ORIGINAL ARTICLE Reproductive epidemiology
The association of maternal factors
with delayed implantation and the
initial rise of urinary human chorionic
A.M.Z. Jukic1,*, C.R. Weinberg2, D.D. Baird1, and A.J. Wilcox1
1Epidemiology Branch, National Institute of Environmental Health Sciences, PO Box 12233, MD A3-05, Durham, NC 27709, USA
2Biostatistics Branch, National Institute of Environmental Health Sciences, PO Box 12233, MD A3-05, Durham, NC 27709, USA
*Correspondence address. E-mail: firstname.lastname@example.org
Submitted on August 4, 2010; resubmitted on January 5, 2011; accepted on January 11, 2011
background: Late implantation and the pattern of early rise in hCG have been associated with early pregnancy loss. We explored
factors that might be predictive of these markers of poor embryonic health in spontaneously conceived pregnancies.
methods: Participants in the North Carolina Early Pregnancy Study collected daily first-morning urine specimens while attempting to
conceive. Samples were assayed for estrogen and progesterone metabolites (to identify day of ovulation) and hCG (to detect conception).
Data were available for 190 pregnancies, 48 of which ended in early loss (within 6 weeks of the last menstrual period). We used logistic
regression to identify characteristics associated with late implantation (≥10 days post-ovulation). For pregnancies surviving at least 6
weeks (n ¼ 142), we used linear mixed models to identify factors associated with variations in hCG rise in the first 7 days from detection.
results: Later implantation was associated with current maternal smoking [odds ratio (OR): 5.7; 95% confidence interval (CI): 1.1–30]
and with oocytes that were likely to have been fertilized late in their post-ovulatory lifespan (OR: 5.1; CI: 1.9–16). Older women had a faster
rise in hCG (P ¼ 0.01), as did women who had relatively late menarche (P for trend ¼ 0.02). Women exposed in utero to diethylstilbestrol
showed an unusual pattern of slow initial hCG rise followed by a fast increase, a pattern significantly different from that of unexposed women
(P ¼ 0.002).
conclusions: Although limited by small numbers and infrequent exposures, our analyses suggest that a woman’s exposures both early
in life and at the time of pregnancy may influence early development of the conceptus.
Key words: smoking / DES / age at menarche / oocyte quality / early pregnancy loss
hCG is secreted by trophoblast cells of the early conceptus and the
developing placenta, and performs vital functions in early pregnancy.
These include maintenance of the corpus luteum (Zeleznik and
Pohl, 2006) and formation of the placental syncytium (Yang et al.,
2003). The appearance of hCG in maternal urine can be used as a
marker of embryonic implantation (Wilcox et al., 1999). Delayed
implantation has been associated with early pregnancy loss (Wilcox
et al., 1999). Lower hCG levels and slower rates of hCG rise early
in pregnancy are seen in ectopic pregnancies (Kadar et al., 1981;
Check et al., 1992; Seeber et al., 2006) and have been associated
with pregnancy loss (Check et al., 1992; Bjercke et al., 1999; Urbanc-
sek et al., 2002; Baird et al., 2003; Alahakoon et al., 2004; Stone et al.,
2006; Shamonki et al., 2009) (reviewed in Chung and Allen, 2008).
Most of these studies have been based on clinical populations under-
going fertility treatment, which may not be representative of spon-
taneously conceived pregnancies. Given that timing of implantation
and early pregnancy hCG rise may be markers of pregnancy health,
we explored maternal and pregnancy characteristics that may influence
these markers. We studied a cohort of women with spontaneously
conceived pregnancies under observation from before the time of
Materials and Methods
Study population and design
The North Carolina Early Pregnancy Study (NCEPS) (1982–1986)
enrolled 221 women at the time they discontinued birth control in
Published by Oxford University Press 2011
Human Reproduction, Vol.26, No.4 pp. 920–926, 2011
Advanced Access publication on February 2, 2011doi:10.1093/humrep/der009
order to conceive a pregnancy. The original purpose of the study was to
determine the incidence of very early pregnancy loss (Wilcox et al., 1988).
Women were eligible to participate if they had no known chronic health or
fertility problems and were not using hormone medications. Participants
collected daily first-morning urine specimens and kept daily diaries that
included information on menstrual bleeding and sexual intercourse. All
participants provided informed consent. The research was approved by
the Institutional Review Board of the National Institute of Environmental
To detect day of ovulation, first-morning urine specimens from a 17-day
mid-cycle window were assayed for estrone 3-glucuronide (E1G) and preg-
nanediol 3-glucuronide (PdG). E1G and PdG were measured by direct
radioimmunoassay (Wright et al., 1978; Samarajeewa et al., 1979). Speci-
mens were analyzed in duplicate or triplicate, and the geometric means of
the steroid hormone concentrations were divided by the corresponding
creatinine concentration to adjust for variations in dilution. The day of ovu-
lation for each cycle was defined based on the rapid drop in the
estrogen-to-progesterone ratio (Baird et al., 1991), a measure validated
by LH measurements (Baird et al., 1995) and by ultrasound (Ecochard
et al., 2001).
We employed a highly sensitive immunoradiometric assay to quantify
hCG in urine samples (Wilcox et al., 1985). Variations in urinary creatinine
were very small compared with the exponential rise in hCG (McChesney
et al., 2005), making the adjustment of hCG for creatinine unnecessary.
All potential correlates except two (season of implantation and oocyte-
waiting time) were based on information reported by the participant at
enrollment. ‘Recent’ oral contraceptive use was defined as use within 90
days of enrollment. Recent use of alcohol, caffeine, marijuana and vitamins
was defined as any use in the 3 months prior to enrollment. Other charac-
teristics of interest included age, reproductive history, menstrual cycle
characteristics and BMI.
We considered season because in a prior analysis, risk of early preg-
nancy loss had been elevated in the last quarter of the year (Weinberg
et al., 1994). We assessed whether late implantation was associated
with season of implantation by assigning each day of the year to an
angle in radians (subtracting 1 January from the date of implantation, divid-
ing by 365 and then multiplying by 2p). By including the sine and cosine of
these angles as exposures in our models using trigonometric regression,
we allow a sinusoidal pattern for the risk of later implantation, with ampli-
tude and day of greatest risk (phase) determined by the data.
Oocyte-waiting time is a measure of the time between ovulation and
fertilization (presumably a matter of hours). We can measure oocyte-
waiting time only indirectly, using the days of sexual intercourse (recorded
in the woman’s daily diary), relative to her measured day of ovulation
(Wilcox et al., 1998). All conceptions in this study occurred with inter-
course during a 6-day window ending on the day of ovulation. No preg-
nancies were observed with intercourse only on the day after ovulation
(Wilcox et al., 1995). From this we can infer that the oocyte is short-lived
and a long oocyte-waiting time would be most likely in pregnancies for
which there was intercourse on the day of ovulation but not on the pre-
vious 5 days. That is, without capacitated sperm present when the oocyte
arrives in the oviduct, the oocyte may need to wait many hours before
capacitated sperm are present and fertilization can occur. The optimum
analysis to address oocyte-waiting time would be limited to conceptions
with intercourse only on the day of ovulation and not during the preceding
5 days. However, very few conceptions met that criterion. At the cost of
some reduced specificity but with the benefit of added cycles, we defined
a long oocyte-waiting time as intercourse on the day of ovulation but not
during the 2 days before ovulation. [Intercourse before those 2 days being
much less likely to result in conception (Wilcox et al., 1995).]
All of the potential correlates were examined with each of the repro-
ductive end-points; however, we only present results from those variables
that were statistically significant or suggestive of an association.
A pregnancy was identified based on elevated hCG (≥0.025 ng/ml) for
three consecutive days (Wilcox et al., 1988). Once a pregnancy was ident-
ified, the day of implantation was assigned as the first day of a sustained
rise in hCG in which each subsequent day exceeded 0.015 ng/ml. We
dichotomized days to implantation as 9 or less and 10 or more. A preg-
nancy was categorized as an early loss if the initial rise in hCG was fol-
lowed by a decline with menstrual-like bleeding within 6 weeks
(42 days) of the start of the previous menstrual period. Pregnancies
lasting longer than 42 days were considered clinical pregnancies.
We used logistic regression to identify factors correlated with late implan-
tation (10 or more days after ovulation). To identify factors related to the
pattern of hCG rise, we used a linear mixed model and generated
P-values. The model was of the following general form for woman i on
ln(hCGij) = b0i+ b1i(j) + b0+ b1(j) + b2(j2) + b3(U) + b4(Uj)
where b0iand b1iare zero-mean woman-specific random effects, j is the
number of days starting with implantation and U (¼1 or 0) indicates a
dichotomous maternal or pregnancy factor that may be associated with
the rise in hCG. This general model was expanded to accommodate mul-
tiple categories of a variable (U1, U2, U3, etc.). To determine whether a
variable was associated with the rate of hCG rise, the importance of b4
and b5 was assessed using a likelihood ratio test, based on a
two-degree-of-freedom x2distribution under the null hypothesis that U
has no effect on the pattern of rise.
Each characteristic was assessed in a separate model; thus, all analyses
are unadjusted for other factors except where specified in the text.
For graphical display, the patterns of rise in hCG over the 7 days begin-
ning with implantation were quantified using an average relative increase in
hCG for each day. This was calculated for Day j as
where ‘ln(hCG)1’ indicates the natural log of the hCG concentration on
Day 1, which is the day of implantation, ‘ln(hCG)j’ indicates the natural
log of the hCG concentration on Day j, which ranges from 2 to 7, and
the ‘average’ is taken across pregnancies.
The absolute hCG curves from this population have been previously
published (Nepomnaschy et al., 2008). In addition, that paper examined
the association of hCG curves with twin pregnancies, pregnancy loss
after 42 days gestation and infant sex. None of these factors were
found to be important and thus all pregnancies are included here unless
There were 199 pregnancies detected in the Early Pregnancy Study. Of
these, 151 were clinical pregnancies and 48 were early pregnancy
losses. There were 10 clinical pregnancies which were missing a day of
ovulation or a day of implantation, leaving 189 pregnancies in the
Factors associated with late implantation and early hCG rise
sample used to analyze late implantation. The patterns of hCG rise were
assessed only among the clinical pregnancies. This is because early losses
often do not last 7 days and do not necessarily have a clear pattern of rise
(Baird et al., 2003). One additional clinical pregnancy could be used in this
analysis because it had a measured day of implantation (day of ovulation
was missing), thus providing 142 clinical pregnancies for the rate of rise
analysis. Clinical pregnancies were mostly singleton live births (n ¼ 121);
other outcomes were 6 twin births, 13 miscarriages, 1 ectopic pregnancy
and 1 molar pregnancy.
Some women contributed more than one pregnancy to the study (3 had
more than one early loss, 21 had both an early loss and a clinical pregnancy
and 1 had two early losses and a clinical pregnancy). We evaluated
the effect of adjustment for this statistical dependency. By design, no
woman had more than one clinical pregnancy in the study. Thus, the
number of pregnancies is related to risk of loss: if a woman had more
than one pregnancy, we know that at least one of those pregnancies
was an early pregnancy loss. When (as in this case) cluster size is ‘informa-
tive’, the standard methods for adjusting for dependent observations
(such as generalized estimating equations) are biased. Thus we used
within-cluster resampling (Hoffman et al., 2001) to account for the mul-
tiple observations per woman. Other than a slight loss of precision,
results were unchanged (data not shown).
The median age was 29, and about two-thirds of the women had pre-
viously been pregnant (Table 1). About half of pregnancies in the study
had implantation on Day 10 or later. Only 11 pregnancies (6%) were
to women who were self-reported smokers. Seven pregnancies (5%)
were to women who reported prenatal diethylstilbestrol (DES)
exposure, and 47 (28%) pregnancies were to women who reported
that their mother had smoked while pregnant with them.
Time from ovulation to implantation
Women who were current smokers had five times the odds of late
implantation as never or former smokers [odds ratio (OR) (95% con-
fidence interval, CI): 5.3 (1.3, 36), P ¼ 0.03] (Fig. 1). There were not
enough current smokers to evaluate a dose–response relationship.
The association between husband’s smoking and late implantation
was also positive but weaker [OR (CI): 1.8 (0.64, 5.7)].
Implantation was also later among conceptions that resulted from a
long oocyte-waiting time [OR (CI): 5.1 (1.9, 16), P ¼ 0.0008] (Fig. 1).
Late implantation was more common in exposed early losses, but not
exclusive to them. When we restricted analysis to clinical pregnancies,
the association between oocyte-waiting time and late implantation was
still evident, but attenuated [OR (CI): 2.2 (0.63, 8.0)].
Given our previous observation that a long oocyte-waiting time led
to early loss (Wilcox et al., 1998), we explored whether that associ-
ation might be mediated by late implantation. We included both
oocyte-waiting time and late implantation as predictors in a logistic
regression of early loss. While the effect of oocyte-waiting time was
attenuated when adjusted for late implantation (from an OR of 3.9
to 2.7), it was still significantly associated with early loss (P ¼ 0.04).
Women who reported that their mother had smoked while preg-
nant with them had less late implantation [OR (CI): 0.48 (0.23,
0.96), P ¼ 0.04]. The odds of late implantation also tended to be
lower for women who had lived with one or more household
smokers (mother, father or other) during their childhood (P ¼ 0.11)
We explored the robustness of these associations with current
smoking and prenatal exposure to maternal smoking by limiting the
analysis to clinical pregnancies. The association between current
smoking and late implantation was similar [5.5 (1.2, 39)] and the pro-
tective association of prenatal exposure to maternal smoking and late
implantation was slightly stronger, 0.35 (0.14, 0.83). After further
restricting to only live births (i.e. excluding the 15 clinical miscarriages),
the associations again became slightly stronger [current smoking, 6.1
(1.3, 44) and prenatal maternal smoking exposure 0.31 (0.11, 0.77)].
Season of the year [previously associated with early loss in these
data (Weinberg et al., 1994)] was not associated with the timing of
implantation (P ¼ 0.97, data not shown).
Rate of hCG rise
Three factors were associated with the steepness of the initial hCG
rise: age, age of menarche and DES. Older women had a faster rise
(P ¼ 0.01) (Fig. 2). This could not be attributed to their increased
gravidity which was not associated with rate of rise (P ¼ 0.25).
When pregnancy losses were removed, the P-value increased to
0.08. The P-value for age when age at menarche was included in the
model was unchanged (0.01). Excluding the DES-exposed women
led to a stronger P-value (P ¼ 0.006). Age at menarche was weakly
associated with hCG rise, with women who were younger at
menarche having a slower hCG rise (P ¼ 0.09) (Fig. 3). A linear
trend test of the age at menarche categories was significant,
P ¼ 0.02. This P-value was not affected by adjustment for BMI (P ¼
0.02) or removing the pregnancy losses (P ¼ 0.03); however removing
the DES-exposed participants increased the P-value (0.06). Exposure
to DES in utero was associated with a distinct pattern of hCG increase
(P ¼ 0.002) (Fig. 4). Exposed women had a slower hCG rise up to
Day 4 and then a faster rise thereafter. Interpretation of this finding
is limited by the fact that only four pregnancies were to
DES-exposed mothers. Removing the pregnancy losses did not alter
the P-value (P ¼ 0.002).
We found a number of maternal factors associated with time to
implantation and with the pattern of initial hCG rise. Current
smoking was associated with late implantation, while prenatal
exposure to maternal smoking was associated with earlier implan-
tation. Conceptions resulting from a long oocyte-waiting time were
also more likely to implant later, but this pathway does not appear
to explain their increased risk of early loss that we previously
reported. Among those conceiving a clinical pregnancy, older
women and women with a later age at menarche experienced a
faster initial rise of hCG. Conceptions to the few women who were
DES daughters showed a distinct pattern of rise, slower over the
first 4 days and faster thereafter.
These data are unique in describing peri-conceptional events in a
group of naturally conceived pregnancies. Nonetheless, the analysis
has notable limitations. One is small numbers. For example, few
women smoked or had been prenatally exposed to DES. While
sample size limits the conclusiveness of our analysis, these
Jukic et al.
preliminary data may serve to generate hypotheses for future
research. Given that we explored a total of ?20 variables and 2
outcomes, a few statistically significant results would be expected
by chance. We have therefore focused our interpretations on bio-
logical plausibility and coherence rather than statistical significance.
Ourdata setrepresentsa relatively
embryos; in order to be observed, embryos had to be able to
implant and secrete hCG. Embryos that failed sooner or were
unable to produce enough hCG to meet our cutoffs are unobserva-
ble; as in any pregnancy study, their unobservability may have influ-
enced the observed associations. Another possible limitation is that
our measure of hCG was in urine. Some of the observed differences
could be due to exposure effects on maternal disposition of hCG
rather than to the actual amount of hCG secreted by the conceptus,
although urinary and serum concentrations are in general highly cor-
related (Wehmann and Nisula, 1981; Norman et al., 1987; McChes-
ney et al., 2005).
Time to implantation
Experimental data suggest that when oocytes wait many hours before
fertilization they produce less viable embryos (Lanman, 1968; Butcher,
1976; Longo and So, 1982; Juetten and Bavister, 1983; Perreault,
Time from ovulation to implantation
,29 92 (49)
Yes 128 (68)
No 60 (32)
History of miscarriage
Yes 27 (14)
No 101 (54)
Age at menarche
,12 24 (13)
12, 13 114 (60)
,29 86 (48)
Yes 162 (86)
No 27 (14)
Recent oral contraceptive use
Yes 17 (9)
Long 23 (12)
,18 18 (10)
18 to ,25 155 (82)
Prenatal DES exposure
Yes 7 (5)
No 135 (95)
Prenatal exposure to maternal smoking
Yes 47 (28)
No 118 (72)
Table I Distribution of maternal and pregnancy
characteristics within the two study samples, all
conceptions (n 5 189) and clinical pregnancies only
(n 5 142).
Number of clinical
97 (51) 72 (51)
48 (34)60 (32)
69 (51)95 (52)
130 (92) 166 (88)
13 (9)16 (8)
Number of smokers in the home when participant was ,10 years old
0 64 (35)44 (31)
1 64 (35)
Husband’s current smoking
Smoking status at enrollment
Never 126 (67)
Any 150 (79)
None 10 (5)
Any 26 (14)
None 163 (86)
Yes 99 (53)
No 89 (47)
Table I Continued
Number of clinical
46 (33) 56 (30)
aThis sample includes early pregnancy losses and clinical pregnancies, women could
have experienced either or both leading to more than one observation per woman.
bThis sample includes pregnancies that survived to clinical recognition. Women only
contributed one clinical pregnancy leading to only one observation per woman.
Factors associated with late implantation and early hCG rise
1992). Our earlier finding of oocyte-waiting time being associated with
early pregnancy loss is consistent with those experimental data, and
suggests that aging of the oocyte prior to its fertilization (even by a
few hours) may be detrimental to embryonic development (Wilcox
et al., 1998). Such effects on development may contribute to delays in
implantation. In the present study, we find that long oocyte-waiting
time is associated with late implantations both in conceptions destined
to be early losses and (albeit more weakly) in surviving conceptions.
After restricting to clinical pregnancies only, a long oocyte-waiting
time still tended to be followed by later implantation. This could
is a natural consequence of later fertilization. Oocytes are thought to
remain viable for ?24 h. Oocytes that are fertilized quickly will
produce embryos that are as much as a day ahead of embryos that
result from late fertilization. Thus, the late fertilizations may be up to 1
day behind in their implantation time. Consistent with this hypothesis,
the implantation delay we observed in the clinical pregnancies was pri-
marily a shift from post-ovulation Day 9 to Day 10. Such a delay may
or may not have negative consequences for the embryo.
Figure 1 ORs and 95% CIs for late implantation (≥10 days post-
Figure 2 Average relative increase in hCG over the first 7 days of
pregnancy beginning with the day of implantation (Day 1), stratified by
participant age at intake, P ¼ 0.01. Solid line represents women 29 or
older; the dotted line represents women under 29.
Figure 3 Average relative increase in hCG over the first 7 days of
pregnancy beginning with the day of implantation (Day 1), stratified by
age at menarche, P ¼ 0.01. The solid line represents women ,12
at menarche, the small dashed line represents women aged 12–13
at menarche and the long dashes represent women .13 at
Figure 4 Average relative increase in hCG over the first 7 days of
pregnancy beginning with the day of implantation (Day 1), stratified by
in utero exposure to DES, P ¼ 0.002. The solid line represents women
not exposed to DES in utero; the dotted line represents women who
did report exposure to DES in utero.
Jukic et al.
The delay in implantation among smokers, if not a chance finding,
could be due to disruption of ovum retrieval by the oviduct or of
tubal transport (Neri and Marcus, 1972; Mitchell and Hammer,
1985; Knoll et al., 1995; Knoll and Talbot, 1998) (reviewed in Lyons
et al., 2006). The IVF literature suggests that maternal smoking can
also have adverse effects on a range of other reproductive functions.
Smoking has been associated with decreased ova retrieval (Van
Voorhis et al., 1996; Joesbury et al., 1998; Fuentes et al., 2010),
lower fertilization rates (Elenbogen et al., 1991; Rosevear et al.,
1992), lower implantation rates (Van Voorhis et al., 1996) and
increased miscarriage risk (Maximovich and Beyler, 1995; Van
Voorhis et al., 1996). A meta-analysis reported lower IVF pregnancy
rates for smokers compared with non-smokers (Augood et al., 1998).
We previously reported that women with prenatal exposure to
maternal smoking had reduced fertility (Weinberg et al., 1989). It is
possible that among these women only the most robust of the
embryos succeed in implanting. This selection could explain both a fer-
tility effect and the observed association between prenatal exposure
to maternal smoking and earlier implantation if the slower-developing
embryos often fail to implant.
The slower initial hCG rise among women with earlier age at
menarche was unexpected. Early menarche has been associated
with endometrial pathology [endometrial cancer (Fujita et al., 2008;
Dossus et al., 2010), adenomyosis (Templeman et al., 2008) and
endometriosis (Treloar et al., 2010)]. Early menarche may also be
associated with endometrial factors that retard early development
of an implanted conceptus (and thus slow the production or release
of hCG). Polymorphisms in chemokine receptor 3 (CCR3) have
been associated with age at menarche and CCR3 is associated with
endometrial inflammation (Yang et al., 2007). Since embryonic implan-
tation is an inflammatory process, it is possible that this gene indirectly
influences the early rise of hCG.
DES was associated with a distinct pattern of hCG rise in these
data. Women who were DES daughters have been found to have
numerous uterine and cervical abnormalities (Kaufman et al., 1984)
that may contribute to their higher risk for infertility (Herbst et al.,
1980; Kaufman et al., 1984) and pre-eclampsia (Troisi et al., 2007).
DES exposure in utero may also influence immune function (Ford
et al., 1983; Ways et al., 1987). Structural abnormalities of the
uterus and immune impairments may influence the ability of an
embryo to invade the endometrium, which might have resulted in
the unusual pattern of hCG rise.
In summary, these data from a group of naturally conceiving women
who participated in the NCEPS provide an opportunity to examine
factors affecting the timing of implantation and the patterns of early
pregnancy hCG. These data suggest that early life factors, as well as
current exposures, may affect early pregnancy.
A.M.Z.J. performed all analyses and wrote the manuscript. C.R.W.
provided statistical expertise. C.R.W., D.D.B. and A.J.W. designed
and implemented the original study, provided input on these analyses
and edited the manuscript.
We appreciate D. Robert McConnaughey’s contributions to data
organization and management.
This research was supported by the intramural research program of
the NIH, National Institute of Environmental Health Sciences.
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