, RDS was associated with a decreased risk of CP in the LP group and ventilator treatment with an increased risk in the VP, LP, and term groups. Infants who needed mechanical ventilation for reasons other than RDS may have had other morbidities, such as asphyxia or infection, which might be more harmful to the developing brain than RDS only. Antenatal steroid treatment predicted a decreased risk of CP in MP infants. According to earlier national guidelines, mothers expected to deliver before 34+0 weeks of gestation were treated with glucocorticoids. The updated guideline recommends antenatal glucocorticoid treatment to be administered later (ie, before 35+0 weeks’ gestation).44 This change seems to be beneficial also in reducing the risk of CP in this group.

    Conclusions

    The incidence of CP increases nonlinearly with decreasing GA. LP and MP infants are at a significantly greater risk compared with term infants. The risk has decreased in all GA groups over time. Asphyxia and intracranial hemorrhage emerge as the most prominent risk factors in all gestation week categories. Efforts to prevent and treat asphyxia are of prime importance in reducing the risk of CP. Antenatal steroid treatment appears to reduce the risk among MP infants. Guidelines for management and risk assessment need to be established for LP and MP infants.

    Footnotes

      • Accepted September 5, 2014.
    • Address correspondence to: Mikko Hirvonen, MD, Central Finland Health Care District, Central Finland Central Hospital, Department of Pediatrics, Keskussairaalantie 19, 40620 Jyväskylä, Finland. E-mail: mikko.hirvonen{at}ksshp.fi.
    • Dr Hirvonen drafted the initial manuscript and participated in the analytic planning; Drs Ojala, Korhonen, Haataja, Eriksson, and Gissler participated in the analytic planning and critically reviewed and revised the manuscript; Ms Luukkaala conducted the statistical analyses and critically reviewed and revised the manuscript; Dr Tammela designed and supervised the study and critically reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: Funding for the full-time research work (Dr Hirvonen) was received from Pirkanmaa Hospital District and Central Finland Health Care District. The funding sources had no role in the study.

    • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

    References

    What’s Known on This Subject:

    The incidence of cerebral palsy is dependent on the gestational age in very preterm infants and risk factors have been identified for term infants. The risk has also proved to be greater among late preterm births compared with term.

    What This Study Adds:

    The incidence of cerebral palsy was 24-fold in moderately preterm and 6-fold in late preterm infants compared with full-term infants. The most prominent risk factors included asphyxia and intracranial hemorrhage. The incidence diminished over time and with increasing gestational age.

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