pregnancy outcome after preconception progesterone in...

Pregnancy Pregnancy outcomeoutcome after after preconception progesterone preconception progesterone in recurrent pregnancy lossin recurrent pregnancy loss

Manuela RussuManuela Russu(1)(1),,

RuxandraRuxandra Stănculescu Stănculescu(3), ŞŞ. Nastasia. Nastasia(1) (1) ,

Maria PăunMaria Păun(2) (2) , J.A MarinJ.A Marin(1) (1) , I. LachanasI. Lachanas(1) (1) ,

JaninaJanina ArseneArsene(3)(3)

““Dr. I. Dr. I. CantacuzinoCantacuzino”” Clinic of Obstetrics & Gynecology Clinic of Obstetrics & Gynecology (1)(1),, andand

Department of Neonatology Department of Neonatology (2)(2);;

““St. St. PantelimonPantelimon”” Emergency Clinic of Obstetrics & Gynecology Emergency Clinic of Obstetrics & Gynecology (3) (3)

““Carol DavilaCarol Davila”” University of Medicine & PharmacyUniversity of Medicine & Pharmacy

Bucharest, ROMANIABucharest, ROMANIA1st Central Eastern European Summit on Preconception Health,

Health Care, and the Prevention of Birth Defects

Budapest, HUNGARY, August 27-30, 2008

ObjectivesObjectives

The assessment of The assessment of

pregnancy outcomes after pregnancy outcomes after

preconception to 36 wks gestation preconception to 36 wks gestation

treatment with treatment with

1mg/d folic acid & 1mg/d folic acid &

200mg/d vaginal 200mg/d vaginal micronizedmicronized progesteroneprogesterone

in recurrent pregnancy lossin recurrent pregnancy loss

Material and methodsMaterial and methods (1)(1)

Patients are diagnosed and enrolled in two university Patients are diagnosed and enrolled in two university

clinics of obstetrics from clinics of obstetrics from ““Carol DavilaCarol Davila”” University of University of

Medicine and Pharmacy, Bucharest, if they accomplished Medicine and Pharmacy, Bucharest, if they accomplished

inclusion & exclusion criteriainclusion & exclusion criteria

Inclusion CriteriaInclusion Criteria:: 2 pregnancy loss (first or third 2 pregnancy loss (first or third

trimester)trimester)

Subjects: Subjects: different by moment of 2 previous different by moment of 2 previous

pregnancies loss: first trimester pregnancies loss: first trimester -- group A and third and third

trimester trimester –– early pretermearly preterm birth with neonatal death or birth with neonatal death or

stillbirthstillbirth,, -- group B


Exclusion CriteriaExclusion Criteria::�� major uterine malformations, major uterine malformations,

�� subtle subtle ovulatoryovulatory dysfunction, as that related to dysfunction, as that related to hyperprolactinemiahyperprolactinemia, ,

�� positivitypositivity for infections as: toxoplasmosis, for infections as: toxoplasmosis, listeriosislisteriosis, CMV, , CMV,

syphilis,syphilis,

�� major chronic medical diseases (e.g.: insulinmajor chronic medical diseases (e.g.: insulin--requiring diabetes requiring diabetes

mellitus or pharmacologically treated hypertension), treatment wmellitus or pharmacologically treated hypertension), treatment with ith

10,000 or more units of 10,000 or more units of unfractionatedunfractionated heparin per day, treatment heparin per day, treatment

with lowwith low--molecularmolecular--weight heparin at any dose or other diagnosed weight heparin at any dose or other diagnosed

blood coagulation protein or platelet defects, blood coagulation protein or platelet defects,

�� previous pregnancies with chromosomal abnormalities as numeric previous pregnancies with chromosomal abnormalities as numeric

abnormalities (abnormalities (aneuploidiesaneuploidies) and structural anomalies (defects in the ) and structural anomalies (defects in the

structure of 1 or more chromosomes),structure of 1 or more chromosomes),

�� previous gestation over 42 weeks with fetal wastageprevious gestation over 42 weeks with fetal wastage


�� An ultrasonic examination was required An ultrasonic examination was required between between 12 and 20 weeks 6 days of 12 and 20 weeks 6 days of gestationgestation: :

-- to confirm the duration of gestation,to confirm the duration of gestation,

-- to screen for major fetal abnormalities, to screen for major fetal abnormalities,

-- for the diagnosis of an ultrasonic large or for the diagnosis of an ultrasonic large or restricted fetus, andrestricted fetus, and

�� repeated at 32 to 34 weeksrepeated at 32 to 34 weeks to evaluate to evaluate fetal growthfetal growth

�� PrimaryPrimary: : birthweightbirthweight, , ApgarApgar scores, congenital scores, congenital

malformations, GA of preterm birth,malformations, GA of preterm birth, composite neonatal composite neonatal

morbidity rate, containing severe respiratory distress morbidity rate, containing severe respiratory distress

syndrome (RDS), syndrome (RDS), bronchopulmonarybronchopulmonary dysplasiadysplasia (BPD), (BPD),

intraventricularintraventricular haemorrhagehaemorrhage (IVH), (IVH), necrozitingnecroziting enterocolitisenterocolitis

(NEC), need of oxygen supplementation, & of mechanic (NEC), need of oxygen supplementation, & of mechanic

ventilation, length of admission in NICU ventilation, length of admission in NICU

�� SecondarySecondary: time to conceive, moment of miscarriage, time : time to conceive, moment of miscarriage, time

until delivery: preterm birth before 32 and 37 weeks, until delivery: preterm birth before 32 and 37 weeks,

maternal morbidity (gestational diabetes, gestational maternal morbidity (gestational diabetes, gestational

hypertension), maternal hospitalization for threatened of hypertension), maternal hospitalization for threatened of

miscarriage/ preterm birth.miscarriage/ preterm birth.

Outcome measuresOutcome measures


Statistical AnalysisStatistical Analysis

Student testStudent test for comparison of each group for comparison of each group

of treated patients to controlsof treated patients to controls ((P valueP value),), by by

ANOVA methodANOVA method

P < 0.01 = statistical significantP < 0.01 = statistical significant

� Treated groups: 32 (group A) + 6 (group B)

6 months preconception treatment with folic acid

1mg/d & vaginal micronized progesterone 200mg/d

(14 days/month, each night, from the 14th day of

menstrual cycle), continued immediately after a positive

pregnancy test (the 7th – 10th days of amenorrhea) and

prolonged till the 36th week gestation

� Control group: 58

treated during pregnancy with non a specific

antispastic muscle-relaxant mixture, when necessary.

ResultsResults (1)(1)

Results Results (2)(2)

11.95 ± 4.7514.33 ± 3.32

p= 0.24

16.77 ± 5.71

p= 0.001

Weight gain (average) kg

158.8

(155-165)

160.5

(155-164)

160.8

(155-168)Height (cm)Average (limits)

55.32 ± 7.3961.33 ± 12

p= 0.09

58.59 ± 9.27

p= 0.13

PreconceptionWeight (average) (kg)

7451231912

Para > 2

Para 2Primigravidas

Para > 2

Para 2

Primigravidas

Para>2

Para 2Primigravidas

Parity

3295

p= 0.39

1

p= 0.00001

22

p= 0.06

10

p= 0.056

gestation > 2 gestation 2 gestation > 2 gestation 2 gestation > 2 gestation 2

Gestation

26.9 ± 4.7731.33 ± 4.54

p= 0.038

31.33 ± 4.54

p= 0.038Age (average) yrs

58(41 + 17 miscarriages)

6(6 + 0 miscarriage)


Number of patients

Group CGroup BGroup APatients characteristics


Primary pregnancy outcomesPrimary pregnancy outcomes

2323

5656%%

≥≥ 3535

wkswks

2929--34 34

wkswks

55

83.483.4%%

≥≥ 3535

wkswks

2929--34 34

wkswks

2121

96.596.5%%

≥≥ 3535

wkswks

2929--34 34

wkswks

2424--28 28

wkswks

2424--

28 28

wkswks

2424--

28 28

wkswksGestation Gestation Age atAge at

deliverydelivery 1616

3939%%

22

4.84.8%%

11

16.616.6%%

0011

4.54.5%%

00

1616440000

11

P = P =

0.00010.000100

< 2500g< 2500g<2500g<2500g< 2500g< 2500g <1500<1500< 1500g< 1500g< 1500g< 1500gFetal Fetal

weightweight(g)(g)

2506.1 2506.1 ±± 699.21 699.21 3216 3216 ±± 537.27537.27

P = 0.022P = 0.022

3100 3100 ±± 489.41489.41

p= 0.001p= 0.001

Fetal Fetal

weightweight(g)(g)

ControlsControls

4141

Group BGroup B

66

Group AGroup A

22 22

Infant Infant outcomeoutcome



665544000022220033

>7.25>7.257.21 7.21 --

7.247.24

>7.25>7.257.217.21--

7.247.24

>>7.257.257.217.21--

7.247.24

< <

7.207.20

< <

7.207.20

< <

7.207.20

15 cases 15 cases

ApgarApgar score <7score <7

2 cases 2 cases

ApgarApgar score <7score <7

5 cases5 cases

ApgarApgar score < 7score < 7

pH blood cord pH blood cord

whenwhen

ApgarApgar < 7/5< 7/5’’

8.05 8.05 ±± 1.981.98

8.2 8.2 ±± 1.991.99

4.83 4.83 ±± 4.574.57

p= 0.14p= 0.14

4.83 4.83 ±± 4.624.62

p= 0.13p= 0.13

8.45 8.45 ±± 1.531.53

p= 0.40p= 0.40

8.77 8.77 ±± 1.111.11

p= 0.21p= 0.21

ApgarApgar ScoreScore-- 1 min1 min

-- 5 min5 min

ControlsControls

4141

Group BGroup B

66

Group AGroup A

2222




000000000000000000551122

CCBBCCBBCCBBCCBB AAAAAAAA

Composite Neonatal MorbidityComposite Neonatal Morbidity

1 Umbilical hernia: control1 Umbilical hernia: control

1 1 HydroceleHydrocele: control : control

1 1 CriptorhydiaCriptorhydia: control : control

NECNECIVHIVHBPDBPDRDSRDS

2 2 HypospadiasHypospadias: : group Agroup A, control, control

MalformationsMalformations

ControlsControls

4141

Group BGroup B

66

Group AGroup A

22 22




13.616.6

61.2

0

100

Need of oxygen

supplementation (%)

Group A

Group B

Group C

21

5

0

5

Mechanical ventilation

(no)

Group A

Group B

Group C

00

5

2

1

5

0

1

2

3

4

5

< 7

days

> 7

days

Lengh of admission in

NICU (total no. of days)

Group A

Group B

Group C


22

37.9%

36

60.7%

11

16.6%16.6%

5 5

83.3%83.3%55

15.6%15.6%

27 27

86%86%

> 6 > 6 monthsmonths



≤≤ 6 6 monthsmonths



Time to Time to conceiveconceive

2- 5%00 11-- 16.6%16.6%

44

7.2%7.2%

1313--23 23

wkswks

00

1313--23 23

wkswks

33

9.3%9.3%

1313--23 23

wkswks

7 7 21.9%21.9%

Stillbirth Stillbirth

1313

22.4%22.4%00

2 2

4.4%4.4%0000

Fetal deaths Fetal deaths before before discharge discharge

< 12 wks< 12 wks< 12 wks< 12 wks< 12 < 12 wkswks

Gestational Gestational age if age if

miscarriagemiscarriage

Group CGroup C


Group B

6

(6 + 0 miscarriage)

Group A


Secondary Secondary pregnancy pregnancy outcomesoutcomes


Secondary pregnancy outcomesSecondary pregnancy outcomes

9

0

26.8

45

0

48.7

9

16.6

19.5

0

5

10

15

20

25

3035

40

45

50

25-28

wks

29- 34

wks

35- 37

wks

Hospitalization for threatened preterm birth

(%)

Group A

Group B

Group C

31.2

16.6

41.4

37.5

33

62

0

10

20

30

40

50

60

70

< 12 wks 13- 24 wks

Hospitalization for threatened miscarriage (%)

Group A

Group B

Group C

00

3 3

19%19%

GroupGroup

CC

n= 41

0000GestationalGestational

DiabetesDiabetes

2 2

33%33%00

Gestational Gestational hypertensionhypertension

Group

B

n= 6

Group

A

n= 22

DiscussionsDiscussions (1)(1)

In the last 40In the last 40-- 50 years 50 years progestinsprogestins and progesterone and progesterone

derivates have been administered during reproductive derivates have been administered during reproductive

years for several reasons: years for several reasons:

�� lutealluteal phase support when phase support when lutealluteal phase defect phase defect or inadequate corpus or inadequate corpus luteumluteum, ,

�� spontaneous pregnancy achievement or IVF spontaneous pregnancy achievement or IVF treatment, treatment,

�� threatening miscarriage, recurrent miscarriage, threatening miscarriage, recurrent miscarriage,

�� prevention of preterm laborprevention of preterm labor. .


Only two formulations are considered safe: Only two formulations are considered safe:

�� natural progesteronenatural progesterone administered vaginally (as administered vaginally (as either a either a pessarypessary or a cream), or a cream),

�� a synthetic a synthetic caproatecaproate esterester of naturally 17 alphaof naturally 17 alpha--hydroxyprogesteronehydroxyprogesterone*, given as a long*, given as a long--acting acting intramuscular injection.intramuscular injection.

*17 alpha*17 alpha--hydroxyprogesteronehydroxyprogesterone is produced by the placenta itselfis produced by the placenta itself


��micronizedmicronized progesteroneprogesterone: the only natural progesterone : the only natural progesterone

available in Romania, and available in Romania, and

�� vaginal route of administrationvaginal route of administration: better bioavailability : better bioavailability

of Progesterone in the uterus (of Progesterone in the uterus (10 fold higher to that of 10 fold higher to that of i.mi.m. . administrationadministration) & ) & minimal systemic undesirable effectsminimal systemic undesirable effects

CicinelliCicinelli E, de Ziegler D, 1999E, de Ziegler D, 1999

TavaniotouTavaniotou A, A, SmitzSmitz J, J, BourgainBourgain C, C, DevroeyDevroey P, 2000P, 2000

�� because of a because of a first uterine pass effectfirst uterine pass effect, explained by: , explained by:

�� direct diffusion through tissuedirect diffusion through tissue, , �� intracervicalintracervical aspirationaspiration,,�� absorption into the venousabsorption into the venous or or lymphatic circulatory lymphatic circulatory systems,systems, andand

�� countercurrent vascular exchange with diffusion from countercurrent vascular exchange with diffusion from uteroutero-- vaginal veins/lymph vessels vaginal veins/lymph vessels toto arteriesarteries


�� In this study: maternal age in studied > controlsIn this study: maternal age in studied > controls

31.33 31.33 ±± 4.54 4.54 vsvs 26.9 26.9 ±± 4.77: 4.77:

P = 0.038P = 0.038

DevotoDevoto L, Vega M, L, Vega M, KohenKohen P, et al, 2002P, et al, 2002

↓↓

�� with aging the molecules (prowith aging the molecules (pro--inflammatory cytokines, inflammatory cytokines,

reactive oxygen species, steroids and inducible nitric oxide reactive oxygen species, steroids and inducible nitric oxide

synthethase) linked to apoptosis of corpus luteum synthethase) linked to apoptosis of corpus luteum

�� are increasing, and are increasing, and

�� are inducing a preferentially diminish of progesterone are inducing a preferentially diminish of progesterone

biosynthesis in mid and late luteal cells in culturebiosynthesis in mid and late luteal cells in culture


•• Preconception Progesterone supplementation by Preconception Progesterone supplementation by binding to the nuclear/membrane receptors: binding to the nuclear/membrane receptors:

�� modulates the contractility of fallopian tubes & modulates the contractility of fallopian tubes & myometrium for gamete/embryo transportation myometrium for gamete/embryo transportation throughout the uterotubal cavities and successful throughout the uterotubal cavities and successful embryo implantation in spontaneous and/or assisted embryo implantation in spontaneous and/or assisted reproduction,reproduction,

Goldenberg RL, Iams JD, et al, 1998Goldenberg RL, Iams JD, et al, 1998

Ayoubi JM, Fanchin R, de Ziegler D, et al, 2001Ayoubi JM, Fanchin R, de Ziegler D, et al, 2001

Bulletti C, De Ziegler D, Bulletti C, De Ziegler D, CicinelliCicinelli E, et al, 2004E, et al, 2004

PalagianoPalagiano A, A, BullettiBulletti C, de Ziegler D, C, de Ziegler D, CiccinelliCiccinelli E, et al, 2004 E, et al, 2004


�� maintains maintains deciduadecidua viabilityviability ((LanLan KKG, KKG, DeMetsDeMets DL, DL,

19831983), together to estrogens ), together to estrogens lower the vascular resistance lower the vascular resistance

in the uterine circulationin the uterine circulation, ,

�� increases the rate of embryo implantationincreases the rate of embryo implantation by effect by effect

on endometrial on endometrial stromastroma cells, cells, acting on different cytokine acting on different cytokine

profilesprofiles which are present as response of the female which are present as response of the female

reproductive tract to the different paternal MHC reproductive tract to the different paternal MHC

histocompatibilityhistocompatibility antigens (the uterus = antigens (the uterus = immunoprivilegedimmunoprivileged

site during pregnancy). site during pregnancy).

Preconception Progesterone supplementation by binding Preconception Progesterone supplementation by binding to the nuclear or membrane receptorsto the nuclear or membrane receptors


�� Th1Th1-- type cytokines are detrimental to pregnancy by type cytokines are detrimental to pregnancy by

stimulating NKstimulating NK-- macrophage system that is involved in macrophage system that is involved in

abortion, whereas abortion, whereas

�� Th2Th2-- type cytokines (and CD81 T cells) prevent type cytokines (and CD81 T cells) prevent

abortions by suppressing of the NKabortions by suppressing of the NK--macrophage macrophage

system, and inhibiting Th1 responses may allow system, and inhibiting Th1 responses may allow

allograft tolerance allograft tolerance

ChaouatChaouat G, G, 1994 1994

Progesterone enhances local production of Th2 Progesterone enhances local production of Th2 and/or LIF cytokines which may contribute to and/or LIF cytokines which may contribute to

the maintenance of pregnancythe maintenance of pregnancy

�� Leukemia inhibitory factorLeukemia inhibitory factor -- produced locally by produced locally by

deciduas, & deciduas, & macrophagemacrophage--stimulating factorstimulating factor (M(M--CSF) are CSF) are

essential for embryo implantation, being associated with essential for embryo implantation, being associated with ThTh--22cells, cells,

•• upup--regulatedregulated by by ILIL--4 4 andand progesteroneprogesterone and and

•• downdown--regulatedregulated by by ThTh--1 1 type cytokines, and by type cytokines, and by ILIL--1212, ,

IFNIFN--γγγγγγγγ,, and and IFNIFN--αααααααα (produced by Th(produced by Th--1)1)

PiccinniPiccinni M, M, BeloniBeloni L, L, LiviLivi C, et al, 1998 C, et al, 1998

PiccinniPiccinni M, M, MaggiMaggi E, E, RomagnaniRomagnani S, 2000S, 2000


Progesterone enhances local production of Th2 Progesterone enhances local production of Th2 and/or LIF cytokines which contribute to the and/or LIF cytokines which contribute to the

maintenance of pregnancymaintenance of pregnancy

�� Our studyOur study: Preconception progesterone supplementation : Preconception progesterone supplementation

during luteal phase was associated to a rate of immediate during luteal phase was associated to a rate of immediate

gestation (in less than 6 months) in gestation (in less than 6 months) in 86%86% respectively respectively 83.3%83.3%in groups in groups AA and and BB vsvs 60.7%60.7% in controls; the supplementation in controls; the supplementation

was continued as soon as was continued as soon as ββ HCG pregnancy test was positive HCG pregnancy test was positive (after 7 to 10 days from fertilization) (after 7 to 10 days from fertilization)

�� The defective The defective decidualdecidual production of LIF, Mproduction of LIF, M--CSF, Il CSF, Il --4, 4, ILIL--10 (which is not found in peripheral10 (which is not found in peripheral--blood Tblood T--cells) and/or cells) and/or Th2 type cytokines may contribute to the development of Th2 type cytokines may contribute to the development of

unexplained recurrent abortionsunexplained recurrent abortions

PiccinniPiccinni M, M, ScalettiScaletti C, C, VultaggioVultaggio A, et al, 2001A, et al, 2001

SzekeresSzekeres--BarthoBartho J, J, BarakonyiBarakonyi A, A, MikoMiko E, et al, 2001E, et al, 2001



�� Our protocol: sustaining corpus Our protocol: sustaining corpus luteumluteum, and both , and both

early & late pregnancy by early & late pregnancy by vaginal vaginal micronizedmicronized

progesteroneprogesterone supplementation, in cases with high risk supplementation, in cases with high risk

for recurrent pregnancy loss. for recurrent pregnancy loss.

�� Proctor A, Hurst BS, Proctor A, Hurst BS, MarshburnMarshburn PB, et al, 2006: PB, et al, 2006:

have used either have used either lutealluteal protocol or first trimester protocol or first trimester

protocol in IVF pregnancies, showing that in the protocol in IVF pregnancies, showing that in the

lutealluteal protocol the rate of miscarriage was higher than protocol the rate of miscarriage was higher than

the first trimester protocol, but the rate of the first trimester protocol, but the rate of lifebirthlifebirth

was better was better (76.8% luteal protocol vs. 75.0% first (76.8% luteal protocol vs. 75.0% first

trimester protocol; P = 0.80)trimester protocol; P = 0.80)


Progesterone supplementation was advocated for Progesterone supplementation was advocated for preterm preventionpreterm prevention

Dodd JM, Dodd JM, FlenadyFlenady V, V, CincottaCincotta R et al, for R et al, for

Cochrane Database Cochrane Database SystSyst RevRev. 2006. 2006

ILIL--1111 is a cytokine with is a cytokine with pleiotropicpleiotropic biological effects, biological effects,

including induction of including induction of ThTh--2 2 type, and inhibition of type, and inhibition of ThTh--11

type cytokine responses, paradoxically, it enhances the type cytokine responses, paradoxically, it enhances the

synthesis of prostaglandins, which induce labor. synthesis of prostaglandins, which induce labor.

ProgestinsProgestins/Progesterone derivates are suppressing /Progesterone derivates are suppressing ThrombinThrombin-- and Iland Il--1{beta}1{beta}--Induced Il Induced Il --1111, which , which are related to preterm delivery, abruption are related to preterm delivery, abruption placentaeplacentae, and , and chorioamnionitischorioamnionitis..

CakmakCakmak H, Schatz F, Huang SH, Schatz F, Huang S--TJ, et al, 2005TJ, et al, 2005

Our protocol:Our protocol: Preconception Preconception –– 36 wks36 wks: the rate of delivery : the rate of delivery

after 35 wks increased from 56% to 96.5%after 35 wks increased from 56% to 96.5%


Natural ProgesteroneNatural Progesterone/ / 17 alpha17 alpha--hydroxyprogesteronehydroxyprogesterone are are administered for miscarriage & preterm birth prevention at administered for miscarriage & preterm birth prevention at different pregnancydifferent pregnancy’’s ages:s ages:

�� from from 1616--20 wks to 36 wks20 wks to 36 wks:: MeisMeis PJ, PJ, KlebanoffKlebanoff M, Thom M, Thom

E, et al (2003) for E, et al (2003) for National Institute for Child Health and National Institute for Child Health and

Human Development: Human Development: reduced the rate of delivery before 32 reduced the rate of delivery before 32

wks from wks from 18.6%18.6% to to 11.4%11.4% ((P: 0.0180P: 0.0180), and before 35 wks ), and before 35 wks

from from 30.6%30.6% to to 20.6 %20.6 % ((P: 0.0165P: 0.0165) )

�� 2424--34 wks34 wks: : dada Fonseca EB, Fonseca EB, BittarBittar RE, RE, CarvalhoCarvalho MH, MH,

ZugaibZugaib M, 2003M, 2003: reduced the rate of delivery before 34 wks : reduced the rate of delivery before 34 wks

from 34% to 19%from 34% to 19%

ConclusionConclusion (1)(1)

Vaginal Vaginal micronizedmicronized progesterone & Folic acid progesterone & Folic acid

preconception, in early and late pregnancy in preconception, in early and late pregnancy in

recurrent pregnancy loss are followed byrecurrent pregnancy loss are followed by::

�� A significant reduction of preterm birth before 34 A significant reduction of preterm birth before 34

wks (13.6% treated wks (13.6% treated vsvs 36.6%controls), 36.6%controls),

�� A reduction of miscarriages (A reduction of miscarriages (23.7%23.7% treated treated vsvs 27,7% 27,7%

controls),controls),

�� An increase of An increase of birthweightbirthweight ((P=.001, group AP=.001, group A; ; P=.022 P=.022

group Bgroup B), less cases with reduced blood cord pH ), less cases with reduced blood cord pH

((P=.0001P=.0001--groupBgroupB) when ) when ApgarApgar score <7/5 minutes, score <7/5 minutes,


Folic acid & vaginal Folic acid & vaginal micronizedmicronized progesterone progesterone



�� Less number of cases who Less number of cases who need oxygen need oxygen

supplementation (supplementation (10.5%10.5% vsvs 61.2%),61.2%), and mechanical and mechanical

ventilationventilation ((7.6% 7.6% studiedstudied vsvs 12.1% 12.1% controlcontrol))

�� Less number of days of admission in the NICU Less number of days of admission in the NICU

(> 7 days: (> 7 days: 7.6% 7.6% studiedstudied vsvs 12.1% 12.1% control)control)


Vaginal Vaginal micronizedmicronized progesterone & Folic acid progesterone & Folic acid



�� less neonatal morbidity (only RDS: less neonatal morbidity (only RDS: 10.3% 10.3% treated treated

vsvs 12.2%controls), 12.2%controls),

�� a a nonsignifiantnonsignifiant difference in difference in perinatalperinatal mortality; mortality;

�� 22 cases with cases with hypospadiashypospadias ((group Agroup A, controls), more , controls), more

other abnormalities in controls.other abnormalities in controls.


Vaginal Vaginal micronizedmicronized progesterone & Folic acid progesterone & Folic acid preconception, in early and late pregnancy in recurrent preconception, in early and late pregnancy in recurrent

pregnancy loss are followed bypregnancy loss are followed by::

�� Less time to conceive (< 6 months: Less time to conceive (< 6 months: 81.3 %81.3 % studied studied vsvs

60.7%60.7% control)control)

�� Lower incidence of gestational hypertension in treated Lower incidence of gestational hypertension in treated ((5.2%)5.2%) vsvs controls (19%), no gestational diabetes, controls (19%), no gestational diabetes,

�� Less hospitalization for miscarriage threaten (Less hospitalization for miscarriage threaten (28.6%28.6%treated treated vsvs 48.8% control), 48.8% control),

�� Less hospitalization for preterm birth threaten (Less hospitalization for preterm birth threaten (35.1%35.1%studied studied vsvs 43.8% control)43.8% control)

pregnancy outcome after preconception progesterone in...

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