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

"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

(Copyright 2003, James Michael Howard, Fayetteville, U.S.A.)

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. This may be why more black women
exhibit these "adverse obstetric outcomes" more than white women.

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.

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.

Competing interests:
None declared

Investigating the relationship between factors such as interpregnancy
interval and adverse outcomes is fraught with problems of confounding, and
Smith et al deserve credit for taking a wide range of confounding factors
into account in their analysis. However, I am not sure I agree with their
conclusion that residual confounding is unlikely.

First, it is not clear how adjustment for maternal age was done. The
relationship between maternal age and adverse outcomes is non-linear, as
both very young and very old mothers are at increased risk of adverse
outcomes. Adjusting for age as a continuous linear variable would
therefore be inappropriate. A better approach would be to adjust for age
in categories, such as 5-year age bands, or to include both linear and
quadratic terms for age. Perhaps Smith et al could clarify which approach
they used.

Second, adjustment for socioeconomic variables was, if I understand
correctly, based solely on postcode of residence. This is a crude measure
of socioeconomic deprivation, as it cannot be assumed that all women
living in the same postcode area will be of equal socioeconomic status.
This crude socioeconomic measure cannot adjust fully for socioeconomic
status, meaning that residual confounding remains a real possibility.

I am also concerned about the choice of reference category used for
calculating odds ratios. The authors do not state their rationale for
using an interpregnancy interval of 18–23 months as the reference
category. If their primary hypothesis was that an interpregnancy interval
of less than 6 months would be associated with adverse outcomes, then
surely a more appropriate reference category would have been all women
with interpregnancy intervals of 6 months or greater. This would have
given greater statistical power. Moreover, the 18–23 months category was
associated with the lowest rates of adverse outcomes of all the
categories. If this was a post-hoc reason for its choice as the reference
category, then this will have the effect of biasing the odds ratios for
the 1–6 months category towards greater values.

Competing interests:  
None declared

The article by Smith et al (1)is interesting but not surprising as is
the experience of us all in India where early pregnancies in adoloscents
and repeated pregnancies at short intervals play a havoc with their lives
with very high maternal and perinatal mortality and morbidity. Nutritional
anaemia plays a significant role in poor pregnancy outcome in India where
anaemia complicates 72-96 percent of all pregnancies ( 2-4). As the women
enter their pregnancies with florid anaemia or with poor iron stores they
have poor pregnancy outcome ( 2). After the childbirth they all breastfeed
putting an extra load on their iron stores and then they enter their next
pregnancy even before their iron stores are fulfilled putting them at
greater risk in their subsequent deliveries ( 2). This cycle must be
broken if we want their iron stores to get any better. They need to
improve their nutritional status and need to practice contraception to
increase interpregnancy interval to improve pregnancy outcome which will
be of vital importance for countries like India. Most women in India are
vegetarian or occasionally meat eaters precluding it to be a factor in
their nutrition.

Refernces;
1. Smith GCJ,Pell JP,Dobbie R. Interpregnancy interval and risk of preterm
birth and neonatal death: retrospective cohort study. BMJ 2003; 327:313
2. Sharma JB. Nutritional anaemia during pregnancy in non-industrialised
countries. In studd JJ ( eds). Progress in Obstetrics and Gynaecology, Vol
15, Churchill Livingstone, Edinburgh, 2003 pages;103-122
3. Sharma JB,Soni D, Murthy NS, Malhotra M. Effect of dietary habits on
prevalence of anaemia in pregnant women of Delhi. J Obstet Gynaecol Res
2003; 29; 73-78
4. Malhotra M, Sharma JB, Batra S, Sharma S, Murthy NS,Arora R. Maternal
and perinatal outcome in varying degrees of anemia. Int J Gynecol Obstet
2002; 79: 93-100

Competing interests:  
None declared