651-654, 1996
CASE REPORT
J0rgen Grinsted1 and Birthe Avery2 Fletcher et al, 1988), rabbits, badgers, weasels, minks
(Martinet and Allain, 1985; Stoufflet et al., 1989), roe deer
'The Fertility Clinique, 0sterbrogade 62, DK-2100 Copenhagen
and ''Department of Reproduction, Royal Veterinary and (Flint et al, 1994), the Japanese brown bear (Tsubota and
Agricultural University, BUlowsvcj 13, DK-1870 Kanagawa, 1993), some bats (Kimura et al., 1987; Van der
Frederiksberg C, Denmark Merwe and van Aarde, 1989; Funakoshi, 1993; Bernard and
2
To whom correspondence should be addressed Bojarski, 1994), the western spotted skunk (Enders et al.,
1986; Berria et al, 1989; Rozell and Mead, 1993), the giant
A possible case of delayed implantation after in-vitro panda (Monfort et al, 1989; Zeng et al, 1992), seals (Temte,
fertilization (TVT) is described. The patient was sterilized 1985; Skinner and Westlin van Aarde, 1989; Reijnders, 1990)
in 1981, and made fertile again by tubal anastomosis in and the horse (Vandeplassche, 1986). In the study of excessively
1988. In 1990 and 1992 the patient had two right-sided prolonged pregnancies in the mare, Vandeplassche (1986)
tuba! pregnancies, the first was treated with prostaglandin concludes that a diapause of 3—5 weeks is rare, but should be
instillation, the second with salpingectomy. In connection considered to be a reasonable differential diagnosis. In the
with the salpingectomy in 1992, the left tube was observed human, a few cases of delayed implantation have been
to be constricted in the middle part and with phimosis of described after ovarian stimulation and ovulation induction, or
the ostium. In 1994 three IVF embryos were transferred, in-vitro fertilization (IVF) treatment; however, these pregnan-
but 15 days after the transfer, serum human chorionic cies were only delayed by < 2 weeks, as measured by detection
gonadotrophln (HCG) was negative (<10 IU/ml). Seven of serum human chorionic gonadotrophin (HCG), with most
weeks after the embryo transfer, menstruation was still of them ending as spontaneous abortions (Naaktgeboren et al.,
missing, and the serum HCG was now positive (329 IU/ 1986, 1987; Hamori et al, 1989). In another report, a tubal
ml). Subsequent ultrasound scans were compatible with an pregnancy presented itself by a delayed appearance of HCG
intrauterine pregnancy, progressing normally, but 5 weeks (Beghin et al, 1992).
delayed compared with the oocyte aspiration. The preg- When prolonged gestation occurs in the human, one should
nancy was successfully carried to term. Such a long delay first try to rule out causes other than delayed implantation,
hi detection of HCG, in association with a normal preg- and critically re-evaluate more likely factors, such as a deviant
nancy, has not been described in the literature before. menstrual pattern and reliability of the date for the last
Key words: diapause/pregnancy diagnosis/prolonged gestation menstruation, occurrence of a bleeding not recognized as
menstrual, cessation of progesterone pill treatment as a cause
of delayed ovulation, and first date for a positive pregnancy
Introduction test. We present a case here which is highly indicative of a 5
week delay of implantation after IVF treatment To our
Delayed implantation, or diapause, is a well described
knowledge, this is the first report in the literature.
phenomenon in several species of mammals and marsupials,
but does not occur in reptiles and birds, because their eggs do
not implant (Sandell, 1990; Mead, 1993). Delayed implantation Case report
can be induced by lactation, stress, hibernation and the season. A 36 year old woman, born in 1958, gravida 7, parity 4, with
In delayed implantation, the embryo becomes temporarily regular menstruations (3/28) and with a 6 year history of
arrested at the blastocyst stage of development In lactating secondary infertility, was admitted to the IVF clinic in 1994
mice and rats, delayed implantation is obligatory, and in for IVF treatment
addition, it is easy to induce experimentally by ovariectomy Her previous history was as follows: she had delivered four
on day 4 of pregnancy. Delayed implantation in mice and rats children, in 1974 (girl, 3000 g/50 cm), 1976 (girl, 3800 g/51
has thus been thoroughly studied (Nieder and Weitlauf, 1984; cm), 1979 (girl, 3740 g/52 cm) and 1981 (boy, 3080 g/51 cm)
Weitlauf, 1985; Oswald and McClure, 1987; Paria etal, 1992, after uneventful pregnancies. The third delivery was apparently
1993a, 1993b; Tsujii and Nakatsuji, 1992; Weitlauf and Knisley, delayed by 5 weeks, the fourth by 2 weeks, based on the date
1992; Das et al, 1994; and many others). Other examples of of the last menstruation. In 1981 she was sterilized by
species with delayed implantation are marsupials (Bryant and laparoscopy with bipolar diathermia. In 1988 reversal of
Rose, 1986; Curlewis et al, 1986; Shaw and Renfree, 1986; the sterilization was performed by laparotomy with tubal
© European Society for Human Reproduction and Embryology 651
J.Grinsted and B-Avery
the endometrium remained in the secretory phase until an could be triggered by a new ovulation; however, this was not
intrauterine pregnancy was demonstrated 5 weeks after embryo demonstrated since ultrasound scans from the embryo transfer
transfer. All of this points toward a case of delayed implanta- and onwards showed endometrium in the secretory phase. This
tion, and not a spontaneous conception, since she did not have case supports the findings of Edwards (1988), who reported a
intercourse in the critical period. case in which the human implantation window was still open
During in-vitro cultivation, human blastocysts secrete HCG when three IVF embryos were replaced 1 week after the
(Fishel et al., 1984), but it is only after implantation that HCG normal time for replacement, and with the uterus being in the
is detected in the maternal blood. A positive pregnancy test is secretory phase.
defined by the arbitrarily chosen serum {5-HCG concentration Although delayed implantation in the human has not been
>10 IU/1. This value is significantly higher than the low basic described before, there is no reason to believe that it does not
concentration of circulating HCG (<4 IU/1) present in the exist An estimate of the incidence is therefore not available.
serum and urine of men and non-pregnant women. HCG values In the horse, which has an average gestation period of 336
>10 IU/1 are usually reached 3-7 days after implantation, days, with a physiological variation of 320-350 days, the
which in turn occurs 6-8 days after conception (Bergh and incidence of extremely prolonged pregnancies (+30-63 days)
Navot, 1992; review by Chard, 1992), meaning that our patient, has been estimated to be ~ 1 % (Vandeplassche, 1986).
with an HCG value <10 IU/1 on November 30, 15 days post- The demonstration of a pregnancy, obtained under controlled
aspiration, should have been diagnosed as non-pregnant With clinical circumstances and excessively prolonged by 5 weeks,
HCG values of 329 and 632 IU/1 measured on January 2 and as judged by HCG measurement and ultrasound scan, allows
3 (7 weeks post-aspiration), the HCG concentration could that the differential diagnosis: delayed implantation, although
theoretically have been >10 IU/1 around December 27, if a rare, should be considered when prolonged gestation is
doubling time of 1.2-1.5 days was used for the calculation observed in the human.
(Hamori et al, 1989; Pellicer et al, 1991; Bergh and Navot,
1992; Zegers-Hochschild et al, 1994). Demonstration of an
intrauterine 10 mm gestation sac and a yolk sac on January Acknowledgements
11 (8 weeks post-aspiration) corresponds with a 3.5-4 but not This study was partly supported by the Animal Biotechnology
an 8 week old conceptus, as demonstrated by Pellicer et al. Research Center. We thank Mrs Inger Heinze for producing copies
of the photographs.
(1991), who determined the time-frames for the first detection
of the embryonic sac, yolk sac and heart beats by ultrasono-
graphy in pregnancies from patients treated with FVF or References
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The mechanisms behind delayed implantation are complex Bernard, R.T.F. and Bojarski, C. (1994) Effects of prolactin and hCG
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