The total number of births in Hungary was 2,146,574 during the study period, thus 38,151 controls represented 1.8% of all Hungarian births. Of these 38,151 newborns, 1,017 (2.7%) had mothers with medically recorded PE in the prenatal maternity logbook. Of these 1,017 pregnant women with PE, 45 (4.4%) had later eclampsia while HELLP was not recorded.
Only 580 (57.0%) women out of total 1,017 who were diagnosed as PE had recorded history of taking folic acid supplementation, while this figure was 54.4% (20,195/37,134) in the reference group, thus pregnant women with PE used somewhat more frequently folic acid. The indication of folic acid supplementation was the prevention of neural tube defects. The distribution of daily folic acid supplementation was the following: 22.5%, 68.6%, and 8.9% of pregnant women used one (3
mg), two (6
mg), and three (9
mg) tablets, respectively. Thus the estimated mean daily dose was 5.6
mg. The onset of folic acid supplementation was in about 10% of pregnant women before conception; however, most women started folic acid use after the first visit in the prenatal care clinic, that is, between the 6th and 12th gestational weeks, thus before the onset of PE. Practically all pregnant women continued folic acid supplementation until the end of pregnancy. Of 580 pregnant women with PE and folic acid use, 440 (75.9%) had medically recorded folic acid use in the prenatal maternity logbook while this figure was 61.3% in the reference group. Our validation study showed that maternal information regarding folic acid use was correct, but some women retrospectively forgot to mention it. Folic acid containing multivitamins was used rarely and it contained different low doses of folic acid, thus these pregnant women were excluded from the study.
Maternal characteristics are shown in . There was no difference in mean maternal age of pregnant women with or without PE, while mean birth order was lower by 0.3
in pregnant women with PE due to the higher proportion of primiparous pregnant women. In addition, the difference in the mean pregnancy order (birth + miscarriages) was 2-fold higher in women with PE (0.4) than in pregnant women without PE (0.2), and these findings indicate a higher rate of miscarriages in the previous pregnancies of women with PE. The proportion of professional women was somewhat lower in pregnant women with PE, while their proportion of managerial women and skilled workers was somewhat higher compared to pregnant women without PE. Pregnant women with PE and folic acid use were somewhat older with higher mean birth order.
Characteristics of pregnant women without pre-eclampsia (PE) as a reference and with PE, in addition pregnant women with PE supplemented with folic acid.
Acute and chronic maternal diseases did not show significant differences between pregnant women with PE and the reference sample.
Among other pregnancy complications, threatened abortion (20.8% versus 17.0%) and placental disorders (2.2% versus 1.5%), particularly abruption placentae occurred more frequently in pregnant women with PE than in pregnant women without PE.
Practically all pregnant women with PE were treated with antihypertensive drugs, most frequently nifedipine (15.1% versus 2.2%) and methyldopa (10.5% versus 0.9%) compared with pregnant women without PE. Dihydralazine, metoprolol, clopamide, and furosemide were also more frequently used by pregnant women with PE. However, magnesium sulphate was used only in two pregnant women with PE.
The diagnosis of PE according to gestational months is shown in . These data reflect the record of PE diagnosis in the prenatal maternity logbook, but it may be near to the onset of this pregnancy complication due to the frequent visits in prenatal care clinics. However, of 1,017 pregnant women with PE, 100 (9.8%) had not unambiguous time of diagnoses. Unexpectedly the diagnosis of PE was recorded in the fourth gestational month in 3.9% of pregnant women. In general, these pregnant women had new-onset hypertension but proteinuria was confirmed after the 20th gestational week. The maximum was found during the last two pregnancy months.
Onset (diagnosis) of pregnant women with pre-eclampsia according to gestational month and their birth outcomes.
The birth outcomes of newborn infants born to pregnant women with PE and without PE as reference are shown in the lower part of . (There was no significant difference in the sex ratio of the study groups.) The mean gestational age was the same in pregnant women with or without PE but the rate of preterm birth was somewhat but not significantly higher in the group of pregnant women with PE (10.2% versus 9.1%). The mean birth weight of newborn infants born to pregnant women with PE was somewhat (41
g) larger compared to the newborns of pregnant women without PE and this small difference was significant. On the contrary, the rate of low birth weight newborns was higher in the group of pregnant women with PE (7.9% versus 5.6%), and this 40% increase is significant on both statistical and clinical aspects.
In the next step, newborns were evaluated according to gestational age and birth weight groups in pregnant women with PE and without PE as reference. A characteristic U-shaped curve was shown; the previously mentioned higher rate of preterm birth and low birth weight associated with a higher rate of postterm birth (11.2% versus 10.1%; OR with 95% CI: 1.1. 0.7–1.7) and large birth weight (10.9% versus 7.4%; OR with 95% CI: 1.5, 1.2–2.0). However, these differences reached the level of significance only in low and large birth weight, and the mean birth weight was higher both in term and the postterm births.
The gestational age at delivery and birth weight were moderately modified by folic acid supplementation from the early pregnancy (). The mean gestational age was 0.3 week longer in pregnant with PE after folic acid supplementation compared to pregnant women with PE, but without folic acid use, These data were in agreement with their lower rate of preterm births (8.8% versus 12.1%). However, folic acid supplement associated with only 46 g larger mean birth weight and with moderate reduction of low birth weight (7.2% versus 8.7%) and these differences were not significant. If only medically recorded folic acid uses were considered, the data of birth outcomes did not differ from the total data.
However, the effect of folic acid increased the rate of postterm birth (11.9% versus 11.2%) with smaller mean birth weight and the rate of large birth weight (11.6% versus 10.9%) with shorter mean gestational age (), though these changes did not reach the level of significance.
Distribution of gestational age (preterm, term, postterm) and birth weight (low, average, large) groups in pregnant women without PE (as reference) and with PE, in addition in pregnant women with PE with folic acid supplementation.
The birth outcomes were evaluated according to the onset of PE (). There was no obvious trend in mean gestational age and birth weight depending on the onset of PE. The fifth and last ninth months had longer gestational age with the lower rate of preterm birth. The fourth month due to possible diagnostic bias associated with extremely high preterm birth. Obviously the major risk for adverse birth outcomes was connected with the onset of PE between the sixth and eighth gestational months.
Finally the effect of folic acid for birth outcomes was evaluated in pregnant women with early (IV–VI months) and late (VII–IX months) onset PE in the study (). Folic acid was able to reduce significantly the rate of preterm birth (OR with 95% CI: 0.41, 0.18–0.94) in pregnant women with early onset PE. There was also a reduction in the rate of low birth weight rate after folic acid use in early pregnancy of women with early onset PE but this reduction did not reach the level of significance (OR with 95% CI: 0.52, 0.19–1.40).
The effect of folic acid for birth outcomes of pregnant women with early and late onset PE.