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Preeclampsia, high blood pressure, and placental abruption

• I have a few questions that all relate to the same topic Preeclampsia. I am looking for very extensive facts about preeclampsia and blood pressure and its affects on someone who has had preeclampsia previously. I am also looking for connections between a rise in blood pressure and placental abruption. Lastly I am looking for connections between alcohol use and second hand smoking and their effects on a pregnancy in relation to preeclampsia and placental abruption. I need links to articles to back up the answers if at all possible. · Can a pregnant woman have high levels of protein (proteinia) in her urine and not have preeclamsia? Once you have preeclampsia during a pregnancy can it ever go away other than when you give birth. · I know high blood pressure is not good anytime much less during pregnancy but my question is; between the following two circumstances which one is more detrimental to the pregnancy and risks an early delivery or placental abruption. 1) Sustained high blood pressure over a long period of time or 2) A quick high spike in blood pressure (a single incidents where the blood pressure gets abnormally high)? Is sustained high better because the body has grown used to the numbers? · Does preeclamsia cause a rise in blood pressure or does high blood pressure cause preeclamsia? (To be more specific, can a stressful situation that causes the blood pressure to rise then cause preeclamsia?) · If you have preeclamsia and your blood pressure reaches stroke level of above 200 what are the chances of a placental abruption? I am looking at a time of how long till abruption, could it be as long as 48 hours later after the spike? · The effects of second hand smoke on pregnancy in general and preeclampsia specifically. I know smoking could be a cause of preeclampsia but I want to know about second hand smoke. · Lastly I would like to know any connection between Cerebral Palsy and drinking alcohol and/or second hand smoking during pregnancy. I have done the basic searches on the net and hit at least 50 websites but these are the question that I have not been able to locate.

• Answer:

  Thank you for your question. Responding to all of your questions directly would require extensive research of medical journals. However, I found some strong journal articles on Pre-eclampsia and its relation to hypertension and placental abruption among other things. The information I have provide is a broad survey of the current medical literature on Pre-eclampsia and should provide you with important information. I start with a broad journal article, then present specific excerpts from articles relating to your specific concernsm and finally I provided a list of sources for further research. Please let me know if I can clarify this response in any way. *Backround Information (this article seems to address a lot of your questions: Lancet 2000; 356 (9237): 1260-1265 October 7, 2000 TITLE: Pre-eclampsia SOURCE: Department of Obstetrics and Gynaecology, St James's University Hospital, Leeds LS9 7TF, UK (Prof J J Walker FRCOG) (e-mail: [email protected]) AUTHOR: James J Walker ABSTRACT: Pre-eclampsia is associated with significant morbidity and mortality for mother and baby, but it resolves completely post partum. Despite a steady reduction in maternal mortality from the disorder in more developed countries, it remains one of the most common reasons for a woman to die during pregnancy. The disorder starts with a placental trigger followed by a maternal systemic response. Because both this systemic response and the woman's reaction to it are inconsistent, the clinical presentation varies in time and substance, with many different organ systems affected. With the increasing understanding of the disease process, there have been advances in management, such as antihypertensive therapy, magnesium sulphate, and fluid restriction. TEXT: In the UK, the number of maternal deaths from hypertension in pregnancy has fallen steadily over the past few decades (figure 1) n1 as has the complication rate. n2 However, in other parts of the world, the rates of mortality and morbidity remain high n3 and will continue to be so until there are general improvements in maternity services. Trials on prevention have been disappointing, n4 so the mainstays of management of hypertension in pregnancy are integrated antenatal care, access to monitoring services, stabilisation of the maternal condition, and delivery of the baby on the best day in the best way to benefit both mother and child. Antenatal care must provide easy access to monitoring services. n5 Epidemiology The epidemiology of pre-eclampsia is complicated by differences in definitions and inaccuracy of diagnosis. A single blood-pressure reading of 140/90 mm Hg or above is not uncommon in pregnancy and was reported in nearly 40% of pregnant women in one study. n6 Such a finding carries little risk to the mother or fetus. Persistent hypertension is diagnosed if a high reading is found on two occasions at least 4 h apart. Persistent hypertension occurs in around 12-22% of pregnancies, n7-n9 depending on the populations and definitions used. The type of hypertension can be further defined on the basis of other clinical signs, particularly proteinuria and abnormalities of coagulation. n10 Hypertension in pregnancy can be classified into two main groups (panel 1): women who are hypertensive when they become pregnant n11 and those who become hypertensive for the first time in the second half of pregnancy. n9 Blood pressure generally falls in the first and second trimesters; therefore women with high blood pressure before the 20th week of gestation are assumed to have pre-existing hypertension. Although these definitions are important for research and epidemiological purposes, they are less important clinically. All women with raised blood pressure must be carefully monitored for the associated features of pre-eclampsia. Although well-controlled essential hypertension is benign, the frequency of superimposed pre-eclampsia is between 15% and 25%, increasing the maternal and fetal risk. n12, n13 Pre-eclampsia is twice as common in primigravid women as in women having second or later pregnancies. n14 However, with a change of partner, the risk in a multiparous woman increases; this effect suggests that primipaternity is important. Particular men seem to have an increased risk of fathering a pre-eclamptic pregnancy. n15 Women who become pregnant with donor eggs have a higher frequency of pre-eclampsia than women pregnant with their own eggs; n16 this finding suggests that any new fetal factors are important, not necessarily those of paternal origin. Pathophysiology Pre-eclampsia is the result of an initial placental trigger, which has no adverse effect on the mother, and a maternal systemic reaction that produces the clinical signs and symptoms of the disorder. n17 Placental trigger Pre-eclampsia occurs only in the presence of a placenta. Although it is associated with a failure of the normal invasion of trophoblast cells, leading to maladaptation of maternal spiral arterioles, n18 it can also be associated with hyperplacentation disorders such as diabetes, hydatidiform mole, and multiple pregnancy. The maternal arterioles are the source of blood supply to the fetus (figure 2), and maladaptation of these vessels can interfere with normal villous development. In some cases, compensation can occur, but, in others, poor villous development results in placental insufficiency. n19 Secondary damage, such as fibrin deposition and thrombosis, can then occur within the placenta. These features are found in cases of placental insufficiency, whether pre-eclampsia is present or not. n20 Not all women with the potential placental trigger develop pre-eclampsia, therefore the maternal response must be the decisive factor in development of systemic disease. Maternal response Although pre-eclampsia is said to be a vascular endothelial disorder, n21 it is a multisystem disorder with various forms. This variation could be due to different vascular beds being affected to varying degrees, but later research has shown that there is a strong maternal inflammatory response. n17 Although this response has been described in the placental bed, n22 there is far broader immunological systemic activity. n17 These changes may explain many of the clinical signs, including the endothelial-cell dysfunction. Because pre-eclampsia is diagnosed by the presence of hypertension and proteinuria, the rest of the systemic features can vary from mild cases with little systemic involvement, to multiorgan failure. How extensively the disease develops depends on various modifying factors, which could be genetic or environmental in origin. Figure 1: Maternal mortality associated with pre-eclampsia and eclampsia [SEE FIGURE IN ORIGINAL] Hereditary factors Pre-eclampsia can be familial, n23 but various groups have studied the genetic basis of this disorder and no persistent results have been obtained with obvious population differences. A single pre-eclampsia gene is unlikely; there are probably several modifier genes along with environmental factors. n24 There have been conflicting results for the genes that encode angiotensinogen, superoxide dismutase, tumour necrosis factor [alpha], methylene-tetrahydrofolate reductase, factor V Leiden, and endothelial nitric oxide synthase. These studies concentrated on maternal genetics and ignored the potential paternal and fetal influences. n15 The results of large multicentre studies with the use of modern chip technology for genome scanning with multiple microsatellite markers are awaited to clarify the role of genetics in the pathophysiology of pre-eclampsia. n24 Panel 1: Classification of hypertension in pregnancy Pre-existing hypertension (3-5% of pregnancies) n11 Hypertension before pregnancy or found earlier than 20 weeks of gestation or persisting after the pregnancy ends. Most such patients have essential hypertension but some have renal disease and other medical disorders. Pregnancy-associated hypertension (12% of pregnancies) n9 Hypertension occurring de novo after the 20th week of pregnancy and settling within 6 weeks of delivery. This category is divided into two groups. Gestational hypertension (6-7%)--Hypertension alone with no associated features. Pre-eclampsia (5-6%)--Hypertension with proteinuria of at least 0.3 g in 24 h (24 h urine collection or protein/creatinine ratio). Superimposed pre-eclampsia (25% of women with pre-existing hypertension) n12, n13 Signs and symptoms of pre-eclampsia in woman with pre-existing hypertension. Eclampsia Convulsions in any woman who has, or then presents with, hypertension in pregnancy of any cause. Diagnosis and assessment Hypertension is the most common diagnostic sign, although some women present with convulsions, abdominal pain, or general malaise. Because there are no specific diagnostic investigations, the initial diagnosis of pre-eclampsia remains clinical. The classification of severity is mainly based on the blood-pressure value and the presence of proteinuria; further characterisation is based on the other accompanying signs. n25 Measurement of blood pressure There has been much controversy about the method of measuring blood pressure in pregnancy. In the UK, Korotkoff phase IV is generally used, but in other parts of the world, clinicians use Korotkoff phase V. A study by Brown and colleagues suggested that Korotkoff phase V is preferable. n26 What is important is that the method used is consistent and documented. For measurement of blood pressure, the woman should be rested and reclining at an angle of 45 [degrees]. The blood-pressure cuff should be of appropriate size and placed at the level of the heart. Because of the normal blood-pressure variation, several readings should be used to confirm the diagnosis. In normal pregnancy, there are substantial cardiovascular changes with a 50% increase in cardiac output and blood volume, which is accompanied by a fall in blood pressure due to peripheral vasodilation. The changes in pre-eclampsia tend to be the reverse. Severe disease is generally associated with a low cardiac output and a high peripheral resistance. However, Bosio and colleagues n27 found both high-output and low-output states and peripheral resistance within a range from normal to high among women with hypertensive disorders of pregnancy. More importantly, serial studies have shown a cross-over effect from high output plus low resistance to low output plus high resistance as the disease progresses. n27 In pre-eclampsia, the urine protein excretion rises above a threshold of 0.3 g per 24 h. This finding is generally associated with the classic pathological finding of glomeruloendotheliosis, n28 which is not permanent but recovers after delivery. The presence of proteinuria confirms the diagnosis of pre-eclampsia and the concomitant increase in risk for both mother and fetus. n29 The risk is related simply to the presence of proteinuria; it is not affected by the absolute value of or the increase in urinary protein excretion. n30 Figure 2: Diagram of maternal/placental interface showing spiral-artery blood flow and villous structure [SEE FIGURE IN ORIGINAL] Blood pressure and proteinuria can be readily assessed in the antenatal-care setting. If abnormalities are found, the woman should be admitted to hospital or referred to an antenatal day unit for further investigations. n5 The loss of serum protein and the increase in capillary endothelial permeability lead to a decrease in intravascular volume and increased tissue oedema. n31 All organs can be affected, including the liver (producing abdominal pain), brain (producing headache and convulsion), and the lungs (producing breathlessness). Peripheral oedema also occurs, but it is variable and is not a useful diagnostic sign. The decrease in blood volume can lead to an increase in maternal haemoglobin concentration and is associated with an increased risk of intrauterine growth restriction. n29 In normal pregnancy, the platelet count can fall below 200 x 10<9>/L because of the normal maternal blood-volume expansion. In pre-eclampsia, the platelet count falls further and is associated with progressive disease. n29 This fall is probably a result of both increased consumption and intravascular destruction. Associated coagulation abnormalities are unlikely if the count is above 100 x 10<9>/L. n32 A low platelet count is one component of the HELLP syndrome (haemolysis, elevated liver enzymes, and low platelets), which carries a particular risk to the mother. n33 Serum concentrations of uric acid fall in normal pregnancy because renal excretion increases. In pre-eclampsia, there can be a rise in uric acid concentrations that correlates with poorer outcome for both mother and baby. n33 This rise is due mostly to a decrease in renal excretion, but there is probably also increased production secondary to tissue ischaemia and oxidative stress. This variable is a particularly sensitive marker of disease progression and risk. Liver involvement in pre-eclampsia is very varied but is the cause of the upper epigastric pain commonly seen in the disorder. The liver swells as a result of local oedema secondary to inflammatory infiltrates and obstructed blood flow in the sinusoids. Haemorrhage can occur beneath the liver capsule and may be so extensive as to cause rupture of the capsule into the peritoneal cavity. If a haematoma or haemorrhage is suspected, the liver should be examined by ultrasonography. n34 Liver involvement can be assessed by measurement of alanine aminotransferase and aspartate aminotransferase activities in serum; they increase in pre-eclampsia as a result of leakage across cell membranes. Rises in these enzymes are part of the HELLP syndrome. n33 With substantial liver involvement there are coagulation abnormalities that result from hepatic dysfunction and not disseminated intravascular coagulation, which is a rare complication of pre-eclampsia in the absence of placental abruption. n35 Renal function is generally maintained in pre-eclampsia until the late stage. In normal pregnancy, there is an increase in creatinine clearance with a concomitant decrease in serum creatinine and urea concentrations. If creatinine concentrations are high early in the disease process, underlying renal disease should be suspected. In severe disease, rises in serum creatinine can be seen and are associated with worsening outcome. n25 Acute renal failure is now rare in pre-eclampsia in more developed countries; n1, n36 most cases are associated with haemorrhage or sepsis. Most cases of renal failure are due to acute tubular necrosis, and most patients recover with no long-term renal impairment. n36 Acute cortical necrosis, a permanent cause of renal failure, occurs in less than 4% of all cases of renal failure in pre-eclampsia. n37 Numbers of neurological sequelae, such as eclampsia and stroke, are decreasing, n2 perhaps because of earlier intervention and delivery or environmental factors. The fall in incidence antedates the use of antihypertensive drugs and magnesium sulphate. n2 Cerebral oedema is associated with convulsions and can be seen on computed tomography and magnetic resonance imaging. This disorder has been described as posterior leucoencephalopathy syndrome (PLES). n38 It is not a new diagnosis but a radiological description. The cerebral oedema may antedate eclampsia, because occipital-lobe blindness n39 can occur in the absence of eclampsia and is completely reversible. *Hypertension and Pre-ecampsia Heart Disease Weekly December 7, 2003 HEADLINE: OBSTETRICS: Brachial artery flow-mediated dilation assessments predict pre-eclampsia BODY: Brachial artery flow-mediated dilation assessments predict pre-eclampsia. "Endothelial injury and increased vascular reactivity are involved in the pathogenesis of pre-eclampsia (pregnancy-induced hypertension). To investigate whether flow-mediated dilation (endothelium-dependent dilation) and the reactive hyperemic response can predict pre-eclampsia, we prospectively measured flow-mediated dilation and the Doppler flow velocity pattern (V, cm/s) in the brachial artery using high-resolution ultrasound in 43 pregnant women (32plusmn5 years old) in the second half of their pregnancy, and compared the findings with traditional risk factors," scientists in Japan stated. "Regarding the Doppler flow velocity pattern, the pulsatility index (PI)=(systolic V-diastolic V)/mean V and resistance index (RI)=(systolic V-diastolic V)/systolic V were calculated," they said. "For the flow-mediated dilation, the per cent diameter changes were determined based on those from baseline to hyperemic conditions. Nine women suffered from pre-eclampsia and 34 women remained normotensive. Only flow-mediated dilation was found to be significantly lower in the subsequently developed pre-eclampsia patients (1.6plusmn1.0% in subsequently developed pre-eclampsia patients vs. 11.0plusmn4.5% in normotensive patients, p<0.05)," reported B. Takase and colleagues, National Defense Medical College, Research Center. "Neither the other traditional factors nor the Doppler flow velocity pattern were significantly different between the subsequently developed pre-eclampsia and normotensive patients. If a normal cutoff value of 3.0% obtained from age-matched 14 nonpregnant women (32plusmn7 years old) in our laboratory was used, the positive predictive value of flow-mediated dilation (<3.0%) for subsequent pre-eclampsia is 90% and the negative predictive value is 100%," they noted. "In conclusion, flow-mediated dilation in brachial artery can be a simple and noninvasive modality to predict pre-eclampsia." Takase and colleagues published their study in Journal of Human Hypertension (Flow-mediated dilation in brachial artery in the second half of pregnancy and prediction of pre-eclampsia. J Hum Hypertension, 2003;17(10):697-704). For additional information, contact B. Takase, National Def Med College, Research Center, 3-2 Namiki, Tokorozawa, Saitama 3598513, Japan. The publisher's contact information for the Journal of Human Hypertension is: Nature Publishing Group, Macmillan Building, 4 Crinan St., London N1 9XW, UK. The information in this article comes under the major subject areas of Angiology, Cardiology, Hypertension Risk Factor and Obstetrics. This article was prepared by Heart Disease Weekly editors from staff and other reports. Lancet 2000; 355 (9198): 81-82 January 8, 2000 TITLE: Maternal blood pressure and birthweight Hypertension in pregnancy is a leading cause of maternal and neonatal mortality and morbidity, so a large proportion of antenatal care goes to the detection and management of this disorder. Antihypertensive drug therapy is an important part of management strategy. The effect of such therapy on the baby's birthweight has been examined by P von Dadelszen and colleagues in their meta- analyses, reported in today's Lancet, of up to 45 randomised controlled trials. The investigators noted the effect of change in mean arterial blood pressure (MAP) in a novel way. MAPs were calculated for blood pressure at entry to the trial and before delivery. Changes in MAPs (DeltaDMAP) between these two times were compared between drug and placebo groups. A DeltaDMAP of 10 mm Hg meant that the MAP had fallen by 10 mm Hg more in the treatment than in the placebo group. Drug/drug and drug/placebo comparisons were made. For drug/drug comparisons beta-blockers were arbitrarily assigned to be the experimental intervention and methyldopa to be the control. 38 trials related to therapy for hypertension of late onset in pregnancy; the remainder were trials of therapy for chronic hypertension. The agents used were alpha-methyldopa, various beta- blockers, thiazides, ketanserin, hydralazine, calcium-channel blockers, and clonidine. Despite this striking heterogeneity, fall in blood pressure was significantly related to the proportion of small-for-gestational-age (SGA) infants and inversely to the mean birthweight. A fall in blood pressure of 10 mm Hg was associated with a 145 g decrease in birthweight. This was the maximum effect between trials. Only one trial showed a mean fall in blood pressure greater than 10 mm Hg and, paradoxically, in that trial the approximately 16 mm Hg fall in blood pressure was associated with no change in birthweight. Nevertheless, the relation held statistically, although only 16% of the variation in birthweight could be accounted for by the change in blood pressure. The investigators excluded two trials. One was by Butters et al,n 1* which showed a remarkably large fall in birthweight for a relatively small fall in blood pressure. This trial has been considered an outlier in other meta-analyses,n 2* and it has also been subject to methodological controversy.n 2* The other trial, which compared nicardipine with labetalol, was also an obvious outlier from inspection of the data of von Dadelszen's meta-analysis. No other predictor variables, such as type of hypertension, severity of hypertension, nature of the hypotensive agent, or the length of therapy was thought to be related to birthweight or rate of SGA births. Oncology Business Week March 28, 2004 HEADLINE: PRE-ECLAMPSIA: Hypertension condition during pregnancy linked to increased cancer risk BODY: Women with a history of pre-eclampsia are at increased risk of cancer, particularly cancers of the stomach, breast, ovary, lung, and larynx, according to new research. Previous studies have shown either no association or have suggested a protective association between pre-eclampsia and cancer, but the evidence is inconsistent. Ora Paltiel, Hadassah-Hebrew University, Israel; and colleagues at the Albert Einstein College of Medicine of Yeshiva University and the Mailman School of Public Health, Columbia University, both in New York, published their findings on the British Medical Journal website on March 5, 2004 (www.bmj.com, Online First section). The researchers compared the incidence of cancer among 37,033 women who delivered babies in three large hospitals in West Jerusalem during 1964-76. After pre-eclampsia there was an overall excess of cancer when all sites were combined. The risk of breast cancer was significantly increased for pre-eclamptic women after taking into account differences in age and number of births prior to entry into the study, Paltiel and associates reported. The risk of cancers of the stomach, ovary, lung, or larynx were also significantly increased after adjusting for age. The authors suggest that certain environmental and genetic factors may contribute to the development of both pre-eclampsia and cancer in Middle Eastern populations. Drug Week January 9, 2004 HEADLINE: HYPERTENSION: Pre-eclampsia correlates with reduced plasma coenzyme Q10 levels BODY: Pre-eclampsia correlates with reduced plasma coenzyme Q10 levels. According to published research from Ecuador, "pre-eclampsia is a common (approximately 7% of all pregnancies) disorder of human pregnancy in which the normal hemodynamic response to pregnancy is compromised. Despite many years of intensive research, the pathogenesis of pre-eclampsia is still not fully understood. The objective of the present study was to investigate the concentration of coenzyme Q10 in normal pregnancy and pre-eclampsia." "Pregnant women (n = 18), women with pre-eclampsia. (n = 12), and nonpregnant normotensive women (n = 22) were included. Plasma levels of coenzyme Q10 were measured by high-performance liquid chromatography. Plasma coenzyme Q10 levels were significantly higher in normal pregnant women (mean = 1.08, SEM = 0.08 micromol/l; p<0.005) in comparison to nonpregnant women (mean = 0.86, SEM = 0.16 micromol/1) and women with pre-eclampsia (mean = 0.7, SEM = 0.03 micromol/l; p<0.0001)," said E. Teran and colleagues, Central University of Ecuador, Biomedical Center. "These results demonstrated that during pre-eclampsia there is a significant decrease in plasma levels of coenzyme Q10 compared to normal pregnant women, and compared to those who are not pregnant," researchers concluded. *Pre-eclampsia and its Relation to Placental Abruption: TITLE: Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial Lancet 1999; 354 (9181): 810-816 September 4, 1999 The primary outcome measure was the ratio PAI-1/PAI-2 and the secondary outcome measure the frequency of pre-eclampsia, which was defined prospectively according to the guidelines of the International Society for the Study of Hypertension in Pregnancy.n 29* Gestational hypertension was defined as two recordings of diastolic blood pressure of 90 mm Hg or higher at least 4 h apart, and severe gestational hypertension as two recordings of diastolic blood pressure of 110 mm Hg or higher at least 4 h apart or one recording of diastolic blood pressure of at least 120 mm Hg. Proteinuria was defined as excretion of 300 mg or more in 24 h or two readings of 2+ or higher on dipstick analysis of midstream or catheter urine specimens if no 24 h collection was available. Women were classified as previously normotensive or with chronic hypertension before 20 weeks' gestation. For previously normotensive women, pre-eclampsia was defined as gestational hypertension with proteinuria and severe pre-eclampsia as severe gestational hypertension with proteinuria. For women with chronic hypertension, superimposed pre-eclampsia was defined by the new development of proteinuria. For this study, all women were allocated to an outcome category on the basis of their blood pressure before delivery. Other adverse perinatal outcomes were: placental abruption (the presence of retroplacental clot at delivery and abdominal pain, bleeding, or both immediately before delivery); spontaneous preterm delivery (before 37 weeks' gestation); intrauterine death; and small- for-gestational-age infants (on or below the 10th centile for gestation and sex, corrected for maternal height, weight, parity, and ethnic origin by customised centile chartsn 30*). Pediatrics 2004; 113: 35-41 January, 2004 Outcomes and Confounding Variables The primary study outcome was presence or absence of risk-adjusted, predischarge mortality or major morbidity, including BPD, severe ICH, severe ROP, or severe NEC. These morbidities were chosen because of demonstrated relationships to long-term neurodevelopmental outcomes of VLBW infants. [n22-n24] Morbidities were counted among survivors and when possible also among infants who died. The composite outcome of death or major morbidity was chosen as the primary outcome to account for possible trade-offs between death and major morbidity. Secondary outcomes included death alone and death in combination with each major morbidity. Information on factors previously shown to affect the selected study outcomes were included as independent variables in multivariable regression analyses. Possible confounders included both infant and maternal variables unrelated to the care provided by clinicians and practice variables related to clinician decision making. The infant and maternal variables were birth weight, gestational age, race (white or nonwhite), gender, multiple gestation pregnancy, SGA status, 5-minute Apgar score <5, and maternal hypertension or preeclampsia. Practice variables included CRIB score, use of antenatal glucocorticoids, and use of intrapartum antibiotic. We chose to evaluate separately practice variables to emphasize possible opportunities to modify care to improve outcome. Pediatrics 2003; 112: 570-577 September, 2003 During week 1, trypsinogen-1 showed a positive correlation with gestational age (r = 0.36, P < .001). The concentration of trypsinogen-1 did not correlate with proteinuric preeclampsia, antenatal glucocorticoid treatment, BW, severity of acute respiratory distress, or duration of mechanical ventilation (data not shown). A weak negative correlation was observed between trypsinogen-2 concentration during week 1 and BW (r = -0.26, P = .005), whereas there was no correlation with gestational age during week 1 or 2 (data not shown). No association existed between trypsinogen-2 and antenatal glucocorticoid treatment. Trypsinogen-2 was significantly higher during weeks 1 and 2 in infants who were born to mothers with proteinuric preeclampsia than in those who were born to mothers with chorioamnionitis or premature rupture of the membranes or in those who were born to mothers without these complications (Fig 2). The infants who were born to mothers with proteinuric preeclampsia (n = 11) were of a higher GA (mean [+/-SD]: 28.6 +/- 1.8 weeks vs 26.6 +/- 1.8 weeks, respectively; P = .003) but had more severe acute respiratory distress as indicated by a lower initial arterial to alveolar oxygen tension ratio (aAPO[2]; mean [+/-SD] 0.15 +/- 0.07 vs 0.33 +/- 0.22; P = .02). A negative correlation existed between trypsinogen-2 during weeks 1 and 2 and surfactant maturity, as measured as L/S ratio in TAF (week 1: r = -0.36, P = .001; week 2: r = -0.66, P < .0001). Furthermore, the presence of phosphatidyl glycerol in TAF was associated with lower trypsinogen-2 levels during weeks 1 and 2 (Table 2). Trypsinogen-2 was higher in infants with an initial aAPO[2] </=0.22 and in those who needed treatment with surfactant (Table 2). The concentration of trypsinogen-2 during week 1 showed a positive correlation with duration of mechanical ventilation (r = 0.30, P = .001). Pediatrics 2003; 112: 583-587 September, 2003 We evaluated predictors that might be associated with failure of the second indomethacin course: gestational age, birth weight, sex, exposure to antenatal betamethasone, maternal diagnoses of chorioamnionitis and preeclampsia, presence of respiratory distress syndrome, ventilator support score, maximum serum creatinine after the initial course of indomethacin, fluid administration (normalized to body weight) during the first 96 hours of life (data not shown), indomethacin treatment approach (symptomatic versus prophylactic), year of birth (December 1, 1991, to December 21, 1996, vs January 1, 1997, to June 15, 2001), number of indomethacin doses and the cumulative dose administered in the initial course, the postnatal age when infants were treated initially and when they were retreated for symptomatic reopening, the number of days between indomethacin treatment courses, the results of the Doppler examination after the initial course of indomethacin, and temporally related sepsis at indomethacin retreatment. These univariate analyses revealed that the only significant predictor of PDA ligation after the second course of indomethacin was the demonstration (by Doppler) of persistent ductus flow after the first course of indomethacin (Tables 1 and 2). Among the 32 newborns who received a second course of indomethacin, 9 had persistent ductus flow on Doppler examination after the initial indomethacin course. All of these newborns ultimately met our criteria for surgical ligation of a hemodynamically significant PDA after the second course of indomethacin. In contrast, only 9 of (39%) 23 newborns with absent Doppler flow after the initial indomethacin course developed a hemodynamically significant PDA and underwent surgical ligation after the second course (P = .002, [chi]<2> analysis). 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Regards, Anthony (adilorenga)