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Cited by 1,084Reproductive System and PregnancyReproductive Biology and FertilityReproductive Health and Contraception

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index; 1 of the 23 sources its claims cite were checked for support.

Time of Implantation of the Conceptus and Loss of Pregnancy

Open access
Wilcox, Allen J., Baird, Donna Day, Weinberg, Clarice R.·1999·New England Journal of Medicine
DOI 10.1056/nejm199906103402304
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Abstract

BACKGROUND: Implantation of the conceptus is a key step in pregnancy, but little is known about the time of implantation or the relation between the time of implantation and the outcome of pregnancy. METHODS: We collected daily urine samples for up to six months from 221 women attempting to conceive after ceasing to use contraception. Ovulation was identified on the basis of the ratio of urinary estrogen metabolites to progesterone metabolites, which changes rapidly with luteinization of the ovarian follicle. The time of implantation was defined by the appearance of chorionic gonadotropin in maternal urine. RESULTS: There were 199 conceptions, for 95 percent of which (189) we had sufficient data for analysis. Of these 189 pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and the remaining 48 pregnancies (25 percent) ended in early loss. Among the pregnancies that lasted six weeks or more, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation; 118 women (84 percent) had implantation on day 8, 9, or 10. The risk of early pregnancy loss increased with later implantation (P<0.001). Among the 102 conceptuses that implanted by the ninth day, 13 percent ended in early loss. This proportion rose to 26 percent with implantation on day 10, to 52 percent on day 11, and to 82 percent after day 11. CONCLUSIONS: In most successful human pregnancies, the conceptus implants 8 to 10 days after ovulation. The risk of early pregnancy loss increases with later implantation.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In 189 naturally conceived pregnancies, implantation usually occurred 8 to 10 days after ovulation, and later implantation was strongly associated with higher risk of early pregnancy loss. The authors conclude that most successful human pregnancies implant 8 to 10 days after ovulation, while late implantation may reflect impaired embryo quality or reduced uterine receptivity.

Key findings

  • Among 189 analyzed pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and 48 (25 percent) ended in early loss.
  • Among pregnancies lasting at least six weeks, first urinary chorionic gonadotropin appeared 6 to 12 days after ovulation; 118 women (84 percent) implanted on day 8, 9, or 10.
  • Risk of early loss increased with later implantation (P<0.001): 13 percent among 102 conceptuses implanting by day 9, 26 percent on day 10, 52 percent on day 11, and 82 percent after day 11.
  • Early losses had a later and broader implantation distribution (mean, 10.5 days; range, 6 to 18 days), whereas live births and clinical losses had mean implantation times of 9.1 and 9.2 days, respectively (P=0.59).

Methods

  • Prospective study of 221 women with no history of fertility problems who were attempting to conceive after stopping contraception; they collected daily first-morning urine specimens through the eighth week of clinical pregnancy or for up to six months.
  • Day of ovulation was estimated from the urinary ratio of estrone 3-glucuronide to pregnanediol 3-glucuronide, validated against the luteinizing hormone surge; implantation was defined as the first day urinary chorionic gonadotropin exceeded 0.015 ng per milliliter, with pregnancy defined as concentrations above 0.025 ng per milliliter for at least three consecutive days.
  • Distributions of implantation times were compared with contingency-table chi-square statistics, and trend in early loss with later implantation was tested by logistic regression with two-sided P values.

Limitations

  • Stated: implantation cannot be directly observed, and chorionic gonadotropin appearance may not mark the earliest implantation steps; random errors in ovulation and chorionic gonadotropin measures may spread the observed implantation distribution, so the true biologic window may be narrower.
  • Stated: fertility treatment may distort reproductive function, so findings from these naturally conceiving women may not apply to treated infertility populations.
  • Evident from the text: 10 pregnancies (5 percent) were excluded because ovulation or implantation day could not be determined due to missing data, and the sample comprised women without known fertility problems, limiting generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1056/nejm199906103402304

Cites

33 of 33 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

1 of 23 cited sources checked · 1 supported · 0 flagged

  • Premisecitation

    There are no undisputed markers in humans of uterine receptivity to a fertilized ovum other than implantation itself.

    “There are no undisputed markers in humans of uterine receptivity to a fertilized ovum other than implantation itself.23,24”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [23] Younis JS, 1996, Fertil Steril source
    • cites [24] Klentzeris LD, 1997, Hum Reprod source
  • Findingown data

    Among the 102 conceptuses that implanted by the ninth day, 13% ended in early loss.

    “Among the 102 conceptuses that implanted by the ninth day, 13 percent ended in early loss.”
    • Also stated in: § RESULTS · plain
      “Early loss was least likely when implantation occurred by the 9th day (13 early losses among 102 pregnancies, or 13 percent)”
    Quote in the paperSubstantial claim
  • Findingown data

    The proportion of early loss rose to 26% with implantation on day 10.

    “This proportion rose to 26 percent with implantation on day 10”
    • Also stated in: § RESULTS · plain
      “rising to 26 percent (14 of 53 pregnancies) when implantation occurred on the 10th day”
    Quote in the paperSubstantial claim
  • Findingown data

    In natural conception cycles, no conceptus resulting in a clinical pregnancy implanted later than 12 days after ovulation.

    “In our data from natural conception cycles, no conceptus resulting in a clinical pregnancy implanted later than 12 days after ovulation.”
    Quote in the paperSubstantial claim
  • Findingown data

    The mean times of implantation were 9.1 days for live births and 9.2 days for clinical losses (P=0.59).

    “The mean times of implantation were 9.1 and 9.2 days after ovulation, respectively (P=0.59).”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 13
  • It may state two separate claims as one. 16
  • The quote only partly states this claim. 1

  • Probably not a substantial claim. It may state two separate claims as one.

    Findingown data

    The remaining 189 pregnancies include all 48 early losses, all 15 clinical losses, and 126 pregnancies ending in live birth.

    “The remaining 189 pregnancies include all 48 that ended in early loss (loss within six weeks after the last menstrual period), all 15 clinical losses (those occurring after six weeks), and 126 pregnancies ending in live birth.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one. The quote only partly states this claim.

    Findingown data

    There were 199 conceptions detected among 221 women attempting to conceive, and 189 (95%) had sufficient data for analysis.

    “There were 199 conceptions, for 95 per- cent of which (189) we had sufficient data for analysis.”
    • Also stated in: § METHODS · plain
      “A total of 199 pregnancies were detected by measurement of maternal urinary excretion of chorionic gonadotropin.19 The day of ovulation or implantation could not be determined for 10 pregnancies (5 percent) because of missing data; these pregnancies were excluded from our analysis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Among the 126 conceptions that culminated in live birth, the initial rise in urinary chorionic gonadotropin occurred 6 to 12 days after ovulation, with the rise in 106 (84%) occurring on day 8, 9, or 10.

    “Among the 126 conceptions that culminated in live birth, the initial rise in urinary chorionic gonadotropin occurred 6 to 12 days after ovulation, with the rise in 106 (84 percent) occurring on day 8, 9, or 10.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Of the 189 pregnancies analyzed, 141 (75%) lasted at least six weeks past the last menstrual period, and 48 (25%) ended in early loss.

    “Of these 189 pregnancies, 141 (75 percent) lasted at least six weeks past the last menstrual period, and the remaining 48 pregnancies (25 percent) ended in early loss.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Among the 15 clinical losses, urinary chorionic gonadotropin was detectable by 7 to 11 days after ovulation, with the rise detected in 12 (80%) on day 8, 9, or 10.

    “Similarly, in the case of the 15 conceptions that ended in loss more than 6 weeks after the last menstrual period (clinical losses), urinary chorionic gonadotropin was detectable by 7 to 11 days after ovulation, with the rise detected in 12 (80 percent) on day 8, 9, or 10 (Fig. 1).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Among pregnancies that lasted at least six weeks, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation, and 118 (84%) had implantation on day 8, 9, or 10.

    “Among the pregnancies that lasted 6 weeks or more, the first appearance of chorionic gonadotropin occurred 6 to 12 days after ovulation; 118 women (84 percent) had implantation on day 8, 9, or 10.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The distribution of implantation times for the 48 pregnancies that ended within 6 weeks after the last menstrual period (early losses) was statistically different (P<0.001) from that of pregnancies continuing past 6 weeks; in early losses implantation tended to occur later (mean, 10.5 days) and over a broader range (6 to 18 days).

    “In contrast, the distribution of implantation times for the 48 pregnancies that ended within 6 weeks after the last menstrual period (early losses) was statistically different (P<0.001); in these pregnancies implantation tended to occur later (mean, 10.5 days), and the times of implantation occurred over a broader range (6 to 18 days) (Fig. 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In another report of 76 term pregnancies with in vitro conception, implantation occurred as early as 7 or 8 days after egg retrieval and as late as 13 or 14 days.

    “In another report of 76 term pregnancies with in vitro conception, implantation occurred as early as 7 or 8 days after egg retrieval and as late as 13 or 14 days.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductown data

    The day of ovulation or implantation could not be determined for 10 pregnancies (5 percent) because of missing data, and these pregnancies were excluded from analysis.

    “The day of ovulation or implantation could not be determined for 10 pregnancies (5 percent) because of missing data; these pregnancies were excluded from our analysis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The 10 pregnancies excluded because of missing data did not differ systematically from the 189 analyzed pregnancies.

  • It may state two separate claims as one.

    Premisecitation

    The receptivity of the endometrium decreases during the late luteal phase, and the corpus luteum is less responsive to chorionic gonadotropin by 11 or 12 days after ovulation.

    “The receptivity of the endometrium decreases during the late luteal phase, 1,2 and the corpus luteum is less responsive to chorionic gonadotropin by 11 or 12 days after ovulation.30”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] source

      Checked before — its earlier verdict is held back until a new check runs.

    • cites [2] source
    • cites [30] source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In a study of 14 pregnancies ending in live births, rises in serum chorionic gonadotropin were detected as early as 8 days and as late as 12 days after the peak serum concentration of luteinizing hormone.

    “In a study of 14 pregnancies ending in live births, rises in serum chorionic gonadotropin were detected as early as 8 days and as late as 12 days after the peak serum concentration of luteinizing hormone.26”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

  • It may state two separate claims as one.

    Interpretationcitation

    Unhealthy zygotes may develop more slowly, or implantation may be abnormal, resulting in later and weaker production of chorionic gonadotropin.

    “Unhealthy zygotes may develop more slowly, or implantation may be abnormal, 31 resulting in later and weaker production of chorionic gonadotropin.32”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [31] source
    • cites [32] Woodward BJ, 1993, Hum Reprod source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    There may be opportunities to increase fertility by extending the time during which implantation can occur.

    “There may be opportunities to increase fertility by extending the time during which implantation can occur.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The study population of 221 women attempting to conceive after ceasing contraception is representative of healthy women generally, so that findings generalize to most successful human pregnancies.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Specimens were collected on 98 percent of possible woman-days.

    “Specimens were collected on 98 percent of possible woman-days.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    In one of the largest studies of in vitro fertilization, implantation was reported in relation to egg retrieval for 140 clinical pregnancies, and implantation was detected 6 to 13 days after egg retrieval.

    “In one of the largest studies, implantation was reported in relation to egg retrieval for 140 clinical pregnancies in which conception occurred in vitro.27 Implantation was detected 6 to 13 days after egg retrieval.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Liu H-C, 1993, Fertil Steril source

  • It may state two separate claims as one.

    Study design and conductcitation

    The measure of ovulation used in the study has been validated against the peak urinary excretion of luteinizing hormone and appears to be as precise as methods based on serum luteinizing hormone.

    “We refined this algorithm, validating it against the peak urinary excretion of luteinizing hormone, 13 which corresponds approximately to the day of ovulation.14 Further analysis has suggested that this method is as precise as methods based on the measurement of serum luteinizing hormone.15”
    • Also stated in: § DISCUSSION · hedged
      “Our measure of ovulation has been validated against the surge in the secretion of luteinizing hormone, which is a standard clinical marker of ovulation, and our marker appears to be as precise as serum luteinizing hormone.15”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] source
    • cites [14] Collins WP. Biochemical approaches to ovulation prediction and detection and the location of the fertile period in women. In: Jeffcoate SL, ed. Ovulation: methods for its prediction and detection. Vol. 3 of Current topics in reproductive endocrinology. Chichester, England: John Wiley, 1983:49-66.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [15] source

  • Probably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.

    Interpretationreasoning

    Factors intrinsic to the zygote could also be at work in late implantation failure.

    “Factors intrinsic to the zygote could also be at work.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The production of chorionic gonadotropin by the conceptus begins early, with expression of messenger RNA reported at the eight-cell stage.

    “Its production by the conceptus begins early, with expression of messenger RNA reported at the eight-cell stage.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Bonduelle ML, 1988, Hum Reprod source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    Pregnancies with late-implanting conceptuses may fail for several reasons.

    “Pregnancies with late-implanting conceptuses may fail for several reasons.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Study design and conductcitation

    The assay for chorionic gonadotropin is sensitive enough to detect low concentrations even among premenopausal women with tubal ligation, so it is likely able to detect the initial increase associated with pregnancy.

    “Our assay for chorionic gonadotropin is sensitive enough to detect low concentrations even among premenopausal women with tubal ligation, 9 so it is likely that the assay is able to detect the initial increase associated with pregnancy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] source

  • Probably not a substantial claim. It may be too vague to check against evidence.

    Interpretationreasoning

    The data may have implications for efforts to manipulate uterine receptivity.

    “The data may have implications for efforts to manipulate uterine receptivity.33,34”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Beier HM, 1994, Hum Reprod source
    • cites [34] source
    • Rests on an assumption: The study population of 221 women attempting to conceive after ceasing contraception is representative of healthy women generally, so that findings generalize to most successful human pregnancies.

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    These three phases of uterine receptivity are also thought to occur in humans.

    “Although specific mechanisms of implantation vary widely among species, 22 these three phases of uterine receptivity are also thought to occur in humans. 2”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [2] source
    • cites [22] Ringler GE, 1990, Curr Opin Obstet Gynecol

  • It may state two separate claims as one.

    Interpretationreasoning

    The abrupt appearance of chorionic gonadotropin and its exponential rise in maternal serum or urine may not mark the very earliest steps in implantation, but they mark the point at which the conceptus has successfully invaded the maternal tissue.

    “The abrupt appearance of chorionic gonadotropin and its exponential rise in maternal serum or urine may not mark the very earliest steps in the implantation process, but they do mark the point at which the conceptus has successfully invaded the maternal tissue.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Study design and conductnone given

    The study was approved by the institutional review board of the National Institute of Environmental Health Sciences, and informed consent was obtained from all participants.

    “The study was approved by the institutional review board of the National Institute of Environmental Health Sciences, and informed consent was obtained from all participants.”
    Quote in the paperNot a substantial claim
24 of 24

  • The paper relies on this without support.

    The study population of 221 women attempting to conceive after ceasing contraception is representative of healthy women generally, so that findings generalize to most successful human pregnancies.

    “We studied 221 couples who had no history of fertility problems and who planned to have children.”
    “In our study, the couples had no known fertility problems, and none of the women were being treated with hormones.”

  • The paper relies on this without support.

    The 10 pregnancies excluded because of missing data did not differ systematically from the 189 analyzed pregnancies.

    “The day of ovulation or implantation could not be determined for 10 pregnancies (5 percent) because of missing data; these pregnancies were excluded from our analysis.”
2 of 2

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. England MA. Life before birth. 2nd ed. London: Mosby–Wolfe, 1996.
  2. Royston JP. Statistical approaches to the prediction and detection of ovulation: detecting the signal among the noise. In: Jeffcoate SL, ed. Ovulation: methods for its prediction and detection. Vol. 3 of Current topics in reproductive endocrinology. Chichester, England: John Wiley, 1983:19-32.
  3. Collins WP. Biochemical approaches to ovulation prediction and detection and the location of the fertile period in women. In: Jeffcoate SL, ed. Ovulation: methods for its prediction and detection. Vol. 3 of Current topics in reproductive endocrinology. Chichester, England: John Wiley, 1983:49-66.
  4. Norman RJ, 1987, Obstet Gynecol, 69, 590
  5. Canfield RE, 1976, Bull World Health Organ, 54, 463
  6. Psychoyos A, 1976, J Reprod Fertil Suppl, 25, 17
  7. Ringler GE, 1990, Curr Opin Obstet Gynecol, 2, 703

Cited by

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Related

Metadata

Authors
Wilcox, A. J., Baird, D. D., & Weinberg, C. R.
Affiliations
National Institutes of Health (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
1999-06-10
Volume
340
Issue
23
Pages
1796-1799
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm199906103402304
OpenAlex
W2325674170
Semantic Scholar
0f1ee50109d173b320c6525e3e4de2c8a0eee943
Cited by
1,081
References
32
Citations by year
2026: 24 · 2025: 34 · 2024: 74 · 2023: 50 · 2022: 55 · 2021: 60 · 2020: 57 · 2019: 47 · 2018: 37 · 2017: 53 · 2016: 50 · 2015: 29 · 2014: 47 · 2013: 45 · 2012: 54
FWCI
4.04
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
  • Health Sciences › Medicine › Reproductive Medicine › Reproductive Biology and Fertility
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Health and Contraception
Keywords
conceptus implantation, implantation timing, early pregnancy loss, miscarriage, human chorionic gonadotropin, ovulation, luteinization, pregnancy outcomes
MeSH terms
Abortion, Spontaneous, Female, Humans, Embryo Implantation, Pregnancy, Risk Factors, Time Factors

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