Placental abruption, defined as complete or partial separation of the placenta before delivery, is an obstetric emergency affecting both the mother and the fetus.1,2 The effect on the fetus is determined primarily by the gestational age and the severity of the abruption.3 However, other factors may also play a role. Some previous studies suggest that neonates born from pregnancies with placental abruption are more likely to have major congenital anomalies such as congenital heart defects or anomalies of the central nervous system.4–6 However, most of these studies are old and have major methodologic limitations such as small sample size, selection bias, or lack of a proper control group. Thus, our knowledge of the association between placental abruption and major congenital anomalies is limited. Because Finland has well-established, validated national health registers, we had an excellent opportunity to examine in detail the association between placental abruption and major congenital anomalies.
MATERIALS AND METHODS
The study included all singleton births in Finland from 1987 to 2005. We used the Medical Birth Register and Finnish Hospital Discharge Register maintained by the National Institute for Health and Welfare to identify all women with the diagnosis of placental abruption by using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes for years 1987–1995 and the International Classification of Diseases, 10th Revision for years 1996–2005 in the Hospital Discharge Register and a check box in the Medical Birth Register (October 1990–2005) among a total of 1,137,502 deliveries during the study period. Information on women with placental abruption found from the Hospital Discharge Register and Medical Birth Register was linked together by using women's unique identification numbers existing in both registers. Three control women without placental abruption were selected for each case from the Medical Birth Register, matched by maternal age, parity, year of birth, and hospital district area. Multiple births were excluded.
The Medical Birth Register collects baseline data on interventions mothers have received during pregnancy and delivery and on the newborn's outcome during the first 7 days from all delivery units on care (since 1987). The Medical Birth Register registers all live births and stillbirths with gestational age of at least 22 weeks or birth weight at least 500 g. The data are compiled at the time of birth using the mother's prenatal charts as one of the information sources. Less than 0.1% of all births are missing from the Medical Birth Register, and information on those cases is routinely obtained from the Central Population Register and the Cause-of-Death Register (maintained by Statistics Finland), which render data complete. For all variables used in this study, the data have been validated and correspond well with information available in hospital records,7,8 minimizing potential sources of bias.
The Hospital Discharge Register collects information on all inpatient episodes in all hospitals (since 1967), all outpatient surgical procedures in public hospitals (since 1994), and all outpatient visits in public hospitals (since 1998). The register contains information on admission and discharge date, diagnosis by ICD-9-CM (1987–1995) and International Classification of Diseases, 10th Revision (since 1996), and surgical procedures (Nordic Classification on Surgical Procedures [http://nomesco-eng.nom-nos.dk/filer/publikationer/NCSP%201_15.pdf]). The Register of Congenital Malformations, also maintained by the National Institute for Health and Welfare (since 1963), includes information on live births and stillbirths and elective terminations of pregnancy for severe fetal anomalies, all with at least one detected major congenital anomaly, including major structural anomalies and chromosomal defects classified and coded according to an extended version of the ICD-9-CM. Minor anomalies are excluded principally according to the exclusion system of the European Surveillance of Congenital Anomalies.9 In case of severe fetal major congenital anomalies or disease, permission for elective termination of pregnancy for serious fetal anomalies may be granted at the woman's request by a National Board at the National Supervisory Authority for Welfare and Health up to the 24th completed gestational week but not later. However, terminated pregnancies were excluded from our data. The Register of Congenital Malformations receives and actively collects data nationwide from several sources, including hospitals, health care professionals, and cytogenetic laboratories as well as from the Medical Birth Register, Hospital Discharge Register, Cause-of-Death Register, and other national health registers and authorities. The coverage and data quality of the Register of Congenital Malformations have been considered good according to several studies.10–12 Women's and children's unique identification numbers were used to link the information from the Register of Congenital Malformations to the study data.
The main outcome measure of this study was a major congenital anomaly associated with placental abruption. Neonates born after placental abruption with major congenital anomalies were identified by linking the three national registers. To classify the detected major congenital anomalies in this study sample, the extended ICD-9-CM classification system used by the Register of Congenital Malformations and the definitions used by the International Clearinghouse for Birth Defects Surveillance and Research for surveillance of selected major congenital anomalies (http://www.icbdsr.org/) were applied.
The duration of gestation calculated from the last menstrual period was confirmed or corrected by ultrasonographic screening examinations at 11–13 weeks or 18–20 weeks of gestation. The Medical Birth Register records the best clinical estimate for gestational age at birth. Smoking habits were recorded during antenatal clinic visits. Women who smoked at least one cigarette per day during pregnancy were defined as smokers. Birth weight and gestational age were used to study the outcome of the newborns. Small-for-gestational-age newborns were defined by birth weight –2 standard deviations or less and large-for-gestational-age newborns as +2 or more standard deviations of the national sex-specific standard.13 Extremely preterm newborns were born before 28 weeks of gestation, very preterm from 28 0/7 weeks to 31 6/7 weeks of gestation, and moderately preterm from 32 0/7 weeks to 36 6/7 weeks of gestation.
Prevalence of at least one major congenital anomaly was analyzed by multivariate logistic regression. All models were adjusted by selected baseline characteristics (maternal age, parity, socioeconomic status, and smoking during pregnancy) or birth-related characteristics (gestational age, birth weight, standardized birth weight, and sex) of the women with placental abruption and control participants without abruption. Missing data were recorded as an unknown category and included in the analyses. Results of the logistic regression models were shown by odds ratios (ORs) with 95% confidence intervals (CIs). Births with selected major congenital anomalies according to the definitions by the International Clearinghouse for Birth Defects Surveillance and Research among pregnancies with and without abruptions were studied by logistic regression adjusting models by the selected baseline characteristics shown previously. Statistical analyses were performed by IBM SPSS Statistics 19.0 release 19.0.02. Statistical significance was defined as P<.05. To avoid problems with multiple testing, a stricter limit for statistical significance (P<.01) was applied for comparisons of selected major congenital anomalies according to the definitions by the International Clearinghouse for Birth Defects Surveillance and Research. All included births with major congenital anomalies were also divided into subgroups according to the pattern of major congenital anomalies (isolated, multiple, or syndrome). Multiple anomalies were defined as having at least two major, unrelated congenital anomalies according to the International Clearinghouse for Birth Defects Surveillance and Research.14
The study was approved by the National Institute for Health and Welfare (the register keeper), which also authorized the use of health register data in scientific research, as required by national data protection legislation.
We identified 4,190 women with singleton birth and placental abruption and 12,570 matched control participants without placental abruption among 1,137,502 deliveries from 1987 to 2005. A total of 261 women with abruption and 415 control participants had a birth with at least one major congenital anomaly. Baseline characteristics of the cases and the control participants are shown in Table 1. In the adjusted analysis, the prevalence of major congenital anomalies was increased among births with placental abruption (OR 1.92, 95% CI 1.63–2.52; prevalence 623/10,000 births compared with 330/10,000 births, respectively). Maternal age, parity, socioeconomic status based on maternal occupation during pregnancy, and smoking during pregnancy were not associated with major congenital anomalies. Birth-related characteristics of the newborns in pregnancies with or without placental abruption are shown in Table 2. Among very preterm and moderately preterm newborns, those born after placental abruption were nearly twice as likely to have a major congenital anomaly (OR 1.94, 95% CI 1.10–3.42 and OR 1.76, 95% CI 1.34–2.32, respectively). Also, small-for-gestational-age newborns born after placental abruption had a significant association with major congenital anomalies (OR 1.83, 95% CI 1.30–2.56). Sex was not associated with major congenital anomalies.
The association with major congenital anomalies in different organ systems between neonates born after placental abruption and neonates born to women without placental abruption is shown in Table 3. Adjusted analysis showed a significant association with central nervous system anomalies (OR 2.33, 95% CI 1.29–4.23), anomalies of the eyes and ears (OR 1.82, 95% CI 1.08–3.09), cardiovascular anomalies (OR 1.78, 95% CI 1.34–2.37), respiratory anomalies (OR 3.51, 95% CI 1.56–7.90), gastrointestinal anomalies (OR 3.81, 95% CI 2.27–6.41), genitourinary anomalies (OR 2.55, 95% CI 1.73–3.74), musculoskeletal anomalies (OR 1.67 95% CI 1.24–2.24), and anomalies of integument (OR 3.29, 95% CI 1.20–8.98). For oral clefts and chromosomal defects, the groups did not differ.
Analyses of selected major congenital anomalies (definitions by the International Clearinghouse for Birth Defects Surveillance and Research) monitored by the Register of Congenital Malformations are shown in the Appendix (available online at http://links.lww.com/AOG/A404). A significant association with major congenital anomalies among births with placental abruption was found for hydrocephaly (OR 7.16, 95% CI 2.23–23.0), esophageal atresia or stenosis (OR 4.92, 95% CI 2.12–11.4), duodenal atresia (OR 6.84, 95% CI 1.25–37.5), anorectal atresia or stenosis (OR 3.06, 95% CI 1.01–9.23), diaphragmatic hernia (OR 16.03, 95% CI 1.86–138.4), and severe forms of hypospadia (OR 7.14, 95% CI 2.47–20.7; P<.001 for all). Otherwise the groups did not differ (P>.01).
All included births with a major congenital anomaly were also divided into subgroups according to the pattern of major congenital anomalies (isolated, multiple, or syndrome). Multiple anomalies were more common among neonates born from pregnancies complicated by placental abruption (OR 1.69, 95% CI 1.05–2.73, data not shown). Further analyses of various combinations of multiple major congenital anomalies and major congenital anomaly diagnosis groups (ICD-9-CM) showed no significant differences between births with or without placental abruption.
We carried out a systematic study of the association between placental abruption and major congenital anomalies. In this large population-based study, we showed that neonates born after placental abruption were twice as likely to have major congenital anomalies compared with control neonates. The association was strongest among very preterm and moderately preterm newborns as well as among newborns with growth restriction. All larger subgroups of major congenital anomalies except oral clefts and chromosomal defects were associated with placental abruption.
Some older studies have suggested that neonates born from pregnancies complicated by placental abruption are at higher risk of having major congenital anomalies.4–6,15,16 In the study by Hibbard and Jeffocate in 1966,4 the prevalence of major congenital anomalies among births with placental abruption was 310 per 10,000, which is high compared with that of the whole hospital population at that time (130/10,000). Paterson5 reported exactly the same prevalence in 1979. In both studies, the majority of major congenital anomalies reported were central nervous system defects. In Sweden in 1986, Kåregård and Gennser15 reported a prevalence of 350 per 10,000, which was twice the prevalence among the general population. The study performed by Raymond and Mills provided stronger evidence (relative risk 2.57) of the association of placental abruption and major congenital anomalies than the studies referred to previously.6 Moreover, the birth prevalence of major congenital heart defects was significantly increased, 330 per 10,000 in the abruption group compared with 70 per 10,000 in the control group (relative risk 4.67). Among newborns with major congenital heart defects, the risk of abruption was 4.5%. In a more recent study, Wyszynski and Wu16 investigated maternal morbid conditions of women carrying offspring with oral clefts and found that these mothers had an increased risk of placental abruption.
In our study, the prevalence of major congenital anomalies among births with placental abruption was similar to previous studies. In Finland, the total birth prevalence of major congenital anomalies was 356 per 10,000 in 1993–2010,17 which is in line with the prevalence of major congenital anomalies among control participants in our study. Like in the previous studies, we also showed that the risk for major congenital anomalies of the central nervous system or the cardiovascular system was increased. However, our study provided more information of other major congenital anomalies also related to placental abruption such as those of gastrointestinal and genitourinary systems. On the other hand, the association for oral clefts was not significant.
The association between placental abruption and major congenital anomalies is difficult to explain. It has been suggested that folate deficiency and low maternal red blood cell folate levels could predispose to placental abruption.4,18,19 In addition, decreased levels of folates are known to threaten the development of the young embryo and its chorion.4 Folic acid indeed plays a role in the prevention of both major congenital anomalies and placental abruption.20,21 There is also evidence that elevated fasting plasma total homocysteine is a risk factor both for placental abruption and congenital developmental defects.22,23
Independent of folic acid deficiency, major congenital anomalies of gastrointestinal or genitourinary systems may also lead to abnormal amount of amniotic fluid (ie, either polyhydramnios or oligohydramnios). These abnormalities of amniotic fluid may predispose to placental abruption. Prolonged preterm premature rupture of the membranes is another risk factor for placental abruption and may also increase the risk for musculoskeletal anomalies.24 However, we did not know how many of our study participants had polyhydramnios, oligohydramnios, or prolonged preterm premature rupture of the membranes.
Smoking is one of the most important risk factors for placental abruption. Of placental abruption episodes, 15–25% are attributable to cigarette smoking.25 Fifteen percent of Finnish pregnant women smoked during the study period.26 According to a recent meta-analysis, smoking also increases the risk for major congenital anomalies.27 However, in our study, major congenital anomalies were not increased among neonates born to women who smoked.
Placental abruption strongly predisposes the fetus to antenatal hypoxia. Thus, the arterial umbilical cord pH values are often low among these newborns.2 Hypoxia can lead to asphyxia, which in turn may result in cerebral insults and hydrocephaly. It may be difficult to differentiate which cases of hydrocephaly are congenital and which are secondary to placental abruption-related hypoxia and cerebral insults. Therefore, the possibility of ascertainment bias has to be taken into account when evaluating the greater amount of hydrocephaly among neonates born from pregnancies with placental abruption reported in this study.
The strengths of our study are that it is large, population-based, and well executed using properly validated national health registers. The limitations of this study include the fact that neonates born from pregnancies complicated by placental abruption were possibly examined more carefully than neonates born without pregnancy complications. Moreover, another limitation is that the Finnish health registers do not obtain information concerning maternal use of folic acid. It is acknowledged worldwide, however, that the recommendations concerning oral folic acid supplements are inadequate and have not yet resulted in a successful decrease in neural tube defects.28
We conclude that major congenital anomalies are nearly twice as common among neonates born from pregnancies complicated by placental abruption. The association is strongest among preterm and among growth-restricted newborns. The exact cause of the association between major congenital anomalies and placental abruption is not known. However, the role of folate deficiency and the metabolism of homocysteine are potential targets for further research for better understanding of the association between major congenital anomalies and placental abruption.
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