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Objective To determine if the discrepancy between gestational age estimated by last menstrual period and by biparietal diameter (GALMP− GABPD) is associated with adverse pregnancy outcome.
Design Population-based follow up study.
Population Singleton pregnancies were studied when a reliable date of last menstrual period and biparietal diameter measured between 12 and 22 weeks of gestation was available (n= 16,469).
Methods Logistic regression analysis and Kaplan-Meier survival analysis were used to analyse the association between GALMP− GABPD and adverse pregnancy outcome.
Main outcome measures Adverse outcome was defined as abortion after 12 weeks of gestation, stillbirth or postnatal death within one year of birth, delivery < 37 weeks of gestation, a birthweight < 2500 g or a sex-specific birthweight lower than 22% below the expected.
Results The risk of death was more than doubled if GALMP− GABPD of ≥ 8 days was compared with GALMP− GABPD of < 8 days (OR 2.2; 95% CI 1.6–3.1). The risk of death was a factor of 6.1 higher if GALMP− GABPD of ≥ 8 days was combined with increased (> 2 × multiple of median) maternal alphafetoprotein measured in the 2nd trimester.
Conclusions A discrepancy between GALMP and GABPD generally reflects the precision of the two methods used to predict term pregnancy. However, a positive discrepancy of more than seven days, particularly with high maternal alpha-fetoprotein, might indicate intrauterine growth retardation and an increased risk of adverse perinatal outcome.
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Ultrasound biometry is routinely used during the second trimester. One of the main reasons for ultrasound examination is to estimate gestational age. If there is a discrepancy between the gestational ages estimated by last menstrual period and biparietal diameter, the ultrasound estimated is more precise1–11. Gestational ages estimated from last menstrual periods tend to overestimate the true gestational age, resulting in a high rate of post-term deliveries12–17. This can be explained by the fact that ‘delayed’ ovulation is more common than ‘early’ ovulation.
Some fetuses may be smaller or larger than expected at the time of scanning in the 2nd trimester. Consequently, GABPD will be shorter or longer than GALMP. Smith et al.18 reported that suboptimal growth might already be observed in the first trimester. Fetuses with a crown-rump length two to six days shorter than expected from the certain last menstrual period were more likely to be either born prematurely or born with a birthweight < 2500 g. Drugan et al.19 showed that this group of smaller than expected fetuses was at increased risk for chromosome anomalies. Data from population-based cohort studies confirmed a strong association between smaller than expected fetuses and the risk of late fetal death20–22. In a recently published study we found that term predicted from biparietal diameter is generally more precise than term predicted from last menstrual period1, and that smaller than expected biparietal diameter is mainly due to an error related to estimated time of ovulation2. However, in this group the relative risk of a low birthweight was slightly increased2.
Since a discrepancy of more than seven days between gestational age predicted by a reliable last menstrual period and biparietal diameter is quite a common clinical phenomenon (about 12.7% among women with reliable last menstrual period in our population), we would wish to investigate the clinical importance of this discrepancy.
The aim of this study was to estimate the risk of adverse pregnancy outcomes in relation to the discrepancy in days between gestational age estimated from last menstrual period and biparietal diameter.
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The study was a population-based follow up study. During the period 1986–1996 obstetric ultrasound data from 21,936 unselected singleton pregnancies in a geographically well defined area were prospectively recorded as part of routine examination in maternity care at Herlev University Hospital of Copenhagen. Trained midwives performed ultrasound scanning and data registration. The database was linked to registered data from the Danish National Board of Health to collect information about pregnancy outcomes. To validate the data from that link, we studied 3893 medical records from women referred for scanning from 1 January 1993 to 31 March 1994. Furthermore, we studied the medical records from all 487 singleton pregnancies that had ultrasounds in the second trimester, were registered in the ultrasound database and resulted in either spontaneous, missed and induced abortions or fetal and postnatal death within one year. Relevant data from patient records were added to the database, including demographic data (e.g. race, age, height, and weight), reproductive histories, last menstrual periods, ultrasound findings and pregnancy outcomes. This made it possible to control the validity of data in the linked registries. The validation study showed a high degree of completeness and correctness of raw data including birth, gender, birthweight and Apgar scores reported from local hospitals to the national registry.
Women were excluded from the study if they had pregnancies with only one measurement of biparietal diameter either before 12 weeks (20 mm) or after 22 weeks of gestation (55 mm) (n= 1152 [5.3%]), had unreliable first day of last menstrual period (n= 4508 [20.6%]), had no recorded last menstrual period (n= 298 [1.4%]), had induced abortions after 12 weeks of gestation (n= 185 [0.8%]), had missed abortions diagnosed at the first ultrasound scan (n= 52 [0.2%]), or had no follow up data (n= 168 [0.8%]) (moved abroad or delivered at other hospitals). Some women had multiple reasons for exclusion. In total, 5467 singleton pregnancies (24.9%) were excluded leaving 16,469 in the study. Of all infants, 16,281 were still alive one year after birth and 188 died between 12 weeks of gestation and one year after birth (81 late abortions, 49 stillbirths, and 58 postnatal deaths during the first year following birth).
Biparietal diameter was measured from the outer to the inner contour of the parietal bone echo. B-K Medical 3535 and Aloka LS SSD-280 ultrasound equipment with 5.0/3.5 MHz curvilinear transducers were used, with the sound velocity calibrated to 1540 m/s. Actual gestational age was calculated by last menstrual period (the date of scanning – last menstrual period), and by biparietal diameter according to Persson's equation23. A date zero, corresponding to the first day of last menstrual period was calculated by subtracting gestational age based on biparietal diameter from the actual date of ultrasound examination.
Gender-specific expected birthweights were calculated according to a Danish-Swedish equation obtained from longitudinal intrauterine ultrasound-estimated fetal weight from 86 normal pregnancies24. Actual weight deviation (%) was calculated as: birthweight minus sex-specific expected birthweight for gestation divided by the estimated weight. Weight deviation of −22% was used as cut off for defining small for gestational age which corresponded to minus 2 standard deviation of the expected birthweight for gestational age. Fetuses were divided into five groups: large, normal, slightly small, small and very small, according to the discrepancy between gestational age from last menstrual period and from biparietal diameter, GALMP– GABPD, (less than −2, between −2 and +2, +3 and +7, +8 and +13, and more than +13 days, respectively). The intra- and inter-observer variation in measurement of biparietal diameter in our department was found to be ±1 mm, corresponding to ±2 days25. The variation of ±1 mm in repeated measurement of biparietal diameter was in accordance with results from other studies6,26–35. Fetuses with GALMP−GABPD between −2 to +2 days were therefore used as reference group to which the other groups were compared.
Adverse outcomes of the pregnancy were defined as:
Death: spontaneous or missed abortion between 12 and 28 weeks of gestation, stillbirth, postnatal death within 30 days or within 31 and 365 days of birth
Preterm delivery: gestational age < 37 weeks of gestation
Low birthweight: < 2500 g
Low birthweight for gestational age: ≥ 22% below the expected birthweight.
Measurement of maternal serum alpha-fetoprotein
All pregnant women were offered an maternal alpha-fetoprotein measurement between 12 and 22 weeks of gestation as a screening procedure for neural tube defects.
In total, 19,150 out of 21,936 women (87.3%) had at least one measurement. Maternal alpha-fetoprotein was measured in kU/L according to World Health Organisation 72/225. To obtain the reference median of maternal alpha-fetoprotein in relation to gestational age, linear regression analysis was performed, using ultrasound gestational age GABPD in days, as the independent variable and maternal alpha-fetoprotein as the dependent variable. The regression line was:
The Kaplan-Meier method was used to estimate survival curves for the five groups of fetuses defined by GALMP− GABPD. The beginning of pregnancy was set to data zero calculated by biparietal diameter. The risk of death was calculated from 12 weeks to 280+365 days after date zero. The risks of the different types of adverse outcomes were analysed using logistic regression analysis. All analyses were performed using the statistical software package SAS version 6.12.
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The risk of fetal loss and postnatal death was significantly increased among fetuses with GALMP− GABPD of ≥ 8 days compared with GALMP− GABPD between ±2 days (Table 1, Fig. 1). The chance of survival was lowest among those classified as small or very small (Fig. 2). The group classified as large had the highest chance of survival after 28 weeks of gestation (Fig. 2).
Table 1. Risk of perinatal death in pregnancies with discrepancy between gestational age estimated by last menstrual period (LMP) and biparietal diameter (BPD) (GALMP–GABPD). Values are given as n,n (%)* or OR [95% CI].
| ||GALMP–GABPD(days)|| |
|Categories of death||<−2 (n= 2642)||−2 to 2† (n= 6619)||3 to 7 (n= 5113)||8 to 13 (n= 1621)||>13 (n= 474)||All groups (n= 16,469)|
|Spontaneous/missed abortion.||10 (0.4)||27 (0.4)||30 (0.6)||9 (0.6)||5(1.1)||81 (0.5)|
| ||0.9 [0.4–1.9]||—||1.4 [0.9–2.4]||1.4 [0.6–2.9]||2.6 [1.0–6.9]|| |
|Stillbirth||5 (0.2)||18 (0.3)||12 (0.2)||10 (0.6)||4 (0.8)||49 (0.3)|
| ||0.7 [0.3–1.9]||—||0.9 [0.4–1.8]||2.3 [1.1–5.0]||3.2 [1.1–9.4]|| |
|Postnatal death within 30 days||5 (0.2)||11(0.2)||8 (0.2)||6(0.4)||2 (0.4)||32 (0.2)|
|Postnatal death within 31–365 days||1.1 [0.4–3.3] 1 (0.04) 8(0.1)||0.9 [0.4–2.3]||2.6 [0.6–11.7] 8 (0.2)||2.2[0.8–6.1]||3 (0.6)||26(0.16)|
| ||0.3 [0.1–2.5]||—||1.3 [0.5–3.5]||6(0.4)||3.1 [1.1–8.9]||5.3 [1.4–20.2]|
|All categories of death||21 (0.8)||64 (1.0)||58(1.1)||31 (1.9)||14(3)||188(1.14)|
| ||0.8 [0.5–1.3]||—||1.2 [0.8–1 .7]||2.0 [1.3–3.1]||3.1 [1.7–5.6]|| |
Figure 1. Odds ratio of death (abortion after 12 weeks of gestation, stillbirth, postnatal death within 30 days and within 31 days and 365 days of delivery) for five groups of fetuses classified according to the discrepancy between gestational age calculated from last menstrual period and biparietal diameter (GALMP− GABPD). A, C, D, E refer to fetuses with (GALMP− GABPD) of less than −2, between 3 and 7, between 8 and 13, and more than 13 days, respectively. Fetuses with (GALMP− GABPD) between −2 and 2 days were used as the reference to which the other groups were compared.
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Figure 2. Estimated survival curves for five groups of fetuses (large, normal, slightly small, small, very small) classified according to the discrepancy between gestational age calculated from last menstrual period and biparietal diameter (GALMP− GABPD). A, B, C, D, E refer to fetuses with (GALMP− GABPD) of less than −2, between −2 and 2, between 3 and 7, between 8 and 13, and more than 13 days, respectively.
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The risk of other adverse outcomes was not found to be significantly different between the three groups of pregnancies with GALMP− GABPD of ≤ 7 days. These data were therefore pooled and compared with the group with GALMP− GABPD of ≥ 8 days. The crude and adjusted risk of adverse outcomes between these two groups is shown in Table 2.
Table 2. Risk of adverse outcome in two categories of discrepancy between gestational age estimated by last menstrual period (LMP) and biparietal diameter (BPD) (GALMP–GABPD).EW = gender.specific expected weight for gestation.
|GALMP–GABPD(days)||Risk of adverse outcomes||n (%)∥||Crude OR [95% CI]||Adjusted OR [95% CI]|
|≥8||Death||45 (2.2)||2.2 [1.6–3.1]||2.3 [1.6–3.2]|
|≥8||Prematurity||175 (8.4)||1.7 [1.4–2.0]||1.7 [1.4–2.0]|
|≥7*||Birth weight < 2500 g||564 (4.0)||1.0||1.0|
|≥8||Birth weight < 2500 g||138 (6.7)||1.7 [1.4–2.1]||1.8 [1.5–2.1]|
|≥7*||Weight deviation < –22%§||820(5.8)||1.0||1.0|
|≥8||Weight deviation < −22%||167 (8.0)||1.4 [1.2–1.7]||1.4 [1.2–1.7]|
The risk of death was more than doubled and the risk of preterm delivery, low birthweight (< 2500 g) and birthweight ≥ 22% below the expected birthweight for gestation was approximately 1.5 times higher in fetuses with GALMP− GABPD of ≥8 days when compared with GALMP− GABPD of ≤ 7 days. The risk of adverse outcomes was significantly different between the groups compared when adjusted for other potential confounding variables (Table 2).
Since high and low maternal alpha-fetoprotein is known to be associated with adverse pregnancy outcomes, the risk of adverse outcomes was analysed in three groups of maternal alpha-fetoprotein (< 0.5, between 0.5 and 2, and > 2). The risk of adverse outcomes was not different for pregnancies with normal and low maternal alpha-fetoprotein. These data were therefore pooled and compared with pregnancies with MoM maternal alpha-fetoprotein of > 2.
The frequency of maternal alpha-fetoprotein measurement of MoM > 2 was 2.5% (385 out of 15,222 with measured maternal alpha-fetoprotein in the studied population). Number of pregnancies with maternal alpha-fetoprotein of MoM > 2 was significantly higher in the group with GALMP− GABPD of ≥ 8 days (3.7%) compared with those with GALMP− GABPD of ≤ 7 days (2.4%) (OR 1.6; 95% CI 1.3–2.0). High maternal alpha-fetoprotein was associated with increased risk of death (OR 6.5; 95% CI 4.5–9.5), preterm delivery (OR 4.3; 95% CI 3.5–5.4), low birthweight (OR 5.0; 95% CI 3.9–6.3), and low birthweight for gestation (OR 3.2; 95% CI 2.5–4.0).
The risks of adverse outcomes were also analysed in a model with both GALMP− GABPD and maternal alpha-fetoprotein included as risk factors (Table 3). Increased risks of adverse outcomes in the five groups of GALMP− GABPD were seen for both maternal alpha-fetoprotein of > 2 and ≤ 2. The risk became higher with maternal alpha-fetoprotein of > 2, thus increasing predictive value of GALMP− GABPD. Only in the analysis of risk of low birthweight for gestational age was a significant effect of the interaction between GALMP− GABPD and maternal alpha-fetoprotein seen. This resulted in a further elevated risk for fetuses with GALMP− GABPD of ≤ 14 and maternal alpha-fetoprotein of > 2 compared with those with GALMP− GABPD of ≤ 14 and maternal alpha-fetoprotein of < 2 (OR 4.3; 95% CI 1.3–14.2). The association between the risks of adverse outcomes in relation to both GALMP− GABPD and maternal alpha-fetoprotein were still significantly different between the groups compared when adjusted for maternal age, previous spontaneous abortion, amniocentesis and fetal malformations (data not shown).
Table 3. Risk of adverse outcomes in pregnancies with discrepancy between gestational age predicted by last menstrual period (LMP) and biparietal diameter (BPD) (GALMP– GABPD), adjusted for multiple median of maternal serum alpha–fetoprotein (AFP–MoM). Values are given as n (%), unless otherwise indicated.
| ||Death||Premature||Birthweight < 2500 g||Weight deviation < −;22%|
| ||Incidence†||OR [95% CI]||Incidence†||OR [95% CI]||Incidence†||OR [95% CI]||Incidence†||OR [95% CI]|
|GALMP– GABPDPD|| || || || || || || || |
|>−3||17 (0.17)||0.7 [0.4–1.3]||90 (3.77)||0.8 [0.6–1]||73 (3.08)||0.8 [0.6–1.1]||90 (3.8)||1 [0.8–1.3]|
|–2 to 2||58 (0.95)||1||305 (4.98)||1||229 (3.76)||1||234(1.55)||1|
|3 to 7||48 (1.01)||1.0 [0.7–1.5]||280 (5.87)||1.2 [1.0–1.4]||215 (4.53)||1.2 [1.0–1.4]||219 (4.62)||1.2 [1.0–1.4]|
|8 to 13||30 (1.99)||2.0 [1.3–3.2]||116(7.68)||1.5 [1.2–1.9]||97 (6.47)||1.7 [1.3–2.2]||93 (6.2)||1.6 [1.3–2.1]|
|≥14||13 (3.0)||3.0 [1.6–5.5]||43 (9.93)||2.0 [1.4–2.8]||28 (6.56)||1.7 [1.1–2.6]||26 (6.09)||1.6 [1.0–2.4]|
|AFP–MoM|| || || || || || || || |
|>2||23 (5.97)||6.1 [3.8–9.6]||73 (18.96)||4.1 [3.2–5.4]||64 (16.86)||4.7 [3.6–6.3]||50(13.16)||3.4 [2.5–4.6]|
|≤2*||143 (0.96)||1||761 (5.13)||1||578 (3.92)||1||612 (4.15)||1|
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The main finding of this study is that a positive discrepancy between GALMP and GABPD of > 8 days is associated with increased risk of death, preterm delivery, a birth-weight < 2500 g and of low birthweight for gestation. Furthermore, high maternal alpha-fetoprotein (MoM > 2) is found to increase the above risks by three to six times.
Fetuses may already be smaller than expected in the first trimester18. The small for gestational age fetus may be a result of constitutional rather than pathological factors36–39. However, it was reported that even in short mothers the late fetal death rate was more than ten times higher in extremely small for gestational age fetuses compared with fetuses of a normal birthweight ratio21. Smaller than expected fetuses had an increased risk of a birthweight < 2500 g, chromosomal abnormality and mortality18–22. We classified fetuses with values of GALMP− GABPD≤−3 days as larger than expected and found that they had a better survival and lower risk of late fetal death than the reference group GALMP− GABPD of −2 to +2 days.
Our study shows, in accordance with many other studies, that the discrepancy between GALMP and GABPD was skewed towards the right. This indicates that if women do not ovulate 14 days after the last menstrual period, they will more often ovulate later3,5,17,18,40,41. Biochemical and biophysical data reflect cycle and ovulation irregularity as well as skewness towards late ovulation in healthy women42–46. However, the question has been raised whether the extent of systematic error in the estimation of GALMP may have been overestimated in the past. From a population of 268,430 single births in Norway, Herman et al.47 showed that among infants with low birthweight (500–2000 g), fetuses with higher GALMP for their birthweight had higher fetal mortality than infants with low GALMP for their birthweight. Low birthweight infants with a high GALMP may have a slower rate of intrauterine growth, rather than an error in estimation of gestational age.
One drawback of this study is that we did not have data about the length of the menstrual cycle. Significant bias might have been introduced by the fact that gestational age calculated from last menstrual period was not corrected for the cycle length. Berg48 reported from a study of 5688 women with regular self-reported menstruation cycles that the proportion of post-term births increased with longer cycle length (4.1%versus 14.6% for cycle length of 21–26 days versus 36–42 days). The Ogino-Knaus method which calculates gestational age as (days from last menstrual period to birth) − (cycle length) −28, however, appeared to overcorrect for cycle length, resulting in an almost equal and reversed association between cycle length and gestational age.
We studied 3338 medical records at our hospital in the year 1993 and found that 2.2% of women with regular menstrual cycle (73.1% of the whole population) reported a cycle length of > 30 days. However, the percentage of pregnancies with discrepancy between GALMP and GABPD of > 7 days in the population studied was much higher (12.7%). Furthermore, only three of the 31 fetuses who were stillborn or died within one year of birth were post-term according to last menstrual period. Therefore, it is unlikely that a correction of gestational age for cycle length would not change the results of our study.
When studying potential confounding variables, we found that young age (< 19 years), previous spontaneous abortion, amniocentesis and fetal malformation were associated with an increased risk of adverse outcomes. However, the most potential confounding variable was maternal alpha-fetoprotein measured in the second trimester. The association between high maternal alpha-fetoprotein and an increased risk of adverse outcomes has been reported in many studies. To our knowledge, it has never previously been demonstrated that a combination of high maternal alpha-fetoprotein (MoM > 2) and positive values of GALMP− GABPD (≥ 8 days) increased the risk of adverse outcomes significantly.
We suggest that pregnancies with a positive discrepancy between GALMP and GABPD of > 7 days and MoM maternal alpha-fetoprotein of > 2 may be suitable for intensive antenatal monitoring. Autopsy findings from fetuses and infants included in this study were inconclusive. A prospective study of the pregnancies with GALMP− GABPB of ≥ 8 and high maternal alpha-fetoprotein may provide better information.