Role of HCG in Preventing Preterm

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					                                                            Original Article



        Role of HCG in Preventing Preterm
            Labour in comparison with
              Vaginal Progesterone
                                V. Usha Rani*, A. Mahita Reddy**, Archana Singh***, P.Malathi****




Background                                                            enzyme responsible for modulating the intracel-
   Preterm birth and stillbirth likely share many                     lular levels of cGMP.
common pathways and mechanisms. In high-                                  Ample evidence is available to suggest that hCG
income countries, 80% of stillbirths are delivered                    can modulate expression of the inducible isoform
preterm. The situation is especially dire in the de-                  of nitric oxide synthase (iNOS), as well as specific
veloping world where 99% of the approximately                         immuno-regulatory cytokines such as the high
4 million perinatal deaths occur. Treatment alter-                    mobility group box 1 (HMGB1) protein in fetal
natives include, progesterone,tocolytics for acute                    membranes. Accumulating evidence as reported in
management and the recent addition of hCG.                            literature [in-vitro and in-vivo studies] suggesting
                                                                      that HCG has a wide spread pregnancy-promoting
    Human Chorionic Gonadotropin (hCG) plays a                        actions that are exerted in various reproductive and
major role in early human development through a                       gestational tissues.
series of well recognized pregnancy promoting ac-
tions that are exerted in the first trimester, including                 Recent evidence also has shown that human
maternal recognition of pregnancy, enhancement                        cervix contains functional LH/hCG receptors,
of embryo implantation and survival, stimulation                      which suggests that LH during the menstrual cycle
of trophoblast growth and differentiation, and                        and hCG during pregnancy may regulate cervical
prolongation of the functional life of the corpus                     functions.
luteum.                                                                  These research reports and other peer reviewed
    Recent research indicates that HCG exerts                         published literature has suggested that hCG has
pregnancy-promoting actions not only in the first                     a formidable role in maintenance of pregnancy
trimester, but also in the later part of pregnancy                    especially in the high risk category of PTL
through its effect on the myometrium and on fetal                     Objective:
membranes. The myometrial action of HCG is due
                                                                         To evaluate the role of HCG in preventing
to the inhibition of smooth muscle cell contractil-
                                                                      preterm labour. This study was conducted at vari-
ity mediated via several mechanisms,that include
                                                                      ous centres in Hyderabad,starting January 2010 to
inhibition of gap junction formation, reduction of
                                                                      January 2011.
intracellular calcium concentration, increase pro-
gesterone receptor expression, and an increase in                        Sixty women, above 20 weeks of gestation were
the expression of phosphodiesterase 5 (PDE5), an                      recruited with previous history of preterm deliv-
*Asst Professor, **Asst Professor, ***Asst Professor, ****Asst Professor, MGMH, Petlaburz,Hyderabad,India -fertilitycell@gmail.com

                                           The Indian Practitioner q Vol. 65 No. 6, June 2012                                        1
                                                     Original Article


eries. Women with singleton pregnancy without                 mediator in maintenance of uterine quiescence dur-
any bleeding or PROM were included. Twenty                    ing pregnancy with clinical potential for tocolysis,
subjects were administered vaginal micronized                 the mechanisms of which are unknown. The large
progesterone tablets 200 mg once daily from 20-               conductance calcium-activated BK channel (BKCa)
36th week or unto delivery [n=20],twenty subjects             is ubiquitously encountered in human uterine tissue
were administered 5000 IU HCG injections between              and plays a significant role in modulating myome-
20th -36th week or unto delivery[n=20] and twenty             trial cell membrane potential and excitability. As
were controls [n=20].                                         demonstrated by the results, with an improvement
                                                              in the mean gestational weeks with HCG, one may
   USG was done for all women for Foetal Biom-
                                                              conclude activation of BKCa channel activity may
etry and Cervical Length. Cervical stitch applied
                                                              explain the potent uterorelaxant effect of hCG lead-
when required , high vaginal swabs taken for C/S,
                                                              ing to an extended gestational period and confer-
Bacterial vaginosis was treated with probiotics.
                                                              ring the clinical benefits.
Mean age at time of delivery, APGAR Score, Baby
Weight, No. of NICU days stay,Complications and
Perinatal outcomes were compared.
                                                              Introduction
                                                                  Preterm labour is defined as delivery occurring
Results                                                       before 37 completed weeks gestation. Preterm labor
• Preterm Deliveries – 23.8 % in the hCG group,               and delivery continues to be a leading cause of
  33.3% in the NMP Group and 42.9% in the Con-                perinatal morbidity and mortality even in advanced
  trol or no treatment group                                  countries like the United States. In a developing
• Gestational Age higher in the hCG Group 14.5%               country like India where the estimated prevalence
  [34-36 weeks] as compared to Progesterone                   of PTL is around 23% and PTB is 20.9%1. The health
  [19.5%]                                                     care burden on the patients family and the over-
• NICU admits were lesser in the hCG Group                    loaded healthcare system Various strategies have
  as compared to the Progesterone and Control                 been adopted to prevent preterm delivery and clini-
  group                                                       cians have largely focused on two strategies: 1. early
                                                              identification of patients at risk for preterm delivery
Conclusion                                                    and 2.pharmacological intervention to stop uterine
   Mean weeks of gestation was high in the hCG                contractions [use of tocolytic therapy]. Despite
group than micronized progesterone group. Both                advances in identifying patients at risk for preterm
groups showed good birth-weight and APGAR                     delivery have not been effective in predicting the
than the control group thereby reducing NICU stay             class of patients who will deliver before term, even
and perinatal mortality.                                      prior to the onset of symptoms.
   The utero-relaxant effect of human chorionic                   These advances, include biochemical screening
gonadotropin (hCG) is regarded as an important                of cervico-vaginal secretions FFN [Fetal Fibronec-

                                                     Table 1
                                      Incidence of Preterm Births & Trends
    Country                                      Preterm Labour              Preterm Birth           Trend
    India [Singh Uma et al1]                          22.00%                     20.90%          Not Available
    USA[(Martin et al3 ]                                  -                      12.30%            Increasing
    United Kingdom [Bibby and Stewart 4]              10.00%                      7.00%            Increasing
    Australia [Robert et al 5]                        14.10%                      5.50%            Stationary
    Sweden [Morten et al 6]                               -                      5 - 6%           Decreasing
    China [Leuing et al7 ]                                -                       7.40%            Increasing
    Zimbabwe [Shingairai et al 8]                         -                                        Increasing

2                                   The Indian Practitioner q Vol. 65 No. 6, June 2012
                                                   Original Article


tin] and ultrasound imaging of the cervix,have been          the mothers. However, Carmichael et al. (2005) have
shown to have increased sensitivity (up to 80%) and          recently reported that maternal intake of progestins
positive predictive value (up to 80%) as compared            in early pregnancy is associated with an increased
with traditional detection methods such as histori-          risk of hypospadiasis in the male offspring9.
cal risk factors, digital examination,cervical length
and uterine contraction monitoring2.                         Methods and Methodology
   Despite advances in detection methods and                     This study was done at various maternity and
identifying patients at risk, the lack of effective          nursing homes in Hyderabad from January 2010
tocolytic therapy remains a major obstacle in the            to January 2011. Informed consent and other ap-
prevention of preterm birth. Magnesium sulfate               provals / clearance were obtained In accordance
remains the leading parenteral tocolytic agent in the        with the Drugs And Cosmetics Rules applicable to
United States, despite its side-effect profile.              clinical trials [Investigator Initiated Trial]

   In the study conducted by Uma et al1. and the                 The pre-requsites for enrolling pregnant women
incidence cited by them [Table 1] is indeed an eye           for eligibility are as follows:
opener as the incidence of preterm births and trends         • Detailed History,Physical and Systemic Exami-
in various countries and in India is rising steadily           nation
despite lack of a medical registry in India.
                                                             • LMP and EDD noted
    Various treatment modalities used as interven-           • Obstetric History,Per Speculum Examination
tion to ensure gestation continues to term, have               and USG Cervical Measurements
met with little success or no success at all. Recently
                                                             • High Vaginal Swabs for Culture Sensitivity
a number of peer-reviewed papers have put forth
                                                               to rule out infections and initiate treatment if
in-vitro and in-vivo mechanisms on the role of hCG
                                                               need be
in prevention of preterm birth. This study was con-
ducted using human chorionic gonadotropin 5000                 Inclusion & Exclusion Criteria
IU, using natural micronised progesterone 200 mg             • Inclusion Criteria – Females aged 18 -35 years,
vaginal tablets as a comparator.                               Singleton Pregnancy
    Human chorionic gonadotropin hormone (hCG),              • Exclusion Criteria – Premature Rupture of Mem-
a heterodimeric glycoprotein hormone, is one of the            branes, First Trimester Bleeding, Abruption, Dia-
major and earliest embryonic signals. hCG is mainly            betes Mellitus, Cardiorespiratory disease, Active
produced by the syncytiotrophoblasts in the cho-               Liver Disease,Genitourinary Infections,Foetal
rionic villi. In normal pregnancy it is detectable in          Anamolies and Uterine Anamolies
maternal serum as early as 1 d after the initiation of
embryo implantation, and its concentration rapidly           Objective
increases, reaching a peak at about the 6 wk, and                The objective of this study was to compare the
then gradually decreases during the second tri-              efficacy of Vaginal Micronised Progesterone 200 mg
mester. However despite decreased levels it exerts           Tablets[Sugest VT] versus 5000 IU hCG[Pubergen
its physiological action beyond the 32nd week to             5000 IU] and in preventing preterm labour. Sixty
ensure continued gestation to 36 weeks.                      [n=60] antenatal women between 20 -24 weeks of
    The role of progesterone is indispensable for the        pregnancy with history of atleast one preterm de-
establishment and maintenance of pregnancy. It               livery were included .the study.
prepares the endometrium for blastocyst implanta-            1. Group A - Twenty women[n=20]200 mg Mi-
tion and controls endometrial development Proges-               cronised Progesterone tablet vaginally ,
terone exhibits anti-inflammatory activities , which
might be beneficial in the prevention of pre-term            2. Group B - Twenty women[n=20]were given 5000
birth. The extensive use of progestational agents               IU hCG injections IM twice weekly, 20 were
during the first and second trimester of pregnancy              given and
in attempt to prevent miscarriage showed that this           3. Group C - Twenty[n=20] were controls with
treatment is not associated with adverse effects in             placebo selected randomly.

                                   The Indian Practitioner q Vol. 65 No. 6, June 2012                           3
                                                    Original Article


                                                     Table 2
                                                 Gestational Age
                                  Group A                   Group B                  Group C                 Total No.of
    Gestational Age
                                 VMP [n=20]                HCG[n=20]               Control[n=20]              Patients

    < 28 weeks                         0                         0                            2                     2

    28 – 31 Wks + 6 Days               2                         1                            3                     6

    32-33 Wks + 6 Days                 3                         1                            2                     6

    34-36 Wks + 6 Days                 2                         3                            2                     7

    Total Preterm                 7 [33.3%]                  5 [23.80%]                 9 [42.86%]                  21
    VMP – Vaginal Micronised Progesterone [200 mg], HCG – Human Chorionic Gonadotropin [5000 IU IM]


Assessments:
                                                                               Table 3
• Maternal                                                                Neonatal Outcomes
  • To determine the mean gesta-
     tional age at delivery                                             Group A               Group B         Group C
                                                  Criteria
  • Number of women who had                                            VMP [n=20]            HCG [n=20]     Control [n=20]
     preterm delivery
                                                  Birth-Weight         2250 ± 600 G          2340 ± 580 G    1780 ± 580 G
• Perinatal
  • Baby Weight                                   NICU Admits                 1                   1                 3

  • APGAR Score                                   NICU < 24 hrs               5                   3                 10
  • No. of days in NICU
                                                  NICU > 24 hrs               2                   1                 6
  • Neonatal Complications
                                                  APGAR < 6                   2                   2                 10
Results                                           APGAR > 6                   17                  18                13
   The number of women with preterm
delivery in HCG group Table II [23.8%]            Neonatal Death              1                   0                 2
was lower in as compared to VMP
group [33.3%].Control group showed                VMP – Vaginal Micronised Progesterone [200 mg], HCG – Hu-
40% preterm delivery. The gestational             man Chorionic Gonadotropin [5000 IU IM]
age at delivery was higher in the HCG
group [14.2%] in 34 – 36 weeks 6 days
when compared to micronised proges-                                             Table 4
terone group[9.5%].HCG prevented                                           Side-Effect Profile
preterm births of < 34 weeks better
                                                  Symptoms                          HCG                       VMP
than VMP.
                                                  Headache                               0                      2
Summary
                                                  Nausea & Vomit-
   The findings of the present study                                                     0                      5
                                                  ting
indicate, hCG 5000 IU injections dem-
onstrate innate ability in suppression of         Vertigo                                0                      1
preterm labour better than vaginal mi-
                                                  Insomnia                               0                      2
cronised progesterone 200 mg OD P/V
and improving perinatal outcomes.                 Injection Site            2 [Induration, Pain]                -


4                                  The Indian Practitioner q Vol. 65 No. 6, June 2012
                                                   Original Article


    Moreover, patients showed better patient com-            mechanisms,including inhibition of gap junction
pliance with hCG injections bi-weekly rather than            formation, reduction of intracellular calcium con-
daily administration of vaginal progesterone with            centration, increase in the expression of progester-
relatively fewer side-effects.                               one receptor, and an increase in the expression of
                                                             phosphodiesterase 5 (PDE5), an enzyme controlling
Conclusion                                                   the intracellular levels of cGMP as already described
    The clinicians are slowly recognizing the benefits       earlier. Further credence has been added to the role
of HCG, that HCG is just a not gonadotropin for              of hCG in preterm labour by Lin et al. who have
induction of ovulation, but it has a role beyond. The        described the presence of LH/HCG receptors in
paper published Sakhavar et al10. Is probably one            the human cervix14.
of the first papers to comapare Magnesium Sulfate
versus HCG (Human Chorionic Gonadotropin) in                    In a recent publication Cole, has summarized,
Suppression of Preterm Labor, and the authors have           the biological functions of hCG during pregnancy,
concluded that both HCG and Magnesium Sulfate                adding further credence to support the role of hCG
have similar efficacy, however HCG is devoid of              in pregnancy promoting actions. The important
any maternal or foetal side-effects.                         functions15:

    Better understanding to the insights of the role         1. Promotion of corpus luteal progesterone pro-
of extra-gonadal LH/HCG receptors, have led us                  duction
to a better understanding that the beneficial effects        2. Angiogenesis of uterine vasculature
exerted by hCG, may have mechanisms that exert
                                                             3. Growth of Uterus in line with fetal growth
its effects on the gap junctions between myometrial
cells and are regulated by hCG, which can affect             4. Quiescence of uterine muscle contractions and
myometrial contractile activity. hCG can affect pros-
                                                             5. Promotion of foetal growth organs
tacyclin metabolism in myometrium and eicosanoid
synthesis in gestational tissues, which again might              In addition to the proven pregnancy-promoting
contribute to the quiescence of the myometrium,              actions, the other clinical benefits are equally impor-
contributing to its action as an effective agent for         tant for continuum of the pregnancy. The actions are
preterm labour11.                                            possible only due to the wide-spread distribution
                                                             of LH /HCG receptors both in the gonadal and
    The utero-relaxant effect of human chorionic
                                                             extra-gonadal tissues.
gonadotropin (hCG) is regarded as an important
mediator in maintenance of uterine quiescence dur-               A better understanding of non-classical actions
ing pregnancy with clinical potential for tocolysis,         could lead to novel therapeutic applications of
the mechanisms of which are unknown. The large               HCG, many of which are undergoing trials. This
conductance calcium-activated K channel (BKCa)               study suggests that HCG may be an ideal thera-
is widely distributed in human uterine tissue and            peutic candidate for prevention of preterm labour
plays a significant role in modulating myometrial            as compared to other tocolytics used in clinical
cell membrane potential and excitability, which              practice. In the current study the drug was devoid
is one of the most important factors contributing            of side-effects, further work is needed to delineate
to myometrial quiescence and probably prolong-               the mechanism of action and also a dose ranging
ing the mean getstational age, without potential             study needs to be done to titrate dosages for use in
adverse effects12.                                           prevention and acute therapy of preterm labour
   CV Rao et al. have made pioneering contribu-
tions to strengthen the role of hCG in Preterm La-              Acknowledgments: The authors wish to
bour, titled Pregnancy Promoting Actions of HCG              express,their sincere thanks to SANZYME Limited
in Human Myometrium and Foetal Membranes13,                  for supplying PUBERGEN 5000 IU and SUGEST
                                                             Vaginal Tablets 200 mg for conduct of this study
the myometrium, HCG promotes the inhibition of
smooth muscle cell contractility through several                 Conflict of Interests - None

                                   The Indian Practitioner q Vol. 65 No. 6, June 2012                             5
                                                     Original Article


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