Prematurity

(More new, potential support below, December 30, 2003; and new material regarding maternal testosterone and growth restriction in utero from August 2006)

(see Increasing Low Birth Weight in America )

Here is very new support:

Endocrinology. 2004 Feb;145(2):790-8. Epub 2003 Oct 23.

Fetal programming: prenatal testosterone excess leads to fetal growth retardation and postnatal catch-up growth in sheep.

Manikkam M, Crespi EJ, Doop DD, Herkimer C, Lee JS, Yu S, Brown MB, Foster DL, Padmanabhan V.

Alterations in the maternal endocrine, nutritional, and metabolic environment disrupt the developmental trajectory of the fetus, leading to adult diseases. Female offspring of rats, subhuman primates, and sheep treated prenatally with testosterone (T) develop reproductive/metabolic defects during adult life similar to those that occur after intrauterine growth retardation. In the present study we determined whether prenatal T treatment produces growth-retarded offspring. Cottonseed oil or T propionate (100 mg, im) was administered twice weekly to pregnant sheep between 30-90 d gestation (term = 147 d; cottonseed oil, n = 16; prenatal T, n = 32). Newborn weight and body dimensions were measured the day after birth, and postnatal weight gain was monitored for 4 months in all females and in a subset of males. Consistent with its action, prenatal T treatment produced females and males with greater anogenital distances relative to controls. Prenatal T treatment reduced body weights and heights of newborns from both sexes and chest circumference of females. Prenatally T-treated females, but not males, exhibited catch-up growth during 2-4 months of postnatal life. Plasma IGF-binding protein-1 and IGF-binding protein-2, but not IGF-I, levels of prenatally T-treated females were elevated in the first month of life, a period when the prenatally T-treated females were not exhibiting catch-up growth. This is suggestive of reduced IGF availability and potential contribution to growth retardation. These findings support the concept that fetal growth retardation and postnatal catch-up growth, early markers of future adult diseases, can also be programmed by prenatal exposure to excess sex steroids.

"Interpregnancy Interval and Risk of Preterm Birth and Neonatal Death"

(Smith, et al., BMJ 2003; 327: 313 )

Explanation May be Due to Reduced DHEA Postpartum Following a First Pregnancy

(Possible new support: Magnesium and Prematurity from JAMA, below, November 26, 2003)

(More, possible new support of the effects of Caesarean section and stillbirth in subsequent pregnancy, also including premature birth and small for gestational age from the Lancet, below, November 28, 2003)

Smith, et al., conclude in their report in the British Medical Journal that: "A short interpregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth." (The abstract is available below.) I suggest these "adverse obstetric outcomes" result from a single phenomenon which should not go unacknowledged vis-à-vis the tremendous burdens in emotional suffering and medical costs. These conditions may be ameliorated by monitoring low levels of, and supplementation with, dehydroepiandrosterone (DHEA) in women who become pregnant again, soon after a first pregnancy.

DHEA has been determined to decline in women "only after a first pregnancy" for remain low sometimes up to 150 months (J Clin Endocrinol Metab. 1987; 64: 111-8). This finding was repeated: "A previous paper in this journal reported that first pregnancy was followed by a marked decrease in dehydroepiandrosterone sulfate (DH[E]AS) and dehydroepiandrosterone (DH[E]A) levels. We report here confirmatory observations from cross-sectional measurements in 460 women. In premenopausal subjects (n = 306), the mean DH[E]AS level was 21% lower (P = 0.005) and the mean DH[E]A level was 32% lower (P less than 0.001) in parous than in nulliparous women." (J Clin Endocrinol Metab. 1990; 70: 1651-3). I suggest these low levels of DHEA are directly connected with "adverse obstetric outcomes" in pregnancies of short intervals following a first pregnancy.

In order to understand the connection of this low DHEA with "adverse obstetric outcomes," in pregnancies following first pregnancies without sufficient time for DHEA to rebound, I have to explain two ideas about DHEA. In 1985, I copyrighted my explanation of the "fight or flight" mechanism. I suggested that the major adrenal steroid, dehydroepiandrosterone (DHEA), was "selected" by evolution because it "optimizes" replication and transcription of DNA. Therefore, DHEA is involved in every tissue, especially nervous tissue, the brain. It follows that DHEA in sufficiently available levels will be involved in increasing, or optimizing, aggression between combatants. Combatants who fight to death or maiming reduce the probability of continuance of a species. DHEA levels would be positively involved in "impulses" or "motivation." I suggest the other major adrenal steroid, cortisol, was selected by evolution to counteract the effects of DHEA. As you may know, cortisol is the "stress" hormone, produced when we experience stress. I suggest cortisol levels are negatively involved in impulses or motivation. The ratio of cortisol to DHEA will be directly tied to our personalities as well as actions. When cortisol is high, we flee, when DHEA is high, we fight. Cortisol antagonizes the effects of DHEA and the ratio of cortisol to DHEA is important in many physiological phenomena, including obstetric outcomes. Too much cortisol for extended periods, especially in low DHEA conditions, may produce very negative effects in all tissues.

Also, one should know that the very abundant source of DHEA in our blood exists as a "sulfated" form. This is known as DHEAS or DHEAsulfate. The active molecule, DHEA, is derived from DHEAS. Now, this is not well known. Therefore, sometimes, when DHEAS levels are measured and found to be high, this literally indicates that abundant DHEA is readily available. However, sometimes when DHEAS levels are measured as high, this also may mean that DHEA is not being produced from DHEAS. Since this is not well known, one has to look at the pattern of this ratio and interpret it in terms of potential pathology. So, sometimes high DHEAS may indicate negative or adverse conditions. I suggest this is the case in the following citations which connect high levels of DHEAS with preterm delivery.

Mazor, et al., reported that "Maternal plasma DHEA-S concentrations were significantly higher in women with preterm labor who delivered preterm than in those who delivered at term." (Arch Gynecol Obstet. 1996; 259: 7-12). Now, if DHEAS is working normally, the relationship of cortisol ratio becomes important as an indication that cortisol is too high and antagonizing the effects of DHEA. (Remember the connection of cortisol to DHEA above.) Yoon, et al., found this in 1998: "An elevation in fetal plasma cortisol but not dehydroepiandrosterone sulfate was followed by the onset of spontaneous preterm labor in patients with preterm premature rupture of the membranes." (Am J Obstet Gynecol. 1998; 179: 1107-14).

Smith, et al., also found: "They [the women of the study] were also shorter, less likely to be married, and more likely to be aged less than 20 years at the time of the second birth, to smoke, and to live in an area of high socioeconomic deprivation." I suggest all of these may be connected with higher levels of testosterone in these women. It is my hypothesis that testosterone exerts negative effects on the availability of DHEA. Therefore, these findings also may fit my explanation of low DHEA. It is my hypothesis that women of higher testosterone are increasing in percentage within our population. This suggests that premature births should be increasing and this is, indeed, the case. Black women produce more testosterone than white women and black mothers produce more testosterone than white mothers (Cancer Causes Control. 2003; 14: 347-55). This may be why more black women exhibit these "adverse obstetric outcomes" more than white women. Testosterone inhibits steroid sulfatase (J Steroid Biochem Mol Biol 2000; 73: 251-6). Testosterone will reduce the availability of DHEA; testosterone will increase the ratio of DHEAS to DHEA.

In 2003, a report was released regarding infertility in women and premature births. Basso and Baird reported that "A TTP >1 [time to pregnancy] year was associated with an increased risk of all outcomes studied, including preterm birth [odds ratios and 95% confidence intervals were 1.5 (1.2, 1.8) among primiparas and 1.9 (1.5, 2.4) among multiparas]. Odds ratios for preterm remained elevated after adjustment for covariates." (Hum Reprod. 2003; 18: 2478-84). In 1986, Colakoglu found in women that "In primary infertility group average DHEAS value is 491 +/- 95 ng/ml so it is meaningful low (p less than 0.01)." (Clin Exp Obstet Gynecol. 1986; 13: 32-4). I suggest the connection of "time to pregnancy" of greater than one year is low DHEA. In women of higher testosterone, this connection would be exacerbated.

I suggest the "adverse obstetric outcomes" connected with a short interval between a first pregnancy and a subsequent pregnancy may result from insufficient DHEA in the mother. These conditions may be ameliorated by monitoring low levels of, and supplementation with, dehydroepiandrosterone (DHEA) in women who become pregnant again, soon after a first pregnancy. (Smith abstract at very end)

New from the Journal of the American Medical Association, November 26. 2003:

Magnesium "for Neuroprotection Before Preterm Birth"

JAMA. 2003; 290: 2669-2676."Effect of Magnesium Sulfate Given for Neuroprotection Before Preterm Birth A Randomized Controlled Trial" C.A. Crowther, et al. "Conclusions: Magnesium sulfate given to women immediately before very preterm birth may improve important pediatric outcomes. No serious harmful effects were seen."

I suggest Crowther, et al., may have added to my explanation of a connection of testosterone with prematurity. Now, some white women exist who produce more testosterone than others; this explanation should also include these white women, however, black mothers produce more testosterone than white mothers so this effect probably predominates within black women. As I pointed out above, black mothers produce more testosterone than white mothers (Cancer Causes Control. 2003; 14: 347-55).

African-American men and women consume less magnesium than whites (Ethn Dis. 1998; 8:10-20). A study of "hypomagnesemia among ambulatory urban African Americans," mainly women patients, concluded that "The prevalence of hypomagnesemia among patients from this urban minority community exceeds that reported in previous studies of the general population." (J Fam Pract. 1999; 48: 636-9). Increased hypomagnesemia was associated with increased morbidity. African-American women consume less magnesium and/or exhibit more magnesium deficiency. Testosterone reduces magnesium in women: "In addition, a decrease in ionized Mg was found with increased testosterone levels." (Fertil Steril. 1998; 69: 958-62). So, women who consume less magnesium, who produce more testosterone may exhibit more hypomagnesemia.

I suggest it is possible that magnesium administered to women prenatally may alter final effects of testosterone on availability of dehydroepiandrosterone and, therefore, "improve important pediatric outcomes."

New from the Lancet, November 28, 2003:

"Caesarean section and risk of unexplained stillbirth in subsequent pregnancy"

Lancet 2003: 362: 1779-84, Gordon C S Smith, Jill P Pell, and Richard Dobbie

Smith, et al., suggest the following from the last paragraph of their Lancet article.

From the Discussion: "The association between unexplained stillbirth and previous caesarean section is biologically plausible. It is possible that intentional or inadvertent ligation of major uterine vessels at the time of first caesarean section could affect uterine blood flow in future pregnancies. Furthermore, previous caesarean delivery is also known to be associated with an increased risk of abnormal placentation leading to abruption, placenta praevia, and morbid adherence of the placenta.8-10 Stillbirth is associated with a high resistance pattern of uterine artery and umbilical artery blood flow, which may indicate maldevelopment of the villous tree.32-34 The association between previous caesarean and stillbirth might be, therefore, another manifestation of abnormal placentation caused by a uterine scar. Consistent with this interpretation, stillbirths in women with a previous caesarean section were more likely to be small for gestational age than stillbirths in other women. Previous caesarean section was also associated with an increased risk of preterm birth and delivering a liveborn small for gestational age infant. This association might also be due to uteroplacental dysfunction or to the association between previous caesarean birth and abruption--since abruption is associated both with fetal growth restriction and with preterm birth.35 We are not aware of any studies in which the effects have been assessed of caesarean delivery on uterine blood flow and mechanisms of placentation in future pregnancies. Such work could identify the biological basis for our results."

I suggest this report, again, may represent "adverse obstetric outcomes" caused by low dehydroepiandrosterone (DHEA). That is, I suggest the Caesarean section may induce a condition of low DHEA in women that may adversely affect future pregnancies. Osorio, et al., reported in 2002 "We found a significant reduction in the concentrations of DHEA-S and IGF-1 on days 2 and 7 after surgery versus the preoperative values." (World J Surg. 2002 Sep; 26: 1079-82)

British Medical Journal 2003; 327: 313.

Interpregnancy interval and risk of preterm birth and neonatal death: retrospective cohort study.

Smith GC, Pell JP, Dobbie R.

OBJECTIVE: To determine whether a short interval between pregnancies is an independent risk factor for adverse obstetric outcome. DESIGN: Retrospective cohort study. SETTING: Scotland. SUBJECTS: 89 143 women having second births in 1992-8 who conceived within five years of their first birth. MAIN OUTCOME MEASURES: Intrauterine growth restriction (birth weight less than the 5th centile for gestational age), extremely preterm birth (24-32 weeks), moderately preterm birth (33-36 weeks), and perinatal death. RESULTS: Women whose subsequent interpregnancy interval was less than six months were more likely than other women to have had a first birth complicated by intrauterine growth restriction (odds ratio 1.3, 95% confidence interval 1.1 to 1.5), extremely preterm birth (4.1, 3.2 to 5.3), moderately preterm birth (1.5, 1.3 to 1.7), or perinatal death (24.4, 18.9 to 31.5). They were also shorter, less likely to be married, and more likely to be aged less than 20 years at the time of the second birth, to smoke, and to live in an area of high socioeconomic deprivation. When the outcome of the second birth was analysed in relation to the preceding interpregnancy interval and the analysis confined to women whose first birth was a term live birth (n = 69 055), no significant association occurred (adjusted for age, marital status, height, socioeconomic deprivation, smoking, previous birth weight vigesimal, and previous caesarean delivery) between interpregnancy interval and intrauterine growth restriction or stillbirth. However, a short interpregnancy interval (< 6 months) was an independent risk factor for extremely preterm birth (adjusted odds ratio 2.2, 1.3 to 3.6), moderately preterm birth (1.6, 1.3 to 2.0), and neonatal death unrelated to congenital abnormality (3.6, 1.2 to 10.7). The adjusted attributable fractions for these associations were 6.1%, 3.9%, and 13.8%. The associations were very similar when the analysis was confined to married non-smokers aged 25 and above. CONCLUSIONS: A short interpregnancy interval is an independent risk factor for preterm delivery and neonatal death in the second birth.

These (5) may add new support. If you are interested in this and do not understand how my explanation of prematurity due to low DHEA explains these reports and want an explanation, contact me with your questions. jmhoward@arkansas.net.

Early Human Development 2002; 70: 3-14

Prenatal maternal stress: effects on pregnancy and the (unborn) child

Background: Animal experiments have convincingly demonstrated that prenatal maternal stress affects pregnancy outcome and results in early programming of brain functions with permanent changes in neuroendocrine regulation and behaviour in offspring. Aim: To evaluate the existing evidence of comparable effects of prenatal stress on human pregnancy and child development. Study design: Data sources used included a computerized literature search of PUBMED (1966–2001); Psychlit (1987–2001); and manual search of bibliographies of pertinent articles. Results: Recent well-controlled human studies indicate that pregnant women with high stress and anxiety levels are at increased risk for spontaneous abortion and preterm labour and for having a malformed or growth-retarded baby (reduced head circumference in particular). Evidence of long-term functional disorders after prenatal exposure to stress is limited, but retrospective studies and two prospective studies support the possibility of such effects. A comprehensive model of putative interrelationships between maternal, placental, and fetal factors is presented. Conclusions: Apart from the well-known negative effects of biomedical risks, maternal psychological factors may significantly contribute to pregnancy complications and unfavourable development of the (unborn) child. These problems might be reduced by specific stress reduction in high anxious pregnant women, although much more research is needed.

Abbreviations: ACTH, adrenocorticotropin-releasing hormone; CRH, corticotropin-releasing hormone; pCRH, placental CRH; CRH-BP, CRH binding protein; GR, glucocorticoid receptors; PG, prostaglandins; Oxyt, oxytocin; DHEA-S, dehydro-epiandrosterone-sulphate; 11-HSD, 11-hydroxysteroid-dehydrogenase

Early Human Development 2003; 71: 39-52

Risk factors for unexplained antepartum fetal death in Norway 1967–1998

Objective: To relate unexplained antepartum fetal death with maternal and fetal characteristics in order to identify risk factors. Design: Population-based study based on records of 1,676,160 singleton births with gestational age 28 weeks. Unexplained antepartum fetal death was defined as fetal death before labour without known fetal, placental, or maternal pathology. Results: Although unexplained fetal mortality in general declined from 2.4 per 1000 births in 1967–1976 to 1.6 in 1977–1998, the proportion among all fetal deaths increased from 30% to 43% during the same period of observation. Unexplained fetal death occurred later in gestation than explained. From 39 weeks of gestation, the risk increased progressively to 50/10,000 in women aged 35 years and <10/10,000 in women <25 years. In birth order 5, the risk was particularly high after 39 weeks of gestation. For birth weight percentile 2.5–9.9 and 97.5, unexplained fetal death was four and three times more likely to occur, respectively. We found an additive effect of maternal age and birth weight percentile 2.5–9.9. Women with less than 10 years education had higher risk than women with 13 years or more (OR=1.6). Weaker associations were observed with female gender, unmarried mothers, and winter season. Conclusions: Unexplained antepartum fetal death occurred later in gestation than explained and was associated with high maternal age, multiparity, low education, and moderately low and high birth weight percentile. The increased risk in post-term pregnancies and the additive effect of maternal age and birth weight percentile 2.5–9.9 suggests that older women would benefit from monitoring of fetal growth.

Early Human Development 2003; 72: 147-157

Energy expenditure and plasma catecholamines in preterm infants with mild chronic lung disease

The present study examined the hypothesis that the energy expenditure (EE) increases during the development of chronic lung disease (CLD) together with serum catecholamines as indicator of stress. Sixteen spontaneously breathing infants with gestational age of 28–34 weeks and birth weight of 870–1920 g were studied. Eight patients were at risk for CLD, eight were healthy controls. Measurements of indirect calorimetry were done weekly at postnatal ages of 2, 3, 4 and 5 weeks. Serum concentrations of adrenaline and noradrenaline were measured by means of a high-pressure liquid chromatography (HPLC) method. The eight CLD risk infants developed mild CLD with FiO2 of 0.27–0.31 and characteristic radiographic signs at 28 days. Compared to the healthy controls, preterm infants with mild CLD showed increases in EE from week 3 (+67%) to week 5 (+46%). Plasma noradrenaline was increased significantly in the CLD infants when compared to the controls at week 3 (0.7±0.3 vs. 0.5±0.1 ng/ml; P<0.05) and more pronounced at week 4 (1.4±0.2 vs. 0.6±0.2 ng/ml; P<0.001) and 5 (1.1±0.3 vs. 0.7±0.2 ng/ml; P<0.01). Plasma adrenaline was markedly higher in the CLD risk group (mean overall value: 0.64±0.1 ng/ml) than in the controls (<0.1 ng/ml in all controls) from week 2 to 5. Regression analysis for the combined values of the infants with and without CLD showed that EE was directly correlated with heart rate, noradrenaline and adrenaline concentration at each of the four study weeks and with respiratory rate at weeks 2 and 3. Increased plasma catecholamine concentrations in preterm infants with CLD suggest that these infants experienced marked stress during the early stages of the disease. Increased EE may in part be a result of this stress.

Early Human Development 2003; 72: 83-95

Developmental outcome at 18 and 24 months of age in very preterm children: a cohort study from 1996 to 1997

Objective: To determine the effect of prematurity (gestational age (GA) <32 weeks) on developmental outcome at the corrected age of 18 and 24 months in a regionally defined, prospective cohort study. Study design: The Leiden Follow-Up Project on Prematurity (LFUPP) includes all live-born infants <32 weeks GA, born in 1996/1997 in three Dutch health regions (n=266). Mental and psychomotor developmental indices (MDI, PDI) were determined with the Bayley Scales of Infant Development I: -1 S.D.: normal, -2 to -1 S.D.: moderate delay and <-2 S.D.: severe delay. Results: At 18 months 168 (71%) and at 24 months, 151 children (64%) of 235 survivors were assessed. Moderate to severely delayed mental and/or psychomotor development occurred in 40% of the children at both ages. Children lost to follow-up were of lower socioeconomic status and more frequently of non-Dutch origin. Since non-Dutch origin negatively affected the outcome at both test ages, availability of the data of these children would probably have worsened the outcome. Postnatal treatment with dexamethasone was associated with an increased risk of delayed development. Other independent predictors of delayed development were bronchopulmonary dysplasia at 18 months and ethnicity, maternal age at birth, birthweight and gender at 24 months. After adjustment for these other predictors of delayed development, the mean PDI of dexamethasone-treated infants was 16.1 points lower than of non-treated infants at 18 months (p=0.03) and 12.7 points lower at 24 months (p=0.04). Conclusions: At 18 and 24 months corrected age, 40% of the very prematurely born children had both delayed mental and/or psychomotor development. Treatment with dexamethasone postnatally was a major risk factor for delayed (psychomotor) development.

Abbreviations: BPD, bronchopulmonary dysplasia; BSID, Bayley Scales of Infant Development; GA, gestational age; IVH, intraventricular haemorrhage; LFUPP, Leiden Follow-Up Project on Prematurity; MDI, Mental developmental index; NICU, Neonatal intensive care unit; PDI, Psychomotor developmental index; PVL, periventricular leucomalacia; SES, socioeconomic status; SGA, small for gestational age

Early Human Development 2003; 73: 61-70

The impact of very premature birth on the psychological health of mothers

Background: The birth of a very premature infant is a critical event in the life of a family and studies have shown that mothers of these infants are at greater risk of psychological distress than mothers of full-term infants. Study design: A total population study of mothers of preterm infants born at less than 32-week gestation at a tertiary referral hospital. Subjects and methods: Sixty-two mothers of very preterm infants (<32 weeks) participated in the present study which examines correlates of maternal depressive symptomatology at 1 month following very premature birth. Information was obtained from structured questionnaires completed by mothers at 1 month after infant admission to neonatal intensive care. Results: Forty percent of the mothers reported significant depressive symptoms on the Edinburgh Postpartum Depression Scale (EPDS). Logistic regression analysis indicated that high maternal stress resulted in an increased likelihood of depressive symptoms (OR 1.15, CI 1.04–1.26, p<0.01). Higher levels of maternal education (p<0.05), and increased perception of support from nursing staff (OR 1.06, CI 0.88–1.00, p<0.05) resulted in decreased likelihood of depressive symptoms. Conclusions: The birth and subsequent hospitalisation of a very premature infant evokes considerable psychological distress in mothers. These results have implications for policy development in order to enhance family centred care in the neonatal intensive care.

Eur J Endocrinol. 2006 Aug;155(2):365-70.

Maternal testosterone levels during pregnancy are associated with offspring size at birth.

· Carlsen SM

· Jacobsen G

· Romundstad P

Department of Public Health and General Practice, Norwegian University of Science and Technology, N-7489 Trondheim, Norway and.

OBJECTIVE: Animal studies have indicated that maternal androgen levels influence the intrauterine environment and development of the offspring. Human data are missing. We therefore investigated the possible association between maternal androgens and offspring size at birth in humans. DESIGN: A random sample of parous Caucasian women (n = 147) was followed prospectively through pregnancy. METHODS: Maternal serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone and sex hormone-binding globulin (SHBG) were measured at gestational weeks 17 and 33. The main outcome measures were weight and length at birth. Associations between maternal androgen levels and offspring birth weight and length were investigated using multiple linear regression modeling adjusted for potential confounding by maternal height, pre-pregnancy body mass index, smoking, parity, offspring gender and gestational age at birth. RESULTS: Elevated maternal testosterone levels at week 17 and 33 were both associated with lower birth weights and lengths. Accordingly, at week 17, an increase in maternal testosterone levels from the 25th to the 75th percentile was associated with a decrease in birth weight by 160 g (95% confidence interval (CI); 29-290 g), while at week 33 that estimate was 115 g (95% CI; 21-207 g). No similar associations were observed for DHEAS, androstenedione or SHBG. CONCLUSIONS: Elevated maternal testosterone levels during human pregnancy are associated with growth restriction in utero. Our results support animal studies, which have indicated that maternal androgen levels influence intrauterine offspring environment and development.